|Person with a headache|
|Types||tension headache, sinus (allergy) headache, cluster headache, migraine headache, hangover headache, Cold-stimulus headache (brain freeze)|
|Treatment||Over-the-counter painkillers, sleep, drinking water, eating food, Head or neck massage|
Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches.
Headaches can occur as a result of many conditions. There are a number of different classification systems for headaches. The most well-recognized is that of the International Headache Society. Causes of headaches may include dehydration, fatigue, sleep deprivation, stress, the effects of medications and recreational drugs, including withdrawal, viral infections, loud noises, common colds, head injury, rapid ingestion of a very cold food or beverage, and dental or sinus issues (such as sinusitis).
Treatment of a headache depends on the underlying cause, but commonly involves pain medication. A headache is one of the most commonly experienced of all physical discomforts.
About half of adults have a headache in a given year. Tension headaches are the most common, affecting about 1.6 billion people (21.8% of the population) followed by migraine headaches which affect about 848 million (11.7%).
There are more than 200 types of headaches. Some are harmless and some are life-threatening. The description of the headache and findings on neurological examination, determine whether additional tests are needed and what treatment is best.
Headaches are broadly classified as "primary" or "secondary". Primary headaches are benign, recurrent headaches not caused by underlying disease or structural problems. For example, migraine is a type of primary headache. While primary headaches may cause significant daily pain and disability, they are not dangerous from a physiological point of view. Secondary headaches are caused by an underlying disease, like an infection, head injury, vascular disorders, brain bleed, stomach irritation, or tumors. Secondary headaches can be dangerous. Certain "red flags" or warning signs indicate a secondary headache may be dangerous.
Ninety percent of all headaches are primary headaches. Primary headaches usually first start when people are between 20 and 40 years old. The most common types of primary headaches are migraines and tension-type headaches. They have different characteristics. Migraines typically present with pulsing head pain, nausea, photophobia (sensitivity to light) and phonophobia (sensitivity to sound). Tension-type headaches usually present with non-pulsing "bandlike" pressure on both sides of the head, not accompanied by other symptoms. Other very rare types of primary headaches include:
- cluster headaches: short episodes (15–180 minutes) of severe pain, usually around one eye, with autonomic symptoms (tearing, red eye, nasal congestion) which occur at the same time every day. Cluster headaches can be treated with triptans and prevented with prednisone, ergotamine or lithium.
- trigeminal neuralgia or occipital neuralgia: shooting face pain
- hemicrania continua: continuous unilateral pain with episodes of severe pain. Hemicrania continua can be relieved by the medication indomethacin.
- primary stabbing headache: recurrent episodes of stabbing "ice pick pain" or "jabs and jolts" for 1 second to several minutes without autonomic symptoms (tearing, red eye, nasal congestion). These headaches can be treated with indomethacin.
- primary cough headache: starts suddenly and lasts for several minutes after coughing, sneezing or straining (anything that may increase pressure in the head). Serious causes (see secondary headaches red flag section) must be ruled out before a diagnosis of "benign" primary cough headache can be made.
- primary exertional headache: throbbing, pulsatile pain which starts during or after exercising, lasting for 5 minutes to 24 hours. The mechanism behind these headaches is unclear, possibly due to straining causing veins in the head to dilate, causing pain. These headaches can be prevented by not exercising too strenuously and can be treated with medications such as indomethacin.
- primary sex headache: dull, bilateral headache that starts during sexual activity and becomes much worse during orgasm. These headaches are thought to be due to lower pressure in the head during sex. It is important to realize that headaches that begin during orgasm may be due to a subarachnoid hemorrhage, so serious causes must be ruled out first. These headaches are treated by advising the person to stop sex if they develop a headache. Medications such as propranolol and diltiazem can also be helpful.
- hypnic headache: moderate-severe headache that starts a few hours after falling asleep and lasts 15–30 minutes. The headache may recur several times during night. Hypnic headaches are usually in older women. They may be treated with lithium.
