Atormac
briv
Neurology India
menu-bar5 Open access journal indexed with Index Medicus
  Users online: 6171  
 Home | Login 
About Editorial board Articlesmenu-bullet NSI Publicationsmenu-bullet Search Instructions Online Submission Subscribe Videos Etcetera Contact
  Navigate Here 
 Search
 
  
 Resource Links
  »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
  »  Article in PDF (852 KB)
  »  Citation Manager
  »  Access Statistics
  »  Reader Comments
  »  Email Alert *
  »  Add to My List *
* Registration required (free)  

 
  In this Article
 »  Abstract
 » Conclusion
 »  References
 »  Article Figures
 »  Article Tables

 Article Access Statistics
    Viewed1138    
    Printed20    
    Emailed0    
    PDF Downloaded29    
    Comments [Add]    

Recommend this journal

 


 
Table of Contents    
REVIEW ARTICLE
Year : 2021  |  Volume : 69  |  Issue : 7  |  Page : 124-134

Cluster Headache: What's New?


Headache and Facial Pain Group, University College London (UCL) Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK

Date of Submission02-Nov-2020
Date of Decision02-Feb-2021
Date of Acceptance13-Feb-2021
Date of Web Publication14-May-2021

Correspondence Address:
Dr. Manjit Matharu
Associate Professor and Honorary Consultant Neurologist, Headache and Facial Pain Group, University College London Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG
UK
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.315983

Rights and Permissions

 » Abstract 


Background: Cluster headache is a highly disabling primary headache disorder which is widely described as the most painful condition a human can experience.
Aim: To provide an overview of the clinical characteristics, epidemiology, risk factors, differential diagnosis, pathophysiology and treatment options of cluster headache, with a focus on recent developments in the field.
Methods: Structured review of the literature on cluster headache.
Results: Cluster headache affects approximately one in 1000 of the population. It is characterised by attacks of severe unilateral head pain associated with ipsilateral cranial autonomic symptoms, and the tendency for attacks to occur with circadian and circannual periodicity. The pathophysiology of cluster headache and other primary headache disorders has recently become better understood and is thought to involve the hypothalamus and trigeminovascular system. There is good quality evidence for acute treatment of attacks with parenteral triptans and high flow oxygen; preventive treatment with verapamil; and transitional treatment with oral corticosteroids or greater occipital nerve injection. New pharmacological and neuromodulation therapies have recently been developed.
Conclusion: Cluster headache causes distinctive symptoms, which once they are recognised can usually be managed with a variety of established treatments. Recent pathophysiological understanding has led to the development of newer pharmacological and neuromodulation therapies, which may soon become established in clinical practice.


Keywords: Cluster headache, diagnosis, pathophysiology, treatment, trigeminal autonomic cephalalgias
Key Messages: Cluster headache can be distinguished by the combination of severe unilateral head pain attacks, presence of cranial autonomic symptoms, and duration between 15 and 180 minutes. Attacks should be treated with parenteral triptans and/or high flow oxygen, and prevented with verapamil as first line treatment.


How to cite this article:
Cheema S, Matharu M. Cluster Headache: What's New?. Neurol India 2021;69, Suppl S1:124-34

How to cite this URL:
Cheema S, Matharu M. Cluster Headache: What's New?. Neurol India [serial online] 2021 [cited 2021 Jun 17];69, Suppl S1:124-34. Available from: https://www.neurologyindia.com/text.asp?2021/69/7/124/315983




Cluster headache (CH) is a primary headache disorder classed as a trigeminal autonomic cephalalgia. It is distinguished by the severe nature of the pain, length of attacks, presence of cranial autonomic symptoms such as lacrimation and conjunctival injection, and the tendency of attacks to occur with circadian and circannual periodicity. There are a number of effective acute and preventive treatment options. However, there is often a delay until the correct diagnosis is made and targeted treatment started. The pathophysiology of CH is still poorly understood, but recent advances in the understanding of the primary headache disorders have led to newer treatments which may help those patients who do not respond to the established ones.

Clinical characteristics

CH is characterized by attacks of severe unilateral head pain in the orbital, supraorbital, or temporal region lasting between 15 minutes and three hours if untreated. The pain is associated with ipsilateral cranial autonomic symptoms such as conjunctival injection, lacrimation, nasal congestion, rhinorrhea, forehead, and facial sweating, ptosis, meiosis, and eyelid edema. Attacks are usually accompanied by restlessness or agitation.[1]

CH is so called because attacks usually occur in 'clusters' (also called bouts or periods) lasting a few weeks or months, during which time attacks occur between once every other day and eight times per day. There is often striking circannual periodicity with bouts occurring predictably during certain times of the year, and circadian periodicity during bouts with attacks occurring predictably at the same time(s) of day, often at night.

Patients are said to have episodic cluster headache (ECH) if bouts are separated by pain-free remissions of at least three months, and chronic cluster headache (CCH) if attacks occur for one year or longer without remission or remissions last less than three months.[1] Approximately 85% of patients have ECH. In some patients, CH attacks can be triggered by alcohol, strong smells, exercise, a warm environment, or nitrate containing medications whilst they are within a bout.

CH is widely described as the most painful condition a human can experience. In females with CH, the pain is often described as worse than childbirth. CH leads to a high degree of headache-related disability, probably the highest of all headache disorders.[2] Depression and anxiety commonly develop after the onset of CH. Individuals with CH are 5.6 times more likely to be depressed,[3] and suicidal ideation was found to occur in 55% of sufferers in a large survey.[4] Fortunately, despite the severity of the pain, CH is not life-threatening or physically damaging to the brain.

Diagnosis

Like all primary headache syndromes, the diagnosis of CH is made clinically based on the patient's history according to consensus criteria – see [Table 1]. Diagnosis will be aided by observation of an attack or photograph or video of an attack demonstrating cranial autonomic symptoms. Between attacks, neurological examination is usually normal though some patients can have a partial Horner's syndrome.
Table 1: ICHD-3 criteria for cluster headache

Click here to view


Primary headache syndromes are currently classified according to the International Classification of Headache Disorders, 3rd Edition.[1] In this classification CH belongs to the group of trigeminal autonomic cephalalgias, which also includes paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks with autonomic symptoms, and hemicrania continua [see [Table 2]].
Table 2: Comparison of the typical clinical features of trigeminal autonomic cephalalgias

Click here to view


Frequently there is a long diagnostic delay before the diagnosis of CH is made and targeted treatment started, and patients are often not given the correct diagnosis on the first presentation to a healthcare professional.[4] The main differential diagnoses of CH are other primary headache disorders, particularly migraine and paroxysmal hemicrania. A variety of secondary causes may rarely present with a CH-like phenotype. Accurate diagnosis is important to determine the optimal treatment.

In comparison with CH, migraine attacks are typically longer in duration (longer than four hours) and associated with prominent migrainous features (i.e., nausea and vomiting, photophobia, phonophobia). Cranial autonomic features can be present in migraine but are more prominent in CH.

