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Cluster headache

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Cluster headacheis aneurological disordercharacterized by recurrent severeheadacheson one side of the head, typically around theeye(s).[1]There is often accompanying eye watering,nasal congestion,or swelling around theeyeon the affected side.[1]These symptoms typically last 15 minutes to 3 hours.[2]Attacks often occur in clusters which typically last for weeks or months and occasionally more than a year.[2]

Cluster headache
Trigeminal nerve
SpecialtyNeurology
SymptomsRecurrent, severeheadacheson one side of the head, eye watering, stuffy nose[1]
Usual onset20 to 40 years old[2]
Duration15 minutes to 3 hours[2]
TypesEpisodic, chronic[2]
CausesUnknown[2]
Risk factorsTobacco smoke,family history[2]
Diagnostic methodBased on symptoms[2]
Differential diagnosisMigraine,trigeminal neuralgia,[2]othertrigeminal autonomic cephalgias[3]
PreventionVerapamil,galcanezumab,oralglucocorticoids,steroid injections,civamide[4]
TreatmentOxygen therapy,triptans[2][4]
Frequency~0.1% at some point in time[5]

The cause is unknown,[2]but is most likely related to dysfunction of the posteriorhypothalamus.[6]Risk factors include a history of exposure totobacco smokeand afamily historyof the condition.[2]Exposures which may trigger attacks includealcohol,nitroglycerin,andhistamine.[2]They are aprimary headache disorderof thetrigeminal autonomic cephalalgiastype.[2]Diagnosis is based on symptoms.[2]

Recommended management includeslifestyleadaptations such as avoiding potential triggers.[2]Treatments for acute attacks includeoxygenor a fast-actingtriptan.[2][4]Measures recommended to decrease the frequency of attacks includesteroid injections,galcanezumab,civamide,verapamil,or oralglucocorticoidssuch asprednisone.[6][4][7]Nerve stimulationor surgery may occasionally be used if other measures are not effective.[2][6]

The condition affects about 0.1% of the general population at some point in their life and 0.05% in any given year.[5]The condition usually first occurs between 20 and 40 years of age.[2]Men are affected about four times more often than women.[5]Cluster headaches are named for the occurrence of groups of headache attacks (clusters).[1]They have also been referred to as "suicide headaches".[2]

Signs and symptoms

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Cluster headaches are recurring bouts of severe unilateral headache attacks.[8][9]The duration of a typical cluster headache ranges from about 15 to 180 minutes.[2]About 75% of untreated attacks last less than 60 minutes.[10]However, women may have longer and more severe cluster headaches.[11]

The onset of an attack is rapid and typically without anaura.Preliminary sensations of pain in the general area of attack, referred to as "shadows", may signal an imminent cluster headache, or these symptoms may linger after an attack has passed, or between attacks.[12]Though cluster headaches are strictly unilateral, there are some documented cases of "side-shift" between cluster periods,[13]or, rarely, simultaneous (within the same cluster period) bilateral cluster headaches.[14]

Pain

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The pain occurs only on one side of the head, around the eye, particularly behind or above the eye, in the temple. The pain is typically greater than in other headache conditions, includingmigraines,and is usually described as burning, stabbing, drilling or squeezing.[15]While suicide is rare, those with cluster headaches may experience suicidal thoughts (giving the alternative name "suicide headache" or "suicidal headache" ).[16][17]The disease is considered among the most painful conditions known to medical science.[18][19]

Dr. Peter Goadsby,Professor of Clinical Neurology at University College London, a leading researcher on the condition has commented:

"Cluster headache is probably the worst pain that humans experience. I know that's quite a strong remark to make, but if you ask a cluster headache patient if they've had a worse experience, they'll universally say they haven't. Women with cluster headache will tell you that an attack is worse than giving birth. So you can imagine that these people give birth without anesthetic once or twice a day, for six, eight, or ten weeks at a time, and then have a break. It's just awful."[20]

Other symptoms

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The typical symptoms of cluster headache include grouped occurrence and recurrence (cluster) of headache attack, severe unilateral orbital, supraorbital and/or temporal pain. If left untreated, attack frequency may range from one attack every two days to eight attacks per day.[2][21]Cluster headache attack is accompanied by at least one of the following autonomic symptoms:drooping eyelid,pupil constriction,redness of theconjunctiva,tearing,runny noseand less commonly,facial blushing,swelling, or sweating, typically appearing on the same side of the head as the pain.[21]Similar to a migraine, sensitivity to light (photophobia) or noise (phonophobia) may occur during a cluster headache. Nausea is a rare symptom although it has been reported.[8]

