@ Differential Diagnosis
@ Emerging Therapy
@ Key points
- Cluster headache (CH) is a primary headache disorder belongs to the trigeminal autonomic cephalalgias (TACs). It has distinct features of unilateral intense pain of a short duration, with cranial autonomic symptoms, and a circadian and circannual rhythm.1
- Description of CH dated back to 1745, but the first complete description was achieved by Wilfred Harris in 1926 who named the disease (migrainous neuralgia).2
- CH is a rare disorder, affecting about 1 in 1000 of the population.
- Men are affected more often than women (4 to 7 times).
- The age of onset of CH is 20 and 50 years; however, it can begin before 20 years or after 50 years.
- Women have a later average age of onset than men.
- Not fully understood.
- Cluster headache is a neurovascular headache.
- Vascular cerebral changes by trigeminal autonomic reflex activation.
- Activation of the trigemino-vascular pathway: Involves first division of trigeminal nerve.
- Nuerons innervate cerebral vessels and dura mater.
- Releases of vasoactive peptides (calcitonin gene-related peptide (CGRP), substance P, and neurokinin A).
- Vasodilatation of dural blood vessels
- Neurogenic inflammation.
- Activation of the trigeminal-autonomic reflex pathway: involves Facial Nerve.
- Parasympathetic outflow from the superior salivatory nucleus and sphenopalatine ganglion.
- Vasodilatation and parasympathetic activation.
- Clinically, this presents as lacrimation, conjunctival injection, and nasal congestion.
- Activation of hypothalamus: Explains the occurrence of attack at the same time each year in a circannual pattern and is evident by:
- Melatonin: During bouts of CH, melatonin secretion has been found to be low.
- Steroids: have a role in the pathophysiology of CH.
- The diagnosis of CH relies on detailed and accurate history.
- Unfortunately CH is underdiagnosed and patients have a delay to their diagnosis. It is sometimes mistaken for sinus or dental diseases.
- Intensity: intense, severe and excruciating.
- Quality: stabbing, boring, deep Red-hot poker and resembles that of childbirth and fractures.
- Location: supraorbital, retro-orbital and temporal
- Radiation: ipsilateral temple, upper teeth, gum and neck.
- Onset: abrupt onset with a maximum intensity within 1- 15 minutes.
- Duration: 15 – 180 minutes. Every other day in the beginning up to 8 attacks a day
- Periodicity: attacks recur around the same time each day during the entire cluster cycle. Attacks occur between 9 p.m. and 10 a.m. About half of all cluster sufferers report nocturnal attacks that awaken them from sleep. Attacks typically occur within 2 hours of falling asleep and are often associated with rapid eye movement sleep.
- Relieving factors: attacks are aborted by oxygen therapy and medication.
- Aggravating factors: pain may be brought about by alcohol, stress, exposure to heat or cold, strong smells and foods such as chocolate, dairy, eggs and nitrate-containing food.
- Associated features: cranial autonomic symptoms of lacrimation, conjunctival injection, nasal symptoms, aural fullness, periorbital swelling and ptosis or miosis. One major feature during attacks is the restlessness and agitation which distinguishes cluster headache from migraine.
- The International Classification of Headache Disorders (ICHD II) defines five clinical criteria for cluster headache.4 (Table 1.1).
|Table 1.1: International Classification of Headache Disorders Criteria for CH|
|1. At least five attacks fulfilling B–D|
|2. Severe or very unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 180 min if untreated|
|3. Headache is accompanied by at least one of the following signs, which have to be present on the pain side:
|4. Attacks have a frequency from one every other day to 8 per day|
|5. Not attributed to another disorder|
- An attacks (lasts 1 to 3 months) recur in cycles.
- Remissions lasting from 1 month to several years.
- One or two bouts yearly.
- Attacks recur on a daily basis for more than 1 year.
- No remission or with remissions lasting less than 1 month.
- Chronic CH is further divided into:
- primary chronic.
- Secondary chronic.
- CH has to be differentiated from other trigeminal autonomic cephalalgias (TACs):
- Hemicrania Continua.
- Paroxysmal Hemicranias.
- Pain can be perceived as arisen from:
- Sinus diseases.
- Dentition problems.
- Differential diagnosis is to include any serious syndromes that present with retroorbital pain and ptosis:
- Carotid artery dissection.
- Cavernous sinus diseases.
- Differential diagnosis of CH is illustrated in (table 1.2).
|Table1.2: Differential Diagnosis of Cluster Headache|
|Cluster Headache||Migraine||Hemicrania Continua||Paroxysmal Hemicrania|
|Sex: Female: Male||1:6||3:1||1.8:1||2.1:3.1
|Age of onset (years)||20 – 40||Teens – 20s||11- 58||6 – 81
|Pain Quality||Stabbing, boring||Dull ache
|Throbbing, pulsatile||Stabbing, pulsatile, throbbing
|Attacks Per Day||0-8||0-1||Varies||1-40
|Duration of Attack||15 – 180 min||4 – 72 h||2 – 45 min||20- 120 min
|Aura||–||+ in 20%||–||–
|Patient’s Behaviour||Pacing/Rocking||Rest/Sleep||Pacing or Rest||Pacing/Rocking
|Aborted by O2||+ in 80%||+ in 20%||–||–
- As we said earlier, CH is a clinical diagnosis that relies on accurate history taking and the structural causes should not be present.
