Pathophysiology of cluster headache: a trigeminal autonomic cephalgia

doi:10.1016/S1474-4422(02)00104-7

The Lancet Neurology

Volume 1, Issue 4, August 2002, Pages 251-257

https://doi.org/10.1016/S1474-4422(02)00104-7 Get rights and content

Summary

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

Section snippets

Genetics of cluster headache

Cluster headache is highly likely to be caused, or at least predisposed to, by inheritance of susceptibility genes,¹⁷ just as is thought to be likely for migraine. Kudrow¹⁸ studied 495 individuals with cluster headache; 27% of the 405 male patients and 37% of the 90 female patients were found to have at least one affected first-degree relative. Of the patients' 990 parents, 1-8% had cluster headache. a proportion much higher than the population prevalence. Kudrow's finding of a probable genetic

Key pathophysiological features of neurovascular headache

The three major features of the pathophysiology of cluster headache are: trigeminal distribution of the pain; cranial autonomic features; and an episodic pattern of attacks. The latter is, in many ways, the defining clinical signature of the disorder compared with migraine.²⁵

These features raise the classic issues of the location of the lesion and the generic terminology that should be applied to these and related headaches, such as migraine. Ekbom's classic observation during angiography in a

Trigeminovascular system

The trigeminovascular system is in a unique, indeed pivotal position in cerebrovascular physiology.³⁰ It is the sole sensory (afferent) innervation of the cerebral vessels and also has an efferent potential in pathophysiological settings (figure 1).³³

The trigeminovascular system consists of the neurons innervating the cerebral vessels and dura mater that have cell bodies located in the trigeminal ganglion. The ganglion contains bipolar cells—the peripheral fibre makes a synaptic connection with

Cluster headache as a TAC

Cluster headache forms part of a broad clinical differential diagnosis of short-lasting headaches (Panel 3). “Short” is a relative term; these headaches contrast with attacks of migraine or tension-type headache, which may persist for many hours or days.¹ The clinically differentiating factor for the TACs as a group is the prominence of cranial autonomic activation, manifest as lacrimation, conjunctival injection, eyelid oedema, or rhinorrhoea.⁶² Although TACs are generally short-lasting, there

Cluster headache—a disorder of the posterior hypothalamic grey matter

Several lines of study suggest that central nervous mechanisms, particularly those involving the hypothalamus, have a role in cluster headache. Clinical observations and neuroendocrine studies suggested such a link, which has been further investigated by functional imaging techniques. Taken together, the results strongly suggest a role for the posterior hypothalamus in cluster headache.

PET studies of cluster headache

PET with oxygen-15-labelled water to trace blood flow has been used to study brain activation during acute cluster headache. Areas activated fell into three categories: areas generally associated with pain; an area that seems specific to cluster headache; and vascular structures.³²

The anterior cingulate was significantly activated, as would be expected, since in most human PET studies of pain, activation of the this region is observed, perhaps as a part of the affective response.⁸⁹ Activation

Unresolved issues

Although there has been progress in understanding of cluster headache, many issues remain unanswered, and some might be usefully highlighted.

Why should there be a male preponderance? Is this related to the hypothalamic involvement, and how do we account for the many female patients involved?

How does the bout begin? More importantly, how does it end? There seems to be some very important photoperiodicity implicated in the start of the bout. Further functional imaging may help to elucidate this

Conclusion

How can we regard cluster headache in pathophysiological terms? Some might suggest that cluster headache is a TAC, in which acute attacks involve activation of the trigeminovascular system, as shown by both the distribution of pain predominantly in the ophthalmic division of the trigeminal nerve and changes in cranial concentrations of neuropeptides. Thus, the acute attack of pain may be regarded as a manifestation of the trigeminal-autonomic reflex. The clinical feature of circannual and

Search strategy

Data for this review were obtained by a search of PubMed and from manual searches of the past 3 years' volumes of Cephalalgia and Headache, as well as articles identified from the author's personal database. Search terms were “cluster headache” and variations of the terms in Panel 2.