This section needs additional citations for verification. (February 2021)
Headaches may be caused by problems elsewhere in the head or neck. Some of these are not harmful, such as cervicogenic headache (pain arising from the neck muscles). The excessive use of painkillers can paradoxically cause worsening painkiller headaches.
More serious causes of secondary headaches include the following:
- meningitis: inflammation of the meninges which presents with fever and meningismus, or stiff neck
- bleeding inside the brain (intracranial hemorrhage)
- subarachnoid hemorrhage (acute, severe headache, stiff neck without fever)
- ruptured aneurysm, arteriovenous malformation, intraparenchymal hemorrhage (headache only)
- brain tumor: dull headache, worse with exertion and change in position, accompanied by nausea and vomiting. Often, the person will have nausea and vomiting for weeks before the headache starts.
- temporal arteritis: inflammatory disease of arteries common in the elderly (average age 70) with fever, headache, weight loss, jaw claudication, tender vessels by the temples, polymyalgia rheumatica
- acute closed angle glaucoma (increased pressure in the eyeball): headache that starts with eye pain, blurry vision, associated with nausea and vomiting. On physical exam, the person will have a red eye and a fixed, mid dilated pupil.
- Post-ictal headaches: Headaches that happen after a convulsion or other type of seizure, as part of the period after the seizure (the post-ictal state)
Gastrointestinal disorders may cause headaches, including Helicobacter pylori infection, celiac disease, non-celiac gluten sensitivity, irritable bowel syndrome, inflammatory bowel disease, gastroparesis, and hepatobiliary disorders. The treatment of the gastrointestinal disorders may lead to a remission or improvement of headaches.
Migraine headaches are also associated with Cyclic Vomiting Syndrome (CVS). CVS is characterized by episodes of severe vomiting, and often occur alongside symptoms similar to those of migraine headaches (photophobia, abdominal pain, etc).
The brain itself is not sensitive to pain, because it lacks pain receptors. However, several areas of the head and neck do have pain receptors and can thus sense pain. These include the extracranial arteries, middle meningeal artery, large veins, venous sinuses, cranial and spinal nerves, head and neck muscles, the meninges, falx cerebri, parts of the brainstem, eyes, ears, teeth and lining of the mouth. Pial arteries, rather than pial veins are responsible for pain production.
Headaches often result from traction to or irritation of the meninges and blood vessels. The pain receptors may be stimulated by head trauma or tumors and cause headaches. Blood vessel spasms, dilated blood vessels, inflammation or infection of meninges and muscular tension can also stimulate pain receptors. Once stimulated, a nociceptor sends a message up the length of the nerve fiber to the nerve cells in the brain, signalling that a part of the body hurts.
Primary headaches are more difficult to understand than secondary headaches. The exact mechanisms which cause migraines, tension headaches and cluster headaches are not known. There have been different hypotheses over time that attempt to explain what happens in the brain to cause these headaches.
Migraines are currently thought to be caused by dysfunction of the nerves in the brain. Previously, migraines were thought to be caused by a primary problem with the blood vessels in the brain. This vascular theory, which was developed in the 20th century by Wolff, suggested that the aura in migraines is caused by constriction of intracranial vessels (vessels inside the brain), and the headache itself is caused by rebound dilation of extracranial vessels (vessels just outside the brain). Dilation of these extracranial blood vessels activates the pain receptors in the surrounding nerves, causing a headache. The vascular theory is no longer accepted. Studies have shown migraine head pain is not accompanied by extracranial vasodilation, but rather only has some mild intracranial vasodilation.
Currently, most specialists think migraines are due to a primary problem with the nerves in the brain. Auras are thought to be caused by a wave of increased activity of neurons in the cerebral cortex (a part of the brain) known as cortical spreading depression followed by a period of depressed activity. Some people think headaches are caused by the activation of sensory nerves which release peptides or serotonin, causing inflammation in arteries, dura and meninges and also cause some vasodilation. Triptans, medications which treat migraines, block serotonin receptors and constrict blood vessels.
