Cluster Headache

Synonyms: Migrainous Neuralgia; Histamine headache; "Alarm Clock Headache"; Ciliary neuralgia; hemicrania neuralgiformis chronica; Horton's headache; petrosal neuralgia; erythroprosopalgia of Bing; suicide headache.

Recognised over 100 years ago, this condition is different from migraine both clinically, aetiologically and genetically. It is a disorder producing extreme, strictly unilateral pain localised in or around the eye and accompanied by ipsilateral autonomic features. More awareness of the condition has reduced the time to diagnosis¹ and better understanding of the pathophysiology along with improvements in treatment should improve help for sufferers of this excruciating pain syndrome. It is quite rare, often misdiagnosed and frequently poorly managed.² Cluster headache sufferers deserve more attention as the pain is often described as one of the most painful conditions known to mankind with female patients describing the pain of attacks as worse than childbirth.³

• The prevalence has been variously estimated to be from 56 to 69 per 100,000 up to 279 per 100,000⁴
• The incidence quoted in a recent study from the Mayo Clinic suggests a figure of 2.07/100,000 person-years in 1989-1990, curiously less than earlier age- and sex-adjusted data from 10 years previously⁵
• This suggests between 1 and 5 sufferers per GP and between 34,000 and 150,000 sufferers in the U.K.
• Prevalence in men is 3 to 4 times higher
• It usually begins between the ages of 20 and 40 years but can start at any age

It is still not known why some individuals suffer from cluster headaches or why they exhibit the characteristic periodicity. However, progress is being made and a number of theories are plausible and may help progress with new treatments. Briefly:

• Recent studies have shown that genetic factors may after all be important.⁶ First degree relatives of cluster headache patients are more likely to have cluster headache than the general population. About 1 in 20 sufferers has another family member who also has cluster headache (with an autosomal dominant inheritance pattern). A significant association between the HCRTR2 gene and the disease has been reported.⁶
• Positron emission tomography during cluster attacks has revealed that the ipsilateral hypothalamic grey matter is the area most activated.⁷ Goadsby has proposed that cluster headache be regarded as a neurovascular headache to emphasise the hypothalamic dysfunction associated with vascular changes.⁸ It is thought that hypothalamic dysfunction causes dilatation of cranial vessels mediated by trigeminoparasympathetic reflexes.⁹
• Recently altered melatonin levels in cluster headache have been found. This finding suggests a mechanism for cluster headache periodicity and some useful therapeutic interventions.^10,11 A double-blind placebo-controlled trial shows melatonin is effective in cluster headache prevention and case reports indicate this may be helpful in chronic and episodic cluster headache.¹²
• It is possible that biological oscillators or synchronizers, postulated to lie within the hypothalamus mediate seasonal changes seen in animals which are linked to photoperiodic changes. Although speculative, these theories offer interesting explanations of the periodicity of cluster headache and suggest further novel therapeutic options. It has been suggested that the relationship of melatonin to the light/dark cycle make light therapy a possible therapeutic option.¹³

An accurate description of the clinical features is essential to diagnosis.
It is important to distinguish between cluster attacks (individual episodes of pain) and cluster bouts (the time over which recurrent attacks occur). It is also important to distinguish between episodic cluster headache and chronic cluster headache. Cluster headaches have the following features:

• The pain comes on rapidly (without aura) over about 10 minutes. The pain maintains an intensity, is excruciating, sharp, and penetrating (not pulsatile as with migraine). It typically lasts from 45 to 90 minutes (range 15 minutes to 3 hours). Attacks of pain occur once or twice daily (occasionally more often, even up to 8 times daily) typically at night 1-2 hours after falling asleep ('alarm clock headache').
• The pain is centred around or behind the eye, temple or forehead, though neck and other parts of the head can be involved.
• Pain is unilateral and mostly stays on the affected side with each attack.
• The circadian pattern is accompanied in 85% of patients (episodic cluster headache) with remissions of 1 to 4 years. About 10-15% of patients suffer chronically with no remission (chronic cluster headache). Often the interval between bouts is the same and there is a tendency for the interval to lengthen with age. Unfortunately in 10 % of episodic sufferers chronic cluster headache develops (about a third of chronic sufferers become episodic).
• Pain is accompanied by ipsilateral lacrimation, rhinorrhoea, nasal congestion, eyelid swelling, facial sweating or flushing and conjunctival injection. A partial Horner's syndrome with miosis and ptosis may occasionally occur ipsilaterally.
• Nausea may accompany the pain, but is much less of a feature than with migraine.
• Sufferers, unlike with migraine, cannot keep still and are described typically as restless. Patients pace around, occasionally banging their heads on walls and furniture.
• Alcohol is a potent precipitant of attacks (It has been found that cluster headache sufferers are protected from hazardous drinking)¹⁴ although in episodic cluster headache normal alcohol consumption can be resumed once the cluster period is over. Histamine and nitroglycerine are also provokers of attacks in chronic cluster headache and during cluster periods in episodic cluster headache. For some patients heat, exercise and solvents can precipitate attacks. Disruption to sleep patterns (for example by shift work, jet lag etc) can also exacerbate or trigger cluster headaches.
• The autonomic features are usually transient lasting only during the attack and there are usually no clinical signs.

The diagnosis is made from the history. The International Headache Society (IHS) guidelines¹⁵ suggest the following diagnostic criteria:

1. At least 5 attacks fulfilling b to d below
2. Severe or very severe unilateral orbital, supraorbital and/or temporal pain lasting 15 to 180 minutes if untreated
3. Headache accompanied by at least one of: ipsilateral conjunctival injection and/or lacrimation;ipsilateral nasal congestion and/or rhinorrhoea; ipsilateral eyelid oedema; ipsilateral forehead and facial sweating; ipsilateral miosis and/or ptosis; a sense of restlessness or agitation
4. Attacks occur from once to 8 times daily, and
5. Not attributable to another disorder

Episodic cluster headache

These are cluster headaches occurring in periods lasting from 7 days to 1 year separated by pain-free periods lasting a month or longer. Cluster periods usually last between 2 weeks and 3 months.

Chronic cluster headache

These are defined as cluster headaches occurring for 1 year without remissions or with shortlived remissions of less than a month. Chronic cluster headache may arise de novo or develop from episodic cluster headache.

This could include a longer list of causes of headache but those most similar to cluster headache in the IHS guidelines¹⁵ are:

• Paroxysmal hemicrania
• Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT)
• Probable diagnoses (of cluster headache, SUNCT and paroxysmal hemicrania) where insufficient attacks have occurred or diagnostic criteria are not fulfilled

History and neurological examination only are required to make the diagnosis usually.
As with any primary headache some patients may need imaging and the red flags of headache indicating the need to search for a secondary cause are:¹⁶

• Change in pattern of headache
• New headache at age over 50
• Onset of seizures
• Headache with systemic illness
• Personality change
• Symptoms suggestive of raised intracranial pressure (morning headache, headache with coughing, sneezing,straining)
• Acute onset of worst headache ever (possible intracranial aneurysm)

It should be remembered that:

• Some patients are likely to have found medical interventions unhelpful or difficult to tolerate
• They may not have had the benefit of up to date review of treatment
• They may be depressed or despondent about the condition
• Whether episodic or chronic it is generally a lifelong condition

It is therefore important to:

• Establish rapport with the patient based on knowledge and understanding of the condition generally and the patients particular experience
• Anticipate that polypharmacy is likely to be required
• Be prepared to follow up closely to monitor efficacy of treatments, side effects etc.
• Consider drawing up a programme of measures perhaps with a patient held record book or diary

General advice

• Be prepared for attacks. Patients should be encouraged to have both acute and preventive treatments available. This may involve completion of Home Oxygen Order Forms (HOOF) if oxygen is to be used.
• Stop smoking as this can increase the risk of chronic cluster headache developing
• Abstain from alcohol during periods of cluster headache and in chronic cluster headache
• Maintain regular sleep routine and good sleep hygiene (avoiding tea, coffee etc.)