- However, some investigations are requested:
- To observe activities in the brain during CH attacks.
- If a trigeminal autonomic cephalalgia is secondary.
- If the clinical presentation is not classical.
- If there is an atypical response to acute treatment.
- If the headache does not respond to traditional preventives.
- Some investigations include:
- Positron Emission Tomography (PET) scans: during acute bouts of cluster headache have revealed increased activation in the region of the hypothalamic gray matter.
- MRI scan of the brain: for secondary cluster headache-like presentations.
- Pituitary function screening: thyroid function tests, plasma prolactin and growth hormone.
- Management targets:
- Acute attack
- Table 1.3 gives the treatment for CH.
|Table 3: Treatment for Cluster Headache|
|Verapamil||240 – 960||Safe and well tolerated. Needs 1 to 2 weeks.|
|Prednisone||60 – 80 in 1st week||Tapered by 10 mg per day in the second week.|
|Valproic Acid||500 – 3000||Useful in all forms.|
|Topiramate||100 – 200||Side effects limit its use.|
|Lithium||300 – 1500||Best for chronic cluster.|
|Maintain prophylaxis longer than the duration of a typical cycle|
|Oxygen||8 – 10 L/min via face mask or nasal cannula for 10 to 15 minutes.|
|Sumatriptan||Subcutaneous 6 mg. No more than 2 dose a day.|
|Zolmitriptan||Nasal spray 5 mg and 10 mg.|
|Dihydroergotamine||0.5–1.0 mg intramuscularly or subcutaneously.|
|Ergot suppositories||in nocturnal attacks.|
|1. Ipsilateral occipital nerve blocks
2. Percutaneous glycerol injections into the trigeminal cistern
3. Percutaneous radiofrequency trigeminal rhizotomy. 5
4. Decompression of the nervus intermedius.
5. Hypothalamic deep brain stimulation
- Non-invasive vagus nerve stimulation (nVNS) :
- Efficacy for the acute treatment in episodic cluster headache.
- Three 2 min ipsilateral stimulations of the cervical branch of the vagus nerve.6
- Sphenopalatine ganglion (SPG) microstimulator:
- Efficacy for the acute treatment in episodic cluster headache.7
Calcitonin gene-related peptide monoclonal antibodies:
- Plasma calcitonin gene-related peptide is elevated in spontaneous and nitroglycerin-triggered cluster attacks.
- Its infusion can trigger attacks in patients with episodic cluster headache.
- Galcanezumab has proven efficacy in reducing the number of weekly cluster headache attacks in episodic cluster headache in a placebo controlled trial.8
|1. Cluster headaches are characterized by attacks of excruciatingly severe, unilateral head pain; 75% of the attacks occur between 9 p.m. and 10 a.m.
2. The pain of cluster begins abruptly, usually without warning, and reaches maximum intensity within 1 to 15 minutes. The pain is excruciating, deep, and boring, and is often described as a “red-hot poker” in or behind the affected eye.
3. In contrast to migraine, men are affected more commonly than women.
4. Both acute and chronic forms of cluster headache exist.
5. The pain physician should be aware of the specific acute and prophylactic therapies that are effective for cluster headache.
- Koehler PJ. Prevalence of headache in Tulp’s Observationes Medicae (1641) with a description of cluster headache. Cephalalgia. 1993;13:318–20.
- Harris W. Neuritis and Neuralgia. 1st ed. London: Humphrey Milford, Oxford University Press; 1926.
- Headache Classification Subcommittee of the International Headache Society. The international classification of headache disorders. Cephalalgia. 2013;32(9):629–808.
- Taha JM, Tew JM Jr. Long-term results of radio frequency rhizotomy in the treatment of cluster headache. Headache. 1995;35:193–196
- Gaul C, Diener H-C, Silver N, et al. Non-invasive vagus nerve stimulation for prevention and acute treatment of chronic cluster headache (PREVA): a randomised controlled study. Cephalalgia 2016;36:534–46
- Barloese M, Petersen A, Stude P, et al. Sphenopalatine ganglion stimulation for cluster headache, results from a large, openlabel European registry. J Headache Pain 2018;19.
- Martinez JM GP, Dodick DW, Bardos JN, et al. Study CGAL: a placebo-controlled study of galcanezumab in patients with episodic cluster headache: results from the 8-week doubleblind treatment phase. Cephalalgia 2018;38(1 suppl):145–6.