AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Background

Cluster headache (CH) is an idiopathic syndrome consisting of recurrent brief attacks of sudden, severe, unilateral periorbital pain.

Pathophysiology

The pathophysiology of CH is not entirely understood. Its typical periodicity has been attributed to hypothalamic (particularly suprachiasmatic nuclei) hormonal influences. More recently, functional neuroimaging with positron emission tomography (PET) and anatomical imaging with voxel-based morphometry have identified the posterior hypothalamic grey matter as the key area for the basic defect in CH. Hypothalamic dysfunction has recently been confirmed by abnormal metabolism based on the N-acetylaspartate neuronal marker in magnetic resonance spectroscopy.

CH pain is thought to be generated at the level of the pericarotid/cavernous sinus complex. This region receives sympathetic and parasympathetic input from the brain stem, possibly mediating occurrence of autonomic phenomena during an attack. The exact roles of immunologic and vasoregulatory factors, as well as the influence of hypoxemia and hypocapnia, in CH are still controversial.

Frequency

United States

The exact prevalence is unknown. Kudrow estimated 0.4% in men and 0.08% in women.

International

In an extensive study of 100,000 inhabitants of the republic of San Marino, the prevalence was 0.07%.

Race

CH has been suggested to be more prevalent in the black population.

Sex

CH is more common in men than in women; the male-to-female ratio is 5:1.

Age

CH affects middle-aged persons.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

History

• Attacks of CH are typically short in duration (5-180 min) and occur with a frequency from once every other day to 8 times a day, particularly during sleep. As opposed to migraine, CH is not preceded by aura, affording patients little or no warning.
• Pain generally is described as excruciating, penetrating, and not throbbing.
• • It may radiate to other areas of the face and neck but is typically periorbital.
  • It may be triggered by stress, relaxation, extreme temperatures, glare, allergic rhinitis, and sexual activity.
  • CH rarely is triggered by ingestion of specific foods, although tobacco or alcohol products may precipitate an attack.
• An attack of CH is a dramatic event during which the patient may be extremely restless. In desperation, CH patients may rock, sit, pace, or bang themselves against a hard surface.
• Classification of CH: The International Headache Society (IHS) classifies CH by duration as episodic or chronic.
• • Episodic CH occurs in periods (clusters) lasting from 7 days to 1 year; clusters are separated by pain-free intervals lasting at least 2 weeks. Typically, a cluster lasts 2 weeks to 3 months.
  • Chronic CH is defined as that occurring for more than 1 year without remission or with remissions lasting less than 2 weeks. It is subdivided into chronic CH from onset and chronic CH evolving from episodic.
  • Chronic CH is notoriously difficult to treat and resistant to standard prophylactic agents.
• Symptomatic clusterlike headache should be suspected if the presentation is atypical. Atypical features may include the following:
• • Absence of a periodic pattern
  • Residual headache between exacerbations
  • Incomplete or minimal response to standard therapy
  • Presence of lateralizing findings on exam (except for those of CH-related Horner syndrome)

Physical

The association of prominent autonomic phenomena is a hallmark of CH. Such signs include ipsilateral nasal congestion and rhinorrhea, lacrimation, conjunctival hyperemia, facial diaphoresis, palpebral edema, and complete or partial Horner syndrome (which may persist between attacks). Tachycardia is a frequent finding.

• A distinctive CH face is described as follows: leonine facial appearance, multifurrowed and thickened skin with prominent folds, a broad chin, vertical forehead creases, and nasal telangiectasias.
• Persons affected by CHs often are tall and rugged-looking.

Causes

Cases of CH affecting multiple members with an autosomal dominant pattern within a single family have been reported, suggesting that a genetic predisposition may exist in those families. Complex segregation analysis, however, has consistently resulted in a sporadic model of inheritance.

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Other Problems to be Considered

Arteriovenous malformations
Brainstem syndromes
Cyclical migraine
Hemicrania continua
Metastatic lung carcinoma
Nasopharyngeal carcinoma
Malignant and nonmalignant pain syndromes
Raeder paratrigeminal syndrome
Vertebral artery aneurysm
Cerebral venous thrombosis

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Imaging Studies

• CH is strictly a clinical diagnosis. Atypical cases may occasionally be found and should prompt consideration of structural etiologies mimicking CH. Any suspicion of a structural lesion should be further investigated with an appropriate neuroimaging study (eg, CT scanning, MRI).
• The following conditions can present with findings suggestive of CH:
• • Meningiomas of the cavernous sinus
  • Arteriovenous malformations
  • Pituitary adenomas
  • Nasopharyngeal carcinoma
  • Vertebral artery aneurysms
  • Metastatic carcinoma of the lung

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Medical Care

Pharmacologic management of CH may be classified as abortive/symptomatic or preventive/prophylactic. See Medication section for a detailed discussion.