Paroxysmal hemicrania is characterized by attacks which are also strictly unilateral and associated with cranial autonomic features, but attacks are of a shorter duration (2-30 minutes) and usually occur more than five times per day.[1] The importance of this diagnosis is that unlike CH, paroxysmal hemicrania responds absolutely to the drug indomethacin. We recommend a trial of indomethacin in patients with probable CH if attacks are shorter than 30 minutes or there are more than five attacks per day, but not all patients as the diagnostic yield is low and indomethacin may in some cases worsen CH headache. We use a trial of oral indomethacin starting at a dose of 25 mg three times a day for three days, followed by 50 mg three times a day for three days, followed by 75 mg three times a day for seven days, taken with a proton-pump inhibitor for gastric protection.

Rarely a patient can present with a clinical syndrome resembling primary CH due to secondary pathology. This may include pituitary tumor, cavernous sinus pathology, arterial dissection, or aneurysm. Our practice is to perform magnetic resonance imaging (MRI) to exclude secondary causes in all patients who present during the first bout or have atypical features. Brain imaging may be performed in some patients who present late for reassurance to the patient, but this decision should be balanced against the chance of incidental findings, which are present in 2-3% of the population on brain MRI.[5]

Dedicated pituitary imaging does not need to be routinely organized unless any clinical features of pituitary tumor are present, as the risk of a pituitary tumor in this population does not appear to be higher than the background risk.[6]

Epidemiology and risk factors

CH affects approximately 0.1% of the population.[7] In contrast to migraine which is more common in females, CH is approximately four times commoner in males.[7] The onset is typically in the third decade of life. The clinical phenotype is similar in men and women, although women may suffer more nausea and vomiting with attacks.[8] Unlike migraine, there is not usually any relationship to the menstrual cycle, pregnancy, or menopause.[9]

There appear to be both genetic and environmental risk factors for the development of CH. Approximately 6% of patients of CH have a family history in a first or second-degree relative,[10] and there are several reports of CH in identical twins. A polymorphism in the hypocretin receptor-2 gene was demonstrated to increase the risk of CH,[11] however this has not been supported by other more recent studies.[12] No other gene has consistently been shown to be strongly associated. However, the genetics studies conducted thus far were relatively small and underpowered. The International Consortium for Cluster Headache Genetics (ICCG) is currently conducting a large genome -wide association study which is due to report shortly and will likely identify some CH susceptibility loci.

Cigarette smoking is extremely common in those with CH, and in most cases, the smoking habit precedes the onset of CH. In non-smokers, there is often a history of passive smoking during childhood. It is possible smoking contributes to the onset of CH via a toxic compound in cigarette smoke. Use of other illicit drugs prior to the onset is also higher in men with CH than the general population, so alternatively the association may be due to a shared risk factor for both CH and addictive behavior.[13] Some studies have also shown a higher rate of an excess of both caffeine and alcohol intake in patients with CH, however many patients' alcohol intake will decrease during bouts due to its ability to trigger attacks.

Previous head injury is commonly reported by patients with CH. Often there is not sufficient close temporal relation to the head injury to meet the criteria for a true post-traumatic headache. When a post-traumatic headache with CH phenotype does occur, it is more likely to be chronic and refractory to treatment.[14]

Pathophysiology

The pathophysiology of CH remains poorly understood. The key features which would be accounted for by a comprehensive pathophysiological model include the trigeminal distribution of the pain, the presence of cranial autonomic symptoms, the periodicity of attacks, and the response to treatments such as triptans and oxygen. Overall there is no universal consensus on the pathophysiology of CH. The current leading view suggests that during attacks the trigeminovascular system and trigeminal-autonomic reflex become activated via a trigeminal-hypothalamic pathway under fluctuating control from the hypothalamus and other central pain-processing regions. [Figure 1] provides an overview of the proposed structures and pathways involved in CH pathophysiology.
Figure 1: Schematic diagram of the central and peripheral pathways thought to be involved in the pathophysiology of cluster headache. Image copyright of 'Headache Academy', reproduced with permission. ACC, anterior cingulate cortex; C1, first cervical nerve root; C2, second cervical nerve root; ICA, internal carotid artery; PFC, prefrontal cortex; PH, posterior hypothalamus; SCG, superior cervical ganglion; SPG, sphenopalatine ganglion; SSC, somatosensory cortex; SSN, superior salivatory nucleus; TNC, trigeminal nucleus caudalis

Click here to view


Vascular hypotheses

CH has in the past been described as a “vascular headache”, as vasodilation of intracranial arteries ipsilateral to the pain is seen during attacks. Experimental studies using induced forehead pain by capsaicin injection have suggested that pain induces vasodilation, not vice-versa.[15] Current thinking is that the attacks originate in the nervous system rather than due to a primary vascular etiology.

It has been hypothesized that CH may be caused by a lesion in the cavernous sinus, a region where incoming trigeminal nociceptive fibers, and outgoing sympathetic and parasympathetic fibers are adjacent.[16],[17] Imaging, angiography and biochemical studies have not shown any evidence of inflammation or another lesion in this region in patients with CH.

Trigeminal nerve

The pain of CH is usually felt in the dermatome of the first division of the trigeminal nerve (V1). The location of the pain in CH and other primary headache syndromes therefore implicates the trigeminal nerve as involved as least in the pain component of attacks. V1 provides sensory innervation to the eye, skin of the upper face and front part of the scalp, as well as the frontal sinuses, cranial vessels, and dura mater.

The assumed importance of the trigeminal nerve to the pain of CH has led some to perform complete trigeminal nerve section or radiofrequency ablation in patients with CCH that is refractory to other treatments. This can be effective in some patients,[18] but not all,[19] indicating that the peripheral trigeminovascular system cannot be the sole explanation for attacks. It is also possible for a syndrome which is otherwise indistinguishable from CH to have attacks outside the trigeminal nerve distribution (for example occipital, parietal and cervical regions).[20]

Trigeminovascular system

The trigeminovascular system is a term used to describe the trigeminal neurons which innervate cerebral blood vessels. The headache phase of migraine has been proposed to develop as the result of an abnormal release of neurotransmitters or peptides in the trigeminovascular system. Peptides involved in this system include calcitonin gene-related peptide (CGRP), substance P, and vasoactive intestinal peptide. Elevated levels of CGRP have been found in patients with migraine and CH, both during spontaneous and nitroglycerine-induced attacks.[21],[22] A specific marker for CH, different to migraine or other headache disorders has not been identified.

Infusion of CGRP can trigger attacks in those with CCH, and with ECH exclusively whilst within a bout.[23] Similar findings in patients with migraine have led to the development of anti-CGRP monoclonal antibodies, which have recently also been trialed in patients with CH.

Trigeminal-autonomic reflex

The autonomic symptoms during attacks of CH and other trigeminal autonomic cephalalgias are thought to result from activation of a trigeminal-autonomic reflex. This is a physiological reflex by which a painful stimulus in the trigeminal region results in reflex activity in the ipsilateral facial parasympathetic system, producing symptoms which may be expected from physical damage to that side of the head or eye such as lacrimation, conjunctival injection, rhinorrhoea, and facial swelling.

