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Cluster Headache

Cluster headache (CH), also known as histamine headache, is a primary neurovascular primary headache disorder, the pathophysiology and etiology of which are not well understood.[1] As the name suggests, CH involves a grouping of headaches, usually over a period of several weeks. According to the diagnostic criteria developed by the International Headache Society (IHS), CH has the following characteristics[2, 3] :

The patient experiences attacks of severe or very severe, strictly unilateral pain (orbital, supraorbital, or temporal pain) that last 15- 180 minutes and occur from once every other day to 8 times a day The attacks are associated with 1 or more of the following (all ipsilateral): conjunctival injection, lacrimation, nasal congestion, rhinorrhea, forehead and facial sweating, miosis, ptosis, or eyelid edema CH may be usefully classified into 2 main forms as follows:

Episodic CH, in which at least 2 cluster phases lasting 7 days to 1 year are separated by a cluster-free interval of 1 month or longer Chronic CH, in which the clusters occur more than once a year without remission or the cluster-free interval is shorter than 1 month

Chronic CH, in which the clusters occur more than once a year without remission or the cluster-free interval is shorter than 1 month

The underlying pathophysiology of CH is incompletely understood.[4, 5] The periodicity of the attacks suggests the involvement of a biologic clock within the hypothalamus (which controls circadian rhythms), with central disinhibition of the nociceptive and autonomic pathways— specifically, the trigeminal nociceptive pathways. Positron emission tomography (PET) and voxel-based morphometry have identified the posterior hypothalamic gray matter as the key area for the basic defect in CH.[1] See the images below.

Cluster headache: Functional imaging shows activation of specific brain areas during pain. Courtesy of Wikipedia Commons.[6] Substance P neurons carry sensory and motor impulses in the maxillary and ophthalmic divisions of the trigeminal nerve. These connect with the sphenopalatine ganglion and interior carotid perivascular sympathetic plexus. Somatostatin inhibits substance P and reduces the duration and intensity of CH. Vascular dilatation may play a role in the pathogenesis of CH, but blood flow studies are inconsistent. Extracranial blood flow (hyperthermia and increased temporal artery blood flow) increases, but only after the onset " id="pdf-obj-1-2" src="pdf-obj-1-2.jpg">

Cluster headache: Functional imaging shows activation of specific brain areas during pain. Courtesy of Wikipedia Commons.

Cluster headache: Functional imaging shows activation of specific brain areas during pain. Courtesy of Wikipedia Commons.[6] Substance P neurons carry sensory and motor impulses in the maxillary and ophthalmic divisions of the trigeminal nerve. These connect with the sphenopalatine ganglion and interior carotid perivascular sympathetic plexus. Somatostatin inhibits substance P and reduces the duration and intensity of CH. Vascular dilatation may play a role in the pathogenesis of CH, but blood flow studies are inconsistent. Extracranial blood flow (hyperthermia and increased temporal artery blood flow) increases, but only after the onset " id="pdf-obj-1-6" src="pdf-obj-1-6.jpg">

Cluster headache (CH): Voxel-based morphometry (VBM) structural imaging shows specific brain area of CH patients' (hypothalamus) being different to non-CH patients' brains. Courtesy of Wikipedia Commons.

Altered habituation patterns and changes have been observed within the trigeminal-facial neuronal circuitry secondary to central sensitization, in addition to dysfunction of the serotonergic raphe nuclei-hypothalamic pathways (though the latter is not as striking as in migraine). Functional hypothalamic dysfunction has been confirmed by abnormal metabolism based on the N-acetylaspartate neuronal marker in magnetic resonance

spectroscopy.[6]

Substance P neurons carry sensory and motor impulses in the maxillary and ophthalmic divisions of the trigeminal nerve. These connect with the sphenopalatine ganglion and interior carotid perivascular sympathetic plexus. Somatostatin inhibits substance P and reduces the duration and intensity of CH.

Vascular dilatation may play a role in the pathogenesis of CH, but blood flow studies are inconsistent. Extracranial blood flow (hyperthermia and increased temporal artery blood flow) increases, but only after the onset

of pain. Vascular change is considered secondary to primary neuronal discharge.

Although the evidence supporting a causative role for histamine is inconsistent, cluster headaches may be precipitated with small amounts of histamine. Antihistamines do not abort cluster headaches. Increased numbers of mast cells have been found in the skin of painful areas of some patients, but this finding is inconsistent.

