INFORMATION ON CLUSTER HEADACHE AND OTHER HEADACHE DISORDERS. Organisation for the Understanding of Cluster Headaches (OUCH ) October 2008 Background

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1 INFORMATION ON CLUSTER HEADACHE AND OTHER HEADACHE DISORDERS Organisation for the Understanding of Cluster Headaches (OUCH ) October 2008 Background Cluster headaches (CH) are part of a group of 'primary' headaches named Trigeminal Autonomic Cephalgias (TACs). There are two other types of TAC, namely Paroxysmal Hermicrania (PH) and SUNCT Syndrome. Primary headaches are defined as those where the headache is the condition itself, as opposed to 'secondary' headaches, which are caused by external factors, such as accidents or infection. All three types of TAC can be identified by the fact that severe pain focuses on one side of the head (often including the face and eye), together with other symptoms occurring on the same side as the pain. These are called 'cranial autonomic' symptoms or features. These are called 'autonomic' because they are involuntary or automatic responses not caused by any conscious effort or external forces. These include reddening and tearing of the eye, a runny or blocked nostril, droopy eyelid, constriction of the pupil, flushing and facial sweating. If none of these autonomic features occur at the same time as the headache, then they are more likely to be other types of 'short-lasting headaches' of which there are five main types. All three TACS are defined as short lasting. However, defining 'short lasting' headaches is difficult but as a guideline, the period of pain for most TACs is less than four hours compared with migraine headaches, which tend to last for more than four hours. The key feature of TACs is the severity of pain involved, and unlike other severe headaches, there is often a sense of restlessness or agitation during the period of pain, whereby the sufferer finds it almost impossible to keep still. It is extremely important to differentiate between the three TACs because the treatment of each type is very different. All three are relatively rare, when compared to migraine for example, which is one of the reasons why GPs fail to diagnose these syndromes. The importance of recognising and differentiating these conditions is emphasised by their often excellent response to different types of treatment. What is Cluster Headache? Cluster headache (CH) always involves pain that is one sided (although it can switch sides) and the main defining feature is the association with one or more of the 'autonomic' features normally described as follows: Reddening and tearing of the eye A runny or blocked nostril Droopy eyelid Constriction of the pupil Flushing and facial sweating Although possible, it is very unusual for any of these not to occur in cluster headache. These features tend to come and go with each attack, however, some sufferers may continue to experience the constricted pupil and/or a droopy eyelid, especially after frequent attacks.

2 In most sufferers the headaches often start at the same time of year and at the same time during the day or night. The pain involved is excruciating and is probably one of the most painful conditions known to humans. Female sufferers have described each attack as being more painful than childbirth. As few as 0.2% (two in a thousand) of the population suffer from CH, approximately the same number as for multiple sclerosis in the UK. Men are more likely to suffer than women, with an estimated male to female ratio of between 5:1 and 7:1, although this ratio appears to be steadily declining. CH can begin at any age, but most sufferers are more likely to start suffering in their 30s or 40s. It is extremely useful for everyone involved to understand the three standard terms used in CH: the cluster headache (or attack), the cluster bout (or period) and the period of remission. A cluster attack is an individual episode of pain that can last from a few minutes to some hours. A cluster bout refers to the time period where a number of attacks re-occur, usually lasting some weeks or months. A remission is the pain-free period between two cluster bouts. Cluster Bout There are two types of cluster headache, which are classified according to the duration of the cluster bout: Episodic Cluster Headache (ECH) and Chronic Cluster Headache (CCH). 1. Episodic Cluster Headache (ECH) Approximately eight out of ten sufferers of cluster headache have ECH, which is diagnosed when they have a series of bouts, each one lasting more than a week and separated by pain-free remission lasting more than two weeks. Most ECH sufferers have one or two cluster bouts per year, each lasting between 1-3 months. Often, these bouts tend to start during the same month(s) of the year. Although the duration of the cluster bout and the period of remission vary between individuals, these periods tend to remain relatively consistent within the same individual. 2. Chronic Cluster Headache (CCH) The remaining 20% of CH sufferers have CCH, whereby no pain-free remission occurs within one year, or the remission periods last less than four weeks. There is only a small amount of literature available regarding the long-term outcome of CH, but all the available evidence suggests that it is a lifelong disorder amongst the majority of sufferers. In one study, about one in ten ECH sufferers became CCH sufferers whereas a third of CCH sufferers became ECH sufferers. A very encouraging piece of information for CH sufferers is that many of them can expect to develop longer periods of remission as they get older. Causes There is, as yet, no known cause for cluster headache. However, cluster headache has two major clinical features: the trigeminal (nerve) distribution of pain and the associated ipsilateral (same-sided) autonomic symptoms. Firstly, the pain producing innervation (stimulation) of the cranium projects through branches of the trigeminal and upper cervical nerves to the trigeminocervical complex from where nociceptive pathways project to higher centres. Secondly, the accompanying ipsilateral (same-sided) autonomic symptoms suggest cranial parasympathetic activation (that's the teary eye, runny and blocked nose) and sympathetic hypofunction (the droopy eye and constriction of the pupil).