The trigeminal-autonomic reflex, which has been studied in animals, has the afferent limb of the trigeminal sensory neurons, and efferent limb of the parasympathetic neurons traveling with the facial nerve from the superior salivatory nucleus via the sphenopalatine ganglion. Various therapies which are effective in trigeminal autonomic cephalalgias have been shown experimentally able to modulate this reflex, although it is not known whether they do this directly or indirectly e.g., via the hypothalamus.[24]

The symptoms of rhinorrhoea, lacrimation, conjunctival injection and nasal congestion in association with CH are related to increased parasympathetic activation. Conversely, the symptoms of ptosis and meiosis are related to reduced sympathetic function.

Hypothalamus

The marked circadian and circannual periodicity observed in CH patients suggests that neuronal populations which have circadian and circannual fluctuations must play a role in the pathophysiology. The human “biological clock” is the suprachiasmatic nuclei located in the anterior hypothalamus. Cells in this area generate a self-sustaining rhythm which is entrained by light signals from the retina via the retino-hypothalamic tract and melatonin secreted by the pineal gland. The outputs from the suprachiasmatic nuclei in turn entrain various parts of the body and brain which have diurnal rhythms, including the secretion of pituitary hormones.

A number of studies have found abnormal levels of pituitary hormones in patients with CH suggesting hypothalamic dysfunction.[25] It is not known whether these changes are specific to CH as abnormal pituitary hormone levels have also been found in migraine and other non-headache chronic pain conditions,[26] and may also be affected by chronic stress or interrupted sleep. The circadian secretion of melatonin has also been found abnormal in patients with CH during bouts.[27]

Orexin-A and -B (also known as hypocretins) are neuropeptides which are produced exclusively by a small area of neurons in the posterior and lateral hypothalamus. They are involved in the regulation of wakefulness and food intake. A polymorphism in an orexin receptor gene has been demonstrated to increase the risk of CH in some genetic studies.[11] Animal experiments have shown that orexin-A and orexin-B given via injection into the posterior hypothalamus or intravenous infusion can differentially modulate the response of trigeminal neurons to dural stimulation, indicating that the posterior hypothalamus can alter the trigeminal nociceptive response to meningeal inputs.[28],[29]

Imaging studies have supported the importance of the hypothalamus in CH. Functional imaging studies using positron emission tomography (PET) and functional MRI have shown activation in the ipsilateral hypothalamic grey matter during attacks.[30],[31],[32]

Functional imaging studies in other trigeminal autonomic cephalalgias have also shown activation in a similar region.[33],[34] This activation may not be specific for trigeminal autonomic cephalalgias as hypothalamic activation has been also seen in spontaneous migraine attacks,[35] and other acute pain states such as induced angina pectoris.[36]

A structural MRI study using voxel-based morphometry reported an increase in bilateral inferior posterior hypothalamic gray matter volume in patients with CH in the same region activated on functional MRI.[37] This structural change has not been supported by other studies using similar methodology.[38]

Magnetic resonance spectroscopy has shown reduced altered metabolite ratios in the hypothalamic region in patients with CH. In a study of 47 patients there was a significantly lower NAA/Cr and Cho/Cr ratio in patients with CH compared with healthy controls and those with chronic migraine. There was no difference in those with ECH between inside and outside a bout.[39]

Functional connection between the trigeminal nerve and hypothalamus is likely important for coordinating endocrine, autonomic and behavioral responses to stimuli and pain in the head and face, blood vessels, and meninges. A “trigeminohypothalamic” tract connecting the hypothalamus and trigeminal nucleus has been shown to exist in animal studies.[40],[41] Connection between the hypothalamus and brainstem regions including the trigeminal nucleus has been demonstrated in humans using probabilistic tractography imaging in patients who underwent deep brain stimulation for refractory CCH.[42]

Cortical factors

The perception of pain is presumed to occur in the cerebral cortex via projections from the thalamus. Cortical processing of pain is incompletely understood and there is no central area for the processing of pain, but most studies have implicated the bilateral insula, anterior cingulate cortex and regions of the frontal cortex as pain processing regions.

Structural neuroimaging studies have shown reduced grey matter volume in cortical pain processing regions in patients with CH,[38],[43] which in one study depended on whether the patient was within or outside a bout.[44] Functional imaging studies have shown activation in central pain processing regions during attacks,[32] and a PET study has shown hypometabolism in the anterior cingulate cortex and prefrontal cortex, suggesting deficient top-down modulation of antinociceptive circuits in patients with CH.[45]

Pain is an unpleasant sensory and emotional experience. The perception of pain is complex and influenced by multiple cognitive, emotional, and behavioral factors. Psychosocial factors including mood, personality traits, social support and 'stress' unrelated to CH itself anecdotally affect the course of CH or trigger attacks in individuals by unclear mechanisms.

Management

The management options in CH are divided into acute, preventive, and transitional treatments. The true effectiveness of any CH treatment is difficult to determine without comparison to a placebo group, as cluster attacks and cluster bouts will spontaneously terminate after an unpredictable amount of time. There is good quality evidence for acute treatment with parenteral triptans and high flow oxygen; transitional treatment with oral corticosteroids and greater occipital nerve blocks including corticosteroids; and preventive treatment with verapamil. Newer drug and neuromodulatory treatments are showing promising results and may soon become established in clinical practice. See [Table 3] for a summary of the established and emerging treatments of CH.
Table 3: Summary of established and emerging treatments for cluster headache

Click here to view


Acute treatments

Acute treatments aim to terminate an individual attack should be taken at the onset of the attack, and ideally should work within seconds or minutes, hence parenteral rather than oral treatments are required. The most established effective acute treatments for cluster attacks are subcutaneous/intranasal tripans and inhaled high-flow oxygen.

Triptans

Subcutaneous sumatriptan is the most effective triptan for CH and can be given up to twice per day. In a randomized controlled trial subcutaneous sumatriptan was effective at aborting 46% of attacks and reducing pain level to mild in 74% of attacks within 15 minutes.[46] Intranasal sumatriptan and intranasal zolmitriptan are also available as alternatives, but have lower efficacy rates and should be reserved for patients who are not able to use a subcutaneous injection. Due to their vasoconstrictive effect, triptans should not be used in those with significant vascular disease or uncontrolled hypertension.

The mechanism of action of triptans in headache disorders is attributed to their selective agonist effect on 5-HT1B and 5-HT1D serotonin receptors on blood vessels causing vasoconstriction, and/or effect on peripheral nociceptors inhibiting the release of neuropeptides such as CGRP and substance P. Recently an animal study has shown that as soon as 1 minute after subcutaneous injection of sumatriptan, the drug can be observed in the hypothalamus at a higher concentration than in both the trigeminal ganglion and the dura, suggesting that triptans may instead work in the central nervous system rather than peripherally.[47]

Oxygen

High flow oxygen is also effective at terminating attacks. One hundred percent oxygen should be given at 7-15 liters per minute (L/min), lower concentration oxygen is unlikely to be effective. In a randomized controlled trial of inhaled 100% oxygen at 12 L/min, 78% patients were pain free after 15 minutes, compared to 20% with placebo air.[48] The mechanism of action of oxygen in CH is not understood. An experimental study has shown it does not affect trigeminal afferents but can inhibit cranial parasympathetic neurons.[49]

Other acute treatments

Alternative acute treatments used but are less effective include intranasal lidocaine spray, intranasal dihydroergotamine, intranasal cocaine, and intranasal capsaicin. Conventional analgesics such as paracetamol, aspirin, and nonsteroidal anti-inflammatory drugs are almost never effective in terminating attacks.