References (110)

A May et al.
Intra-cranial vessels in trigeminal transmitted pain: a PET Study
Neurolmage
(1999)
A May et al.
Hypothalamic activation in cluster headache attacks
Lancet
(1998)
H Kaube et al.
Expression of c-Fos-like immunoreactivity in the caudal medulla and upper cervical cord following stimulation of the superior sagittal sinus in the cat
Brain Res
(1993)
M Fanciullacci et al.
Increases in plasma calcitonin gene-related peptide from extracerebral circulation during nitroglycerin-induced cluster headache attack
Pain
(1995)
PJ Goadsby et al.
Stimulation of the trigeminal ganglion increases flow in the extracerebral but not the cerebral circulation of the monkey
Brain Res
(1986)
PJ Goadsby et al.
The peripheral pathway for extracranial vasodilatation in the cat
J Auton Nerv Syst
(1984)
PJ Goadsby et al.
Extracranial vasodilatation mediated by VIP (Vasoactive Intestinal Polypeptide)
Brain Res
(1985)
SE Spencer et al.
CNS projections to the pterygopalatine parasympathetic preganglionic neurons in the rat: a retrograde transneuronal viral cell body labeling study
Brain Res
(1990)
PJ Goadsby et al.
Stimulation of an intracranial trigeminally-innervated structure selectively increases cerebral blood flow
Brain Res
(1997)
A May et al.
Experimental cranial pain elicited by capsaicin: a PET-study
Pain
(1998)

SWG Derbyshire et al.

Pain processing during three levels of noxious stimulation produces differential patterns of central activity

Pain

(1997)

A Bahra et al.

Brainstem activation specific to migraine headache

Lancet

(2001)

J Ashburner et al.

Voxel-Based morphometry—the methods

Neuroimage

(2000)

Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain

Cephalalgia

(1988)

J Olesen

Revision of the International Headache Classification: an interim report

Cephalalgia

(2001)

PJ Koehler

Prevalence of headache in Tulp's observationes medicae (1641) with a description of cluster headache

Cephalalgia

(1993)

H Isler

Episodic cluster headache from a textbook of 1745: Van Swieten's classic description

Cephalalgia

(1993)

R Bing

Uber traumatische Erythromelalgie und Erthroprosopalgie

Nervenarzt

(1930)

MH Romberg

(1840)

W Harris

Ciliary (migrainous) neuralgia and its treatment

BMJ

(1936)

K Ekbom

Ergotamine tartrate orally in Horton's ‘histaminic Cephalalgia’ (also called Harris's diary neuralgia)

Acta Psychiatr Scand

(1947)

BT Horton

Histaminic cephalalgia

J Lancet

(1952)

G Sluder

The syndrome of sphenopalatine ganglion neurosis

Am J Med

(1910)

HH Vail

Vidian neuralgia

Ann Otol Rhinol Laryngol

(1932)

A Eulenburg

(1878)

L Kudrow

Cluster headache: mechanisms and management

(1980)

O Sjaastad

Cluster headache syndrome

(1992)

J Olesen et al.

(1999)

DW Dodick et al.

Cluster headache

Cephalalgia

(2000)

MB Russell et al.

Cluster headache is an inherited disorder in some families

Headache

(1996)

MB Russell et al.

Cluster headache is an autosomal dominantly inherited disorder in some families: a complex segregation analysis

J Med Genet

(1995)

M Leone et al.

Increased familial risk of cluster headache

Neurology

(2001)

C Roberge et al.

Cluster headache in twins

Neurology

(1992)

O Sjaastad et al.

Cluster headache in identical twins

Headache

(1993)

EG Couturier et al.

The first report of cluster headache in identical twins

Neurology

(1991)

J Haan et al.

No involvement of calcium channel gene (CACNA1A) in a family with cluster headache

Cephalalgia

(2001)

C Sjostrand et al.

CACNA1A gene polymorphisms in cluster headache

Cephalalgia

(2001)

JW Lance et al.

Mechanism and management of headache

(1998)

K Ekbom et al.

Carotid angiography in cluster headache

Acta Radiol

(1970)

MA Moskowitz

Cluster Headache—evidence for a pathophysiologic focus in the superior pericarotid cavernous sinus plexus

Headache

(1988)

JE Hardebo

How cluster headache is explained as an intracavernous inflammatory process lesioning sympathetic fibres

Headache

(1994)

IN Remahl et al.

Cluster headache is not associated with signs of a systemic inflammation

Headache

(2000)

PJ Goadsby et al.

Effect of stimulation of trigeminal ganglion on regional cerebral blood flow in cats

Am J Physiol

(1987)

A May et al.

The trigeminovascular system in humans: pathophysiological implications for primary headache syndromes of the neural influences on the cerebral circulation

J Cereb Blood Flow Metab

(1999)

H Gushing

The sensory distribution of the fifth cranial nerve

Bull Johns Hopkins Hosp

(1904)

W Penfield et al.

Dural headache and the innervation of the dura mater

Arch Neurol Psychiatry

(1940)

FL McNaughton

The innervation of the intracranial blood vessels and dural sinuses

Proc Assoc Res Nervous Ment Dis

(1938)

FL McNaughton et al.

