Cluster Headache


Article Author:
Sharon Kandel


Article Editor:
Pujyitha Mandiga


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
6/22/2019 3:14:26 PM

Introduction

Cluster headaches are the most common of the primary headache type known as trigeminal autonomic cephalgia. They are relatively rare, plaguing 0.1% of the population, making a study of the disease process difficult at best. They have earned consideration as one of if not the most severe type of headache, and so, despite their rarity, recognition and treatment are vital. There is some degree of genetic correspondence, as first-degree family members are 18 times more likely to be diagnosed with cluster headaches. However, the mode of inheritance is unclear. Some families seem to pass the symptoms along with an autosomal recessive pattern, while others seem to be autosomal dominant. 

The definition of cluster headaches is a unilateral headache with at least one autonomic symptom ipsilateral to the headache. These headaches occur between every other day up to eight times a day. They usually occur at approximately the same time of day, most often at night. Most patients are episodic, with daily attacks for weeks to months, followed by a remission for months to years.[1][2][3]

Etiology

The exact etiology of cluster headaches is not clear. There have been several theories suggested and tested. Unfortunately, due to the relative rarity of patients suffering from this condition, sample sizes are limited. There is a known association between the trigeminovascular system, the parasympathetic nerve fibers involved in the trigeminal autonomic reflex, and the hypothalamus. However, it is not certain how these structures interact to cause these headaches. Moreover, as there is a definite familial connection, considerable effort has gone into studying the genetics of the condition, which has also led to a biochemical assessment. 

There is a definitive link between vasodilation and a pain attack. Activation of the trigeminovascular system causes perivascular afferent nerves to cause vasodilation. The belief is that the activation of the trigeminal nerve is unilateral; that said, it has not been detected and confirmed with functional imaging. Also, complete trigeminal nerve root section does not affect the number or frequency of attacks. This lack of change does not rule out the trigeminovascular system as a component of the cluster headache; it merely shows that there are other components.

The hypothalamus has a definite association with cluster headaches. The attacks have a circadian periodicity, happening most often at night. PET scans have shown activation of the inferior hypothalamic grey matter while the patient is having an attack. Morphology studies have also demonstrated anatomic abnormalities within this same region of the hypothalamus. Of note, though, stimulation of hypothalamus does not trigger attacks. There is even some research suggesting that stimulation of the hypothalamus may abort an attack.

The parasympathetic nerve fibers are part of the trigeminal autonomic reflex, which is what causes the autonomic symptoms, including conjunctival injection or lacrimation, rhinorrhea, and facial vasodilation. Like the hypothalamus, it is a known component of the cluster headache, but the exact trigger of how the trigeminal reflex is activated is uncertain.[1][3][4]

Epidemiology

Cluster headaches occur in 0.1% of the general population. Any age is possible for onset, but the typical age is approximately 30 years old. Men are three times more likely to suffer from this condition than women, though current research has shown that the ratio has been decreasing over time. This incidence may be due to an improvement in diagnostic accuracy; often, women receive an erroneous diagnosis of migraines rather than cluster headaches. Of interest, 85% of all patients diagnosed with cluster headaches are cigarette smokers. Patients are 18 times more likely to be diagnosed if they have a 1st-degree relative who also had a diagnosis of cluster headaches. There is a broad spectrum in research suggesting anywhere between 30 to 80% of patients with cluster headaches will also have sleep apnea.[1][3][4][5]

Pathophysiology

As stated above, there is no single clear source of cluster headaches. There is a circadian periodicity, leading to investigation of the hypothalamus, which ultimately shows abnormalities in morphology studies. There is also the involvement of the trigeminovascular system and the parasympathetic nerve fibers. Some research studies have suggested a defect in the central pathway of pain control and autonomic nervous system dysregulation leading to dysfunction in supraspinal control of pain and cognitive processing. Researchers have also noted dysfunction in inter and intracellular signaling pathways of GABA, ion channels, and inflammation-related molecules, including IL-2, adhesion molecules, and histamine.

Genetic analysis has many possible sources, including PER3 (associated with the circadian rhythm), orexin-B (associated with the sleep-wake cycle, food intake, and modulation of nociceptive neurotransmission), and PACAP receptor gene, being that PCAP (pituitary adenylate cyclase activating polypeptide) increases in the blood during attacks. More research is necessary for all suggested genetic pathways.[1][3][4][6][7] 

History and Physical

A thorough history is essential to the diagnosis of cluster headaches. Patients will reveal that they experience ten out of ten unilateral pain, most often located intra or supraorbitally. Patients must have at least one autonomic symptom ipsilateral to the side with pain.