Octreotide, a somatostatin analog has been shown to be effective in the acute treatment of CH when compared with placebo.[50] It is potentially useful in those patients unable to take triptans, but not used in clinical practice as it is expensive, needs to be stored in a fridge, and is not licensed for use in CH. There is an ongoing phase II study of an analogue pasireotide.

Non-invasive vagus nerve stimulation

A hand-held device which is held against the neck and delivers an electrical current in order to stimulate the vagus nerve (gammaCore®) has been investigated in two randomized sham-controlled trials for the acute treatment of CH attacks. In both trials the primary endpoint was negative, but post-hoc analysis showed that it was significantly effective in patients with ECH but not CCH.[51],[52]

Non-invasive neuromodulatory therapies, which aim to alter nerve activity through targeted delivery of electrical stimulation, are an attractive option as they do not typically cause systemic side effects. Vagus nerve stimulation is thought to modulate the trigeminal-autonomic reflex but may alternatively work via a connection from the nucleus tractus solitarius to the hypothalamus.

Preventive medications

Preventive treatments aim to prevent further attacks from occurring and usually do not have their full effect for a number of weeks after being started. The most established and well evidenced preventive treatment for CH is verapamil and this should be used as the first line preventive medication. A number of other medications have shown benefit but generally only in small open label trials, and in clinical practice are less effective and/or more likely to cause side effects. In patients with ECH our practice is to start preventive medications at the onset of the bout, continue for the duration of the bout and if subsequently pain-free for at least one month to gradually decrease the dose until stopped. Patients with CCH should continue to take a preventive medication long term if it is having a beneficial effect and they continue to have regular headaches.

Verapamil

Verapamil is a calcium channel blocker. In a randomized controlled trial verapamil was significantly more effective than placebo at a dose of 120 mg three times per day for fourteen days,[53] and in an open-label study 69% of patients improved more than 75%.[54]

Verapamil is usually given starting at a dose of 240 mg daily in two or three divided doses and increased in 80-120 mg increments in two weekly intervals, up to a maximum dose of 960 mg daily. Due to its effect on cardiac conduction, before verapamil is started, and prior to each dose increase, electrocardiography (ECG) should be performed. In an audit of ECGs in patients who had received verapamil for CH, 19% had arrhythmias, and in another 4% of patients, verapamil had to be stopped due to bradycardia.[55]

The mechanism of verapamil in CH is incompletely understood. It has been hypothesized to be due to effects on CGRP release, circadian rhythms, or by reducing vasodilation. A recent study using machine learning techniques has shown that responsiveness to verapamil can be predicted with moderate accuracy based on high dimensional modelling of routinely collected clinical and imaging data. In this study an area in lobule VI of the cerebellum, an area is known to be activated with trigeminal nociceptive stimulation, was found to have higher gray matter concentration in verapamil non-responders compared to responders.[56]

Lithium

Lithium has been used for CH since the 1970s. A comparison trial of lithium and verapamil showed that both were similarly effective, but verapamil caused fewer side effects.[57] One small, short, placebo-controlled trial of lithium did not show a significant improvement over placebo.[58] Therapeutic drug monitoring is required due to its narrow therapeutic range and the possibility of toxicity.

Topiramate

Topiramate is an anti-epileptic drug which is widely used as a preventive treatment in migraine. It appears to also be effective in some patients with CH. A number of open trials and case series have reported its efficacy,[59],[60] but no randomized placebo-controlled trials have been conducted.

Melatonin

Melatonin is a hormone naturally secreted from the pineal gland in response to darkness and involved in the regulation of sleep-wake cycles. Melatonin has been shown to be beneficial in CH in case studies and a small double-blind placebo-controlled study,[61] however this was not confirmed in another study.[62] Melatonin is safe with minimal side effects.

Other preventive medications

A variety of other medications have been reported to be helpful in patients with CH, but generally in small series of patients and not compared to placebo. Gabapentin has been reported as effective in two small open-label series.[63],[64] Sodium valproate also has open-label evidence, but there was no difference to placebo in a randomized controlled double-blind trial.[65] The ergot derived drug methysergide was recognized as an effective treatment in some patients but is no longer available due to safety concerns. Other treatments reported include baclofen, pregabalin, levetiracetam, chlorpromazine, candesartan, pizotifen, tizanidine, and transdermal clonidine. [Table 4] shows typical dosing, common side effects, and monitoring requirements for the most commonly used preventative medications.
Table 4: Preventive medications for cluster headache

Click here to view


Botulinum toxin injections have also been reported as effective in open-label studies and case reports, but again no randomized controlled trials have been performed. The local injection of botulinum toxin towards the sphenopalatine ganglion has also been trialed in patients with refractory CCH.[66]

CGRP monoclonal antibodies

Monoclonal antibodies targeting CGRP or its receptor have recent good quality evidence for the treatment of episodic and chronic migraine in multiple large randomized controlled trials. They have also recently been investigated for use in CH. A randomized controlled trial of the anti-CGRP humanized monoclonal antibody galcanezumab given subcutaneously at a dose of 300 mg once per month in patients with ECH showed a small but significant reduction in headache frequency compared with placebo, with a good safety profile.[67] A trial in CCH did not show a significant reduction in attack frequency versus placebo.[68] Fremanezumab has also been trialed in ECH and CCH, however, the trial was discontinued early as interim analysis showed it was unlikely to meet its primary endpoint.

Non-invasive vagus nerve stimulation

Non-invasive vagus nerve stimulation with the gammaCore® device has been also trialed as a preventive treatment for CCH. In an open-label trial compared with standard care there was a significant reduction in the number of attacks per week compared to the control group (-5.9 vs. -2.1 respectively).[69] Sham controlled studies are required, similar to those performed to assess its use in acute treatment.

Transitional treatments

Transitional treatments have an intermediate onset and duration of action and are usually used either whilst waiting for a preventive treatment to be up titrated, or in an attempt to terminate a bout in patients with ECH, especially those with short and infrequent bouts.

Oral steroids

Short term use of high dose corticosteroids has been used as a transitional treatment for many years with good effectiveness in clinical practice. A recent placebo-controlled trial has confirmed the efficacy of corticosteroids using prednisone 100 mg for five days then tapered by 20 mg every three days.[70] Our usual practice is to use oral prednisolone starting at 60 mg and reducing by 10 mg every three days until stopped. Dexamethasone and intravenous methylprednisolone have also been used.