Innervation of intracranial structures: a reappraisal

W Feindel et al.

The tentorial nerves and localization of intracranial pain in man

Neurology

(1960)

PJ Goadsby et al.

The distribution of trigeminovascular afferents in the non-human primate brain Macaca nemestrina: a c-fos immunocytochemical study

J Anat

(1997)

Cited by (362)

Symptomatic trigeminal autonomic cephalalgias in neuromyelitis optica spectrum disorders
2023, Multiple Sclerosis and Related Disorders
The pathophysiology of trigeminal autonomic cephalalgias (TACs) is poorly understood at present. Symptomatic TACs are rarely reported in neuromyelitis optica spectrum disorders (NMOSD). To better clarify this distinct clinical manifestation in NMOSD and to investigate its possible pathophysiology, we reviewed articles describing such cases including our own case.
We performed a search of all clinical studies of TACs in NMOSD published up to September 1st, 2022. We put no restrictions on the year of English publication in our search. The following keywords were searched: trigeminal autonomic cephalalgias, cluster headache, short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), short-lasting unilateral neuralgiform headache with autonomic symptoms (SUNA), hemicrania continua, paroxysmal hemicrania, neuromyelitis optica, neuromyelitis optica spectrum disorder, Devic's disease.
We reviewed six cases (five published reports and our own case study) that fulfilled the diagnosis of NMOSD and TACs. Four of them were SUNCT, one was SUNA, and one was paroxysmal hemicrania. In three of these cases, headache was the initial sole manifestation. Only one case had a good response to routine TACs’ treatment. All these patients had lesions in the medulla oblongata and cervical cord. Three cases’ TACs were side-locked, and two of them had a left dorsolateral medulla oblongata lesion that corresponded with the left side TACs, while three cases’ headaches happened on either side of the head. The phenomenon could be explained by the activation of trigeminal-autonomic reflex and ephaptic coupling.
TACs could be the initial sole brainstem manifestation of NMOSD. An underlying cause for SUNCT/SUNA should be considered, especially if there is a limited response to anti-epileptic medication. The activation of trigeminal-autonomic reflex and ephaptic coupling might be the underlying mechanism of symptomatic TACs in NMOSD.
Symptoms and pathophysiology of cluster headache. Approach to combined occipital and supraorbital neurostimulation
2023, Revista Espanola de Anestesiologia y Reanimacion
La cefalea en racimos (CR) se encuadra dentro del apartado 3 de la clasificación de la Sociedad Internacional de Cefaleas (IHS), que es el reservado para las llamadas cefaleas trigémino autonómicas (CTA).
Se trata de uno de los procesos de cefalea primaria más frecuentes, dolorosos e incapacitantes. Los tratamientos farmacológicos agudos y preventivos son, en muchos casos, mal tolerados y de efectividad limitada.
Debido a la mejora en la comprensión de su fisiopatología de la CR, los dispositivos de neuromodulación se han posicionado como opciones seguras y eficaces de tratamiento preventivo y el tratamiento agudo de la CR. Haremos un recorrido sobre la información disponible hasta el momento y además, exponemos el caso de un paciente con CR incapacitante, muy resistente al tratamiento médico, tratado en nuestra Unidad del Dolor con el implante de un sistema de neuroestimulación de nervio periférico de nervios supraorbitario (SON) y nervio occipital mayor (GON).
A continuación revisaremos los criterios diagnósticos que la definen la CR, lo datos que conocemos, a día de hoy, sobre su fisiopatología y la posición que ocupa actualmente la neuromodulación en el abordaje terapéutico de la misma. Con la descripción del caso clínico de un paciente tratado en nuestra Unidad del Dolor con una cefalea especialmente severa y resistente al tratamiento farmacológico.
Cluster headache (CH) is included under section 3 - Trigeminal autonomic cephalalgias (TAC) of the International Headache Society (IHS) classification. It is one of the most frequent, painful and disabling primary headaches. Acute and preventive pharmacological treatments are often poorly tolerated and of limited effectiveness. Due to improved understanding of the pathophysiology of CH, neuromodulation devices are now considered safe and effective options for preventive and acute treatment of CH. In this paper, we review the information available to date, and present the case of a patient with disabling cluster headache highly resistant to medical treatment who underwent implantation of a peripheral nerve neurostimulation system to stimulate the supraorbital nerves (SON) and greater occipital nerve (GON) in our Pain Unit. We also review the diagnostic criteria for CH, the state of the knowledge on the pathophysiology of CH, and the role played by neuromodulation in treating this condition
Nursing care of a patient with cluster headache based on the Nola Pender health promotion model: Case report
2023, Revista Cientifica de la Sociedad Espanola de Enfermeria Neurologica
La cefalea en racimos fue descrita por B.T. Horton como un fuerte dolor unilateral en la región orbitaria de predominio cíclico, que afecta principalmente a hombres. No se conocen exactamente las anormalidades estructurales y funcionales de su etiología, aunque se relaciona con un gen autosómico. El diagnóstico se basa en la clínica del paciente y el tratamiento en el manejo del dolor y supresión de los factores precipitantes del episodio.
Desarrollar un plan de cuidados de enfermería para paciente con cefalea en racimos y establecer una conducta promotora de salud.
Se realizó revisión de la literatura sobre la cefalea en racimos. Basados en la taxonomía de valoración por dominios de Nanda Internacional, la clasificación de Resultados de Enfermería (NOC) y la clasificación de Intervenciones de Enfermería (NIC), se desarrolló un plan de cuidados individualizado. Seguidamente se aplicó en el paciente el modelo de promoción de la salud de Nola Pender con el fin de promover conductas promotoras de salud.