These autonomic symptoms are as follows:

  • Conjunctival injection or lacrimation (90% of patients)
  • Nasal congestion or rhinorrhea (84% of patients)
  • Eyelid edema or forehead/facial swelling (59% of patients)
  • Miosis or ptosis (unknown percentage)

Up to 33% of patients will also experience general allodynia; this is more common in women, patients with recent attacks, those who had a low age at the time of onset, and those with comorbid depression or migraines. There is often suicidal ideation associated with the attacks, but the risk of actual suicide is rare. 

Unlike patients with migraines, these patients are unlikely to hold still. Many pace or rock in place; there are descriptions of patients even banging their heads to distract themselves from the headache. Attacks typically last anywhere from 15 minutes to 3 hours. They can occur up to eight times a day, although most commonly, patients experience attacks twice a day, usually at night. Most patients will have attacks for weeks to months and then have remission for months up to years. This pattern usually lasts up to fifteen years.[1][2][3][4][7]

Evaluation

Diagnosis is clinical. While there are some lab abnormalities, such as increased histamine in the blood during attacks, and anatomical changes found on a morphology study, these have not been found to be useful in a clinical setting. A questionnaire asking about headache duration (less than 180 minutes) and autonomic symptoms (conjunctival injection or lacrimation) has a sensitivity of 81% and a specificity of 100%. Clinicians must have a degree of suspicion, as cluster headaches are usually misdiagnosed, and patients do not receive a clinical diagnosis for up to five years.[2]

Treatment / Management

There are two sides to the treatment of cluster headaches: treatment of the acute attack and preventative treatment.

Acute treatment

Perhaps the most well-known treatment for cluster headaches is 100% oxygen therapy. This approach is a level A recommendation and is unique to cluster headaches vs. all other types of headaches. At least 66% of patients respond to oxygen therapy. It is effective in less than 10 minutes. Oxygen use carries no risks or side effects, making it an excellent choice for treatment. Unfortunately, insurance often will not pay for oxygen therapy for the cluster headache patient, and it can be difficult to obtain.

Triptans are the only other level A recommended treatment. Delivery of these drugs can be subcutaneous sumatriptan or zolmitriptan delivered via nasal spray. Oral medication of any form is not a recommendation, as the time of onset is often longer than the headache is.

Other treatment options include intranasal lidocaine (with reported 33% response), octreotide, and ergotamine. Unfortunately, 10 to 20% of patients with chronic cluster headaches develop drug resistance. Patients should be instructed to avoid triggers, especially alcohol. While there is no proof that smoking cessation will decrease the risk of headaches, patients should also be encouraged to stop smoking. 

Preventative treatment

The only level A recommended treatment for the prevention of cluster headaches is a suboccipital blockade. Adverse events are nonserious, including transient injection site pain and low-level headache. 

Verapamil is the most widely prescribed preventative drug. It is recommended to do regular ECGs to monitor cardiac function when a patient is using this drug. Curiously, despite verapamil's popularity among providers, it only has a level C recommendation. 

Other pharmacological options include lithium, oral steroids, valproic acid, melatonin, intranasal capsaicin.

There has been much research into electrical stimulation. Sites of stimulation include the sphenopalatine ganglion, occipital nerve, and vagus nerve. Deep brain stimulation of the hypothalamus has been very successful and has been proven quite useful in the treatment of drug-resistant patients. Vagus nerve stimulation can be an option with a nonimplanted device.[1][2][3][8][9]

Differential Diagnosis

Cluster headache often goes undiagnosed for years. Other differential diagnoses are as follows:

  • Migraine: the most common description of this headache is a unilateral "throbbing" headache. Patients tend to lie quietly in a dark room. It is associated with fatigue, nausea, photophobia, phonophobia, and vomiting. Up to 50% of patients can have bilateral autonomic symptoms; this is the most common condition with which cluster headache is confused.
  • Paroxysmal Hemicrania: this is a unilateral headache that only lasts 2 to 30 minutes. It responds to indomethacin.
  • Short-Lasting Unilateral Neuralgiform Headaches with Conjunctival Injection and Tearing (SUNCT syndrome): this is an extremely rare unilateral headache lasting 5 to 240 seconds. They can occur three to 200 times a day and are usually refractory to treatment.
  • Tension Headache: this is a bilateral headache that is described as a dull ache or squeezing ache. It is associated with fatigue, pericranial muscle tenderness, or sleep disturbances. 
  • Trigeminal Neuralgia: this is an inconsistent, paroxysmal headache described as an electrical, sharp, or stabbing pain in the trigeminal distribution. Events last for a few seconds.[2]

Staging

Episodic: 85 to 90% of patients. Patients experience daily attacks for weeks to months and then have a remission lasting months or years. Patients typically have 1 to 2 episodes a year, most often in spring or autumn.