People who are more susceptible to experience migraines without headache are those who have a family history of migraines, women, and women who are experiencing hormonal changes or are taking birth control pills or are prescribed hormone replacement therapy.
|Tension headache||New daily persistent headache||Cluster headache||Migraine|
|mild to moderate dull or aching pain||severe pain||moderate to severe pain|
|duration of 30 minutes to several hours||duration of at least four hours daily||duration of 30 minutes to 3 hours||duration of 4 hours to 3 days|
|Occur in periods of 15 days a month for three months||may happen multiple times in a day for months||periodic occurrence; several per month to several per year|
|located as tightness or pressure across head||located on one or both sides of head||located one side of head focused at eye or temple||located on one or both sides of head|
|consistent pain||pain describable as sharp or stabbing||pulsating or throbbing pain|
|no nausea or vomiting||nausea, perhaps with vomiting|
|no aura||no aura||auras|
|uncommonly, light sensitivity or noise sensitivity||may be accompanied by running nose, tears, and drooping eyelid, often only on one side||sensitivity to movement, light, and noise|
|exacerbated by regular use of acetaminophen or NSAIDS||may exist with tension headache|
Most headaches can be diagnosed by the clinical history alone. If the symptoms described by the person sound dangerous, further testing with neuroimaging or lumbar puncture may be necessary. Electroencephalography (EEG) is not useful for headache diagnosis.
The first step to diagnosing a headache is to determine if the headache is old or new. A "new headache" can be a headache that has started recently, or a chronic headache that has changed character. For example, if a person has chronic weekly headaches with pressure on both sides of his head, and then develops a sudden severe throbbing headache on one side of his head, they have a new headache.
It can be challenging to differentiate between low-risk, benign headaches and high-risk, dangerous headaches since symptoms are often similar. Headaches that are possibly dangerous require further lab tests and imaging to diagnose.
The American College for Emergency Physicians published criteria for low-risk headaches. They are as follows:
- age younger than 30 years
- features typical of primary headache
- history of similar headache
- no abnormal findings on neurologic exam
- no concerning change in normal headache pattern
- no high-risk comorbid conditions (for example, HIV)
- no new concerning history or physical examination findings
A number of characteristics make it more likely that the headache is due to potentially dangerous secondary causes which may be life-threatening or cause long-term damage. These "red flag" symptoms mean that a headache warrants further investigation with neuroimaging and lab tests.
In general, people complaining of their "first" or "worst" headache warrant imaging and further workup. People with progressively worsening headache also warrant imaging, as they may have a mass or a bleed that is gradually growing, pressing on surrounding structures and causing worsening pain. People with neurological findings on exam, such as weakness, also need further workup.
The American Headache Society recommends using "SSNOOP", a mnemonic to remember the red flags for identifying a secondary headache:
- Systemic symptoms (fever or weight loss)
- Systemic disease (HIV infection, malignancy)
- Neurologic symptoms or signs
- Onset sudden (thunderclap headache)
- Onset after age 40 years
- Previous headache history (first, worst, or different headache)
|Red Flag||Possible causes||Reason why red flag indicates possible causes||Diagnostic tests|
|New headache after age 50||Temporal arteritis, mass in brain||Temporal arteritis is an inflammation of vessels close to the temples in older people, which decreases blood flow to the brain and causes pain. May also have tenderness in temples or jaw claudication. Some brain cancers are more common in older people.||Erythrocyte sedimentation rate (diagnostic test for temporal arteritis), neuroimaging|
|Very sudden onset headache (thunderclap headache)||Brain bleed (subarachnoid hemorrhage, hemorrhage into mass lesion, vascular malformation), pituitary apoplexy, mass (especially in posterior fossa)||A bleed in the brain irritates the meninges which causes pain. Pituitary apoplexy (bleeding or impaired blood supply to the pituitary gland at the base of the brain) is often accompanied by double vision or visual field defects, since the pituitary gland is right next to the optic chiasm (eye nerves).||Neuroimaging, lumbar puncture if computed tomography is negative|
