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Headache, Cluster
Jeffrey Phillips, MD
image BASICS
DESCRIPTION
  • Primary headache disorder
  • Multiple attacks of unilateral, excruciating, sharp, searing, or piercing pain. Typically localized in the periorbital area and temple accompanied by signs of ipsilateral autonomic features
  • Autonomic symptoms: parasympathetic hyperactivity signs (ipsilateral lacrimation, eye redness, nasal congestion) and sympathetic hypoactivity (ipsilateral ptosis and miosis)
  • Patients often pace, rubbing their heads to try to alleviate the pain.
  • Symptoms usually remain on the same side during a single cluster attack.
  • Individual attacks last 15 to 180 minutes if untreated and occur from once every other day to 8 times per day.
  • Attacks usually occur in series (cluster periods) lasting for weeks or months separated by remission periods usually lasting months or years. However, about 10-15% of patients have chronic symptoms without remissions.
EPIDEMIOLOGY
Incidence
1-year incidence: 53/100,000
Prevalence
  • Lifetime prevalence 124/100,000 (˜0.1%)
  • Predominant sex: male > female (4.3:1)
  • Mean age of onset: between 29.6 and 35.7 years
  • Episodic/chronic ratio 6:1
ETIOLOGY AND PATHOPHYSIOLOGY
  • Complex and incompletely understood
  • Proposed mechanisms include the following:
    • Activation of posterior hypothalamus may trigger an attack, causing activation of the trigeminal nerve, leading to intense pain symptoms.
    • Autonomic symptoms: activation of craniofacial parasympathetic nerve fibers secondary to pathologic activation of trigemino-autonomic brainstem reflex
Genetics
  • Usually sporadic: autosomal dominant in 5% of cases; autosomal recessive or multifactorial in other families
  • Evidence varies: first-degree relatives carry 5- to 8-fold; second degree, 1- to 3-fold increased relative risk of disease
RISK FACTORS
  • Male gender
  • Age (70% onset before age 30 years)
  • Cigarette smoking
  • Family history of cluster headache (CH)
  • Head trauma
  • Alcohol induces attacks during a cluster but not during remission.
  • Small amounts of vasodilators (e.g., alcohol, nitroglycerin, sildenafil)
  • Strong odors
COMMONLY ASSOCIATED CONDITIONS
  • Depression (24%)
  • Increased risk of suicide secondary to the extreme nature of the pain
  • Medication-overuse headache
  • Asthma (9%)
  • History of migraine, frequently in female patients
  • Sleep apnea (14%)
  • Increased prevalence of cardiac right-to-left shunt and patent foramen ovale (relationship unclear)
image DIAGNOSIS
  • Diagnosis is clinical.
  • International Classification of Headache Disorders (2nd edition) criteria: at least five attacks of severe or very severe unilateral orbital, supraorbital, or temporal pain lasting 15 to 180 minutes if untreated
  • At least one of the following:
    • Ipsilateral
      • Conjunctival injection and/or lacrimation
      • Nasal congestion and/or rhinorrhea
      • Eyelid edema
      • Forehead and facial sweating
      • Miosis and/or ptosis
    • Sense of restlessness or agitation
  • Attack frequency: one every other day to eight per day
  • Episodic CH: at least two cluster periods lasting 7 days to 1 year, separated by a pain-free interval of >1 month (80-90% of cases)
  • Chronic CH: cluster-free interval of <1 month in a ≥12-month period
PHYSICAL EXAM
  • Usually patients seen between attacks
  • Acute distress, crying, screaming, restless, and/or agitated during attacks
  • Ipsilateral lacrimation, injected conjunctivae, ptosis, and miosis
  • Nasal stuffiness or rhinorrhea
  • Bradycardia or tachycardia
DIFFERENTIAL DIAGNOSIS
  • Paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT)
  • Hemicrania continua, hypnic headaches, trigeminal and other facial neuralgias, migraine, temporal arteritis, herpes zoster
  • Secondary CH:
    • Vertebral or carotid artery dissection, brain arteriovenous malformations, intracranial artery aneurysms
    • Pituitary tumors
    • Nasopharyngeal carcinoma
    • Maxillary sinus with foreign body/sinusitis
    • Cavernous hemangioma
    • Meningiomas/carcinomas/metastases
DIAGNOSTIC TESTS & INTERPRETATION
  • Diagnosis is primarily clinical.
  • Diagnosis is often delayed (>40% report 5-year delay in diagnosis).
  • Consider neuroimaging (MRI/CT head and vascular imaging of brain):
    • Abnormal neurologic exam
    • Suspect secondary CH
image TREATMENT
Many of the medications discussed in the following section are used off-label in the treatment of CH.
GENERAL MEASURES
  • Avoid major changes in sleep habits.
  • Stop smoking.
  • Avoid use of alcohol during cluster period.