Restlessness (for example, pacing or rocking back and forth) may occur. Secondary effects may include the inability to organize thoughts and plans, physical exhaustion, confusion, agitation, aggressiveness, depression, and anxiety.[16]

People with cluster headaches may dread facing another headache and adjust their physical or social activities around a possible future occurrence. Likewise they may seek assistance to accomplish what would otherwise be normal tasks. They may hesitate to make plans because of the regularity, or conversely, theunpredictabilityof the pain schedule. These factors can lead to generalizedanxiety disorders,panic disorder,[16]seriousdepressive disorders,[22]social withdrawal and isolation.[23]

Cluster headaches have been recently associated with obstructivesleep apneacomorbidity.[24]

Recurrence

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Cluster headaches may occasionally be referred to as "alarm clock headache" because of the regularity of their recurrence. Cluster headaches often awaken individuals from sleep. Both individual attacks and the cluster grouping can have a metronomic regularity; attacks typically striking at a precise time of day each morning or night. The recurrence of headache cluster grouping may occur more often aroundsolstices,or seasonal changes, sometimes showing circannual periodicity. Conversely, attack frequency may be highly unpredictable, showing no periodicity at all. These observations have prompted researchers to speculate an involvement or dysfunction of the hypothalamus. The hypothalamus controls the body's "biological clock" andcircadian rhythm.[25][26]In episodic cluster headache, attacks occur once or more daily, often at the same time each day for a period of several weeks, followed by a headache-free period lasting weeks, months, or years. Approximately 10–15% of cluster headaches arechronic,with multiple headaches occurring every day for years, sometimes without any remission.[27]

In accordance with the International Headache Society (IHS) diagnostic criteria, cluster headaches occurring in two or more cluster periods, lasting from 7 to 365 days with a pain-freeremissionof one month or longer between the headache attacks may be classified as episodic. If headache attacks occur for more than a year without pain-free remission of at least three months, the condition is classified as chronic.[21] Chronic cluster headaches both occur and recur without any remission periods between cycles; there may be variation in cycles, meaning the frequency and severity of attacks may change without predictability for a period of time. The frequency, severity, and duration of headache attacks experienced by people during these cycles varies between individuals and does not demonstrate complete remission of the episodic form. The condition may change unpredictably from chronic to episodic and from episodic to chronic.[28]

Causes

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Positron emission tomography(PET) shows brain areas being activated during pain.
Voxel-based morphometryshows brain area structural differences.

The specific causes and pathogenesis of cluster headaches are not fully understood.[6]The Third Edition of the International Classification of Headache disorders classifies cluster headaches as belonging to thetrigeminal autonomic cephalalgias.[29]

Some experts consider the posteriorhypothalamusto be important in the pathogenesis of cluster headaches. This is supported by a relatively high success ratio ofdeep-brain stimulation therapyon the posterior hypothalamicgrey matter.[6]

Nerves

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Therapies acting on thevagus nerve(cranial nerveX) and thegreater occipital nervehave both shown efficacy in managing cluster headache, but the specific roles of these nerves are not well-understood.[6]Two nerves thought to play an important role in cluster headaches include the trigeminal nerve and thefacial nerve.[30]

Genetics

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Cluster headache may run in some families in anautosomal dominantinheritance pattern.[31][32]People with afirst degree relativewith the condition are about 14–48 times more likely to develop it themselves,[1]and around 8 to 10% of persons with cluster headaches have a family history.[31][33]Several studies have found a higher number of relatives affected among females.[33]Others have suggested these observations may be due to lower numbers of females in these studies.[33]Possible genetic factors warrant further research, current evidence for genetic inheritance is limited.[32]

Genes that are thought to play a role in the disease are the hypocretin/orexin receptor type 2 (HCRTR2), alcohol dehydrogenase 4(ADH4), G protein beta 3 (GNB3), pituitary adenylate cyclase-activating polypeptide type I receptor (ADCYAP1R1), and membrane metalloendopeptidase (MME) genes.[31]

Tobacco smoking

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About 65% of persons with cluster headache are, or have been, tobacco smokers.[1]Stopping smoking does not lead to improvement of the condition, and cluster headaches also occur in those who have never smoked (e.g., children);[1]it is thought unlikely that smoking is a cause.[1]People with cluster headaches may be predisposed to certain traits, including smoking or other lifestyle habits.[34]

Hypothalamus

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A review suggests that thesuprachiasmatic nucleusof thehypothalamus,which is the major biological clock in the human body, may be involved in cluster headaches, because cluster headaches occur with diurnal and seasonal rhythmicity.[35]

