The Clinical Features of Cluster Headache: Differential Diagnosis and Treatment Recommendations
Sajan Thomas, MD Assistant Program Director
Deepika Kanupuru, MD Resident Internal Medicine Residency Program Westlake Hospital Melrose Park, Ill
Cluster headache is one of the most debilitating pain syndromes seen in clinical practice. This idiopathic condition consists of recurrent attacks of brief, sudden, severe, unilateral pain in the periorbital region. “Cluster” refers to a grouping of headaches, usually occurring over a period of several weeks. The attacks can be episodic or chronic. Once the condition is accurately diagnosed, available therapies are effective for acute attacks as well as for prophylaxis. Patients refractory to medical treatment may benefit from surgery. The diagnosis and optimal treatment of cluster headache continue to present challenges to the treating physician.
Cluster headache, also known as histamine headache or Horton’s headache, is characterized by a strictly unilateral severe headache accompanied by ipsilateral autonomic phenomena. The pain of cluster headache is probably the most severe of all pain known to humans. The pathophysiology is still poorly understood; however, clinical observations suggest that the hypothalamus may play a role in cluster headache attacks.
Epidemiology The exact prevalence of cluster headache is unknown. Cluster headache is less common than migraine, affecting only about 0.1% of the population.1 A recent population-based study of the residents of Olmsted County, Minnesota, suggests that the prevalence may be decreasing.2 Investigators found an overall age- and sex-adjusted incidence of 2.07 per 100,000 person-years in 1989-1990 compared with 9.8 per 100,000 person-years in 1979-1981.
Cluster headache is the only type of headache that is more common in men than in women, with a male-to-female ratio of approximately 2.1-3.7:1.3,4 Some authors have speculated that this gender gap, which was 6.2:1 among those with headache onset in the 1960s, has narrowed because of lifestyle changes, such as increased use of nicotine, coffee, and alcohol, among women in recent decades.3 Middle-aged persons are predominantly affected, with an average age at onset of about 32 years.4
Genetics The increased incidence of cluster headache in family members and identical twins is well documented, suggesting that there may be a genetic predisposition.5,6 An analysis of the families of 220 patients with cluster headache determined that first-degree relatives were at a 39-fold increased risk of cluster headache and second-degree relatives at an 8-fold risk compared with the general population.7
Pathophysiology The pathophysiology of cluster headache has not been well identified. The 3 major features are8:
• Trigeminal distribution of pain • Cranial autonomic signs and symptoms • Episodic attack.
Proposed mechanisms include:
Circadian rhythm. The headache tends to recur at about the same time every day, suggesting that the hypothalamus, which controls the circadian rhythms, may be the site of activation.
Trigeminal autonomic cephalgia. Acute attacks involve the activation of the trigeminovascular system,8 as shown by the distribution of the pain predominantly in the ophthalmic division of the trigeminal nerve.
Histamine. Small amounts of histamine may precipitate cluster headaches; however, antihistamines do not abort them. Evidence supporting histamine as a cause has not been consistent.
Hemodynamics. Vascular dilatation may play a role, but the results of blood flow studies have also been inconsistent.
Clinical Manifestations The age at onset is usually 20 to 40 years.9 Cluster headache is so named because the attacks occur in groups or clusters separated by pain-free intervals. The attacks are typically short in duration, lasting from 5 minutes to 3 hours and occurring from once every other day to 8 times daily. Periodicity is the most striking characteristic.
The pain is usually excruciating and has been described as penetrating, lancinating, or like a “hot poker in the eye.”1 It usually escalates to excruciating levels rapidly, within 15 minutes. Some patients have said that the pain is worse than that of childbirth, renal stones, or multiple limb fractures.8 The pain is typically unilateral, occurring in the periorbital region, but it may spread to other areas of the face and neck. Attacks are usually nocturnal, awakening the patient 2 to 4 hours after sleep onset. Patients may exhibit restlessness. During an attack, they may pace to and fro, sit upright in a chair holding their head in their hands, or even bang their head against a wall.1 The pain paroxysms are so severe that some patients are driven to desperate measures, including suicide.1
During acute attacks, the patient experiences 1 or more autonomic features ipsilateral to the headache, such as miosis, ptosis, conjunctival injection, lacrimation, nasal congestion, or rhinorrhea. Ptosis and miosis may be apparent between attacks.10 Other symptoms include flushing of the face, tenderness of the ipsilateral carotid artery, and an abnormal feeling of scalp hairs.11
Table 1
Triggering factors for cluster headache
Alcohol use Allergic rhinitis Exposure to extreme temperatures Glare Hypoxia Nitroglycerin Sexual activity Stress Tobacco use
Several factors are known to trigger cluster headaches (Table 1). Cluster headache and migraine have many similarities. However, in contrast to migraine, cluster headaches are more prevalent in men, are usually not preceded by an aura, and always recur on the same side. Atypical cluster headaches have been reported that include aura,12 persistent or unremitting clustering,13 Valsalva’s maneuver (eg, cough and sneeze) triggering,13 and hemiparesis.14
Chronic versus Episodic Headache The International Headache Society (IHS) categorizes cluster headache as being either episodic or chronic.9 The former occurs in periods (clusters) lasting from 1 week to 1 year, and includes at least 2 cluster periods separated by pain-free intervals lasting a minimum of 4 weeks. Chronic cluster headache occurs for more than 1 year, with either no remission or with remission lasting less than 4 weeks.