Due to the many long-term side effects of corticosteroids, they should be used sparingly and for short time period: a maximum of four weeks (including taper) per course, and maximum of two courses per year. Attacks often recur once the steroid dose is tapered, meaning their use should usually be accompanied by starting a longer-acting preventive medication such as verapamil. The mechanism of action of corticosteroids in CH is not known but has been hypothesized to be due to their influence on inflammatory, hypothalamic, histaminergic, or opioid systems.

Greater occipital nerve injection

Suboccipital injection targeting the greater occipital nerve (GON) using local anesthetic agents and/or corticosteroids are well tolerated and effective in the transitional treatment of CH. Two placebo-controlled trials have been conducted in CH, both of which used steroid injections without the addition of local anesthetic, and both showed significant improvement in the treatment group compared with placebo injection.[71],[72] GON injection is relatively easy to perform and preferred to oral steroids due to similar clinical effectiveness and avoidance of systemic steroid side effects. The mechanism of action is thought to be an interruption of the pathways involved in the trigeminal autonomic reflex via functional connectivity between the trigeminal and occipital nerves.[73]

Other transitional treatments

Multiple cranial nerve blocks targeting the greater and lesser occipital, supraorbital, supratrochlear, and auriculotemporal nerves have also been used. In an open-label report 36/52 (69%) of patients with CCH responded.[74] Sphenopalatine ganglion blockade has been used, with various approaches requiring technical expertise.[75],[76] Intravenous dihydroergotamine is also occasionally used as a transitional treatment and is usually effective within a few days. Rarely it is given periodically in patients with treatment-refractory CCH.

Lifestyle factors

No lifestyle factor has strong suggestion of benefit in CH, other than avoidance of triggers, especially alcohol. Patients are usually recommended to stop smoking, but this rarely improves their headaches.

Medication overuse headache, which is a common problem in migraine, may also rarely occur in patients with CH, usually those who have a personal or family history of migraine.[77] Due to the excruciating nature of the pain, acute treatments should not usually be rationed in patients with CH, but it should be considered in patients who develop a chronic daily headache in temporal association with regular use of acute treatments.

Surgical treatments and invasive neurostimulation

Destructive surgery of the trigeminal nerve originally used for trigeminal neuralgia has be attempted in those with CH. This has included the trigeminal nerve section, glycerol rhizotomy and radiosurgery of the trigeminal nerve. The results have been mixed and side effects potentially serious, which can include infection, cerebrospinal fluid leak, corneal anesthesia and anesthesia dolorosa.

More recently, neuromodulatory therapies have been preferred which deliver electrical stimulation with the aim of manipulating central or peripheral pain pathways. Due to the surgical risks these treatments are reserved for patients with CCH who are refractory to multiple medical preventive treatments.

Occipital nerve stimulation

Occipital nerve stimulation (ONS) involves peripheral stimulation of the occipital nerves by implanted suboccipital electrodes, which are connected to an implantable pulse generator sited in the subcutaneous tissue of the chest or abdomen. Two large open-label reports of ONS in CCH have shown a response rate of 53-67% at long term follow up.[78],[79] Placebo-controlled trials of ONS in CCH have not been conducted. Placebo controlled trials of ONS in chronic migraine have shown a small but statistically significant improvement in headache days compared with sham stimulation,[80] although trials are limited by difficulty in blinding as the paraesthesia is usually felt whilst the stimulator is active. There are potential complications of ONS surgery including infection and the need for revision surgery for lead migration.

Sphenopalatine ganglion stimulation

An implantable sphenopalatine ganglion stimulator has been developed for aborting attacks. Two randomized sham-controlled trials have been performed in patients with medically refractory CCH, showing effectiveness both for abortion of attacks and preventive reduction in attack frequency.[81],[82] In a large open-label registry 55% of patients had a >50% reduction in attack frequency, and 32% of patients benefited acutely.[83] There are risks from the implantation procedure as with any surgical procedure. Unfortunately, the manufacturer of this device has recently gone out of business, therefore this is not a current treatment option.

Deep brain stimulation

Informed by the neuroimaging studies showing activation of the posterior hypothalamus during attacks, deep brain stimulation (DBS) of the posterior hypothalamic region has been attempted.[84] Though many of the reports describe the procedure as posterior hypothalamic DBS, the electrodes are in fact implanted in the ventral tegmental region.[85] Open-label studies have shown that DBS is effective in 60-80% of patients.[86],[87] Only one randomized sham-controlled controlled trial has been performed, which included 11 patients.[88] During the randomized phase there was no significant difference between active and sham stimulation, however, the duration of the blinded trial was only 1 month. Open-label studies have shown that some patients may take longer than this time to respond, and in the open 1-year extension of the trial, a number of patients did become responders. The delayed response argues against a simple deactivation of the region of the electrode. A PET study has shown altered activity in central pain processing regions such as the anterior cingulate cortex and insula in patients treated with DBS.[89] This procedure should only be performed in a specialist center and considered when all other treatments have failed. Serious adverse effects such as intracerebral hemorrhage are possible but rare. The most common side effects are transient dizziness or diplopia.

Prognosis

In the majority of patients, CH has a long duration and can be lifelong. In a ten year follow up study 81% of patients with ECH had remained in that state and 12.9% had transitioned into CCH; 52.4% of patients with CCH had remained in that state, and 32.6% had improved to episodic; and in only 10% of patients it appeared to have resolved with no attacks for the prior three years.[90]


 » Conclusion Top


CH is an excruciatingly painful and severely disabling primary headache disorder. Clinical, biochemical, and imaging evidence points towards the hypothalamus and trigeminovascular system as being central to its pathophysiology. The current core of management should include parenteral triptans and oxygen as acute treatments, GON injection as a transitional treatment, and verapamil as a preventive treatment. Newer therapies such as anti-CGRP monoclonal antibodies, non-invasive vagus nerve stimulation, and deep brain stimulation are showing promise, especially for those with treatment-refractory CCH.

Disclosures

SC has no disclosures. MSM serves on the advisory board for Abbott, Allergan, Eli Lilly, Medtronic, Novartis and TEVA and has received payment for the development of educational presentations from Allergan, electroCore, Eli Lilly, Novartis and TEVA.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38:1-211.  Back to cited text no. 1
    
2.
D'Amico D, Raggi A, Grazzi L, Lambru G. Disability, quality of life, and socioeconomic burden of cluster headache: A critical review of current evidence and future perspectives. Headache 2020;60:809-18.  Back to cited text no. 2
    
3.
Liang JF, Chen YT, Fuh JL, Li SY, Liu CJ, Chen TJ, et al. Cluster headache is associated with an increased risk of depression: A nationwide population-based cohort study. Cephalalgia 2013;33:182-9.  Back to cited text no. 3
    
4.
Rozen TD, Fishman RS. Cluster headache in the United States of America: Demographics, clinical characteristics, triggers, suicidality, and personal burden. Headache 2012;52:99-113.  Back to cited text no. 4
    
5.
Morris Z, Whiteley WN, Longstreth WT Jr, Weber F, Lee YC, Tsushima Y, et al. Incidental findings on brain magnetic resonance imaging: Systematic review and meta-analysis. BMJ 2009;339:b3016.  Back to cited text no. 5
    