3 However, the third and possibly most important clinical feature is the uncanny timing of both attacks and bouts themselves, which originally suggested an involvement in the brain's master-clock: the hypothalamus or more particularly the suprachiasmatic nucleus (SCN). It is now thought that an abnormality within the hypothalamus is the root cause of the pain, which, when in cycle, releases hormones and chemicals that innervate the trigeminal ganglion, in turn causing the domino effect of pain and cranial autonomic symptoms through the trigeminal nerve down one side of the face and head (and sometimes the neck). This theory is backed up by the regularity of attacks (circannual [time of year] and circadian [time of day]), much lower levels of plasma testosterone (in males) during attacks and bouts, and alterations in the natural production of a variety of hormones/chemicals that affect the biologic clock. Furthermore, PET (positron emission tomography) studies conducted on the brains' of CH sufferers in the late 1990s demonstrated that there is also ipsilateral (same-sided) hypothalamic activation within the brain: there are direct hypothalamic-trigeminal connections and the hypothalamus is known to have a modulatory role on the nociceptive and autonomic pathways. In summary these studies showed an increase in functional activity of the hypothalamus amongst CH sufferers which is not seen in migraine, and is the prime reason why CH is thought to be caused by an abnormality within the hypothalamus. These abnormalities were seen both when sufferers were undergoing an attack and also whilst pain free and were interpreted as an excessive growth of grey cells within the hypothalamus, or more possibly, within the SCN. There is also evidence that genetic factors may play an important role in CH, and although the type and number of genes involved is unclear, one recent study focussed upon orexin (or hypocretin), a neuropeptide used by the hypothalamus for signalling. Diagnosis On the face of it, the symptoms, as described, make it sound like it's relatively easy to diagnose CH as a syndrome. However, this is often very difficult because other types of headache can mimic the symptoms and features of CH. Apart from the other TACs as mentioned, the main alternative options that are considered include 'secondary' causes of CH, migraine and hypnic headache. 1. Secondary causes of CH Before CH is definitively diagnosed, it is usual to attempt to exclude any possible secondary or external causes. Symptoms of CH can also be caused through abnormalities caused by disease or injury. Any such circumstances reported by the sufferer, with the exception of sinking in of the eyeball, drooping of the eyelid or pupil constriction (known as partial Horner's Syndrome) warrants further investigation by the neurologist to search for potential organic causes. 2. Migraine One-sided headaches, migraine symptoms and autonomic features can occur in both migraine and CH, and therefore, differentiating between the two can be difficult in some cases. The most useful features for differentiating CH from migraine include: - Short-lasting headaches Abrupt start and finish Occurring at regular times during the day Triggered within an hour of drinking alcohol Restlessness during an attack Clustering of attacks broken by periods of pain-free remission (in ECH)

4 3. Hypnic Headache Hypnic headache differs in that it is more likely to occur amongst much older people and females. Sufferers of hypnic headache are often awakened from sleep by headaches that frequently occur on both sides of the head but may also be one sided. These are also not usually associated with autonomic features. The headaches are brief - lasting between 5 minutes and 3 hours - and can occur up to three times per night. These can be effectively treated by bedtime dosages of lithium, indomethacin or caffeine. The diagnosis of CH is based purely on assessing the history of the sufferer and a detailed neurological examination. Because of the difficulty in differentiating other types of headache, a magnetic resonance image (MRI) scan of the brain is a very good screening investigation. Treatments Overview The treatment of CH includes offering advice on general measures to sufferers; actually stopping individual attacks; helping to stop the attacks happening in the first place; and very rarely, brain surgery. Sufferers should avoid drinking any alcohol during cluster