Cluster headache

Subjects

Abstract

Cluster headache is an excruciating, strictly one-sided pain syndrome with attacks that last between 15 minutes and 180 minutes and that are accompanied by marked ipsilateral cranial autonomic symptoms, such as lacrimation and conjunctival injection. The pain is so severe that female patients describe each attack as worse than childbirth. The past decade has seen remarkable progress in the understanding of the pathophysiological background of cluster headache and has implicated the brain, particularly the hypothalamus, as the generator of both the pain and the autonomic symptoms. Anatomical connections between the hypothalamus and the trigeminovascular system, as well as the parasympathetic nervous system, have also been implicated in cluster headache pathophysiology. The diagnosis of cluster headache involves excluding other primary headaches and secondary headaches and is based primarily on the patient's symptoms. Remarkable progress has been achieved in developing effective treatment options for single cluster attacks and in developing preventive measures, which include pharmacological therapies and neuromodulation.

Introduction

Headache is one of the most common pain symptoms in humans. It is extremely rare to have never had a headache, even when experiencing influenza infection or a mild head trauma. Headache is a normal physiological reaction; however, when headaches occur regularly and without adequate triggers, they are regarded not as a symptom but as a disease, examples of which include migraine and cluster headache. The International Classification of Headache Disorders (ICHD-3), which was updated in 2018, uses explicit diagnostic criteria based on symptoms and medical history for all headache disorders1. No single examination is able to define, ensure or differentiate idiopathic headache syndromes2. The ICHD-3 summarizes one group of headache syndromes as the trigeminal-autonomic cephalalgias (TACs; Box 1)1, of which cluster headache is the most prominent and common subtype.

Cluster headache is probably the most severe pain known and is characterized by ipsilateral headache, with pain localized to the orbit, supraorbital and/or temporal regions and associated autonomic features. Autonomic symptoms, such as lacrimation (tearing), conjunctival injection (redness of the sclera), rhinorrhoea, nasal congestion, hyperhidrosis (excessive sweating) and eyelid oedema, usually occur on the ipsilateral side to the pain3 and are absent in only 3% of cases. Cluster headache can be subclassified as either episodic or chronic, of which the episodic form is more common and affects 80–90% of patients3. Based on the ICHD-3 criteria, diagnosis of episodic cluster headache requires at least two cluster periods (also known as cluster bouts), each lasting from 7 days to 1 year1. These cluster periods are separated by pain-free periods (also known as out-of-bout periods or remission periods) that last ≥3 months. Diagnosis of chronic cluster headache requires cluster attacks that occur for >1 year without remission periods or with remission periods of <3 months in duration. Cluster headache attacks usually also occur with clocklike regularity during the day and are common during the night.

The pathophysiology of cluster headache is not fully understood but includes alterations in both the central and peripheral nervous systems, including activation of the trigeminovascular system (that is, divisions of the trigeminal nerve that innervate the cranial blood vessels) and the parasympathetic nervous system, which are speculated to underlie the pain and autonomic features of cluster headache, respectively. In addition, the hypothalamus — which interacts with several components of the trigeminovascular system — is believed to have an important role in the pathophysiology of cluster headache.

This Primer focuses on the current evidence of pathophysiology and diagnosis of cluster headache and how to manage patients, including those who are difficult to treat. This Primer also gives an up-to-date overview of the clinical features of cluster headache and a topical summary of the current state of research for this debilitating disease that is, in principle, easily treatable if certain principles are followed.

Epidemiology

Sociodemographic factors

Cluster headache is a rare headache disorder that occurs globally in 0.1% of the general population but accounts for <3% of all patients with headache in Asia46. Cluster headache has a male preponderance; the Cluster Headache Survey completed by 1,134 individuals in the United States confirmed earlier reports that 72% of patients are male7. A decreasing male to female ratio has been reported in the past 30 years8. This difference is probably attributable to better epidemiological tools, improved adherence to the diagnostic criteria and increased knowledge of the disease9; a lack of awareness of the disorder probably led to frequent misdiagnosis as migraine10. Indeed, a large proportion of patients with cluster headache have migraine-like features, such as photophobia (sensitivity to light) or osmophobia (hypersensitivity to odours), in addition to the typical trigeminal-autonomic symptoms, such as ptosis (drooping of the upper eyelid), sweating and miosis (constriction of the pupils). These patients (up to 46% in a large Italian study) also show a relatively younger age of onset and attacks that are longer in duration than cluster headache attacks without migraineous features11.

The age at onset of cluster headache ranged from 10 years to 68 years of age in one study in Sweden, with a peak between 20 years and 29 years of age for both sexes12. In the United States, cluster headache onset has been shown to occur before 20 years of age in 35% of patients and between 21 years and 30 years of age in 36% of patients7. Onset is less likely to occur between 31 years and 40 years of age (observed in 16% of patients) and between 41 years and 50 years of age (observed in 10% of patients)7. Only 3% of patients were >51 years of age at onset in the United States7. Other studies conducted in the United States and Italy have shown an onset of cluster headache before 50 years of age in 83.3% of women and 91.3% of men13,14. In a large Italian study, the mean age at onset was 30.2 years. In this study, women with primary chronic cluster headache (cluster headache that was chronic from onset) had a mean age at onset of 42.8 years; the age at onset in women with secondary chronic cluster headache (cluster headache that was episodic at onset and later became chronic) did not differ much from those with episodic cluster headache. In patients with chronic cluster headache who had onset prior to 16 years of age or after 49 years of age, the traditional male to female ratio was inverted15. Thus, the clear male predominance in cases with onset in the central age groups became attenuated in the extreme age groups.

Cluster bout periods seem to be more frequent in spring and autumn; although there are some reports in this regard, data are not available from all countries. However, one study in Taiwan stated that the cluster periods were more likely to occur in autumn and winter and are determined by the temperature of the preceding periods16.

In regard to life habits and possible risk factors, cigarette smoking, head trauma and family history of headache were associated with cluster headache in an Italian epidemiological case–control study17.

Genetic factors

Previous twin and family studies have highlighted the importance of genetic factors in cluster headache4,18. Individuals with first-degree and second-degree relatives with cluster headache have an increased risk compared with the general population19,20. Some studies suggest that cluster headache is an autosomal recessive inherited disorder, although others have suggested an autosomal dominant or multifactorial inheritance pattern21.

Genetic association studies focusing on the identification of candidate genes for cluster headache have suggested a modulatory role for HCRTR2 (encoding hypocretin (orexin) receptor type 2) in posterior hypothalamic neurons that are involved in the trigeminal pain pathway2224; however, this hypothesis was contradicted in a recent meta-analysis25. Other studies have associated homozygosity for the 1246G>A allele of HCRTR2 with an increased risk of cluster headache26,27, but this finding was not confirmed in a large multinational study22. Given the association between polymorphisms in HCRTR2 and cluster headache as well as the role of the orexin system in the pathophysiology (see Mechanisms/pathophysiology, below), sleep disorders such as narcolepsy have been suggested to be associated with cluster headache28. Other genetic association studies have revealed negative or conflicting results for the association of several genetic alterations with cluster headache, including mitochondrial DNA mutation29, genes encoding nitric oxide synthase (NOS1, NOS2A and NOS3)30, CACNA1A (encoding calcium voltage-gated, P/Q-type, α-1A subunit) for paroxysmal characteristics31 and a number of clock genes for rhythmicity, such as PER3, and the T3111C and 3092 T>C polymorphisms in CLOCK3234.