6.
Grangeon L, O'Connor E, Danno D, Ngoc TMP, Cheema S, Tronvik E, et al. Is pituitary MRI screening necessary in cluster headache? Cephalalgia 2021. doi: 10.1177/0333102420983303.  Back to cited text no. 6
    
7.
Fischera M, Marziniak M, Gralow I, Evers S. The incidence and prevalence of cluster headache: A meta-analysis of population-based studies. Cephalalgia 2008;28:614-8.  Back to cited text no. 7
    
8.
Rozen TD, Niknam RM, Shechter AL, Young WB, Silberstein SD. Cluster headache in women: Clinical characteristics and comparison with cluster headache in men. J Neurol Neurosurg Psychiatry 2001;70:613-7.  Back to cited text no. 8
    
9.
Manzoni GC, Micieli G, Granella F, Martignoni E, Farina S, Nappi G. Cluster headache in women: Clinical findings and relationship with reproductive life. Cephalalgia 1988;8:37-44.  Back to cited text no. 9
    
10.
O'Connor E, Simpson BS, Houlden H, Vandrovcova J, Matharu M. Prevalence of familial cluster headache: A systematic review and meta-analysis. J Headache Pain 2020;21:37.  Back to cited text no. 10
    
11.
Rainero I, Gallone S, Rubino E, Ponzo P, Valfre W, Binello E, et al. Haplotype analysis confirms the association between the HCRTR2 gene and cluster headache. Headache 2008;48:1108-14.  Back to cited text no. 11
    
12.
Weller CM, Wilbrink LA, Houwing-Duistermaat JJ, Koelewijn SC, Vijfhuizen LS, Haan J, et al. Cluster headache and the hypocretin receptor 2 reconsidered: A genetic association study and meta-analysis. Cephalalgia 2015;35:741-7.  Back to cited text no. 12
    
13.
Rossi P, Allena M, Tassorelli C, Sances G, Di Lorenzo C, Faroni JV, et al. Illicit drug use in cluster headache patients and in the general population: A comparative cross-sectional survey. Cephalalgia 2012;32:1031-40.  Back to cited text no. 13
    
14.
Grangeon L, O'Connor E, Chan CK, Akijian L, Pham Ngoc TM, Matharu MS. New insights in post-traumatic headache with cluster headache phenotype: A cohort study. J Neurol Neurosurg Psychiatry 2020;91:572-9.  Back to cited text no. 14
    
15.
May A, Buchel C, Turner R, Goadsby PJ. Magnetic resonance angiography in facial and other pain: Neurovascular mechanisms of trigeminal sensation. J Cereb Blood Flow Metab 2001;21:1171-6.  Back to cited text no. 15
    
16.
Moskowitz MA. Cluster headache: Evidence for a pathophysiologic focus in the superior pericarotid cavernous sinus plexus. Headache 1988;28:584-6.  Back to cited text no. 16
    
17.
Hardebo JE. How cluster headache is explained as an intracavernous inflammatory process lesioning sympathetic fibers. Headache 1994;34:125-31.  Back to cited text no. 17
    
18.
Jarrar RG, Black DF, Dodick DW, Davis DH. Outcome of trigeminal nerve section in the treatment of chronic cluster headache. Neurology 2003;60:1360-2.  Back to cited text no. 18
    
19.
Matharu MS, Goadsby PJ. Persistence of attacks of cluster headache after trigeminal nerve root section. Brain 2002;125:976-84.  Back to cited text no. 19
    
20.
Torelli P, Cologno D, Cademartiri C, Manzoni GC. Application of the International Headache Society classification criteria in 652 cluster headache patients. Cephalalgia 2001;21:145-50.  Back to cited text no. 20
    
21.
Goadsby PJ, Edvinsson L. Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies. Brain 1994;117:427-34.  Back to cited text no. 21
    
22.
Fanciullacci M, Alessandri M, Figini M, Geppetti P, Michelacci S. Increase in plasma calcitonin gene-related peptide from the extracerebral circulation during nitroglycerin-induced cluster headache attack. Pain 1995;60:119-23.  Back to cited text no. 22
    
23.
Vollesen ALH, Snoer A, Beske RP, Guo S, Hoffmann J, Jensen RH, et al. Effect of infusion of calcitonin gene-related peptide on cluster headache attacks: A randomized clinical trial. JAMA Neurol 2018;75:1187-97.  Back to cited text no. 23
    
24.
Moller M, May A. The unique role of the trigeminal autonomic reflex and its modulation in primary headache disorders. Curr Opin Neurol 2019;32:438-42.  Back to cited text no. 24
    
25.
Leone M, Bussone G. A review of hormonal findings in cluster headache. Evidence for hypothalamic involvement. Cephalalgia 1993;13:309-17.  Back to cited text no. 25
    
26.
Holle D, Obermann M. Cluster headache and the hypothalamus: Causal relationship or epiphenomenon? Expert Rev Neurother 2011;11:1255-63.  Back to cited text no. 26
    
27.
Waldenlind E, Gustafsson SA, Ekbom K, Wetterberg L. Circadian secretion of cortisol and melatonin in cluster headache during active cluster periods and remission. J Neurol Neurosurg Psychiatry 1987;50:207-13.  Back to cited text no. 27
    
28.
Bartsch T, Levy MJ, Knight YE, Goadsby PJ. Differential modulation of nociceptive dural input to [hypocretin] orexin A and B receptor activation in the posterior hypothalamic area. Pain 2004;109:367-78.  Back to cited text no. 28
    
29.
Holland PR, Akerman S, Goadsby PJ. Modulation of nociceptive dural input to the trigeminal nucleus caudalis via activation of the orexin 1 receptor in the rat. Eur J Neurosci 2006;24:2825-33.  Back to cited text no. 29
    
30.
May A, Bahra A, Buchel C, Frackowiak RS, Goadsby PJ. Hypothalamic activation in cluster headache attacks. Lancet 1998;352:275-8.  Back to cited text no. 30
    
31.
Morelli N, Pesaresi I, Cafforio G, Maluccio MR, Gori S, Di Salle F, et al. Functional magnetic resonance imaging in episodic cluster headache. J Headache Pain 2009;10:11-4.  Back to cited text no. 31
    
32.
Sprenger T, Boecker H, Tolle TR, Bussone G, May A, Leone M. Specific hypothalamic activation during a spontaneous cluster headache attack. Neurology 2004;62:516-7.  Back to cited text no. 32
    
33.
Matharu MS, Cohen AS, McGonigle DJ, Ward N, Frackowiak RS, Goadsby PJ. Posterior hypothalamic and brainstem activation in hemicrania continua. Headache 2004;44:747-61.  Back to cited text no. 33
    
34.
Matharu MS, Cohen AS, Frackowiak RS, Goadsby PJ. Posterior hypothalamic activation in paroxysmal hemicrania. Ann Neurol 2006;59:535-45.  Back to cited text no. 34
    
35.
Denuelle M, Fabre N, Payoux P, Chollet F, Geraud G. Hypothalamic activation in spontaneous migraine attacks. Headache 2007;47:1418-26.  Back to cited text no. 35
    