Positron emission tomography(PET) scans indicate the brain areas which are activated during attack only, compared to pain free periods. These pictures show brain areas that are active during pain in yellow/orange color (called "pain matrix" ). The area in the center (in all three views) is activated only during cluster headaches. The bottom rowvoxel-based morphometryshows structural brain differences between individuals with and without CH; only a portion of thehypothalamusis different.[36]

Diagnosis

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Cluster-like head pain may be diagnosed as secondary headache rather than cluster headache.[21]

A detailed oral history aids practitioners in correct differential diagnosis, as there are no confirmatory tests for cluster headache. A headache diary can be useful in tracking when and where pain occurs, how severe it is, and how long the pain lasts. A record of coping strategies used may help distinguish between headache type; data on frequency, severity and duration of headache attacks are a necessary tool for initial and correct differential diagnosis in headache conditions.[37]

Correct diagnosis presents a challenge as the first cluster headache attack may present where staff are not trained in the diagnosis of rare or complex chronic disease.[10]Experienced ER staff are sometimes trained to detect headache types.[38]While cluster headache attacks themselves are not directly life-threatening,suicide ideationhas been observed.[16]

Individuals with cluster headaches typically experiencediagnostic delaybefore correct diagnosis.[39]People are often misdiagnosed due to reported neck, tooth, jaw, and sinus symptoms and may unnecessarily endure many years of referral toear, nose and throat (ENT) specialistsfor investigation of sinuses; dentists for tooth assessment;chiropractorsand manipulative therapists for treatment; orpsychiatrists,psychologists,and other medical disciplines before their headaches are correctly diagnosed.[40]Under-recognition of cluster headaches by health care professionals is reflected in consistent findings inEuropeand theUnited Statesthat the average time to diagnosis is around seven years.[41]

Differential

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Cluster headache may be misdiagnosed asmigraineorsinusitis.[41]Other types of headache are sometimes mistaken for, or may mimic closely, cluster headaches. Incorrect terms like "cluster migraine" confuse headache types, confound differential diagnosis and are often the cause of unnecessary diagnostic delay,[42]ultimately delaying appropriate specialist treatment.

Other types of headaches that may be confused with cluster headache include:

Prevention

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Management for cluster headache is divided into three primary categories: abortive, transitional, and preventive.[48]Preventive treatments are used to reduce or eliminate cluster headache attacks; they are generally used in combination with abortive and transitional techniques.[8]

Verapamil

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The recommended first-line preventive therapy isverapamil,acalcium channel blocker.[2][49]Verapamil was previously underused in people with cluster headache.[8] Improvement can be seen in an average of 1.7 weeks for episodic cluster headache and 5 weeks for chronic cluster headache when using a dosage of ranged between 160 and 720 mg (mean 240 mg/day).[50]Preventive therapy with verapamil is believed to work because it has an effect on the circadian rhythm and on CGRPs. As CGRP-release is controlled by voltage-gated calcium channels.[50]

Glucocorticoids

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Since these compounds aresteroids,there is little evidence to support long-term benefits fromglucocorticoids,[2]but they may be used until other medications take effect as they appear to be effective at three days.[2]They are generally discontinued after 8–10 days of treatment.[8]Prednisone is given at a starting dose of 60–80 milligrams daily; then it is reduced by 5 milligrams every day. Corticosteroids are also used to break cycles, especially in chronic patients.[51]

Surgery

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Nerve stimulators may be an option in the small number of people who do not improve with medications.[52][53]Two procedures,deep brain stimulationoroccipital nerve stimulation,may be useful;[2]early experience shows a benefit in about 60% of cases.[54]It typically takes weeks or months for this benefit to appear.[53]A non-invasive method usingtranscutaneous electrical nerve stimulation(TENS) is being studied.[53]

A number of surgical procedures, such as arhizotomyormicrovascular decompression,may also be considered,[53]but evidence to support them is limited and there are cases of people whose symptoms worsen after these procedures.[53]

Other

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Lithium,methysergide,andtopiramateare recommended alternative treatments,[49][55]although there is little evidence supporting the use of topiramate or methysergide.[2][56]This is also true fortianeptine,melatonin,andergotamine.[2]Valproate,sumatriptan,andoxygenare not recommended as preventive measures.[2]Botulinum toxininjections have shown limited success.[57]Evidence forbaclofen,botulinum toxin,andcapsaicinis unclear.[56]

Management

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There are two primary treatments for acute CH:oxygenandtriptans,[2]but they are underused due to misdiagnosis of the syndrome.[8]During bouts of headaches, triggers such asalcohol,nitroglycerine,and naps during the day should be avoided.[10]

