Cluster Headache: What's New?
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.315983
Source of Support: None, Conflict of Interest: None
Keywords: Cluster headache, diagnosis, pathophysiology, treatment, trigeminal autonomic cephalalgias
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.
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.
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. 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. Depression and anxiety commonly develop after the onset of CH. Individuals with CH are 5.6 times more likely to be depressed, and suicidal ideation was found to occur in 55% of sufferers in a large survey. Fortunately, despite the severity of the pain, CH is not life-threatening or physically damaging to the brain.
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.
Primary headache syndromes are currently classified according to the International Classification of Headache Disorders, 3rd Edition. 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]].
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. 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. 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.
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.
Epidemiology and risk factors
CH affects approximately 0.1% of the population. In contrast to migraine which is more common in females, CH is approximately four times commoner in males. 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. Unlike migraine, there is not usually any relationship to the menstrual cycle, pregnancy, or menopause.
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, 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, however this has not been supported by other more recent studies. 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. 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.
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.
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. 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., Imaging, angiography and biochemical studies have not shown any evidence of inflammation or another lesion in this region in patients with CH.
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, but not all, 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).
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., 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. 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.
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.
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.
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. 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, 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.
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. 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.,
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.,,
Functional imaging studies in other trigeminal autonomic cephalalgias have also shown activation in a similar region., This activation may not be specific for trigeminal autonomic cephalalgias as hypothalamic activation has been also seen in spontaneous migraine attacks, and other acute pain states such as induced angina pectoris.
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. This structural change has not been supported by other studies using similar methodology.
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.
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., 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.
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,, which in one study depended on whether the patient was within or outside a bout. Functional imaging studies have shown activation in central pain processing regions during attacks, 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.
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.
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.
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.
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. 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.
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. 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.
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. 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.,
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 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 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, and in an open-label study 69% of patients improved more than 75%.
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.
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.
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. One small, short, placebo-controlled trial of lithium did not show a significant improvement over placebo. Therapeutic drug monitoring is required due to its narrow therapeutic range and the possibility of toxicity.
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,, but no randomized placebo-controlled trials have been conducted.
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, however this was not confirmed in another study. 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., Sodium valproate also has open-label evidence, but there was no difference to placebo in a randomized controlled double-blind trial. 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.
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.
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. A trial in CCH did not show a significant reduction in attack frequency versus placebo. 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). Sham controlled studies are required, similar to those performed to assess its use in acute treatment.
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.
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. 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., 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.
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. Sphenopalatine ganglion blockade has been used, with various approaches requiring technical expertise., 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.
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. 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., 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, 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., In a large open-label registry 55% of patients had a >50% reduction in attack frequency, and 32% of patients benefited acutely. 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. Though many of the reports describe the procedure as posterior hypothalamic DBS, the electrodes are in fact implanted in the ventral tegmental region. Open-label studies have shown that DBS is effective in 60-80% of patients., Only one randomized sham-controlled controlled trial has been performed, which included 11 patients. 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. 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.
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.
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.
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.
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Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2], [Table 3], [Table 4]