36.
Rosen SD, Paulesu E, Frith CD, Frackowiak RS, Davies GJ, Jones T, et al. Central nervous pathways mediating angina pectoris. Lancet 1994;344:147-50.  Back to cited text no. 36
    
37.
May A, Ashburner J, Buchel C, McGonigle DJ, Friston KJ, Frackowiak RS, et al. Correlation between structural and functional changes in brain in an idiopathic headache syndrome. Nat Med 1999;5:836-8.  Back to cited text no. 37
    
38.
Naegel S, Holle D, Desmarattes N, Theysohn N, Diener HC, Katsarava Z, et al. Cortical plasticity in episodic and chronic cluster headache. Neuroimage Clin 2014;6:415-23.  Back to cited text no. 38
    
39.
Wang SJ, Lirng JF, Fuh JL, Chen JJ. Reduction in hypothalamic 1H-MRS metabolite ratios in patients with cluster headache. J Neurol Neurosurg Psychiatry 2006;77:622-5.  Back to cited text no. 39
    
40.
Abdallah K, Artola A, Monconduit L, Dallel R, Luccarini P. Bilateral descending hypothalamic projections to the spinal trigeminal nucleus caudalis in rats. PLoS One 2013;8:e73022.  Back to cited text no. 40
    
41.
Malick A, Burstein R. Cells of origin of the trigeminohypothalamic tract in the rat. J Comp Neurol 1998;400:125-44.  Back to cited text no. 41
    
42.
Akram H, Miller S, Lagrata S, Hariz M, Ashburner J, Behrens T, et al. Optimal deep brain stimulation site and target connectivity for chronic cluster headache. Neurology 2017;89:2083-91.  Back to cited text no. 42
    
43.
Absinta M, Rocca MA, Colombo B, Falini A, Comi G, Filippi M. Selective decreased grey matter volume of the pain-matrix network in cluster headache. Cephalalgia 2012;32:109-15.  Back to cited text no. 43
    
44.
Yang FC, Chou KH, Fuh JL, Huang CC, Lirng JF, Lin YY, et al. Altered gray matter volume in the frontal pain modulation network in patients with cluster headache. Pain 2013;154:801-7.  Back to cited text no. 44
    
45.
Sprenger T, Ruether KV, Boecker H, Valet M, Berthele A, Pfaffenrath V, et al. Altered metabolism in frontal brain circuits in cluster headache. Cephalalgia 2007;27:1033-42.  Back to cited text no. 45
    
46.
Treatment of acute cluster headache with sumatriptan. The Sumatriptan Cluster Headache Study Group. N Engl J Med 1991;325:322-6.  Back to cited text no. 46
    
47.
Muzzi M, Zecchi R, Ranieri G, Urru M, Tofani L, De Cesaris F, et al. Ultra-rapid brain uptake of subcutaneous sumatriptan in the rat: Implication for cluster headache treatment. Cephalalgia 2020;40:330-6.  Back to cited text no. 47
    
48.
Cohen AS, Burns B, Goadsby PJ. High-flow oxygen for treatment of cluster headache: A randomized trial. JAMA 2009;302:2451-7.  Back to cited text no. 48
    
49.
Akerman S, Holland PR, Lasalandra MP, Goadsby PJ. Oxygen inhibits neuronal activation in the trigeminocervical complex after stimulation of trigeminal autonomic reflex, but not during direct dural activation of trigeminal afferents. Headache 2009;49:1131-43.  Back to cited text no. 49
    
50.
Matharu MS, Levy MJ, Meeran K, Goadsby PJ. Subcutaneous octreotide in cluster headache: Randomized placebo-controlled double-blind crossover study. Ann Neurol 2004;56:488-94.  Back to cited text no. 50
    
51.
Silberstein SD, Mechtler LL, Kudrow DB, Calhoun AH, McClure C, Saper JR, et al. Non-invasive vagus nerve stimulation for the acute treatment of cluster headache: Findings from the randomized, double-blind, sham-controlled ACT1 study. Headache 2016;56:1317-32.  Back to cited text no. 51
    
52.
Goadsby PJ, de Coo IF, Silver N, Tyagi A, Ahmed F, Gaul C, et al. Non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: A randomized, double-blind, sham-controlled ACT2 study. Cephalalgia 2018;38:959-69.  Back to cited text no. 52
    
53.
Leone M, D'Amico D, Frediani F, Moschiano F, Grazzi L, Attanasio A, et al. Verapamil in the prophylaxis of episodic cluster headache: A double-blind study versus placebo. Neurology 2000;54:1382-5.  Back to cited text no. 53
    
54.
Gabai IJ, Spierings EL. Prophylactic treatment of cluster headache with verapamil. Headache 1989;29:167-8.  Back to cited text no. 54
    
55.
Cohen AS, Matharu MS, Goadsby PJ. Electrocardiographic abnormalities in patients with cluster headache on verapamil therapy. Neurology 2007;69:668-75.  Back to cited text no. 55
    
56.
Tso AR, Brudfors M, Danno D, Grangeon L, Cheema S, Matharu M, et al. Machine phenotyping of cluster headache and its response to verapamil. Brain 2020. doi: 10.1093/brain/awaa388.  Back to cited text no. 56
    
57.
Bussone G, Leone M, Peccarisi C, Micieli G, Granella F, Magri M, et al. Double blind comparison of lithium and verapamil in cluster headache prophylaxis. Headache 1990;30:411-7.  Back to cited text no. 57
    
58.
Steiner TJ, Hering R, Couturier EG, Davies PT, Whitmarsh TE. Double-blind placebo-controlled trial of lithium in episodic cluster headache. Cephalalgia 1997;17:673-5.  Back to cited text no. 58
    
59.
Wheeler SD, Carrazana EJ. Topiramate-treated cluster headache. Neurology 1999;53:234-6.  Back to cited text no. 59
    
60.
Leone M, Dodick D, Rigamonti A, D'Amico D, Grazzi L, Mea E, et al. Topiramate in cluster headache prophylaxis: An open trial. Cephalalgia 2003;23:1001-2.  Back to cited text no. 60
    
61.
Leone M, D'Amico D, Moschiano F, Fraschini F, Bussone G. Melatonin versus placebo in the prophylaxis of cluster headache: A double-blind pilot study with parallel groups. Cephalalgia 1996;16:494-6.  Back to cited text no. 61
    
62.
Pringsheim T, Magnoux E, Dobson CF, Hamel E, Aube M. Melatonin as adjunctive therapy in the prophylaxis of cluster headache: A pilot study. Headache 2002;42:787-92.  Back to cited text no. 62
    
63.
Schuh-Hofer S, Israel H, Neeb L, Reuter U, Arnold G. The use of gabapentin in chronic cluster headache patients refractory to first-line therapy. Eur J Neurol 2007;14:694-6.  Back to cited text no. 63
    
64.
Leandri M, Luzzani M, Cruccu G, Gottlieb A. Drug-resistant cluster headache responding to gabapentin: A pilot study. Cephalalgia 2001;21:744-6.  Back to cited text no. 64
    