Se describe el proceso de enfermería partiendo de los diagnósticos dolor, fatiga y conocimiento y conducta de salud con sus respectivos objetivos, intervenciones y acciones de enfermería. Se evidenció mejoría al administrar al paciente oxígeno venturi al 50% a 15 litros por minuto, por 30 minutos; topiramato cada 12 horas y generación de conductas saludables orientadas desde el modelo de promoción de la salud propuesto por Pender.
Se resalta la importancia no solo del abordaje en la severidad del cuadro clínico, sino de la promoción de los estilos de vida adecuados sobre factores de riesgos desencadenantes de la enfermedad.
Cluster headache was described by B.T. Horton as a strong unilateral pain in the orbital region of cyclical predominance, which affects mainly men. The structural and functional abnormalities of its aetiology are not exactly known, although it is related to an autosomal gene. The diagnosis is based on the patient's symptoms and the treatment on pain management and suppression of the precipitating factors of the episode.
To develop a nursing care plan for patients with cluster headaches and establish health-promoting behaviour.
A review of the literature on cluster headache was conducted. Based on the Nanda International domain assessment taxonomy, Nursing Outcomes Classification (NOC) and Nursing Interventions Classification (NIC), an individualised care plan was developed. Next, the Nola Pender health promotion model was applied to the patient to promote health-promoting behaviours.
The nursing process is described starting from the diagnoses of pain, fatigue, knowledge, and health behaviour with their respective objectives, interventions, and nursing actions. Improvement was evidenced when the patient was administered 50% venturi oxygen at 15 l/min, for 30 min; topiramate every 12 h and generation of healthy behaviours based on the health promotion model proposed by Pender.
The importance of not only addressing the severity of the clinical picture is highlighted, but also the promotion of appropriate lifestyles on risk factors that trigger the disease.
Diagnostic protocols and newer treatment modalities for cluster headache
2022, Disease-a-Month
Cluster Headaches are one of the most arguably severe forms of primary headache syndrome that affects humans. Although it is relatively uncommon, it has a significant impact on the quality of life. It is a multifactorial disease that has risk factors ranging from seasonal changes, lifestyle habits to genetics. It occurs in 2 forms- Episodic and Chronic, each having its well-defined Diagnostic Criteria. Moreover, Cluster Headache has an exhaustive list of options for both Preventive and Abortive treatment. This article focuses on Cluster Headache, its pathophysiology, risk factors, differentials, and its diverse treatment modalities.
In this study, an all-language literature search was conducted on Medline, Cochrane, Embase, and Google Scholar till October 2021. The following search strings and Medical Subject Headings (MeSH) terms were used: "Cluster Headache," "Triptans," "Neuromodulation," and "Migraine." We explored the literature on Cluster Headache for its epidemiology, pathophysiology, the role of various genes and how they bring about the disease as well as its episodic and chronic variants, and treatment options. Although we have a wide variety of options for Preventive and Abortive therapy, newer more effective pharmacological and non-pharmacological interventions are being developed, and must be integrated into new treatment protocols.
Localization of the Sphenopalatine Ganglion Within the Pterygopalatine Fossa on Computed Tomography Angiography—A Potential Role in the Setting of Sphenopalatine Ganglion Microstimulator Implantation
2021, Neuromodulation
Citation Excerpt :
The SPG is believed to play a key role in the pain and autonomic symptoms associated with CH. The pathogenesis is felt to be related to the trigeminal-autonomic reflex in which neural elements activate vessel dilatation and trigeminal nociceptive fibers, together with a central reflex that is mediated through the postganglionic parasympathetic fibers of the SPG (13). Due to its role in the initiation and maintenance of the clinical manifestations of CH, the SPG has long been a target for ablative and neuromodulating interventions (12, 14–16).
A recent approach to treatment of cluster headaches (CH) employs a microstimulator device for on-demand neuromodulation of the sphenopalatine ganglion (SPG) during an acute CH attack. A precise anatomical localization of the SPG within the pterygopalatine fossa (PPF) is optimal in order to position the SPG electrode array. This study aims to investigate a novel approach for SPG localization using computed tomography angiographic studies (CTA).
Two independent observers identified the location of the SPG on 54 computed tomography angiographic studies (CTA) and measured its position relative to the vidian canal (VC). The qualitative confidence of identification, morphology, position within the PPF and its relation to vascular structures were also recorded.
The SPG was detectable in 88% of cases with a variable position. The most frequent positions were superior (56%) and lateral (99%) relative to the VC with a mean (±SD) craniocaudal distance of 0.34 mm (±1.38) and a mean mediolateral distance of 3.04 mm (±1.2). However, in a considerable proportion of cases, the SPG was identified inferiorly to the VC (33%). Interobserver and intraobserver agreement for SPG location were moderate and strong respectively.
Since localization of SPG on CTAs is feasible and reproducible, it has future clinical potential to aid placement, optimal positioning and individualized programming of the electrode array.
Pathophysiology of cluster headache: From the trigeminovascular system to the cerebral networks
2024, Cephalalgia