ADH4 (encoding alcohol dehydrogenase 4) has been studied in patients with cluster headache in light of the identification of alcohol as a trigger for attacks35. One study identified a positive association between the ADH4 rs1126671 single nucleotide polymorphism (SNP) and the risk of cluster headache in an Italian cohort35; another study reported an association between the ADH4 rs1800759 SNP and cluster headache36. However, these findings were not confirmed in a recent large case–control cohort study in Sweden37.

A recent genome-wide association study in a cohort of 99 Italian patients with cluster headache and 360 age-matched, cigarette-smoking, healthy controls demonstrated that ADCYAP1R1 (encoding pituitary adenylyl cyclase-activating polypeptide type I receptor, also known as PACAP) and MME (encoding membrane metalloendopeptidase, also known as neprilysin) variants were associated with cluster headache susceptibility, suggesting roles for genes implicated in pain processing38. However, a case–control study in Sweden did not find an association between cluster headache and ADCYAP1R1, MME or an intergenic variant on chromosome 14q21 (Ref. 39). Thus, additional exploration of specific gene abnormalities in cluster headache is warranted, and additional studies with larger sample sizes are needed; hitherto, no gene has been clearly associated with cluster headache.

Mechanisms/pathophysiology

Our understanding of the pathophysiology of cluster headache has advanced greatly owing to findings from preclinical and clinical studies, clinical observations, genetics and neuroimaging studies, but still remains incompletely understood. Previously, cluster headache was considered to be a type of vascular headache, but more recent evidence suggests that the pathophysiology of cluster headache involves the brain, trigeminovascular system and cranial parasympathetic system9,40. Whether cluster headache pain originates peripherally or centrally remains controversial; both are hypotheses of cluster headache pathophysiology. Collectively, the pathophysiology of cluster headache seems to involve the hypothalamus and pain-processing areas of the central nervous system, as well as peripheral structures, such as the trigeminal nerve, parasympathetic nerves and cranial vasculature. However, changes in peripheral structures (such as peripheral blood vessels) have a secondary role in cluster headache pathophysiology. Structural and functional changes in the hypothalamus and other brain networks that transmit nociceptive information have also been implicated in cluster headache, and the functional changes dynamically change between cluster-bout periods and out-of-bout periods. Moreover, anatomical and functional links between the hypothalamus and brain areas that are traditionally not considered as pain processing (for example, the occipital cortex and cerebellum) are altered in cluster headache and may also contribute to the pathophysiology.

Pathogenesis of peripheral origin

Proposed model of cavernous sinus involvement. Several characteristics of cluster headache attacks are consistent with pathology in the region of the cavernous sinus, mainly the triad of a predominantly trigeminal pain distribution, parasympathetic hyperactivity and sympathetic deficits. Indeed, the cavernous sinus is the only peripheral site where trigeminal C-fibres (which have a role in the transmission of nociceptive information to the central nervous system) and sympathetic fibres can be affected by a single cause41. However, clinical evidence for the involvement of the cavernous sinus in cluster headache is lacking. For example, the frequency of abnormal findings observed at orbital venography in cluster headache was not higher than those in other forms of headache42,43, suggesting that the cavernous sinus is unlikely to be the sole origin of pain in cluster headache. Furthermore, no clinical or biochemical evidence suggests a role of systemic inflammation in patients with cluster headache44.

Proposed vascular model. Another, albeit obsolete, hypothesis is that cluster headache is a variant of migraine such that the vascular headaches in cluster headache are related to changes in intracranial and extracranial blood vessels. Indeed, vasoconstricting ergot alkaloid derivatives are effective for the treatment of cluster headache45. However, neuroimaging studies using single-photon emission computed tomography (SPECT) have yielded contradictory results, with studies showing increased, decreased or unchanged cerebral blood flow in patients with cluster headache44,4649. Furthermore, intracranial vasodilation has been proposed to occur in cluster headache, although this is not specific as it also occurs in forehead pain50. Notably, exogenous histamine and other vasodilators (for example, alcohol, nitroglycerine and 5-hydroxytryptamine 2B (5-HT2B) agonists) can trigger cluster headache attacks during cluster-bout periods in patients51,52. This finding does not prove that vasodilatation is the initial event of cluster headache but suggests that vascular or other changes generate a permissive state in the cluster headache brain. Thus, vasodilation may be a trigger for the onset of cluster headache attacks, but it does not seem to be the primary cause.

Proposed trigeminal nerve model. According to the trigeminal nerve model of cluster headache, activation of the first division of the trigeminal nerve (that is, the ophthalmic nerve) by headache triggers — such as changes in weather, alcohol consumption, histamine release and strong odours — produces severe unilateral headache. This activation of the trigeminal nerve leads to the reflex activation of parasympathetic efferents (through the trigeminal-autonomic reflex), which produce autonomic symptoms, such as lacrimation, rhinorrhoea and nasal congestion53.

In support of this model, triptans (particularly, sumatriptan), which activate postsynaptic 5-HT1B (causing intracranial vasoconstriction) and 5-HT1D receptors (inhibiting brainstem trigeminal neuron neurotransmitter release), have been successfully used to treat acute cluster headache attacks54. However, to date, no evidence supports that sumatriptan crosses the blood–brain barrier during acute attacks55, and whether triptans act through an effect on peripheral trigeminovascular neurons or predominantly through a central nervous system effect in the brainstem is debated56. Surgical lesioning of the trigeminal nerve is not effective in patients with cluster headache57, suggesting that the potentially central effects of sumatriptan on the trigeminal nucleus caudalis (TNC; that is, the caudal region of the spinal trigeminal nucleus)58 are partly responsible for the success of this treatment in cluster headache, in addition to a possible peripheral trigeminovascular effect59.

Other lines of evidence supporting the trigeminal nerve model of cluster headache include increased levels of markers of both trigeminal nerve and parasympathetic activation. For example, increased expression of calcitonin gene-related peptide (CGRP; a marker of trigeminal activation) and vasoactive intestinal peptide (VIP; a marker of parasympathetic neuronal activation) have been found in jugular vein blood samples, ipsilateral to cluster headache attacks compared with out-of-bout periods and in healthy individuals60. Moreover, CGRP is increased in the plasma of patients during acute cluster headache attacks compared with out-of-bout periods61, and increased plasma CGRP levels during nitroglycerine-induced attacks can be attenuated by sumatriptan injection in patients62. In addition, increased CGRP levels have been reported between headaches (interictally) in patients during a cluster-bout period, which were reduced after short-term prophylaxis with corticosteroids63. Pretreatment with methylprednisolone could suppress IL-1β, but not prostaglandin E2-induced CGRP release from cultured trigeminal ganglia neurons64, and a blockade of cytokine-mediated trigeminal activation may mediate the preventive effect of methylprednisolone on cluster headache pathophysiology64. However, despite increased levels of CGRP in cluster headache, similar changes have been reported during migraine attacks and during therapeutic lesioning of the trigeminal ganglion65,66. Thus, although the trigeminal nerve may be involved in cluster headache, its activation alone cannot account for the disorder, and other factors are probably involved.

The neuropeptide PACAP is pharmacologically similar to VIP, is involved in pain processing in animal models and has been implicated in migraine pathogenesis67. Indeed, the intravenous administration of PACAP in healthy individuals can induce migraine-like headaches68. Interestingly, one study demonstrated the presence of PACAP in plasma during acute attacks in patients with cluster headache69. In addition, PACAP can induce activation of neurons in regions that are thought to be involved in cluster headache pathophysiology, such as the superior salivatory nucleus, the sphenopalatine ganglion (SPG; a parasympathetic ganglion) and the trigeminal ganglion70.