The exact cause of CH is unknown. The disorder is sporadic, though rare cases of an autosomal dominant pattern within a single family have been reported.

Several factors have been shown to provoke CH attacks. Subcutaneous injection of histamine provokes attacks in 69% of patients. Stress, allergens, seasonal changes, or nitroglycerin may trigger attacks in some patients. Alcohol induces attacks during a cluster but not during remission. About 80% of CH patients are heavy smokers, and 50% have a history of heavy ethanol use.

Risk factors for CH include the following:

Male sex

Age older than 30 years Small amounts of vasodilators (eg, alcohol) Previous head trauma or surgery (occasionally)

The exact prevalence of CH in the United States is unknown; Kudrow estimated it to be 0.4% in men and 0.08% in women.[7] Compared with classic migraine, CH is relatively uncommon, with an incidence equivalent to only 2-9% of that of migraine. Prevalence in males is 0.4- 1%. In an extensive study of 100,000 inhabitants of the republic of San Marino, the prevalence was 0.07%. The incidence of CH in the United Kingdom is equivalent to that of multiple sclerosis.

Age-, sex-, and race-related demographics

CH usually begins in middle adult life (eg, in the 30s); however, it has been reported in patients as young as 1 year and as old as 79 years.

CH is more common in males than in females; the male-to-female ratio was 6:1 in the 1960s but is now closer to 2:1. Presentations in females may differ from those in males, according to data from the United States Cluster Headache Survey.[8] For example, women tend to develop CH at an earlier age and are also more likely to exhibit a second peak of CH incidence after the age of 50.

Racial and ethnic differences have not been well studied, but CH may be slightly more prevalent in African Americans and may be underdiagnosed in black women.

Pharmacologic management of cluster headache (CH) may be classified into 2 general approaches as follows:

Abortive/symptomatic (eg, oxygen, triptans, ergot alkaloids, and anesthetics) Preventive/prophylactic (eg, calcium channel blockers, mood stabilizers, and anticonvulsants) Olanzapine[10] and kudzu[11] have also been used to treat CH, but their effectiveness has not been determined. Antihistamines, such as chlorpromazine, do not appear to be helpful in relieving CH symptoms. Nonsteroidal anti-inflammatory drugs (NSAIDs) may be given for pain relief.

Various procedures may be performed on trigeminal nerve or autonomic pathways, including alcohol injections and section or avulsion of nerves for chronic refractory cases. Surgical treatment may be initiated if the patient has contraindications to medications or if medications are not effective; it is employed only in strictly unilateral cases. Radiofrequency (RF) thermocoagulation of the trigeminal ganglion has had promising results in some patients with intractable pain.

Treatment guidelines are available from the American College of Emergency Physicians and the National Headache Foundation.[12, 13] Neurologic consultation may be useful if the diagnosis is in doubt or for management of difficult cases.

Management of pregnant patients

CH is rare during pregnancy, but when it does occur, episodes tend to have the same character and severity as in nonpregnant patients.[14] Treatment options for pregnant women are poorly documented. The first line of treatment is pure oxygen via a nonrebreather mask (see image below). Triptans and ergot alkaloids should be avoided. The use of selected preventive medications, which are rated pregnancy category B, should be discussed thoroughly with the patient and her obstetrician.[15]

Non-rebreather oxygen mask with reservoir for the acute treatment of cluster headache. Courtesy of Wikipedia Commons.[16, 17] T he mechanism of action is unknown. 5-Hydroxytryptamine-1 (5-HT ) receptor agonists, such as triptans or ergot alkaloids with metoclopramide, are often the first line of treatment. Stimulation of 5-HT receptors produces a direct vasoconstrictive effect and may abort the attack. The triptan that has received the most study in the setting of CH is sumatriptan. [13, 16, 17] S ubcutaneous injections can be effective, in large part because of the rapidity of onset. Studies have indicated that intranasal administration is more effective than placebo but not as effective as injections; there is no evidence that oral administration is effective. A typical dose is 6 mg subcutaneously, which may be repeated in 24 hours. Nasal spray (20 mg) may also be used. Other triptans that may be considered for abortive treatment of CH are zolmitriptan, naratriptan, rizatriptan, almotriptan, frovatriptan, and eletriptan. In addition, researchers have begun to explore the possibility of using triptans for prophylaxis of CH. [18] " id="pdf-obj-4-2" src="pdf-obj-4-2.jpg">

Non-rebreather oxygen mask with reservoir for the acute treatment of cluster headache. Courtesy of Wikipedia Commons.