|Headaches increasing in frequency and severity||Mass, subdural hematoma, medication overuse||As a brain mass gets larger, or a subdural hematoma (blood outside the vessels underneath the dura) it pushes more on surrounding structures causing pain. Medication overuse headaches worsen with more medication taken over time.||Neuroimaging, drug screen|
|New onset headache in a person with possible HIV or cancer||Meningitis (chronic or carcinomatous), brain abscess including toxoplasmosis, metastasis||People with HIV or cancer are immunosuppressed so are likely to get infections of the meninges or infections in the brain causing abscesses. Cancer can metastasize, or travel through the blood or lymph to other sites in the body.||Neuroimaging, lumbar puncture if neuroimaging is negative|
|Headache with signs of total body illness (fever, stiff neck, rash)||Meningitis, encephalitis (inflammation of the brain tissue), Lyme disease, collagen vascular disease||A stiff neck, or inability to flex the neck due to pain, indicates inflammation of the meninges. Other signs of systemic illness indicates infection.||Neuroimaging, lumbar puncture, serology (diagnostic blood tests for infections)|
|Papilledema||Brain mass, benign intracranial hypertension (pseudotumor cerebri), meningitis||Increased intracranial pressure pushes on the eyes (from inside the brain) and causes papilledema.||Neuroimaging, lumbar puncture|
|Severe headache following head trauma||Brain bleeds (intracranial hemorrhage, subdural hematoma, epidural hematoma), post-traumatic headache||Trauma can cause bleeding in the brain or shake the nerves, causing a post-traumatic headache||Neuroimaging of brain, skull, and possibly cervical spine|
|Inability to move a limb||Arteriovenous malformation, collagen vascular disease, intracranial mass lesion||Focal neurological signs indicate something is pushing against nerves in the brain responsible for one part of the body||Neuroimaging, blood tests for collagen vascular diseases|
|Change in personality, consciousness, or mental status||Central nervous system infection, intracranial bleed, mass||Change in mental status indicates a global infection or inflammation of the brain, or a large bleed compressing the brainstem where the consciousness centers lie||Blood tests, lumbar puncture, neuroimaging|
|Headache triggered by cough, exertion or while engaged in sexual intercourse||Mass lesion, subarachnoid hemorrhage||Coughing and exertion increases the intra cranial pressure, which may cause a vessel to burst, causing a subarachnoid hemorrhage. A mass lesion already increases intracranial pressure, so an additional increase in intracranial pressure from coughing etc. will cause pain.||Neuroimaging, lumbar puncture|
Old headaches are usually primary headaches and are not dangerous. They are most often caused by migraines or tension headaches. Migraines are often unilateral, pulsing headaches accompanied by nausea or vomiting. There may be an aura (visual symptoms, numbness or tingling) 30–60 minutes before the headache, warning the person of a headache. Migraines may also not have auras. Tension type headaches usually have bilateral "bandlike" pressure on both sides of the head usually without nausea or vomiting. However, some symptoms from both headache groups may overlap. It is important to distinguish between the two because the treatments are different.
The mnemonic 'POUND' helps distinguish between migraines and tension type headaches. POUND stands for:
- Pulsatile quality of headache
- One-day duration (four to 72 hours)
- Unilateral location
- Nausea or vomiting
- Disabling intensity
One review article found that if 4–5 of the POUND characteristics are present, migraine is 24 times as likely a diagnosis than tension type headache (likelihood ratio 24). If 3 characteristics of POUND are present, migraine is 3 times more likely a diagnosis than tension type headache (likelihood ratio 3). If only 2 POUND characteristics are present, tension type headaches are 60% more likely (likelihood ratio 0.41). Another study found the following factors independently each increase the chance of migraine over tension type headache: nausea, photophobia, phonophobia, exacerbation by physical activity, unilateral, throbbing quality, chocolate as headache trigger, cheese as headache trigger.