Acute attack

Sumatriptan (by subcutaneous injection) and oxygen are likely to be the mainstay of treatment for most patients:

• Sumitriptan 6mg s/c is effective.¹⁷ The best evidence for benefit is from sumatriptan subcutaneously.¹⁸However for regular attacks over several weeks there is a danger of overdosage. Other acute therapies like oxygen should be used in addition to preventive measures.
• Sumatriptan nasal spray works less well for most patients
• Oxygen - 100% oxygen given for 15 mins up to 5 times per day is safe and effective in 80% of cases. It is given by a tight fitting mask (not a standard mask or nasal cannulae) at 8-10 l/min. It is particularly useful for night attacks. Most convenient form is 460 litre CD Oxygen cylinder (lasts about 40 minutes at high flow rates) with concentration venturis. HOOF forms will need to be completed for oxygen supply. Useful guidance for patients is available on the OUCH (UK) website.²

Other possible treatments for acute attacks include:

• Ergotamine is of limited use in view of its poor oral absorption and side effect profile. Before the advent of sumatriptan it was used more often.¹⁹
• Anti-inflammatories such as indomethacin can be used
• Metoclopramide may be useful as an adjunct to acute treatments
• Lidocaine 1ml of 4% lidocaine can be given intranasally to the affected side

Prophylaxis

• Prednisolone High dose steroids in a short course (30 to 60mg) can be effective at the onset of a cluster. It is important that it is taken in the morning to minimize sleep disturbance. Prednisolone suppresses attacks and can buy time whilst acute treatments are organised and other preventive treatments which are slower to become effective (like verapamil) are started.^20,21 This is sometimes called transitional prophylaxis.
• Verapamil has gained favour in recent years.²¹ It is started at doses of 40mg twice daily, building up to as much as 960mg daily. Side effects may limit use in some. ECG monitoring is required at doses over 120mg daily and requires fortnightly ECG monitoring with successive dose increases (because of the risk of dysrhythmias).

Other possible prophylactic treatments include:

• Melatonin is a safe and promising addition to the list of prophylactic agents for nocturnal attacks.¹² It is taken at night at doses of 7.5-10 mg but with currently available formulations administration has to be timed to 1/2 hr before the anticipated attack (difficult). Slow release preparations may be more effective, but this is speculative until more evidence is forthcoming.
• Topiramate may be useful but only under specialist supervision and only in chronic cluster headache.
• Sodium valproate has also been used for prophylaxis usually in chronic cluster headache.²¹
• Ergotamine can be used 2 hours prior to a predicted attack. 2mg orally or 1mg rectally. Addiction is rare.
• Methysergide Up to 6mg in divided doses can be used (more if under specialist care) and is most useful in the episodic form (used for less than 6 months at a time). There is a risk of retroperitoneal fibrosis if used for several weeks.
• Lithium is useful in the chronic form of Cluster Headaches.
• Calcium Channel Blockers Verapamil and Nifedipine can also be useful in the chronic form.
• Deep brain stimulation for intractable chronic cluster headache seems to be effective in limited reports with complete relief and apparently few side effects.^22,23 The ipsilateral posterior hypothalamus is targeted for electrical stimulation.
• Surgery Occipital nerve blockade gives temporary relief if medical therapy is not helping.²⁴

More invasive procedures are used as a last resort. These involve chemical or physical ablation to parts of the trigeminal nerve. These can be effective and are likely to be reserved for chronic cluster headache.

Alternative therapies such as acupuncture have anecdotally been very helpful to some patients. Unfortunately the evidence of benefit is poor and better trials are needed.²⁵

Referral guidance

Referral should be to a neurologist interested and expert in this condition. Indications include:

• Diagnostic uncertainty
• Imaging or further investigation
• Failure of treatment
• For new or invasive treatments

• Identify and review cluster headache patients (there will not be many!)
• How well managed are their cluster headaches? Identify ways in which management might be improved with new or different treatments, by referral, by changes in lifestyle.
• Take an interest and encourage regular review
• Encourage patients to be better informed by, for example, joining OUCH(UK)