bouts. Otherwise, other food and drink don't seem to affect CH whatsoever. Although yet to be clinically proven, it is also suggested that sufferers should avoid being exposed to volatile substances such as solvents and oil based paints. Sufferers should also avoid afternoon naps, as sleeping can be a trigger amongst some sufferers. There are currently three main types of prescriptive medication available for CH sufferers: Abortive medication Short Term Preventatives Long Term Preventatives Abortive Treatments Drugs used to help stop individual attacks are called abortive agents or acute treatments. The pain of CH builds up so quickly and to such an excruciating peak that most drugs that are designed to be 'swallowed' do not work quickly enough. The most effective abortive agents are those that are either administered through the lungs or nose, or by means of injection: either beneath the skin, through the muscle, or into a vein. Triptans Oxygen Lignocaine Ergotamine Analgesics Others Triptans The most successful abortive treatment of a cluster attack is a self-administered injection, just beneath the skin, of a drug called sumatriptan (Imigran/Imitrex). It tends to work very quickly amongst a high proportion of sufferers. In CH, unlike in migraine, injecting sumatriptan beneath the skin can be done twice a day, amongst most sufferers, without the risk of the pain reoccurring after the drug has worn off (a rebound headache).

5 However, sumatriptan is relatively expensive, and accordingly, many GPs and neurologists are sometimes reluctant to prescribe sufferers with this drug. It is generally felt that given the extreme nature of CH, and the excruciating pain involved, that it is unethical for this drug not to be used because of its high cost. Sumatriptan can also be inhaled through the nose using a nasal spray, but it is much less effective than injecting beneath the skin. There is no definitive evidence that sumatriptan works for CH in tablet form. 100mg tablets taken three times daily do not prevent an attack and should not therefore be used as a preventative measure. Zolmitriptan taken in 5mg tablet form does help the pain in some sufferers of ECH but not in CCH. However, the effectiveness is modest and isn't as effective or as fast acting as oxygen therapy (see below) or sumatriptan injected beneath the skin. Oxygen Breathing in pure oxygen at a rate of between 7 to 15 litres per minute is relatively fast acting in providing pain relief amongst most sufferers. It should be inhaled continuously for minutes using a non-breathing mask i.e. one without holes. Sufferers of CH should use the high flow rate regulator, which now come integral to all oxygen cylinders supplied for home use in the England and Wales for CH. The low rate regulator (2-4 litres per minute) is generally unhelpful. In Scotland, sufferers of CH should use a bespoke high flow rate regulator, which unfortunately is not available on the NHS in most areas and therefore is not usually an option for sufferers who can't afford it (although a loan regulator is still available through OUCH (UK). Lignocaine Lignocaine in liquid form can be given as either nose drops or nasal spray, deep in the nostril on the painful side. This can bring mild to moderate relief in some sufferers though only a few experience complete pain relief. This drug, therefore, is very rarely useful on its own but can be helpful when taken with other preventative and abortive drugs. Ergotamine Ergotamine used as suppositories or in tablet form is generally too slow acting to provide any meaningful pain relief. Analgesics Analgesics are drugs that are used to relieve pain in normal circumstances. These include opiates - derived from the opium poppy, such as morphine etc. - and other non-steroidal anti-inflammatory drugs such as aspirin, ibuprofen, and indomethacin. None of these are effective as an abortive drug in CH attacks. Preventative Treatments Drugs used to help prevent CH occurring in the first place are called prophylactics or preventative treatments. The aim of preventative treatment is to attempt to reduce the number of attacks with minimal side effects until the cluster bout is over in ECH, or for a longer period in CCH. There are two types of preventative treatments: - 1. Short term preventatives - designed for quickly controlling the attack frequency but not suitable for long term use. 2. Long term preventatives - designed for long term management of CH.