Diagnosis Cluster headache is identified by the history and clinical signs. In 2004, the IHS issued the following updated criteria for the diagnosis9:
1. At least 5 attacks of severe unilateral orbital, supraorbital, or temporal pain lasting from 15 to 180 minutes if untreated.
2. A frequency of attacks ranging from 1 every other day to 8 daily.
3. One or more of the following signs and symptoms: ipsilateral conjunctival injection or lacrimation, ipsilateral nasal congestion or rhinorrhea, ipsilateral eyelid edema, ipsilateral forehead and facial sweating, ipsilateral miosis or ptosis, or a sense of restlessness or agitation.
4. The pain cannot be attributed to any other disorder.
Imaging studies, such as computed tomography or magnetic resonance imaging (MRI), are not diagnostic but are useful for excluding other causes in appropriately selected patients. MRI of the head is indicated only in atypical cases or in patients with a suspected neurologic abnormality.
Differential Diagnosis Few other headache syndromes share the strict unilaterality and periodicity of cluster headache; these include trigeminal neuralgia, chronic paroxysmal hemicrania, cyclical migraine, hemicrania continua, and pericarotid syndrome.10 However, each has distinguishing features that can aid in sorting through the differential diagnosis.
The pain of trigeminal neuralgia is lancinating or shooting and lasts from a few seconds to a few minutes. This syndrome lacks the autonomic features of cluster headache. In addition, the pain is localized to the maxillary area of the trigeminal nerve.
Chronic paroxysmal hemicrania is characterized by multiple, short-lived, unilateral attacks that occur on a daily basis for years. Unlike cluster headache, more women than men are affected. The attacks recur 1 to 40 times daily. Indomethacin (Indocin) is the treatment of choice for paroxysmal hemicrania and has been deemed the sine qua non for establishing the diagnosis.1
In cyclical migraine, the attacks are typical of migraine headache and lack the autonomic features of cluster headache.
The pain of hemicrania continua is continuous and unilateral and has been described as a steady ache or throbbing; usually autonomic symptoms are not involved. This type of headache also responds well to indomethacin.
The pericarotid syndrome consists of unilateral headache that is triggered by trauma to the carotid sheath and neck.
Structural lesions of the central nervous system may produce pain that resembles cluster headache. Clusterlike symptoms may be caused by meningioma of the cavernous sinus, arteriovenous malformations, pituitary adenoma, nasopharyngeal carcinoma, vertebral artery aneurysm, or metastatic lung cancer.10
Treatment Standards of care for the diagnosis and treatment of cluster headache, based on the consensus of an expert panel, were issued by the National Headache Foundation (NHF) in 2004.15 The NHF recommends nondrug measures that can minimize the risk for cluster headache. Patients should avoid the following behaviors and situations: alcohol consumption, taking afternoon naps, changes in sleeping habits, extended exposure to chemicals, excessive bursts of anger or extreme emotions, prolonged physical exertion, and extreme altitude changes. They should also avoid taking nitroglycerin.
Pharmacotherapy for cluster headache consists of abortive and prophylactic strategies. Because oral preparations are absorbed slowly, they are not ideal for the treatment of acute attacks. Abortive agents are used to shorten or abolish an individual attack of cluster headache, but most patients will also need prophylactic therapy. The attacks may be too short-lived and severe in intensity to benefit from abortive therapy alone.
Abortive therapy Effective abortive treatments that provide rapid onset of action include inhaled oxygen, sumatriptan (Imitrex), and dihydroergotamine mesylate in the form of nasal spray (Migranal) or injection (DHE 45) (Table 2).