View all citing articles on Scopus

View full text

ReviewPathophysiology of cluster headache: a trigeminal autonomic cephalgia

Summary

Section snippets

Genetics of cluster headache

Key pathophysiological features of neurovascular headache

Trigeminovascular system

Cluster headache as a TAC

Cluster headache—a disorder of the posterior hypothalamic grey matter

PET studies of cluster headache

Unresolved issues

Conclusion

Search strategy

Neurolmage

Lancet

Brain Res

Pain

Brain Res

J Auton Nerv Syst

Brain Res

Brain Res

Brain Res

Pain

Pain

Lancet

Neuroimage

Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain

Cephalalgia

Revision of the International Headache Classification: an interim report

Cephalalgia

Prevalence of headache in Tulp's observationes medicae (1641) with a description of cluster headache

Cephalalgia

Episodic cluster headache from a textbook of 1745: Van Swieten's classic description

Cephalalgia

Uber traumatische Erythromelalgie und Erthroprosopalgie

Nervenarzt

Ciliary (migrainous) neuralgia and its treatment

BMJ

Ergotamine tartrate orally in Horton's ‘histaminic Cephalalgia’ (also called Harris's diary neuralgia)

Acta Psychiatr Scand

Histaminic cephalalgia

J Lancet

The syndrome of sphenopalatine ganglion neurosis

Am J Med

Vidian neuralgia

Ann Otol Rhinol Laryngol

Cluster headache: mechanisms and management

Cluster headache syndrome

Cluster headache

Cephalalgia

Cluster headache is an inherited disorder in some families

Headache

Cluster headache is an autosomal dominantly inherited disorder in some families: a complex segregation analysis

J Med Genet

Increased familial risk of cluster headache

Neurology

Cluster headache in twins

Neurology

Cluster headache in identical twins

Headache

The first report of cluster headache in identical twins

Neurology

No involvement of calcium channel gene (CACNA1A) in a family with cluster headache

Cephalalgia

CACNA1A gene polymorphisms in cluster headache

Cephalalgia

Mechanism and management of headache

Carotid angiography in cluster headache

Acta Radiol

Cluster Headache—evidence for a pathophysiologic focus in the superior pericarotid cavernous sinus plexus

Headache

How cluster headache is explained as an intracavernous inflammatory process lesioning sympathetic fibres

Headache

Cluster headache is not associated with signs of a systemic inflammation

Headache

Effect of stimulation of trigeminal ganglion on regional cerebral blood flow in cats

Am J Physiol

The trigeminovascular system in humans: pathophysiological implications for primary headache syndromes of the neural influences on the cerebral circulation

J Cereb Blood Flow Metab

The sensory distribution of the fifth cranial nerve

Bull Johns Hopkins Hosp

Review
Pathophysiology of cluster headache: a trigeminal autonomic cephalgia