6 SHORT TERM PREVENTION Short term prevention tends to be better amongst sufferers who have either short bouts (perhaps in weeks rather than months) or for sufferers where it is necessary to quickly control the frequency of attacks. These drugs cannot be used in the long term because of the potential side effects. Steroids The most effective and fast acting steroids are called corticosteroids. However, careful monitoring of the sufferer is necessary because of the potential for serious side effects. Treatments are normally limited to between 2-3 weeks whereby the amount of drug taken over this period is reduced over time. The tablets, called prednisolone (1mg per kg), are prescribed starting at a maximum dosage of 60mg once a day for five days, and from then on, a decreased dosage (by 10mg) every three days. Unfortunately, this necessary 'tapering' effect (reducing the dosage) means that in most sufferers the CH returns, and for this reason, steroids are only used as a first-step treatment alongside other preventatives until these become effective. Methysergide Methysergide is very effective preventative treatment amongst CH. It is an ideal choice for sufferers whose bouts last less than 4-5 months and doses of up to 12mg per day can be used if the side effects are tolerated. Sufferers can be started on 1mg once a day and then the dose is increased by a further 1mg after every three days until the dose is 5mg per day. After this, the dose is increased by 1mg every five days. Although rare, prolonged use of this drug can cause side effects including damage to the heart, lungs and kidneys. Although this drug can be used in CCH, it is necessary to keep a close eye on possible side effects and a break from taking the drug (a drug holiday) is recommended every six months. Ergotamine Ergotamine is very useful in the short-term prevention of those attacks that predictably occur at the same time of day and night. It can be prescribed as a tablet or a suppository (1-2mg) and is taken either at bedtime or about an hour before an attack is due. It is rarely suitable for CCH sufferers. It is not recommended that ergotamine is taken at the same time as sumatriptan. LONG TERM PREVENTION Some ECH sufferers (those with particularly long bouts) and CCH sufferers require preventative treatment over many months or even years. The two most favoured long-term drugs are verapamil and lithium. Verapamil Verapamil is currently the most preferred drug amongst sufferers of both ECH and CCH. Medical research has shown that higher doses are needed than for other uses of the drug. Dosages of the drug vary from between 240mg to 960mg per day, normally taken in tablet form three times a day. The strength of the tablet is increased every two weeks until it is effective in stopping cluster attacks or until the maximum dose of 960mg per day is reached. However, verapamil can have side effects including 'heart block' (a block in the conduction of the normal impulses of the heart). It is therefore mandatory that individuals are given an ECG before taking the drug, and then again each time the dose is increased to check for any potential abnormalities.