Surgical Care

• Invasive nerve blocks and ablative neurosurgical procedures (eg, percutaneous radiofrequency, trigeminal gangliorhizolysis, rhizotomy) all have been implemented successfully in cases of refractory CH. Percutaneous radiofrequency ablation may achieve success in 50% of patients, with fair-to-good results in 20% and failure in about 30%. Side effects include facial dysesthesia, corneal sensory loss, and anesthesia dolorosa.
• Gamma-knife radiosurgery has provided a less invasive alternative for pervasive CH.
• The implantation of stimulating electrodes under stereotactic guidance into the posterior inferior hypothalamus has become an effective, safe, and well-tolerated alternative to ablative surgery in patients with chronic, pharmacologically refractory CH. The procedure is performed in limited centers around the world.

MEDICATION

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

The pharmacologic management of CH may be divided into abortive/symptomatic and preventive/prophylactic strategies. Abortive therapy is directed at stopping or reducing the severity of an acute attack, while prophylactic agents are used to reduce the frequency and intensity of individual headache exacerbations. Due to the fleeting, short-lived nature of the attacks, effective prophylactic therapy should be considered the cornerstone of treatment. The prophylactic therapy 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.

Drug Category: Abortive agents

These agents are administered to abort an attack of CH. Because of the duration of the attacks, they must provide immediate relief.

Drug Category: Ergot alkaloids

These agents are highly effective in relieving acute CH pain.

Drug Name	Dihydroergotamine (D.H.E. 45 injection, Migranal)
Description	Available in IV or intranasal preparations, tends to cause less arterial vasoconstriction than ergotamine tartrate.
Adult Dose	Up to 2 mg IV; not to exceed 2 mg/dose or 6 mg/wk 1 mg IM/SC at first sign of onset; not to exceed 3 mg total 1 spray (0.5 mg) into each nostril; not to exceed 6 sprays/d or 8 sprays/wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; within 24 h of sumatriptan, zolmitriptan, other serotonin agonists, or ergotlike agents; use of MAOIs within last 2 wk
Interactions	May increase effects of heparin; erythromycin, clarithromycin, nitroglycerin, propranolol, and troleandomycin may increase toxicity
Pregnancy	X - Contraindicated in pregnancy
Precautions	Use caution in patients with hypertension, angina, peripheral vascular disease, or impaired renal or hepatic function

Drug Name	Sumatriptan (Imitrex); naratriptan (Amerge, Naramig)
Description	zolmitriptan (Zomig, Zomig-ZMT); rizatriptan (Maxalt, Maxalt-MLT); almotriptan (Axert); frovatriptan (Frova); eletriptan (Relpax)--As selective agonists of serotonin 5HT1 receptors in cranial arteries, cause vasoconstriction and reduce inflammation associated with antidromic neuronal transmission in CH. Can reduce severity of headache within 15 min of SC injection. Intranasal form recently introduced in US, offering attractive alternative to self-injections.
Adult Dose	Sumatriptan: 6 mg SC, followed by second injection prn at least 1 h after first; not to exceed 2 injections/d 25-100 mg PO, followed by second dose 2 h later prn; not to exceed 300 mg/d 1 spray (5-20 mg) in 1 nostril or 1 spray (5 mg) in each nostril; may repeat in 2 h prn; not to exceed 40 mg/d Zolmitriptan: 2.5-5 mg PO; repeat after 2 h prn; not to exceed 10 mg/d; 5 mg intranasally prn may repeat in 2 h prn Naratriptan: 2.5 mg PO Rizatriptan: 10 mg PO Almotriptan: 6.25-12.5 mg PO at onset of migraine; may repeat once, not to exceed 25 mg/d Frovatriptan: 2.5 mg PO once at onset of migraine Eletriptan: 20-40 mg/dose PO at onset of migraine; if initial dose ineffective, may repeat dose once after 2 h; not to exceed 80 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; ischemic heart disease; uncontrolled hypertension; use of MAOIs in last 2 wk
Interactions	Not to be used on the same day as another ergot derivative or triptan; toxicity increases when administered concomitantly with ergot-containing drugs, selective serotonin reuptake inhibitors, and MAOIs
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May cause facial flushing, numbness, paresthesias, and chest pain of noncardiac origin; significant elevation in blood pressure, including hypertensive crisis, has been reported in patients without history of hypertension; peripheral vascular ischemia, colonic ischemia with abdominal pain, and bloody diarrhea have occurred

Drug Category: Anesthetics

Local anesthetics stabilize the neuronal membrane so the neuron is less permeable to ions. This prevents initiation and transmission of nerve impulses, thereby producing the local anesthetic action.

Drug Category: Oral opioids and other analgesics

The short-lived and unpredictable character of CH precludes the effective use of oral narcotics or analgesics. Despite their lack of efficacy, these substances are abused by some CH sufferers.

Drug Category: Calcium channel blockers

These agents inhibit the initial vasoconstrictive phase of CH.

Drug Category: Mood stabilizers

Mechanism of action of lithium in CH is unclear, although preliminary evidence suggests that it may interfere with substance P and vasoactive intestinal peptide–induced arterial relaxation.