Studies using animal models have shown that stimulation of the pontine superior salivatory nucleus (SSN; which is the origin of cells in the parasympathetic vasodilator pathway and contains cell bodies of neurons that innervate the salivary glands and a host of other tissues) independently produces short-term neuronal activation in the trigeminocervical complex (TCC), which is associated with autonomic cranial symptoms, such as lacrimation and rhinorrhoea, and is inhibited by oxygen treatment in cluster headache71,72. The TCC consists of the dorsal horn of cervical spinal cord level 1 and level 2 and the TNC and acts as a relay centre that conveys nociceptive information from the head and neck to higher brain regions, such as the thalamus. In addition, the SSN receives direct projections from the paraventricular hypothalamic nucleus, which might modulate trigeminovascular nociceptive processing73. Neurons from the SSN project to the SPG, which is associated with cranial pain and autonomic symptoms, such as lacrimation and rhinorrhoea, and mediate the trigeminal-autonomic reflex40 (Fig. 1). Indeed, studies have suggested that the activation of postganglionic SPG neurons mediates the dilation of local meningeal vessels and the activation of trigeminal nociceptive fibres40. The activation of trigeminal nociceptive fibres can also trigger a reflex connection in the SSN, which contributes to increased cranial parasympathetic activity mediated by the SPG74,75. Consequently, SPG stimulation is minimally invasive and a potentially effective treatment option for patients with intractable chronic cluster headache (see Neuromodulation, below)7679. Of note, purely peripheral activation of the cranial parasympathetic system is not sufficient to cause cluster headache attacks8082.

Figure 1: Schematic pathway representation summarizing the trigeminal-parasympathetic reflex.
figure1

In patients with cluster headache, autonomic symptoms are thought to be mediated through the trigeminal-autonomic reflex. The trigeminal nucleus caudalis (TNC) is connected to the superior salivatory nucleus (SSN), from which parasympathetic efferent fibres of the facial nerve arise. During the trigeminal-autonomic reflex, activation of the trigeminal nerve is thought to lead to activation of parasympathetic efferents, producing autonomic symptoms such as lacrimation, rhinorrhoea and nasal congestion. These parasympathetic efferents originate in the SSN synapse with postganglionic fibres that innervate the dural vessels in the sphenopalatine ganglion (SPG), resulting in vasodilation. C1, C1 cervical nerve; C2, C2 cervical nerve; TCC, trigeminocervical complex.

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Although the above data suggest peripheral involvement in the pathogenesis of cluster headache, such theories cannot explain the cyclical recurrence of this disorder. Indeed, cluster headache-specific features, such as circadian and circannual rhythmicity, and behavioural features, such as agitation and restlessness, during acute attacks might be attributable to central rather than peripheral mechanisms.

Pathogenesis of central origin

The pain network. Pain is a complex, multifactorial and subjective experience that involves a large distributed brain network including both sensory–discriminatory and affective–cognitive evaluative neuroanatomical components83. Several neurophysiological studies have shown altered pain perception and decreased pain thresholds in patients with cluster headache, suggesting dysfunction of the pain control system8487. Furthermore, neurophysiological studies have implicated deficits in supraspinal pain control, such as the diffuse noxious inhibitory controls (neuronal pathways that underlie the physiological inhibition of pain by another painful stimulus) in cluster headache88,89. Dysfunction of the descending pain control system may facilitate primary headache disorders, including cluster headache, by disinhibiting or facilitating nociceptive signalling90.

Functional imaging studies have demonstrated dysfunction of the pain modulatory system in cluster headache91,92. Indeed, studies using 18F-fluorodeoxyglucose PET showed increased glucose metabolism in frontal brain areas (such as the perigenual anterior cingulate and prefrontal cortices) in addition to the thalamus, posterior cingulate, insular cortex and temporal cortex during cluster-bout periods compared with out-of-bout periods in patients with episodic cluster headache, suggesting that dynamic functional differences in central descending pain modulation between cluster-bout (interictally between headaches) and out-of-bout periods may facilitate attacks91.

In addition, studies using T1 voxel-based morphometry (VBM) have demonstrated grey matter volume reductions in the middle frontal gyrus, left superior gyrus and medial frontal gyrus during cluster-bout periods in patients compared with healthy controls93. Furthermore, grey matter volume increases were observed in the left anterior cingulate, insular cortex and fusiform gyrus during cluster-bout periods compared with out-of-bout periods. Thus, these dynamic changes in grey matter volume may reflect insufficient capacity for pain modulation in frontal areas in episodic cluster headache that are potentially associated with cluster headache pathophysiology.

Studies using diffusion-tensor imaging (DTI) to investigate white matter microstructural changes in patients with cluster headache have offered contradictory findings9496. One study revealed the absence of white matter diffusivity abnormalities compared with healthy controls94, although two other studies reported widespread white matter microstructural changes in the brain, particularly in the pain network, such as the frontal lobe, parietal lobe, temporal lobe and thalamus95,96. In addition, white matter microstructural differences have been reported in frontal pain modulation areas during the cluster-bout period in patients with cluster headache compared with healthy controls, and these changes mostly persisted during out-of-bout periods97. Probabilistic tractography showed consistent anatomical connections between the altered areas (between the cluster-bout periods and out-of-bout periods) and the hypothalamus, suggesting that these connections explain the shift between the two periods. Further research is required to determine the association. The discrepancies in the DTI studies may be attributable to differences in study populations at the time of scanning (for example, during cluster bouts or between cluster-bout periods).

Hypothalamus. The regularity and seasonal pattern of cluster headache (with a peak in occurrence of attacks in the autumn and spring), in conjunction with a relapsing–remitting presentation and ipsilateral cranial autonomic features, suggest that cluster headache may be related to alterations in the biological clock, such as that found in the hypothalamus98,99. In addition, several other lines of evidence, including data from anatomical, neuroimaging, hormonal and genetic studies implicate the hypothalamus in the pathophysiology of cluster headache. For example, patients with cluster headache often have neuro-endocrinological changes such as a blunted circadian testosterone rhythmicity and abnormal levels of other hormones regulated by the hypothalamus, including cortisol, growth hormone, thyroid-stimulating hormone, prolactin, melatonin, follicle-stimulating hormone and luteinizing hormone99,100.

Several neuronal connections exist between the hypothalamus and regions of the trigeminovascular system (Fig. 2). Studies in rodents have shown that the hypothalamus receives sensory input, including nociceptive information, from areas of the face and cranium innervated by the trigeminal nerve via the trigeminohypothalamic tract101,102. Additionally, the posterior hypothalamus is a physiological modulator of TNC neuronal activity103. Interestingly, disturbances in the hypothalamic–orexin system have been associated with cluster headache pathophysiology104. For example, injection of orexin A into the posterior hypothalamus of rats activates neurons in the TNC, whereas the injection of orexin B inhibits activity in the TNC24. In addition, one study showed decreased levels of orexin A in the cerebrospinal fluid of patients with cluster headache during cluster-bout periods105, which may be due to decreased function of the hypothalamic descending antinociceptive pathway or may represent an epiphenomenon of pain affecting hypothalamic activity105. The evidence for potential involvement of the orexin system in cluster headache pathophysiology is supported by human genetic association studies, which have revealed an association between a polymorphism of HCRT2 and risk of cluster headache26.