7 Lithium Lithium is effective as a preventative amongst many sufferers, more so amongst CCH. Kidney and thyroid tests are required prior to prescribing the drug. Sufferers are then started on 300mg tablets twice a day and the amount of the drug in the body is then monitored until it reaches the desired medical concentration in the body as outlined in the BNF (British National Formulary). Many sufferers benefit at levels between mg per day. It is not recommended that lithium is taken at the same time as non-steroidal anti-inflammatory drugs, diuretics or carbamazepine. Other Drugs Other frequently used drugs used for preventative treatment include sodium valproate, pizotifen, topiramate, gabapentin and melatonin. The effectiveness for these, however, is as yet medically unproven. Surgery Current surgical methods are only used amongst sufferers who have tried all of the available preventative and abortive treatments and hence are a last resort measure amongst carefully selected sufferers. Only sufferers whose headaches are exclusively one sided should be considered for surgery because there is a risk that the CH will re-occur on the opposite side following the surgery. There are a number of surgical procedures available though few offer long-term results and the side effects can be devastating. There have, however, been recent reports of less evasive surgical techniques involving electronic surgical implants (ONSI), which are currently being investigated further. Other Headaches Most people experience at least occasional headaches during their lifetime and it is often important for sufferers to know that most recurring headaches are benign, that is, they are not usually dangerous to health, or recurrent or progressive. It is also reassuring to know that very few people with brain tumours have the symptoms of headache alone. Within this section you will find a brief summary of other headache syndromes that are sometimes associated with cluster headache. Migraine Due to the similarity of the underlying symptoms, many cluster headache (CH) sufferers (particularly females) are often misdiagnosed with migraine. Migraine affects up to 12% of the population compared with just 0.2% for CH [see CH diagnosis]. As with CH, migraine can be either episodic or chronic and there are two main types: attacks with and attacks without aura, the former being much less prevalent. When present, the aura relates to accompanying symptoms such as visual, sensory and other disturbances. No single criterion is normally used for the diagnosis of migraine. However, the most common characteristics include unilateral (one-sided) headaches, throbbing, moderate to severe in nature and the pain is generally worsened by moving around or physical activity. Associated symptoms often include sensitivity to light and sound, feeling sick, and actually vomiting. Other factors commonly identified with migraine include onset around menstruation in female sufferers and certain premonitory symptoms, such as food cravings, lethargy and mood changes.

8 Triggers of migraine amongst some sufferers include cheese, chocolate and alcohol (particularly red wine), although unlike CH sufferers, where drinking alcohol can almost immediately trigger an attack, migraine sufferers generally have a headache some hours after a drink. Migraine attacks (as in CH) can also often seem to be related to the cessation of stress. Most sufferers of migraine are able to self medicate with over the counter medication. However, there are a number of prescriptive medications available for both acute and preventative treatment in more severe cases. Non-steroidal anti-inflammatory drugs (NSAIDs) are normally the first choice analgesics and although opiates can be useful, their continued use can lead to a dull background headache. Triptans (selective 5-HT1 agonists), also used in CH, can be a very effective abortive medication, even in tablet form. Migraine prevention can often be successful with beta-blockers or pizotifen; and methysergide, sodium valproate, tricyclic anti-depressants and regular use of NSAIDs can also be effective. A variety of other types of medication have been successful for some sufferers of migraine, including: Calcium channel blockers Anti-epileptics Selective serotonin re-uptake inhibitors (SSRIs) Riboflavin Magnesium As with CH, the diagnosis of migraine is based purely on assessing the history of the sufferer coupled with a detailed neurological examination. Paroxysmal Hemicrania Paroxysmal hemicrania (PH) involves one-sided attacks (headaches) that have closely similar characteristics of pain and associated (autonomic) symptoms of cluster headache (CH). However, they tend to be very much shorter in duration. Each attack normally lasts between minutes, but can be as short as two minutes or as long as 45 minutes. They also tend to occur on average more frequently than CH (five per day or more - and sometimes up to 40 per day) and appear to be more prevalent amongst females. As with both CH and migraine there are two variants of PH: chronic and episodic, defined in exactly the same way as in CH. Like many of the other shorter lasting primary headaches, PH responds almost absolutely to a medication called indomethacin (a non-steroidal anti-inflammatory drug), and it is noteworthy that this course of action is often used as a screening investigation to rule out CH amongst some sufferers. As with CH, the diagnosis of paroxysmal hemicrania is based purely on assessing the history of the sufferer coupled with a detailed neurological examination. SUNCT Syndrome Short lasting unilateral neuralgiform headache attacks with conjuntival injection and tearing (SUNCT) also manifests itself as a one-sided headache and is associated with the autonomic symptoms as described in cluster headache (CH). It can be distinguished from other closely similar primary headaches because of the usually very brief attack duration ( seconds) which can occur very frequently (up to 30 per hour), and the presence of extremely prominent tearing and redness of the eye on the same side as the pain. Until recently, SUNCT was thought to be very difficult to treat, but partial improvement with carbamazepine has been observed in several sufferers. More recently, a drug called lamotrigine has been reported to be effective amongst a small number of sufferers, and gabapentin and topiramate are thought to be reasonable second line agents in sufferers who fail to respond to this. Several surgical techniques may also be considered.