65.
El Amrani M, Massiou H, Bousser MG. A negative trial of sodium valproate in cluster headache: Methodological issues. Cephalalgia 2002;22:205-8.  Back to cited text no. 65
    
66.
Bratbak DF, Nordgard S, Stovner LJ, Linde M, Folvik M, Bugten V, et al. Pilot study of sphenopalatine injection of onabotulinumtoxinA for the treatment of intractable chronic cluster headache. Cephalalgia 2016;36:503-9.  Back to cited text no. 66
    
67.
Goadsby PJ, Dodick DW, Leone M, Bardos JN, Oakes TM, Millen BA, et al. Trial of Galcanezumab in Prevention of Episodic Cluster Headache. N Engl J Med 2019;381:132-41.  Back to cited text no. 67
    
68.
Dodick DW, Goadsby PJ, Lucas C, Jensen R, Bardos JN, Martinez JM, et al. Phase 3 randomized, placebo-controlled study of galcanezumab in patients with chronic cluster headache: Results from 3-month double-blind treatment. Cephalalgia 2020;40:935-48.  Back to cited text no. 68
    
69.
Gaul C, Diener HC, Silver N, Magis D, Reuter U, Andersson A, et al. Non-invasive vagus nerve stimulation for PREVention and Acute treatment of chronic cluster headache (PREVA): A randomised controlled study. Cephalalgia 2016;36:534-46.  Back to cited text no. 69
    
70.
Obermann M, Nagel S, Ose C, Sonuc N, Scherag A, Storch P, et al. Safety and efficacy of prednisone versus placebo in short-term prevention of episodic cluster headache: A multicentre, double-blind, randomised controlled trial. Lancet Neurol 2021;20:29-37.  Back to cited text no. 70
    
71.
Ambrosini A, Vandenheede M, Rossi P, Aloj F, Sauli E, Pierelli F, et al. Suboccipital injection with a mixture of rapid- and long-acting steroids in cluster headache: A double-blind placebo-controlled study. Pain 2005;118:92-6.  Back to cited text no. 71
    
72.
Leroux E, Valade D, Taifas I, Vicaut E, Chagnon M, Roos C, et al. Suboccipital steroid injections for transitional treatment of patients with more than two cluster headache attacks per day: A randomised, double-blind, placebo-controlled trial. Lancet Neurol 2011;10:891-7.  Back to cited text no. 72
    
73.
Busch V, Jakob W, Juergens T, Schulte-Mattler W, Kaube H, May A. Occipital nerve blockade in chronic cluster headache patients and functional connectivity between trigeminal and occipital nerves. Cephalalgia 2007;27:1206-14.  Back to cited text no. 73
    
74.
Miller S, Lagrata S, Matharu M. Multiple cranial nerve blocks for the transitional treatment of chronic headaches. Cephalalgia 2019;39:1488-99.  Back to cited text no. 74
    
75.
Devoghel JC. Cluster headache and sphenopalatine block. Acta Anaesthesiol Belg 1981;32:101-7.  Back to cited text no. 75
    
76.
Pipolo C, Bussone G, Leone M, Lozza P, Felisati G. Sphenopalatine endoscopic ganglion block in cluster headache: A reevaluation of the procedure after 5 years. Neurol Sci 2010;31(Suppl 1):S197-9.  Back to cited text no. 76
    
77.
Paemeleire K, Bahra A, Evers S, Matharu MS, Goadsby PJ. Medication-overuse headache in patients with cluster headache. Neurology 2006;67:109-13.  Back to cited text no. 77
    
78.
Miller S, Watkins L, Matharu M. Treatment of intractable chronic cluster headache by occipital nerve stimulation: A cohort of 51 patients. Eur J Neurol 2017;24:381-90.  Back to cited text no. 78
    
79.
Leone M, Proietti Cecchini A, Messina G, Franzini A. Long-term occipital nerve stimulation for drug-resistant chronic cluster headache. Cephalalgia 2017;37:756-63.  Back to cited text no. 79
    
80.
Chen YF, Bramley G, Unwin G, Hanu-Cernat D, Dretzke J, Moore D, et al. Occipital nerve stimulation for chronic migraine--A systematic review and meta-analysis. PLoS One 2015;10:e0116786.  Back to cited text no. 80
    
81.
Schoenen J, Jensen RH, Lanteri-Minet M, Lainez MJ, Gaul C, Goodman AM, et al. Stimulation of the sphenopalatine ganglion (SPG) for cluster headache treatment. Pathway CH-1: A randomized, sham-controlled study. Cephalalgia 2013;33:816-30.  Back to cited text no. 81
    
82.
Goadsby PJ, Sahai-Srivastava S, Kezirian EJ, Calhoun AH, Matthews DC, McAllister PJ, et al. Safety and efficacy of sphenopalatine ganglion stimulation for chronic cluster headache: A double-blind, randomised controlled trial. Lancet Neurol 2019;18:1081-90.  Back to cited text no. 82
    
83.
Barloese M, Petersen A, Stude P, Jurgens T, Jensen RH, May A. Sphenopalatine ganglion stimulation for cluster headache, results from a large, open-label European registry. J Headache Pain 2018;19:6.  Back to cited text no. 83
    
84.
Leone M, Franzini A, Bussone G. Stereotactic stimulation of posterior hypothalamic gray matter in a patient with intractable cluster headache. N Engl J Med 2001;345:1428-9.  Back to cited text no. 84
    
85.
Matharu MS, Zrinzo L. Deep brain stimulation in cluster headache: Hypothalamus or midbrain tegmentum? Curr Pain Headache Rep 2010;14:151-9.  Back to cited text no. 85
    
86.
Leone M, Franzini A, Broggi G, Bussone G. Hypothalamic stimulation for intractable cluster headache: Long-term experience. Neurology 2006;67:150-2.  Back to cited text no. 86
    
87.
Akram H, Miller S, Lagrata S, Hyam J, Jahanshahi M, Hariz M, et al. Ventral tegmental area deep brain stimulation for refractory chronic cluster headache. Neurology 2016;86:1676-82.  Back to cited text no. 87
    
88.
Fontaine D, Lazorthes Y, Mertens P, Blond S, Geraud G, Fabre N, et al. Safety and efficacy of deep brain stimulation in refractory cluster headache: A randomized placebo-controlled double-blind trial followed by a 1-year open extension. J Headache Pain 2010;11:23-31.  Back to cited text no. 88
    
89.
May A, Leone M, Boecker H, Sprenger T, Juergens T, Bussone G, et al. Hypothalamic deep brain stimulation in positron emission tomography. J Neurosci 2006;26:3589-93.  Back to cited text no. 89
    
90.
Manzoni GC, Micieli G, Granella F, Tassorelli C, Zanferrari C, Cavallini A. Cluster headache--course over ten years in 189 patients. Cephalalgia 1991;11:169-74.  Back to cited text no. 90
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

Top
Print this article  Email this article
   
Online since 20th March '04
Published by Wolters Kluwer - Medknow