Figure 2: Schematic peripheral and central pathway representation summarizing the pathogenesis of cluster headache.
figure2

Pain and autonomic features in cluster headache probably arise from activation of peripheral structures, such as the trigeminovascular system. The pathophysiology initially involves structural and functional changes in the hypothalamus and specific brain networks that transmit nociceptive input, and these functional changes can differ between cluster-bout and out-of-bout periods. In addition, anatomical and functional links between the hypothalamus and brain areas that are traditionally not considered to be involved in pain processing (such as the occipital cortex (OCC) and cerebellum (CERE)) are altered in cluster headache and may have contributory roles in its pathophysiology. ACC, anterior cingulate cortex; AMYG, amygdala; HYP, hypothalamus; INS, insular cortex; LC, locus coeruleus; NRM, nucleus raphe magnus; PAG, periaqueductal grey; PFC, prefrontal cortex; S1, primary sensory cortex; SPG, sphenopalatine ganglion; SSN, superior salivatory nucleus; TG, trigeminal ganglion; THA, thalamus; TNC, trigeminal nucleus caudalis. Adapted from Ref. 111, Sage.

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Increased ipsilateral posterior hypothalamic activation has been observed in patients with cluster headache during nitroglycerine-triggered attacks compared with both out-of-bout periods and with healthy individuals106,107. In addition, similar hypothalamic activation was observed in a patient with a spontaneous attack108,109. In addition, bout-independent bilateral grey matter volume increases have been reported in the hypothalamus of patients with cluster headache106,110. These findings are under debate as some groups could not reproduce them111, whereas another study recently did110. The use of different MRI sequences and procedures for image processing may partly explain this discrepancy. Proton magnetic resonance spectroscopy studies have provided additional evidence in support of hypothalamic dysfunction in cluster headache: low N-acetylaspartate to creatine ratios in the hypothalamus of patients with cluster headache were found, which again supports hypothalamic dysfunction in the pathophysiology112,113.

Further evidence supporting the role of the hypothalamus in cluster headache pathophysiology stems from neuromodulation. Deep brain stimulation (DBS) of the posterior hypothalamus has been evaluated for the treatment of intractable chronic cluster headache114117 and leads to improvement in 60% of patients115, although ongoing attacks are unaffected (see Neuromodulation, below)118.

Other brain structures. Brainstem nuclei, including the locus coeruleus and dorsal raphe nucleus (which modulate vascular activity and pain input from the trigeminal nucleus), have been implicated in cluster headache pathogenesis119,120. The dysfunction of related monoaminergic pathways, which is related to brainstem descending pain modulation (noradrenaline and 5-HT as neurotransmitters), may link the hypothalamus and brainstem in cluster headache121 (Fig. 2).

Altered intrinsic fluctuations in sensorimotor and primary visual networks have been reported in patients during out-of-bout periods, suggesting that these functional changes extend beyond the antinociceptive system of the brain122. In addition, abnormal functional connectivity between the hypothalamus and areas associated with pain processing and visual networks, such as the sensorimotor and the primary visual networks, has been reported during and between attacks122. Bout-dependent changes in hypothalamic dynamic functional connectivity with regions of the frontal and occipital lobes and the cerebellum and cerebellar areas have also been reported in patients with cluster headache123. Additionally, a decrease in functional co-activation of the hypothalamus and salience network areas in patients with cluster headache has been observed, suggesting the association with the defective central pain control pathway and autonomic nervous system dysregulation124. Dynamic functional connectivity in the frontal and dorsal attention networks between cluster-bout periods and out-of-bout periods in patients with cluster headache has also been reported, implicating these changes in discrete cortical areas within networks outside traditional pain-processing areas125.

As previously mentioned, behavioural disturbances, including agitation and restlessness, are frequently observed in patients during attacks9; these symptoms are thought to be associated with the autonomic fight-or-flight response rather than a reaction to pain126,127. Previous studies have suggested the association between the cerebellum and the motor agitation128,129. Furthermore, trigeminal nociceptive processing has been reported in the cerebellar lobules V and VI, ipsilateral to the stimulus, suggesting that the cerebellum might have a functional influence on nociceptive and trigeminal processing130. Cluster headache-related functional changes in the cerebellum have been demonstrated in recent imaging studies and implicated in acute attacks131. Thus, we hypothesize that alterations in the activity or connectivity of the cerebellum may be associated with agitation or restlessness in cluster headache. Further research is required to confirm this hypothesis and may reveal neuromodulatory targets for specific symptoms.

Diagnosis, screening and prevention

Cluster headache features

The typical features of cluster headache have been described in studies from Denmark, the United Kingdom, Germany and the United States, collectively including 1,924 individuals7,132134. These studies provide fairly consistent results regarding the age of onset of cluster headache, the number and duration of attacks, the number of cluster periods per year, headache location and associated symptoms. Cluster attacks might begin with premonitory features that occur 10–20 minutes before the attack and include pain symptoms in the same regions as the cluster headache pain, cranial autonomic symptoms and general symptoms, such as difficulty concentrating and restlessness135. Pain intensity is consistently described as severe, and the most common headache locations are periorbital and retro-orbital, followed by temporal. The most common symptom associated with cluster headache is lacrimation (reported by >90% of patients), but other common symptoms include conjunctival injection, nasal congestion and rhinorrhoea, irritability, motor agitation, ptosis, eyelid swelling, forehead sweating and light sensitivity. Of note, in Asian individuals, lower frequencies of restlessness (50%) have been reported compared to western populations (>80%)5,6.

Circadian rhythmicity is reported by 80% of patients, and circannual rhythmicity is noted by >50%. In the Danish study, the worsening of attacks or the onset of cluster-bout periods was most common at the end of autumn and the beginning of winter, but in the US study, onset or worsening of attacks was most common in the spring and autumn7. The circadian and circannual rhythmicity is preserved in chronic cluster headache136. The average number of daily attacks ranges from two to four, with a mean duration of 100 minutes for untreated attacks. In individuals with episodic cluster headache, the average duration of a cluster period is 8–9 weeks, and patients experience an average of one to two cluster periods per year.

Commonly reported trigger factors for cluster attacks include sleep, alcohol consumption, relaxation, warmth, stress, high altitude and changes in weather. Indeed, in a questionnaire-based study of 275 individuals with cluster headache, 80% reported sleep as a trigger for their attacks28. Alcohol can trigger cluster attacks in 50–80% of patients and, accordingly, some individuals with cluster headache avoid alcohol completely137.

Diagnostic evaluation

Diagnostic criteria for cluster headache are available from the ICHD-3 (Ref. 138) (Box 2). Cluster headache is subcategorized into episodic and chronic forms based on whether cluster-bout periods are separated by pain-free intervals (out-of-bout periods) that last at least 3 months. The official classification, including several translations, can also be found online139.

The diagnosis of cluster headache is based on the patient's symptoms and the exclusion of a secondary headache. As secondary headaches that have a cluster headache phenotype and primary cluster headache are difficult to differentiate according to symptoms alone140, all patients with suspected cluster headache should undergo brain imaging to determine whether conditions are present that could cause a secondary headache with a cluster phenotype. The recommended technique is MRI with or without contrast enhancement and with fine slices through the region of the pituitary gland (as pituitary tumours can manifest with secondary headaches with a cluster phenotype)141. If a pituitary gland lesion is suspected or confirmed by imaging, laboratory testing for levels of pituitary hormones is indicated. In addition, as many patients with cluster headache have attacks that wake them from sleep, some patients have sleep disturbances before the attacks142 and sleep disorders are common comorbid conditions, investigations for sleep disorders are often indicated (see Comorbidities, below).