  • Avoid extreme changes in altitude due to changes in oxygen levels.
  • Avoid exposure to chemical agents/solvents.
MEDICATION
  • Avoid pain therapy, especially narcotic analgesics, for acute attacks.
  • Goal is abortion of acute attack and prophylaxis for expected duration of the cluster.
  • Assess cardiovascular risk before instituting a vasoactive drug, such as triptans or ergot derivatives.
First Line
For acute attacks:
  • Oxygen
    • 100% at 6 to 12 L/min for 15 minutes via nonrebreathing mask provides relief within 15 minutes (1)[A].
    • Avoid in severe chronic obstructive pulmonary disease (COPD) as might affect hypoxic respiratory drive.
  • Sumatriptan (Imitrex)
    • 6 mg SC, max 12 mg/24 hr with at least 1 hour between injections is most effective medication for acute attacks. NNT (needed to treat) 2.4 for headache relief in 15 minutes. Sumatriptan nasal spray: 20 mg. May repeat in 2 hours, max dose 40 mg/24 hr NNT 3.2 for headache relief at 30 minutes (2)[A].
  • Zolmitriptan
    • Nasal spray: 5- and 10-mg dosage both effective. May repeat in 2 hours, max 10 mg/24 hr. NNT 12 and 4.9 for headache relief in 15 minutes for 5 and 10 mg, respectively. Zolmitriptan tablet: 5- and 10-mg dosage both effective. May repeat in 2 hours, max dose 10 mg/24 hr. NNT 6.7 and 4.5 for headache relief in 30 minutes for 5 and 10 mg, respectively (2)[A].
  • Prophylaxis: used at start of cluster period to prevent and shorten further attacks. Start as soon as possible:
    • Verapamil
      • Can start at 240 mg/day and increase by 40 to 80 mg every 10 to 14 days. Short- or long-acting equivalent. Most patients respond to daily dose of 200 to 480 mg but up to 960 mg/day may be needed. NNT = 1.2 (3)[A]
      • ECG monitoring for doses/increments >480 mg/day required because of risk of bradycardia (q3mo used as a guideline)
      • Similar efficacy to lithium, but fewer adverse effects and faster onset make it the preferred choice.
      • Often used in conjunction with another agent
P.439

Second Line
  • Acute attack
    • Lidocaine/cocaine: 10 mg (1 mL) of lidocaine or 40 to 50 mg of 10% cocaine intranasal. No well-controlled randomized controlled trials (RCTs) done. Most common side effects are nasal congestion, unpleasant taste (4)[B].
    • Octreotide: SC 100 &mgr;g. Can be considered in patients when triptans are contraindicated. Main side effect is GI upset (5)[A].
    • Ergotamine/dihydroergotamine (DHE): original treatments for CH. Now rarely used because of significant side effects. No controlled trials done. Still used for transitional prophylaxis (see below)
  • Prophylaxis
    • Lithium: Start 300 mg BID, titrate to therapeutic range of 0.8 to 1.1 mEq/L. Most patients benefit from 600 to 1,200 mg/day. Widely used without formal evidence of efficacy. Retrospective case series show that lithium led to >50% reduction in attack frequency within 2 weeks in 77% of the patients with episodic CH. Must monitor levels of liver, renal, and thyroid function. Caution with nephrotoxic drugs, diuretics. Inferior to verapamil (6)[B]
    • Melatonin: 10 mg in the evening showed reduction in headache frequency versus placebo in small RCT. No side effects were reported.
    • Antiepileptics: topiramate, sodium valproate, gabapentin: Open studies showed reduction of cluster duration and frequency of headache, but RCT did not show superiority to placebo. Significant adverse effects
    • Civamide: 100 &mgr;L of 0.025% into each nostril daily. Only studied in episodic CH in one trial of 28 patients. Not available in the United States. Most common side effects were nasal burning, lacrimation, pharyngitis, and rhinorrhea.
    • Capsaicin: 0.025% ipsilateral nostril for 7 days, shows benefit in small RCT.
    • Methysergide: No studies available to confirm efficacy. Has serious adverse effects, including pulmonary and retroperitoneal fibrosis. Cannot be given with triptans and ergots
    • Pizotifen: Modest benefit limited by fatigue and weight gain
ADDITIONAL THERAPIES
Transitional preventive treatment are as follows:
  • Used until longer-term preventive treatment becomes effective. Longer term maintenance agents are started concurrently:
    • Steroids: Several open studies suggested benefit, but no rigorous trials to prove efficacy. Studies support at least 40 mg/day (up to 80 mg/day) prednisone with a 10- to 30-day taper provides benefit to 60-90% patients. Adverse effects for short-term use: insomnia, psychosis, hyponatremia, edema, hyperglycemia, peptic ulcer
Pregnancy Considerations
Collaboration between headache specialist, obstetrician, and pediatrician strongly encouraged. Patient should be informed of treatment benefits and risks as well as drug's potential teratogenic effect. For abortive treatment, oxygen is most appropriate first-line therapy. Nasal lidocaine (pregnancy Category B) can be used as second-line therapy. As preventive therapy, verapamil (pregnancy Category C) and steroids (pregnancy Category C) remain the preferred options. Use of SC or intranasal sumatriptan (pregnancy Category C) should be limited as much as possible. Avoid ergotamines (pregnancy Category X).