Table 2
Abortive drug therapy for cluster headache
Drug
Dosage
Comments
Capsaicin (Not available in the United States)
3 µg/mL administered intranasally ipsilaterally twice daily for 7 days
Side effects: transient intranasal burning, rhinorrhea, sneezing
Dihydroergotamine mesylate Nasal spray (Migranal)
0.5 mg; 1 spray into each nostril; may repeat in 15 min; maximum 6 sprays/d
Contraindicated in patients with CAD, uncontrolled hypertension, or PAD Nasal spray has less bioavailability than IV form
IV form (DHE 45)
1 mg; may repeat in 1 h; total dose not to exceed 2 mg/d or 6 mg/wk
Oxygen, 100%
7-10 L/min for 10 min via face mask
Treatment of choice
Sumatriptan (Imitrex) Subcutaneous Nasal spray
6 mg 20 mg Each may be repeated once within 24 h, >1 h interval from first dose
Contraindicated in patients with CAD, uncontrolled hypertension, or PAD
CAD = coronary artery disease; IV = intravenous; PAD = peripheral artery disease.
According to the NHF, inhalation of 100% oxygen, 7 to 10 L/min using a face mask for 15 minutes, is the standard recommended treatment for cluster headache. As many as 70% of patients respond within 5 minutes.15 Oxygen is believed to relieve the pain by means of cerebral vasoconstriction, although the precise mechanism of action is still not clear.
Sumatriptan, 6 mg subcutaneous injection, may be particularly beneficial for patients who have 1 or 2 cluster headache attacks daily.15 This agent is also available as a nasal spray. Sumatriptan has been shown to abort attacks in 74% to 89% of patients using 3- and 2-mg doses of subcutaneous formulation (those doses are associated with fewer side effects than the standard 6-mg dose)16 and in 57% to 47% of patients at 30 minutes after use of the intranasal formulation.17 Sumatriptan is generally well tolerated but may cause dizziness, numbness, weakness, hot flashes, or chest tightness. It is contraindicated in patients with coronary artery disease, uncontrolled hypertension, or peripheral artery disease.
Dihydroergotamine, as an injection or intranasal spray, can lessen the intensity of an attack and sometimes completely abort the pain.15 In a study of patients with refractory cluster headache, outpatient intravenous (IV) injection of dihydroergotamine completely resolved pain in 73% of patients with episodic cluster headache and in 46% of those with chronic cluster headache.18 Dihydroergotamine is contraindicated in patients with coronary artery disease, uncontrolled hypertension, and peripheral artery disease. It causes less vasoconstriction than ergotamine tartrate (Ergomar).
Intranasal capsaicin appears to be an effective abortive treatment for episodic cluster headache but is currently not available in the United States.19
Prophylactic therapy Daily use of a prophylactic agent during the cluster period is an important component of management. The 2 goals of management are rapid suppression of a single attack (eg, with corticosteroids or ergotamine derivatives) and maintaining remission through the individual’s usual cluster period, with medications such as verapamil HCl (Calan), methylergonovine maleate (Methergine), lithium (Eskalith, Lithobid), topiramate (Topamax), or valproic acid (Table 3). For refractory headache, more than 1 drug may be required.1 A prophylactic agent should be used daily and continued for 2 weeks after the headache has been relieved.
Table 3
Prophylactic oral drug therapy for cluster headache
Drug
Dosage
Comments
Transitional prophylaxis or rapid suppression of attacks
Ergotamine tartrate (Ergomar)
2-4 mg/d in divided doses
Contraindicated with sumatriptan, dihydroergotamine
Methylergonovine (Methergine)
0.2 mg 3 times daily
Avoid use >6 mo, to prevent fibrotic complications
Monitor liver function, platelets Monitor drug levels
Topiramate (Topamax)
Start at 25 mg/d, titrate up to 200 mg/d, as needed
Verapamil HCl (Calan)
120-480 mg/d
Very effective in reducing attack frequency
Oral ergotamine tartrate may be best for patients who experience attacks soon after falling asleep.15 It is available in the United States only in the form of sublingual tablets. Concurrent use of this agent with sumatriptan or dihydroergotamine is contraindicated.
Methylergonovine has been shown to decrease headache frequency and intensity within 1 week of starting therapy.20 This agent is an ergot derivative with vasoconstrictive properties. It is more potent than its parent drug methysergide and, hence, may be used in lower doses (eg, 0.2 mg 3 times daily); as a result it has fewer side effects.20 This agent should be reserved for refractory cases. Because of the possibility of retroperitoneal fibrosis, pleural fibrosis, pulmonary fibrosis, or cardiac fibrosis, use should be limited to no longer than 6 months at a time.