Drug Category: Anticonvulsants

Efficacy in the prophylaxis of CH has been demonstrated in a few relatively small controlled studies. Unclear mechanism of action for the prevention of CH. May act by regulating central sensitization.

Drug Name	Topiramate (Topamax)
Description	Effective in several small prospective studies. Exact mechanism of action in CH headache unknown.
Adult Dose	Typically started at 25 mg qhs; titrate up very slowly by 25-mg weekly increments to a bid dosing; target dose should be 100-200 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May increase phenytoin levels; use with ethosuximide may augment risk for CNS depression; may reduce effectiveness of estrogen-containing contraceptives; concomitant use with carbonic anhydrase inhibitors may increase risk of nephrolithiasis
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in patients with history of nephrolithiasis; caution in severe dehydration or diarrhea

Drug Category: Corticosteroids

These agents 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. The simultaneous use of standard prophylactic agents (eg, verapamil) is recommended. The mechanism of action in CH is still subject to speculation.

Drug Name	Methysergide (Sansert)
Description	Useful in patients unresponsive to lithium. Although of ergotamine chemical class, actions differ, since has minimal ergotaminelike vasoconstrictive properties and significantly greater serotoninlike properties. Very effective in episodic and chronic CH prophylaxis. Often effective in reducing pain frequency, particularly in younger patients with episodic CH. If no improvement after 3 wk, unlikely to be beneficial. Do not give continuously for > 6 mo. Drug-free interval of 3-4 wk must follow each 6-mo course. Product no longer available in the United States.
Adult Dose	2-8 mg/d PO
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; peripheral vascular disease; severe arteriosclerosis; pulmonary disease; severe hypertension; phlebitis; serious infections
Interactions	None reported
Pregnancy	X - Contraindicated in pregnancy
Precautions	Use > 6 mo discouraged, because long-term therapy may cause retroperitoneal fibrosis and fibrotic thickening of cardiac valves (drug holiday recommended to avoid these effects); adverse GI reactions most commonly affect compliance; use caution in renal or hepatic impairment; adverse effects include leg cramps, paresthesias, edema, and skin discoloration

Drug Category: Antimigraine agents

These agents may reduce the inflammation associated with migraine headaches.

FOLLOW-UP

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Prognosis

• Eighty percent of patients with episodic CH tend to maintain the episodic form.
• Episodic CH eventually transforms into chronic CH in 4-13% of patients. Intermediate (mixed) forms may occur.
• Prolonged, spontaneous remissions have been described in up to 12% of patients in some series, particularly in episodic CH. Chronic CH is more relentless and may persist in this form in up to 55% of cases. Less frequently, chronic CH may remit into an episodic form.
• Generally, CH is a lifelong problem.
• Pharmacologic intervention may play a part in the transformation of chronic CH into the episodic form; otherwise, it does not influence outcome.
• Late onset of this disorder, along with male sex and a previous history of episodic CH, predict a less favorable course.

Patient Education

• For excellent patient education resources, see eMedicine's Headache Center. Also, visit eMedicine's patient education articles Causes and Treatments of Migraine and Related Headaches, Cluster Headache, Alternative and Complementary Approaches to Migraine and Cluster Headaches, Cluster Headache FAQs, and Understanding Migraine and Cluster Headache Medications.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

• Ekbom K, Nappi G. Diagnosis, differential diagnosis, and prognosis of cluster headache. In: The Headaches. 1993;585-589. [Medline].
• Franzini A, Ferroli P, Leone M, Broggi G. Stimulation of the posterior hypothalamus for treatment of chronic intractable cluster headaches: first reported series. Neurosurgery. May 2003;52(5):1095-9; discussion 1099-101. [Medline].
• Goadsby PJ. Pathophysiology of cluster headache: a trigeminal autonomic cephalgia. Lancet Neurol. Aug 2002;1(4):251-7. [Medline].
• Kudrow L. Cluster headache: diagnosis and management. Headache. Apr 1979;19(3):142-50. [Medline].
• Lance JW. Headache: Mechanism and Management. 5th ed. Boston, Mass: Butterworth-Heinemann; 1993.
• Leone M, Franzini A, Broggi G, Bussone G. Hypothalamic stimulation for intractable cluster headache. Neurology. 2006;67(1):150-2. [Medline].
• Lodi R, Pierangeli G, Tonon C, et al. Study of hypothalamic metabolism in cluster headache by proton MR spectroscopy. Neurology. 2006;66(8):1624-6. [Medline].
• Mathew NT. Cluster Headache. Neurology. 1992;42 (suppl 2):22-31. [Medline].
• May A, Leone M. Update on cluster headache. Curr Opin Neurol. Jun 2003;16(3):333-40. [Medline].
• Mendizabal JE, Umana E, Zweifler RM. Cluster headache: Horton''s cephalalgia revisited. South Med J. Jul 1998;91(7):606-17. [Medline].
• Peterlin BL, Levin M, Cohen JA, Ward TN. Secondary cluster headache: a presentation of cerebral thrombosis. Cephalalgia. 2006;26(8):1022-4. [Medline].

Article Last Updated: Oct 13, 2006