ISSUES FOR REFERRAL
Consider a neurology or headache center referral for refractory or complicated patients.
SURGERY/OTHER PROCEDURES
  • Surgery may be considered only for patients who are refractory to, or have contraindications to, medical therapy.
  • Various techniques focus on stimulation or ablation of segments of trigeminal nerve root and sphenopalatine ganglion. Other techniques are aimed at decreasing pain and inflammation surrounding the greater occipital nerve.
  • Greater occipital nerve steroid injection: A retrospective analysis showed ˜80% of patients with partial or complete response. Effect lasted 3.5 weeks; 21 mg of betamethasone and 2 mL of 2% lidocaine were used. One class I RCT showed benefit within 72 hours in 85% of lidocaine/betamethasone group compared with none in lidocaine/saline group. Cortivazol injection reduced severity and frequency of headache compared with placebo in an RCT (7)[A].
  • No evidence for Botox or hyperbaric oxygen treatment
  • Neurostimulation
    • Occipital nerve stimulation (ONS) was shown to reduce severity and attack frequency in chronic CH patients.
    • Deep brain stimulation (DBS) of the posterior inferior hypothalamus shows moderate therapeutic effect.
    • Currently investigating sphenopalatine ganglion stimulation
INPATIENT CONSIDERATIONS
Suicidal ideation, unwilling to contract for safety
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • Anticipate cluster bouts and initiate early prophylaxis.
  • Monitor for depression.
  • Watch for adverse medication response and side effects, such as unmasking of underlying cardiovascular disorder when using medications to treat CH.
PROGNOSIS
  • Unpredictable course. With aging, attack frequency often decreases.
  • Poor prognosis associated with older age of onset, male gender, disease duration of >20 years for episodic form
  • Possibility of transformation of episodic cluster to chronic cluster and occasionally chronic cluster to episodic cluster
REFERENCES
1. Cohen AS, Burns B, Goadsby PJ. High-flow oxygen for treatment of cluster headache: a randomized trial. JAMA. 2009;302(22):2451-2457.
2. Law S, Derry S, Moore RA. Triptans for acute cluster headache. Cochrane Database Syst Rev. 2010;(4):CD008042.
3. Leone M, D'Amico D, Frediani F, et al. Verapamil in the prophylaxis of episodic cluster headache: a double-blind study versus placebo. Neurology. 2000;54(6):1382-1385.
4. Costa A, Pucci E, Antonaci F, et al. The effect of intranasal cocaine and lidocaine on nitroglycerininduced attacks in cluster headache. Cephalalgia. 2000;20(2):85-91.
5. Matharu MS, Levy MJ, Meeran K, et al. Subcutaneous octreotide in cluster headache: randomized placebo-controlled double-blind crossover study. Ann Neurol. 2004;56(4):488-494.
6. Stochino ME, Deidda A, Asuni C, et al. Evaluation of lithium response in episodic cluster headache: a retrospective case series. Headache. 2012;52(7):1171-1175.
7. Leroux E, Valade D, Taifas I, et al. Suboccipital steroid injections for transitional treatment of patients with more than two cluster headache attacks per day: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2011;10(10): 891-897.
Additional Reading
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  • Ashkenazi A, Schwedt T. Cluster headache—acute and prophylactic therapy. Headache. 2011;51(2):272-286.
  • Beck E, Sieber WJ, Trejo R. Management of cluster headache. Am Fam Physician. 2005;71(4):717-724.
  • Fontaine D, Lanteri-Minet M, Ouchchane L, et al. Anatomical location of effective deep brain stimulation electrodes in chronic cluster headache. Brain. 2010;133(Pt 4):1214-1223.
  • Hainer BL, Matheson EM. Approach to acute headache in adults. Am Fam Physician. 2013;87(10):682-687.
  • International Headache Society: http://www.ihs-headache.org
See Also
&NA;
Algorithm: Headache, Chronic
Codes
&NA;
ICD10
  • G44.009 Cluster headache syndrome, unspecified, not intractable
  • G44.019 Episodic cluster headache, not intractable
  • G44.029 Chronic cluster headache, not intractable
Clinical Pearls
&NA;
  • CHs are rare but disabling. Patients are often agitated and restless during the attack.
  • Oxygen and triptans, not narcotics, are first-line therapy for acute attacks.
  • Abortive, transitional, and prophylaxic treatment must all be considered.