Oxygen

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Oxygen therapymay help to abort attacks, though it does not prevent future episodes.[2]Typically it is given via anon-rebreather maskat 12–15 liters per minute for 15–20 minutes.[2]One review found about 70% of patients improve within 15 minutes.[10]The evidence for effectiveness of 100% oxygen, however, is weak.[10][58]Hyperbaric oxygen at pressures of ~2 times greater than atmospheric pressure may relieve cluster headaches.[58]

Triptans

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The other primarily recommended treatment of acute attacks is subcutaneous or intranasalsumatriptan.[49][59]Sumatriptan andzolmitriptanhave both been shown to improve symptoms during an attack with sumatriptan being superior.[60]Because of the vasoconstrictive side-effect of triptans, they may be contraindicated in people withischemic heart disease.[2]The vasoconstrictorergotcompounds may be useful,[10]but have not been well studied in acute attacks.[60]

Opioids

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The use ofopioidmedication in management of cluster headache is not recommended[61]and may make headache syndromes worse.[62][63]Long-term opioid use is associated with well known dependency, addiction, and withdrawal syndromes.[64]Prescription of opioid medication may additionally lead to further delay in differential diagnosis, undertreatment, and mismanagement.[61]

Other

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Intranasallidocaine(sprayed in the ipsilateral nostril) may be an effective treatment with patient resistant to more conventional treatment.[11]

Octreotideadministered subcutaneously has been demonstrated to be more effective than placebo for the treatment of acute attacks.[65]

Sub-occipital steroid injections have shown benefit and are recommended for use as a transitional therapy to provide temporary headache relief as more long term prophylactic therapies are instituted.[66]

Epidemiology

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Cluster headache affects about 0.1% of the general population at some point in their life.[5]Males are affected about four times more often than females.[5]The condition usually starts between the ages of 20 and 50 years, although it can occur at any age.[1]About one in five of adults reports the onset of cluster headache between 10 and 19 years.[67]

History

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The first complete description of cluster headache was given by the London neurologistWilfred Harrisin 1926, who named the diseasemigrainous neuralgia.[68][69][70]Descriptions of cluster headache date to 1745 and probably earlier.[71]

The condition was originally named Horton's cephalalgia afterBayard Taylor Horton,a US neurologist who postulated the first theory as to their pathogenesis. His original paper describes the severity of the headaches as being able to take normal men and force them to attempt or die by suicide; his 1939 paper said:

"Our patients were disabled by the disorder and suffered from bouts of pain from two to twenty times a week. They had found no relief from the usual methods of treatment. Their pain was so severe that several of them had to be constantly watched for fear of suicide. Most of them were willing to submit to any operation which might bring relief."[72]

CH has alternately been called erythroprosopalgia of Bing, ciliary neuralgia,erythromelalgiaof the head, Horton's headache, histaminic cephalalgia, petrosal neuralgia, sphenopalatine neuralgia, vidian neuralgia, Sluder's neuralgia, Sluder's syndrome, and hemicrania angioparalyticia.[73]

Society and culture

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Robert Shapiro, a professor of neurology, says that while cluster headaches are about as common asmultiple sclerosiswith a similar disability level, as of 2013, the USNational Institutes of Healthhad spent $1.872 billion on research into multiple sclerosis in one decade, but less than $2 million on cluster headache research in 25 years.[74]

Research directions

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Some case reports suggest that ingesting tryptamines such asLSD,psilocybin(as found in hallucinogenic mushrooms), orDMTcan abort attacks and interrupt cluster headache cycles.[75][76]The hallucinogen DMT has a chemical structure that is similar to the triptan sumatriptan, indicating a possible shared mechanism in preventing or stopping migraine and TACs.[51]In a 2006 survey of 53 individuals, 18 of 19 psilocybin users reported extended remission periods. The survey was not a blinded or a controlled study, and was "limited by recall and selection bias".[75]The safety and efficacy of psilocybin is currently being studied in cluster headache, with the extension phase of one randomized controlled trial demonstrating reduced cluster attack burden after a 3-dose pulse of psilocybin.[77][78][79]

Fremanezumab,a humanizedmonoclonal antibodydirected againstcalcitonin gene-related peptidesAlpha and beta, was in phase 3 clinical trials for cluster headaches, but the studies were stopped early due to a futility analysis demonstrating that a successful outcome was unlikely.[80][81]

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Clusterbusterspatient support and advocacy

Organisation for the Prevention of Intense Suffering (OPIS)resource page on cluster headaches

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