Differential diagnosis. Cluster headache must be differentiated from other headache types that have overlapping features, including other TACs (Box 1), side-locked migraine (in which every migraine attack occurs on the same side of the head) and secondary headaches manifesting with a cluster phenotype. Although the symptoms of cluster headache are similar to those of other TACs, they can be differentiated by the duration and frequency of attacks and therapeutic response to indomethacin (Table 1). Hemicrania continua consists of continuous unilateral headache, although exacerbations of headache severity that are often associated with ipsilateral cranial autonomic features can occur episodically; the continuous pain and the complete therapeutic response to indomethacin in patients with hemicrania continua differentiate this disorder from cluster headache138. Attacks of paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) have key differences in their duration, frequency and response to indomethacin compared with cluster headache (Table 1).

Table 1 Characteristics of cluster headache and other headache types that can have overlapping features

Occasionally, phenotypic overlap is apparent between migraine attacks and cluster headache, such as in side-locked migraine, when migraine is associated with ipsilateral cranial autonomic features and when cluster headache is associated with photophobia, phonophobia, nausea or vomiting7,143. Characteristics that are consistent with side-locked migraine rather than cluster headache are the longer duration of untreated attacks with migraine and the differences in patient activity during the attack (Table 1). As previously mentioned, secondary headaches with a cluster phenotype cannot be differentiated from primary cluster headache based on clinical features alone, and a diagnostic evaluation is required.

Diagnostic challenges. In patients with typical cluster headache symptoms, the phenotype should be easily recognized and the diagnosis of primary cluster headache should be made after the exclusion of a secondary headache. However, patients with cluster headache often experience delayed diagnosis or misdiagnosis, leading to suboptimal and inappropriate treatments144,145. In one study of 85 patients seen at the Danish Headache Center, the average delay between onset and diagnosis was 9 years, whereas in another survey of 351 patients within the Danish Headache Survey, the average time to diagnosis was 6.2 years and half of the patients initially received the wrong diagnosis132,146. In general, the time to diagnosis is variable between countries; the average time to diagnosis was 2.6 years in the United Kingdom144, 4.6 years in Spain147, 5 years in the United States7, 5.3 years in Italy148, 8 years in Taiwan5 and 11 years in Norway4. In the US Cluster Headache Survey, 25% of patients were diagnosed within 1 year of symptom onset and 58% of patients were diagnosed within 5 years, but 22% were not diagnosed for ≥10 years7. In that study, 79% of patients initially received an incorrect diagnosis, including migraine, sinusitis, allergies or tooth-related issues7. Overlapping features between cluster headache and migraine, such as the presence of aura, photosensitivity, phonosensitivity and side-shifting of headache (that is, from one side of the head to the other), probably contribute to misdiagnosis133,134,149.

Comorbidities

Individuals with cluster headache should be screened for possible comorbidities or other lifestyle factors, including smoking, alcohol abuse, illicit drug use, depression and sleep disorders9.

Smoking, alcohol and illicit drug use. As many as 70–90% of individuals with cluster headache smoke7,150. Smoking is associated with more severe manifestations of cluster headache (for example, longer cluster-bout periods and more frequent attacks), although only 18% of patients stopped smoking after cluster headache onset based on results from a US survey7. Smoking cessation does not affect the course of the disorder150,151. Different studies have provided conflicting results regarding whether the rates of alcohol use and abuse are higher in individuals with cluster headache than the general population151,152. However, alcohol can trigger cluster attacks in 50–80% of patients, making its use problematic within this population and leading some individuals with cluster headache to avoid alcohol137. Illicit drug use is more common in individuals with cluster headache than in the general population153, although this observation might be true only in men154. In an Italian study of 210 patients (including 162 men) with cluster headache, the rates of cannabis, opioids, cocaine, amphetamine and ecstasy use were higher in those with cluster headache than in the general population155. The use of illicit drugs, such as psilocybin and forms of lysergic acid, as self-treatments is not uncommon for patients with cluster headache156. However, some studies suggest that most illicit drug users first used the drugs before the onset of cluster headache155.

Depression and other psychological comorbidities. Depression is frequent in patients with cluster headache. Indeed, data from a population-based, cross-sectional study of 462 patients showed the lifetime prevalence of depression was 2.8-fold higher in those with cluster headache compared with healthy individuals157. In addition, the 2.5-year incidence of depression was 5.6-fold higher in patients with cluster headache than healthy individuals in a population-based follow-up study using the Taiwan National Health Insurance database, and more cluster-bout periods per year was a risk factor for depression158. In the US Cluster Headache Survey, 55% of patients reported suicidal thoughts, and 2% had attempted suicide7. Chronic cluster headache is associated with a higher prevalence of lifetime depression than episodic cluster headache157. Despite the high frequency, the rates of diagnosis and treatment of depression are low in patients with cluster headache, emphasizing the importance of screening for this condition157.

Whether anxiety and certain personality profiles are more common in individuals with cluster headache is a matter of debate. Although some studies have suggested high rates of anxiety and obsessive-compulsive and anti-social traits, other studies have found no differences between those with cluster headache and comparator groups, including healthy controls159162. Further studies are needed to define the psychological comorbidities of cluster headache and to assess how personality traits might affect pain coping, quality of life and optimal treatment recommendations.

Sleep disorders. As cluster headache attacks are frequently initiated during sleep, several studies have evaluated patients with cluster headache for sleep disorders28,133,163,164. Indeed, patients with cluster headache had higher scores on the Pittsburgh Sleep Quality Index than healthy individuals, which indicates a poorer self-assessment of sleep quality28. Patients who reported sleep as a trigger for their cluster attacks had higher scores than patients who did not report sleep as a trigger28. One polysomnography study showed a reduced percentage of rapid eye movement (REM) sleep, longer REM latency and fewer arousals in patients with cluster headache compared with healthy individuals164. No relationship was observed between the occurrence of nocturnal attacks and a specific sleep stage164.

Whether sleep-disordered breathing is more common in patients with cluster headache is debated. In one study, the rate of obstructive sleep apnoea was not higher in patients with cluster headache compared with healthy controls; however, sleep-disordered breathing was present in 80% of patients (using an apnoea-hypopnea index cut-off of ≥5)163,164 and in 44% of patients (using an apnoea-hypopnea index cut-off of ≥10)163. A higher rate of obstructive sleep apnoea has been reported during cluster-bout periods in patients with cluster headache than in healthy controls (29% versus 7%, P = 0.018)165.

Although the existence and nature of the relationship between cluster headache and sleep disorders are not clearly understood, screening patients with cluster headache for sleep disorders is reasonable as sleep is a trigger for attacks. Several studies suggest sleep disorders in patients, and some evidence suggests treating sleep disorders can reduce cluster attack frequency for a subset of patients.

Management

The treatment of cluster headache is based on empirical data and only a few clinical trials. Pharmacological treatment can be divided into acute attack abortion and prophylaxis, and most patients receive both types of treatment. Several nonpharmacological treatments (excluding neurostimulation) have been trialled but are ineffective in nearly all patients. Pharmacological treatment has a placebo rate that is similar to that for migraine treatment (25%)166. International treatment guidelines are available for cluster headache167,168, and the superiority of guideline-adherent treatment compared with non-guideline treatment in cluster headache has been reported169.