Corticosteroids may be the most rapid-acting prophylaxis,21 and they provide complete pain relief in up to 50% of patients.15 Oral prednisone (eg, Meticorten, Orasone, Panasol-S) may be used for prophylaxis at dosages of 40 to 60 mg/day for 3 days and should be tapered over a period of 7 to 9 days. Dexamethasone (Decadron), 4 mg twice daily for 2 weeks, followed by 4 mg/day for 1 week, may also be used.15 A single high-dose IV injection (30 mg/kg of body weight) of methylprednisolone was recently shown to reduce the frequency of daily attacks from 1.38 to 0.83.21
Although patients may report improvement after 2 days of oral therapy, the headache usually recurs at the end of the tapering period. Thus, oral corticosteroids should be taken concurrently with another prophylactic agent. The NHF recommends using prednisone or dexamethasone at the onset of a cluster period for up to 3 weeks, while initiating a maintenance prophylactic agent and waiting for the latter to take effect.15
Verapamil is the most effective calcium channel blocker for prophylaxis and has been shown to be effective in 94% of patients with episodic and 55% of those with chronic cluster headache.22 Side effects include constipation, dizziness, and swelling of the ankles or legs.
Valproic acid, in the form of divalproex sodium (Depakote, Depakote ER), relieved pain in 73% of patients with cluster headache in one study and was generally well tolerated.23 Adverse effects include dizziness, somnolence, insomnia, weight gain, anorexia, weakness, and thrombocytopenia. It should be used with caution in patients with renal or hepatic insufficiency.
Topiramate has been associated with the rapid remission of cluster headache, a more than 50% decrease in the number of attacks, and a reduced headache duration.24 The NHF recommends starting treatment at 25 mg, given at night, and then increasing the dosage by 25 mg every 5 days, as tolerated.15 The mechanism of action may be related to gamma-aminobutyric acid augmentation.25
According to the NHF, lithium has been shown effective for both episodic and chronic cluster headache. However, one double-blind, placebo-controlled trial was stopped early because the effects of lithium were not better than those of placebo.26 Lithium’s mechanism of action is unknown. Side effects include polyuria, tremor, nausea, diarrhea, fatigue, weight gain, and thyroid dysfunction.
Surgical therapy Approximately 10% of patients with cluster headaches either do not respond to pharmacotherapy or are prevented from taking effective medications because of contraindications.15 Such patients are candidates for surgical intervention. Procedures are aimed at ablating the components of the sensory portion of the trigeminal nerve and the cranial parasympathetic system or nervus intermedius,15 using techniques such as radiofrequency thermocoagulation of the trigeminal ganglion, glycerol injection into the trigeminal cistern, and gamma-knife radiosurgery. Radiofrequency thermocoagulation is the preferred surgical treatment at many institutions.27 However, a good-to-excellent success rate has been reported with microvascular decompression of the trigeminal nerve in 46.6% of patients who were followed for an average of 5.3 years.27
Conclusion Because cluster headache causes significant pain and disability, early diagnosis is vital to institute therapy that can abort acute attacks and prevent future ones. Prophylactic therapy is needed in the majority of patients. The condition is generally a lifelong problem. Patients with episodic cluster headache tend to maintain the episodic pattern. Patients refractory to medical management may benefit from referral to institutions that provide surgical treatment.
Self-assessment test 1. All the following features are characteristic of cluster headache, except: A. Periorbital pain B. Unilateral pain C. Autonomic symptom on contralateral side of head D. Nocturnal attacks
2. Which of these signs and symptoms is NOT generally associated with cluster headache? A. Tinnitus B. Miosis C. Ptosis D. Rhinorrhea
3. All these statements about the differential diagnosis of cluster headache are true, except: A. Trigeminal neuralgia is also characterized by autonomic symptoms B. More women than men experience chronic paroxysmal hemicrania C. The pain of hemicrania continua is characterized by a steady ache or throbbing D. The pericarotid syndrome is triggered by trauma
4. Which of these options is considered the treatment of choice for abortive therapy? A. Oxygen inhalation B. Sumatriptan subcutaneous injection C. Dihydroergotamine D. Methylergonovine
5. Which of the following prophylactic therapies would be best for a patient whose attacks occur shortly after falling asleep? A. Oral prednisone B. Verapamil C. Oral ergotamine D. Topiramate
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2. Black DF, Swanson JW, Stang PE. Decreasing incidence of cluster headache: a population-based study in Olmsted County, Minnesota. Headache. 2005;45:220-223.