Abortive agents are given to stop or reduce the severity of an acute CH attack, whereas prophylactic agents are used to reduce the frequency and intensity of individual headache exacerbations. In view of the fleeting, short-lived nature of the attacks, effective prophylaxis should be considered the cornerstone of management. The prophylactic regimen should start at the onset of a CH cycle and continue until the patient is headache-free for at least 2 weeks. The agent then may be tapered slowly to prevent recurrences.

Abortive agents

Oxygen (8 L/min for 10 minutes or 100% by mask) may abort the headache if used early.[16, 17] The mechanism of action is unknown.

5-Hydroxytryptamine-1 (5-HT 1 ) receptor agonists, such as triptans or ergot alkaloids with metoclopramide, are often the first line of treatment. Stimulation of 5-HT 1 receptors produces a direct vasoconstrictive effect and may abort the attack.

The triptan that has received the most study in the setting of CH is sumatriptan.[13, 16, 17] Subcutaneous injections can be effective, in large part because of the rapidity of onset. Studies have indicated that intranasal administration is more effective than placebo but not as effective as injections; there is no evidence that oral administration is effective. A typical dose is 6 mg subcutaneously, which may be repeated in 24 hours. Nasal spray (20 mg) may also be used.

Other triptans that may be considered for abortive treatment of CH are zolmitriptan, naratriptan, rizatriptan, almotriptan, frovatriptan, and eletriptan. In addition, researchers have begun to explore the possibility of using triptans for prophylaxis of CH.[18]

Dihydroergotamine can be an effective abortive agent. It is commonly given intravenously (IV) or intramuscularly (IM) and may be self- administered; it can also be given intranasally (0.5 mg bilaterally).[17] Dihydroergotamine tends to cause less arterial vasoconstriction than ergotamine tartrate and is more effective when given early in a cluster attack.

Parenteral opiates may be used if relief is inadequate. The short-lived and unpredictable character of CH precludes effective use of oral narcotics or analgesics, though oral regimens may sometimes be helpful for residual soreness. Abuse potential does exist. Narcotics are not generally recommended for aborting CH.

Intranasal civamide and capsaicin have yielded good results in clinical trials. Application of capsaicin to the nasal mucosa led to a clinically significant decrease in the number and severity of cluster headaches; nasal burning was the most common adverse effect.

Intranasal administration of lidocaine drops (1 mL of a 10% solution placed on a swab in each nostril for 5 minutes) is possibly helpful; however, it requires a specific and, for many patients, difficult technique.

Prophylactic agents

Calcium channel blockers may be the most effective agents for CH prophylaxis.[17] They can be combined with ergotamine or lithium. Of the calcium channel blockers, verapamil may be the most useful, though others, including nimodipine and diltiazem, have also been reported to be effective.

Lithium has been suggested as an option because of the cyclical nature of CH, which is similar to that of bipolar disorders. It effectively prevents CH (particularly in its more chronic forms)[19] and treats bipolar mood disorder, another cyclic illness. Responses vary (with chronic CH patients generally being more responsive), but lithium is still a recommended first-line agent for CH. There is a tendency for the effect to wane after dramatic relief is seen in the first week.

Methysergide, though no longer available in the United States, is very effective for episodic and chronic CH prophylaxis. It can often reduce pain frequency, particularly in younger patients with episodic CH. If it yields no improvement after 3 weeks, it is unlikely to be beneficial. It should not be given continuously for longer than 6 months; a drug-free interval of 3-4 weeks must follow each 6-month course.

A few relatively small controlled studies have found anticonvulsants (eg, topiramate and divalproex) to be effective in the prophylaxis of CH, though the mechanism of action remains unclear.

Corticosteroids are extremely effective in terminating a CH cycle and in preventing immediate headache recurrence. High-dose prednisone is prescribed for the first few days, followed by a gradual taper. Simultaneous use of standard prophylactic agents (eg, verapamil) is recommended. The mechanism of action in CH is still subject to speculation.

Tricyclic antidepressants are more helpful as prophylaxis of other headache syndromes. Beta blockers may worsen bradycardia occurring during the cluster attack.