During an attack

Oxygen. The inhalation of pure oxygen is effective at aborting attacks170. Inhalation should start as soon as possible but can commence at any point during the attack and should last for 15 minutes while the patient is in a sitting, upright position. The oxygen should be delivered through a non-rebreather mask with reservoir or, preferably, with a demand valve oxygen mask171. Apart from chronic obstructive pulmonary disease, there are no common contraindications to oxygen therapy, as this therapy is safe and without relevant adverse effects170. More than 70% of all patients with cluster headache respond to oxygen therapy with a substantial pain reduction within 30 minutes170. Thus, oxygen is the first-choice treatment for the abortion of cluster attacks, although little is known about its mechanism of action71.

Triptans. Subcutaneous injection of sumatriptan, a 5-HT1B and 5-HT1D agonist, can render 75% of patients pain-free within 20 minutes of injection and can be administered at any point during the attack172,173. Sumatriptan injections are safe and without adverse effects in most patients, even with frequent use (including daily use for several years), and their effectiveness is not reduced over time174. Contraindications are cardiovascular and cerebrovascular disorders and risk factors including untreated arterial hypertension, hyperlipidaemia, diabetes mellitus, smoking and old age. The most specific and unpleasant adverse effects are chest pains and distal paraesthesia, which can occur in up to 10% of patients174. A zolmitriptan nasal spray has been shown to reduce pain and accompanying symptoms during attacks in two placebo-controlled trials and has been approved by the European Medicines Agency (EMA) for the acute treatment of cluster headache175,176. A sumatriptan nasal spray177,178 and oral zolmitriptan therapy179 have also shown efficacy within 30 minutes in single, open-label and double-blind, placebo-controlled trials.

Ergotamine. Oral ergotamine has been used for the treatment of cluster headache attacks for >50 years and is probably effective within 15 minutes if administered early in the attack; however, placebo-controlled trials are lacking. Short-term prophylaxis using ergotamine is not recommended because of severe adverse effects, such as vasoconstriction, soft tissue necrosis, distal paraesthesia and ulcers. Intranasal dihydroergotamine was not superior to placebo in a single trial at aborting attacks180, although intravenous administration was shown to abort severe attacks in an open-label retrospective181 and an open-label prospective182 trial.

Others. The nasal installation of lidocaine — a local anaesthetic that blocks neuronal voltage-gated sodium channels — is probably effective in at least one-third of patients when administered within 15 minutes of attack onset, although this has only been reported in open-label trials183185. Intranasal lidocaine is safe but might cause nasal discomfort; other adverse effects are unknown. Subcutaneous octreotide is effective in the treatment of acute attacks in a double-blind, placebo-controlled trial when given within 15 minutes of attack onset186. No adverse effects were reported in this trial. Further trials are not ongoing.

Preventive treatments

Verapamil. Verapamil — a voltage-dependent calcium channel blocker — is the first drug of choice for the prophylaxis of episodic and chronic cluster headache in most countries. Although only a few sufficiently powered double-blind, controlled trials have been conducted, they demonstrate that 70% of patients are responders9. In one controlled trial, verapamil was shown to have a more rapid action of onset than lithium, although both drugs showed efficacy in attack prophylaxis compared with placebo187. In another trial, verapamil was superior to placebo188. Adverse effects of verapamil are bradycardia, oedema of the legs, constipation, gastrointestinal discomfort, gingival hyperplasia and dull headache. As verapamil can increase cardiac conduction time, regular electrocardiography (ECG) testing is necessary189. Verapamil should be administered for 1.5 times of the assumed duration of the cluster-bout period, starting at the beginning of the period. The full effectiveness of verapamil can be expected within 2–3 weeks after drug onset187. Slow-release formulations are available that enable fewer administrations per day. When patients initially start verapamil, corticosteroids are also administered by some clinicians for 2 weeks to bridge the time period of dose escalation of verapamil.

Corticosteroids. There are no sufficiently powered randomized, placebo-controlled trials for the use of oral corticosteroids in cluster headache, although they are regarded as highly effective and several open-label studies and case series have been published and reviewed190. All studies showed the efficacy of the different regimens. Corticosteroids are recommended for short-term use, such as for 2–3 weeks after onset of the cluster bout when the rapid control of attacks is desired. Some patients are attack-free only with steroid treatment, and continuous administration of steroids is rarely required by the patient. Chronic use of corticosteroids is associated with high morbidity and, accordingly, caution and short-course therapy should be used; corticosteroids should be avoided for chronic cluster headache. In particular, the risk of opportunistic infections with corticosteroid use should be carefully considered in medium to long-term use. At high doses, 70–80% of patients respond to steroids. The injection of corticosteroids at the greater occipital nerve has shown efficacy in placebo-controlled trials for prevention191193; this procedure is easy to perform, has a very low rate of adverse effects compared with other treatments, and the effect can last for days.

Lithium. More than 20 open-label trials have evaluated the use of lithium carbonate for prophylaxis starting at the beginning of a cluster-bout period194. An attack frequency reduction of >50% has been reported in up to 78% of patients with chronic cluster headache and 63% of patients with episodic cluster headache194. However, one placebo-controlled trial did not show any efficacy of lithium in the prevention of episodic cluster headache195, and one study showed a more rapid improvement in headache frequency and better tolerability for verapamil than lithium187. Liver, renal and thyroid function, in addition to electrolyte levels, should be monitored regularly in patients using lithium as the major adverse effects are hypothyroidism, tremor and renal dysfunction194.

Anticonvulsants. Two open-label trials have suggested a moderate efficacy of valproic acid for prevention196,197, although one controlled study did not show a difference compared with placebo198. The scientific evidence is that valproic acid has no proven efficacy in either episodic or chronic cluster headache because the controlled trial was negative but can be tried as a third-line drug in patients who do not respond to verapamil or lithium. On the basis of results from open-label studies, other anticonvulsants, such as topiramate199,200 and gabapentin201,202, have a probable efficacy in the prophylaxis of episodic and chronic cluster headache. The main adverse effects of topiramate are cognitive disturbances, paraesthesia and weight loss, and this drug is contraindicated in patients with nephrolithiasis.

Other therapies. The pre-emptive or prophylactic use of triptans in patients with cluster headache remains controversial. In one study, sumatriptan administered orally was not effective in preventing attacks in a placebo-controlled trial203, although in open-label trials, eletriptan204 or naratriptan205 reduced the number of attacks in patients with episodic cluster headache.

The ipsilateral intranasal application of capsaicin has been studied in two open-label trials206,207 and one double-blind, placebo-controlled208 trial, and showed an efficacy in approximately two-thirds of patients with episodic cluster headache after repeated application in all trials. Also, the intranasal application of civamide (cis-capsaicin) showed moderate efficacy in a double-blind, placebo-controlled study in patients with episodic cluster headache209. However, although these studies are categorized as blinded, the nasally applied treatments irritate the mucosa. No evidence suggests that a combination of prophylactic drugs is superior to single use; however, this question has not yet been systematically studied.