Chronic: 15 to 20% of patients. Patients experience attacks lasting more than a year without remission or remission that lasts less than one month;10 to 20% of these patients will develop drug resistance.

Probable: patients whose attacks fulfill all but one criterion.[2]

Prognosis

Around 25% of patients who experience a cluster headache will never have another one. Another 15 to 20% of patients will have chronic cluster headaches, 10-20% of which will develop drug resistance. This condition often resolves in approximately 15 years.

Patients can experience detriments to their mental health. There will be physical burdens and loss of quality of life. Many patients describe suicidal ideation, but actual follow-through action is rare.[1][4]

Complications

There is a frequent association with psychiatric conditions, including depression, anxiety, and aggressive behavior. Suicidal attempts are rare, but these conditions do increase the disease burden. There is evidence supporting systemic autonomic function being affected, which is usually subclinical and includes bradycardia, tachycardia, hypertension, and arrhythmias (such as AV block and SA block). The most concerning of the autonomic dysregulation is an increased risk of dysregulation of systemic blood pressure. As in sleep apnea, patients have an increased risk of not undergoing physiological blood pressure dipping during sleep., which can lead to end organ damage and increases the risk of cardiovascular disease. This situation is accompanied by an increased risk of an abnormal ABI, indicating peripheral arterial disease, which, confirms that there is also an increased risk for cardiovascular disease.[1][5][10]

Deterrence and Patient Education

Alcohol is the most common trigger for a pain attack. Most patients recognize this trigger and stop alcohol use on their own, but it may be necessary to provide patients with cessation counseling. While no evidence exists that quitting smoking affects the number of pain attacks, patients should be encouraged to stop. Patients should also be educated on pharmacological triggers, specifically vasodilators. Patients may require aid in lifestyle management, and patients should receive an offer for psychiatric counseling.[2]

Pearls and Other Issues

  • Cluster headaches are unilateral periocular headaches occurring between 15 minutes to 3 hours, with episodes usually occurring twice a day for weeks to months with remissions of months to years.
  • There is associated autonomic symptoms on the ipsilateral side.
  • Exact etiology and pathophysiology are unknown.
  • Acute treatment includes oxygen and nonoral triptans.
  • Prophylactic treatment is a suboccipital blockade.

Enhancing Healthcare Team Outcomes

The average cluster headache patient can take approximately five years to diagnose and only after visiting several different physicians. Cluster headaches are often confused for migraines. The healthcare provider must strive to recognize the episodic nature of cluster headaches, the autonomic dysregulation, and even the activity of the patient during an attack.

Verapamil is generally regarded as prophylactic maintenance therapy by healthcare providers despite only a level C recommendation. There is discordance between evidence-based medicine and provider activity.

Unfortunately, though oxygen is a level A recommended treatment for cluster headaches, it may not be covered by insurance - this may be due to a lack of understanding about cluster headaches by the insurance companies or a misunderstanding about the price differential between prescribing a triptan versus prescribing oxygen. The out of pocket cost for a patient buying oxygen depends on the state and can be anywhere from $500 to $10000 per year. Some patients ask about welder's oxygen, which is non-medical grade oxygen; however, this is usually not any cheaper than medical oxygen and may have impurities. Practitioners are recommended to refer insurers to the American Headache Society Guidelines during peer to peer conversations. Medicare and Medicaid have ruled that they will not cover oxygen at all for cluster headaches.[1][8][9]

Cluster headaches require an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level V]

This research was supported (in part or whole) by HCA Healthcare and/or an HCA healthcare affiliated entity. The views expressed in this publication represent those of the author and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities.


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Cluster Headache - Questions

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Which of the following has been shown to be effective in the treatment of cluster headaches, but not in the treatment of migraine headaches?



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A patient presents for the establishment of care. He states that he was diagnosed with a type of headache, but cannot remember what it is called. He takes verapamil daily for prevention, and when he has a headache, he borrows a family member's oxygen tank to abort it. This type of headache is most common in what population?



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A patient presents to the office to establish care. He notes that his brother was diagnosed with a type of headache, but he is not sure what type. He does know that his brother uses 100% oxygen when he has the headache. What is another possible treatment for this type of headache?



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A patient presents with severe unilateral headaches. They are located in the left periorbital area and are associated with rhinorrhea and lacrimation. Which is the most likely diagnosis?



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A 28-year-old male complains of a 3 day history of a severe pain behind his right eye with nasal stuffiness and tearing. He has awakened each night around 1 AM secondary to pain. Which of the following is the most likely diagnosis?