9 Hypnic Headache Hypnic headache involves attacks of a dull headache that always awakens sufferers from sleep. Unlike cluster headache (CH) there are normally no associated autonomic symptoms. Although the pain is normally classified as mild to moderate, severe pain can exist amongst up to 20% of sufferers and the headache is bi-lateral (both sides) in up to two thirds of cases. Hypnic headache also differs from CH in that it is more likely to occur amongst much older people and females. The headaches are brief - lasting between 5 minutes and 3 hours - and can occur up to three times per night. These can generally be effectively treated by bedtime dosages of lithium, indomethacin or caffeine. Trigeminal Neuralgia (TN) Trigeminal neuralgia (TN) was first described in medical literature in the late 18th century and is still often referred to as Tic Douloureux. Unlike cluster headache (CH) and the other short lasting primary headaches, it is classified as a secondary headache due to a disorder of the 5th and largest cranial nerve (the trigeminal) and it manifests itself as very short episodes of intense, electric-shock like pain in the eyes, nose, scalp, forehead, jaws, and even the lips. As with CH, the pain is most likely to be one-sided, but some sufferers experience the pain at different times on both sides. TN can begin at any age but sufferers are most likely to start suffering in their 50s. Unlike CH, however, TN attacks can be physically triggered by touch, and hence normal routines such as teeth brushing, applying make-up or even a slight breeze can trigger an attack. A less common form of the disorder is called atypical trigeminal neuralgia which is less intense, but causes constant, dull, boring or aching pain, sometimes accompanied with the electric-shock like stabs of pain. TN can normally be successfully treated with medications called anticonvulsants; namely carbamazapine, dilantin, carbatrol or trileptal. Intractable chronic cases of the condition often require surgery. Primary Stabbing Headache Primary stabbing headache (also previously known as idiopathic stabbing headache, ice-pick headache, jabs and jolts, ophthalmodynia periodica) manifests itself in very brief, sharp or jabbing pain in the head (not usually the face), either as a single stab or a series of brief repeated volleys of pain. The pain itself generally lasts a fraction of a second but can last for up to one minute in some sufferers, and may move from one area to another in either the same or opposite side of the head. The cranial autonomic symptoms associated with cluster headache and other trigeminal autonomic cephalgias are normally absent in primary stabbing headache. As with other shorter lasting primary headaches, primary stabbing headache tends to respond well to a medication called indomethacin (a non-steroidal anti-inflammatory drug). Other Headaches The most common of all headache types, affecting up to three quarters of all people at some stage is the tension-type headache. Other primary headaches include: New daily persistent headache (NDPH) Hemicrania Continua Primary cough headache Primary exertional headache Primary thuderclap headache Primary headache associated with sexual activity Medication overuse/rebound headache

10 Information and Support There are a number of sources of information, support and help lines. These include: Tel: Tel: There is a Migraine and Severe Headache Self help group for Cheshire and Merseyside, which meets every three months at the Neurosupport Centre, Liverpool. For further information please contact: Patient Advice and Liaison Service (PALS) on or Pal.Service@thewaltoncentre.nhs.uk or Information Officer, The Mersey Neurological Trust on If you require this information in other formats or languages, please speak to a member of staff for details Produced by: Dr Nicholas Silver, October 2008 Version: 2 Review Date: March 2010 The Walton Centre for Neurology & Neurosurgery NHS Trust. All rights reserved. No reproduction by or for commercial organisations is allowed without the express written permission of The Walton Centre.