Third-line treatments. Several treatments can be considered for refractory cluster headache. Methysergide — a 5-HT receptor antagonist — has been successfully used as a prophylactic drug for episodic cluster headache but is no longer manufactured. However, this issue may change as the licence for drug production is still valid. Oral melatonin was effective in reducing attack frequency in a single double-blind, placebo-controlled study in patients with episodic cluster headache210 but did not provide any additional efficacy when used as an adjunctive therapy to standard treatment in patients with refractory disease211. Warfarin was reported to effectively reduce attack frequency in a small controlled trial and in case reports of patients with episodic cluster headache212,213 but should not be used as a treatment given its adverse effect profile (including bleeding). Weak evidence from a small open-label study showed the efficacy of baclofen214 in prophylaxis, and another open-label study showed no evidence for transdermal clonidine215 in prophylaxis of episodic cluster headache.

Unsuccessful treatments. Candesartan is effective in migraine treatment but was not effective in a placebo-controlled trial in cluster headache prophylaxis216. Patients with episodic cluster headache did not benefit from botulinum toxin type A injections for prophylactic treatment217,218, but there might be some prophylactic benefit following onabotulinumtoxinA administered to the SPG in patients with chronic cluster headache219. Hyperbaric oxygen inhalation is not effective in preventing attacks in episodic or chronic cluster headache220. Cannabis, other cannabinoids and similar psychotropic drugs are frequently used by patients with cluster headache153, but self-reported effectiveness is very low154.

Neuromodulation

Substantial progress has been achieved in the management of cluster headache using invasive and noninvasive neuromodulation techniques (such as SPG stimulation, invasive occipital nerve stimulation (ONS), DBS and noninvasive vagus nerve stimulation (VNS) (Fig. 3)), which have given new hope to patients with refractory cluster headache. However, large sham-controlled trials are scarce, and data from some open-label studies have to be confirmed.

Figure 3: Neuromodulation therapies for cluster headache.
figure3

Neuromodulation methods that have been investigated for the treatment of cluster headache. For example, postganglionic neurons of the sphenopalatine ganglion (SPG) have been implicated in cluster headache-associated pain and autonomic features, and SPG stimulation has been shown to effectively abort cluster headache attacks and to reduce the frequency of attacks in some patients78,79. Invasive occipital nerve stimulation (ONS) has been evaluated for the prevention of cluster headache owing to the anatomical overlap between the trigeminal and cervical afferents, which is consequently termed the trigeminocervical complex, and accordingly, ONS could modulate antinociceptive activity in the trigeminocervical complex and the pain network257. The vagus nerve is a mixed motor and sensory nerve with projections to brain areas involved in pain modulation, including the trigeminal nucleus caudalis. Accordingly, noninvasive vagus nerve stimulation (VNS) has been suggested to inhibit nociceptive processing258 and has proved effective mainly in episodic cluster headache acute therapy. Hypothalamic deep brain stimulation (DBS) has been investigated for the prevention of cluster attacks owing to clinical and neuroimaging data, which proved the implications of hypothalamic function in the pathophysiology and the circadian and circannual manifestations of this condition. Figure adapted from Ref. 259, Macmillan Publishers Limited.

PowerPoint slide

SPG stimulation. Invasive techniques are generally considered when patients fail to respond to usual pharmacological therapies (and/or have intolerance to these treatments)221,222. The rationale for the use of SPG stimulation in cluster headache was based on the strong cranial ipsilateral autonomic features that are frequently observed during attacks (see Mechanisms/pathophysiology, above) and from data from pilot studies77. In the seminal randomized controlled trial (Pathway CH-1)78, 28 patients with refractory chronic cluster headache received surgical implantation of a stimulation device into the pterygopalatine fossa (in which the SPG is located). The devices could be remotely controlled by the patient and could randomly deliver one of three different stimulation patterns when activated (no stimulation or sham, subthreshold stimulation, or full stimulation). Pain relief was reported in 67.1% of attacks treated with full-dose stimulation and in 7.4% of attacks with sham stimulation; pain freedom within 15 minutes of stimulation was achieved in 34.1% of attacks with full-dose stimulation and in 1.5% of attacks with sham stimulation. The acute responder rate was 32%, and 43% of patients reported a ≥50% reduction in attack frequency compared with baseline78. Adverse events related to maxillofacial surgery were frequent (such as pain, swelling and haematoma), but most of the events were fully reversible. Furthermore, 81% of patients had sensory disturbances in the region of the face innervated by the maxillary nerve (likely because this nerve is located near the SPG), but these were mostly reversible. Six patients had to be re-intervened.

The Pathway CH-1 study was followed by an open-label trial involving 33 patients with chronic cluster headache who had 5,956 cluster attacks over 24 months79. In this trial, 30% of patients had ≥1 out-of-bout period(s) lasting ≥1 month (that is, they evolved to an episodic cluster headache form)223, 65% of attacks were successfully relieved by SPG stimulation and pain freedom was obtained in 50% of attacks. The 50% acute responder rate was 45%, and 35% of evaluable patients had an attack frequency reduction of ≥50% compared with baseline after 24 months. Headache frequency increased in 35% of patients and remained stable in 29%. Because the study was designed to assess the efficacy of SPG stimulation in acute therapy in those with chronic cluster headache, a continuous monitoring of attack frequency was not available in the Pathway CH-1 study or the follow-up. Patients were asked to record their average attack frequency (in the past 4 weeks) every 3 months. Accordingly, further studies are needed to determine the long-term effect of SPG stimulation on attack frequency in chronic cluster headache.

Invasive ONS. Invasive ONS is being used for refractory headache management and has been assessed for cluster headache prevention in several open-label studies224229. Although most trials reported encouraging results with follow-up periods of several years, sham-controlled trials of invasive ONS in cluster headache prevention have not been carried out. Overall, the open-label trials have included 172 patients with chronic cluster headache, usually those with drug-refractory forms224229. The attack frequency improved in 58.1% of patients, but most patients also required concomitant pharmacological prophylaxis. Similar to SPG stimulation, evolution from chronic to episodic cluster headache has been described with invasive ONS in 10–40% of patients. Despite a reduction in the attack frequency, invasive ONS had little or no effect on the intensity of attacks or the duration of pain230.

Stimulator-related adverse events are quite common with this treatment, mainly lead migration or device infection, and battery depletion may require replacement surgeries in up to 100% of patients. Other adverse events include paraesthesia induced by the stimulation, which cannot be tolerated by some patients. In addition, at least two long-term trials of up to 10 years in duration have described a tolerance phenomenon with invasive ONS228,231, which required the adjustment of the stimulation parameters and could be related to neuroplasticity in the opioid system232. A large multicentre randomized controlled trial is currently underway to evaluate invasive ONS for prevention of cluster headache (ICON study233).

Hypothalamic DBS. DBS targeting the hypothalamus is a neuromodulation technique that has been used to treat drug-refractory patients with cluster headache116 and is based on the activation of the posterior hypothalamus during attacks107. Several case series have been published over the past 20 years with encouraging results, including a reduction in attack frequency and intensity234, but a significant risk of serious adverse events, including a fatal haemorrhage, has been reported235. Only one hypothalamic DBS trial included a sham group117, and no differences were observed between the active and sham procedures in patients with chronic cluster headache, although the duration of the sham period might have been too short to detect a change. In the subsequent open-label phase of this trial, the mean attack frequency improved in 6 out of 11 patients.

Some controversies regarding the accuracy of the hypothalamic DBS stereotactic coordinates and the structures that are modulated have led to new trials based on different techniques236238. The aim of these trials was also to reduce the risk of serious adverse events. One study used a modified target in five patients239, and another study evaluated DBS of the ventral tegmental area (VTA) in 21 patients with chronic cluster headache114. The rationale of using the VTA for DBS was based on imaging studies in patients previously treated with hypothalamic DBS that showed a maximal activation that was centred over the VTA114. The median daily attack frequency decreased by 60%, and 52% of patients had a 50% reduction in median frequency of attacks114. The feasibility and efficacy of endoventricular hypothalamic DBS using a floating electrode that stimulates the floor of the third ventricle was reported in seven patients with chronic cluster headache240.