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A 22 year old male experiences the acute onset of severe painful unilateral headache lasting 20 seconds. The pain is described as boring and drilling and located primarily around the eye. During the attack, he develops red eye, rhinorrhea, and red flushed face. What is the most likely diagnosis?



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A male patient comes into the emergency department with a severe unilateral periorbital headache. He states that he has had the headache for an hour and that yesterday he had the same headache. Physical exam shows the patient with conjunctival injection on the right side as well as facial flushing. What is the best treatment?



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Cluster headaches often occur in the evening. Based on this information, which structures in the brain have been found to have morphological abnormalities in patients suffering from this condition?



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Which of the following is closest to the lifetime prevalence of cluster headache?



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Select the safest preventive medication for episodic and chronic cluster headaches.



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A patient has headaches that occur every day shortly after dinner for the past year. He used to use subcutaneous sumatriptan to abort the headaches, but he notes the headaches have started becoming increasingly resistant to treatment. What treatment option can the patient have for this drug-resistant headache?



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A type of headache is diagnosed clinically. Features include an intraorbital pain with associated ipsilateral flushing. What is the duration of this type of headache?



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A patient comes into the clinic with headaches. She would like to know if there are any lifestyle changes she can make to avoid triggering them. On further probing, she states the headache starts every day at approximately 6 pm. It lasts 3 hours before fading. She notes that it is a stabbing pain in her right eye. Her husband points out that when she has the headache, the right side of her face turns red and her nose starts running. Which of the following can trigger a headache of this kind?



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A male patient reports severe unilateral headaches for 4 years. The pain is rated 10 out of 10, lasts for 3 hours, and is associated with ipsilateral nasal congestion and tearing. The headaches may occur nightly for 3 weeks and then not again for 3 months. Select the best treatment for this headache.



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A 32-year old comes to the emergency department with complaints about an intense headache. He says the headache woke him up from his sleep but denies having any photophobia, nausea or vomiting. However, he does complain of tearing and nasal congestion. He describes the headache as excruciating, limited to one side of the face and feels like his eye is being pushed out. He had a similar headache last year when he consumed alcohol before bedtime. Physical exam reveals a male with facial flushing and in severe distress. He is screaming in pain. He has ipsilateral lacrimation and conjunctival injection. Also, he has multiple furrows and thickened skin with prominent forehead fold. This is his third such episode this year. What prophylactic treatment is available to prevent such headaches?



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A 30-year-old male presents to the emergency department complaining of excruciating pain over his left eye that started 1 hour ago. He said he felt similar pain last night that lasted for 2 hours but this time the pain is much worse. He denies photophobia or visual changes. Vital signs: HR: 100, BP: 125/82, RR: 18, O2: 100%. On examination, there was ptosis of his left eye and mild rhinorrhea. Upper and lower limb motor strength was 5/5 and touch, pain and temperature sensations were intact. Which of the following is the next best step?



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Cluster Headache - References

References

Hoffmann J,May A, Diagnosis, pathophysiology, and management of cluster headache. The Lancet. Neurology. 2018 Jan;     [PubMed]
Weaver-Agostoni J, Cluster headache. American family physician. 2013 Jul 15;     [PubMed]
Láinez MJ,Guillamón E, Cluster headache and other TACs: Pathophysiology and neurostimulation options. Headache. 2017 Feb;     [PubMed]
Tepper DE, Cluster headache. Headache. 2015 May;     [PubMed]
Barloese MC, A Review of Cardiovascular Autonomic Control in Cluster Headache. Headache. 2016 Feb;     [PubMed]
Eising E,Pelzer N,Vijfhuizen LS,Vries B,Ferrari MD,'t Hoen PA,Terwindt GM,van den Maagdenberg AM, Identifying a gene expression signature of cluster headache in blood. Scientific reports. 2017 Jan 11;     [PubMed]
Wilbrink LA,Louter MA,Teernstra OPM,van Zwet EW,Huygen FJPM,Haan J,Ferrari MD,Terwindt GM, Allodynia in cluster headache. Pain. 2017 Jun;     [PubMed]
Robbins MS,Starling AJ,Pringsheim TM,Becker WJ,Schwedt TJ, Treatment of Cluster Headache: The American Headache Society Evidence-Based Guidelines. Headache. 2016 Jul;     [PubMed]
Tepper D, Oxygen for Cluster Headache. Headache. 2017 Oct;     [PubMed]
Lasaosa SS,Diago EB,Calzada JN,Benito AV, Cardiovascular Risk Factors in Cluster Headache. Pain medicine (Malden, Mass.). 2017 Jun 1;     [PubMed]

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