3. Manzoni GC. Gender ratio of cluster headache over the years: a possible role of changes in lifestyle. Cephalalgia. 1998;18:138-142.
4. van Vliet JA, Eekers PJ, Haan J, et al. Features involved in the diagnostic delay of cluster headache. J Neurol Neurosurg Psychiatry. 2003; 74:1123-1125.
5. El Amrani M, Ducros A, Boulan P, et al. Familial cluster headache: a series of 186 index patients. Headache. 2002;42:974-977.
6. Sjaastad O, Shen JM, Stovner LJ, et al. Cluster headache in identical twins. Headache. 1993;33: 214-217.
7. Leone M, Russell MB, Rigamonti A, et al. Increased familial risk of cluster headache. Neurology. 2001;56:1233-1236.
8. Goadsby PJ. Pathophysiology of cluster headache: a trigeminal autonomic cephalgia. Lancet Neurol. 2002;1:251-257.
9. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia. 2004;24(suppl 1):9-160.
10. Mendizabal JE, Umana E, Zweifler RM. Cluster headache: Horton’s cephalalgia revisited. South Med J. 1998;91:606-617.
11. Beck E, Sieber WJ, Trejo R. Management of cluster headache. Am Fam Physician. 2005;71:717-724.
12. Silberstein SD, Niknam R, Rozen TD, et al. Cluster headache with aura. Neurology. 2000;54: 219-221.
13. Rozen TD. Atypical presentations of cluster headache. Cephalalgia. 2002;22:725-729.
14. Siow HC, Young WB, Peres MF, et al. Hemiplegic cluster. Head-ache. 2002;42:136-139.
15. Biondi D, Mendes P. Treatment of primary headache: cluster headache. In: Standards of Care for Headache Diagnosis and Treatment. Chicago, Ill: National Headache Foundation; 2004: 59-72.
16. Gregor N, Schlesiger C, Akova-Ozturk E, et al. Treatment of cluster headache attacks with less than 6 mg subcutaneous sumatriptan. Headache. 2005;45:1069-1072.
17. van Vliet JA, Bahra A, Martin V, et al. Intranasal sumatriptan in cluster headache: randomized, placebo-controlled, double-blind study. Neurology. 2003;60:630-633.
18. Magnoux E, Zlotnik G. Outpatient intravenous dihydroergotamine for refractory cluster headache. Headache. 2004;44:249-255.
19. Marks DR, Rapoport A, Padla D, et al. A double-blind, placebo-controlled trial of intranasal capsaicin for cluster headache. Cephalalgia. 1993;13:114-116.
20. Mueller L, Gallagher RM, Ciervo CA. Methylergonovine maleate as a cluster headache prophylactic: a study and review. Headache. 1997; 37:437-442.
21. Antonaci F, Costa A, Candeloro E, et al. Single high-dose steroid treatment in episodic cluster headache. Cephalalgia. 2005;24:290-295.
22. Blau JN, Engel HO. Individualizing treatment with verapamil for cluster headache patients. Headache. 2004;44:1013-1018.
23. Gallagher RM, Mueller LL, Freitag FG. Divalproex sodium in the treatment of migraine and cluster headaches. J Am Osteopath Assoc. 2002;102:92-94.
24. Lainez MJ, Pascual J, Pascual AM, et al. Topiramate in the prophylactic treatment of cluster headache. Headache. 2003;43:784-789.
25. Rozen TD. Antiepileptic drugs in the management of cluster headache and trigeminal neuralgia. Headache. 2001;41(suppl 1):S25-S32.
26. Steiner TJ, Hering R, Couturier EG, et al. Double-blind, placebo-controlled trial of lithium in episodic cluster headache. Cephalalgia. 1997;17:673-675.
27. Lovely TJ, Kotsiakis X, Jannetta PJ. The surgical management of chronic cluster headache. Headache. 1998;38:590-594.
Practice points
The only type of headache that is more common in men than in women is cluster headache.
Periodicity and unilaterality are distinguishing features of the attacks of cluster headache.
The pain rapidly escalates to excruciating levels and is characterized by a concentration in the periorbital region.
Abortive drug therapy consists of medications that provide rapid onset of action.
Most patients will need prophylactic therapy with one of several agents, such as prednisone, topiramate, or verapamil.
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