Noninvasive VNS. Noninvasive VNS is the only noninvasive neuromodulation technique that has been evaluated in cluster headache. In the ACT-1 randomized controlled trial, 133 patients (of whom two-thirds had episodic cluster headache), were asked to use noninvasive VNS to treat five attacks each241. A trend to pain relief or pain freedom was reported in patients who received the active treatment compared with the sham, and a significant difference was observed in patients with episodic cluster headache. In addition, exploratory efficacy end points (such as pain freedom at 15 minutes and changes in attack duration) were significantly improved in the episodic cluster headache subpopulation. The ACT-2 study provided similar results: noninvasive VNS was superior to sham in the episodic cluster headache subgroup only242. The open-label controlled PREVA study evaluated the use of noninvasive VNS add-on therapy twice daily (to a total of 12 minutes) for 1 month in 97 patients with chronic cluster headache compared with patients who continued their usual pharmacological prophylaxis (standard of care group)243. In the intention-to-treat analysis, a mean change in weekly attack frequency of −5.9 was reported in the noninvasive VNS group compared with −2.1 in the standard of care group. An estimation of adherence to therapy was 64% in the controlled phase (that is, 64% of patients performed ≥80% of the recommended treatment sessions). Further evidence is needed to confirm the usefulness of noninvasive VNS in attack prevention.

Quality of life

Given the intense pain of cluster headaches, surprisingly few studies have investigated the effect of the disorder on quality of life. Some studies suggest that patients have a poorer quality of life during active cluster bouts than the general population and that the impairment is greater in patients with an older age of onset244. No difference was reported in the quality of life of patients during cluster-bout periods in those with episodic compared with chronic cluster headache244. During the out-of-bout period in patients with episodic cluster headache, quality-of-life scores tended to improve and were similar to scores in those who are headache-free245,246, although other studies have reported high levels of disability in patients with episodic chronic headache during out-of-bout periods146,247. The degree of impairment that continues beyond the cluster-bout period might be attributed to the unpredictability of the next cluster bout.

The consequences of cluster headache have been underlined by a recent US survey, which revealed that 20% of patients had lost their job secondary to cluster headache and 8% were unemployed7. One study in Denmark reported that 16% of patients had lost their job, and 8% needed early retirement; this occurred in episodic and chronic cluster headache146. Given that most attacks occur during the night, a major problem in patients is sleep deprivation. Generally, up to one-third of patients found that the disorder limited their career146,247.

Compared with migraine, in which several questionnaires that measure the impact or disability of headache have been validated, only one scale has been developed for cluster headache248. This scale assesses the restriction on activities of daily living, the impact on mood and interpersonal relationships, pain and anxiety, and lack of vitality248. However, using the Headache Impact Test-6 (HIT-6) scale, 74% of patients with cluster headache were classified as severely affected (HIT-6 grade IV disability)249, with 78% of patients reporting restrictions in daily living and 96% needing to make a lifestyle change146. Social and leisure activities, family life and housework were disrupted. Agoraphobic symptoms have been reported in 33% of patients, depressive symptoms in 56% of patients and suicidal tendencies in 22% of patients247,249. In general, patients live in fear and uncertainty because of their condition250, and patients have high levels of self-aggression and depression, which correlates with greater emotional and functional impairment251. Self-aggression and depression substantially impair the patient's life and, accordingly, should be considered as important therapeutic targets.

Outlook

In the past 20 years, great advances in our understanding of the pathophysiology of cluster headache have come from findings in the central and peripheral nervous systems. The vascular model, involving an inflammation of the walls of the cavernous sinus, has been rendered outdated by the recognition that the neurovascular phenomena and a hypothalamic impulse generator, or ‘oscillator,’ seem to be more important. However, at present, the molecular and genetic background of cluster headache remains largely unknown, possibly due to the low prevalence compared with migraine.

Hypothalamic DBS has been used for the treatment of drug-refractory chronic cluster headache and can decrease attack frequency in 60% of patients. However, DBS is an invasive technique that is associated with serious complications in some patients116; accordingly, other minimally invasive or noninvasive neurostimulation techniques, such as SPG stimulation and noninvasive VNS, have been evaluated in patients with cluster headache230. Although these techniques have demonstrated efficacy in several trials, most trials have been open-label studies or have included only a limited number of patients in the placebo (sham) group. Accordingly, double-blind, randomized controlled studies with long-term outcomes are needed to expand the repertoire of therapeutic options for treating drug-refractory disease. To this end, several new therapies are under study, including neuromodulation and pharmacological therapies (Table 2).

Table 2 Selected planned or ongoing trials in patients with cluster headache

As previously mentioned, circulating levels of CGRP are increased during attacks62, suggesting a key role for this system in cluster headache. Several selective CGRP receptor antagonists are under development and seem to be effective in inhibiting nociceptive trigeminal processing in both animal models and patients252,253. However, the development of some older CGRP receptor antagonists has been halted because of severe adverse effects, such as hepatotoxicity254. The more recent and promising development of monoclonal antibodies targeting free CGRP and CGRP receptors has enabled clinicians to circumvent these adverse effects. These antibodies have promising efficacy in patients with migraine255,256 and are likely to be effective in cluster headache, although these trials are still ongoing. Future development of monoclonal antibodies and pharmacological agents targeting CGRP and possibly PACAP might improve the clinical management of cluster headache. Further studies to identify new biomarkers other than CGRP, accompanied by supportive brain imaging data, are warranted.

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How to cite this article

May, A. et al. Cluster headache. Nat. Rev. Dis. Primers 4, 18006 (2018).

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Contributions

Introduction (A.M.); Epidemiology (P.P.-R. and D.M.); Mechanisms/pathophysiology (A.M. and S.-J.W.); Diagnosis, screening and prevention (T.J.S.); Management (S.E. and D.M.); Quality of life (P.P.-R.); Outlook (S.-J.W. and A.M.); Overview of the Primer (all authors).

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Correspondence to Arne May.

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Competing interests

A.M. has been a consultant or speaker for Allergan, Autonomic Technologies, Desitin, Electrocore and Teva and is the Editor in Chief for Cephalalgia. T.J.S. has acted as a consultant or has served on the advisory boards of Allergan, Amgen, Autonomic Technologies, Avanir, Dr. Reddy's, Nocira, Novartis and Teva; has stock options in Nocira and Second Opinion; and has received royalties from UpToDate. D.M. has received research and travel grants from ElectroCore LLC. P.P.-R. has received honoraria as a consultant or speaker from Allergan, Almirall, Chiesi, Eli Lilly, Novartis and Teva. S.E. has received honoraria as a speaker from or is a member of an advisory board for Allergan, Johnson & Johnson, Novartis, Reckitt Benckiser and TAD Pharma. S.-J.W. has served on the advisory boards of Daiichi-Sankyo, Eli Lilly and Taiwan Pfizer and has received honoraria as a moderator from the Taiwan branches of Bayer, Eisai, Eli Lilly and Pfizer.

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May, A., Schwedt, T., Magis, D. et al. Cluster headache. Nat Rev Dis Primers 4, 18006 (2018). https://doi.org/10.1038/nrdp.2018.6

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