Cluster headaches are relatively rare (1 in 1000 people) and are more common in men than women. They present with sudden onset explosive pain around one eye and are accompanied by autonomic symptoms (tearing, runny nose and red eye).
For chronic, unexplained headaches, keeping a headache diary can be useful for tracking symptoms and identifying triggers, such as association with menstrual cycle, exercise and food. While mobile electronic diaries for smartphones are becoming increasingly common, a recent review found most are developed with a lack of evidence base and scientific expertise.
New headaches are more likely to be dangerous secondary headaches. They can, however, simply be the first presentation of a chronic headache syndrome, like migraine or tension-type headaches.
One recommended diagnostic approach is as follows. If any urgent red flags are present such as visual loss, new seizures, new weakness, new confusion, further workup with imaging and possibly a lumbar puncture should be done (see red flags section for more details). If the headache is sudden onset (thunderclap headache), a computed tomography test to look for a brain bleed (subarachnoid hemorrhage) should be done. If the CT scan does not show a bleed, a lumbar puncture should be done to look for blood in the CSF, as the CT scan can be falsely negative and subarachnoid hemorrhages can be fatal. If there are signs of infection such as fever, rash, or stiff neck, a lumbar puncture to look for meningitis should be considered. If there is jaw claudication and scalp tenderness in an older person, a temporal artery biopsy to look for temporal arteritis should be performed and immediate treatment should be started.
The US Headache Consortium has guidelines for neuroimaging of non-acute headaches. Most old, chronic headaches do not require neuroimaging. If a person has the characteristic symptoms of a migraine, neuroimaging is not needed as it is very unlikely the person has an intracranial abnormality. If the person has neurological findings, such as weakness, on exam, neuroimaging may be considered.
All people who present with red flags indicating a dangerous secondary headache should receive neuroimaging. The best form of neuroimaging for these headaches is controversial. Non-contrast computerized tomography (CT) scan is usually the first step in head imaging as it is readily available in Emergency Departments and hospitals and is cheaper than MRI. Non-contrast CT is best for identifying an acute head bleed. Magnetic Resonance Imaging (MRI) is best for brain tumors and problems in the posterior fossa, or back of the brain. MRI is more sensitive for identifying intracranial problems, however it can pick up brain abnormalities that are not relevant to the person's headaches.
The American College of Radiology recommends the following imaging tests for different specific situations:
|Clinical Features||Recommended neuroimaging test|
|Headache in immunocompromised people (cancer, HIV)||MRI of head with or without contrast|
|Headache in people older than 60 with suspected temporal arteritis||MRI of head with or without contrast|
|Headache with suspected meningitis||CT or MRI without contrast|
|Severe headache in pregnancy||CT or MRI without contrast|
|Severe unilateral headache caused by possible dissection of carotid or arterial arteries||MRI of head with or without contrast, magnetic resonance angiography or Computed Tomography Angiography of head and neck.|
|Sudden onset headache or worst headache of life||CT of head without contrast, Computed Tomography Angiography of head and neck with contrast, magnetic resonance angiography of head and neck with and without contrast, MRI of head without contrast|
A lumbar puncture is a procedure in which cerebral spinal fluid is removed from the spine with a needle. A lumbar puncture is necessary to look for infection or blood in the spinal fluid. A lumbar puncture can also evaluate the pressure in the spinal column, which can be useful for people with idiopathic intracranial hypertension (usually young, obese women who have increased intracranial pressure), or other causes of increased intracranial pressure. In most cases, a CT scan should be done first.
Headaches are most thoroughly classified by the International Headache Society's International Classification of Headache Disorders (ICHD), which published the second edition in 2004. The third edition of the International Headache Classification was published in 2013 in a beta version ahead of the final version. This classification is accepted by the WHO.
The International Classification of Headache Disorders (ICHD) is an in-depth hierarchical classification of headaches published by the International Headache Society. It contains explicit (operational) diagnostic criteria for headache disorders. The first version of the classification, ICHD-1, was published in 1988. The current revision, ICHD-2, was published in 2004.
The classification uses numeric codes. The top, one-digit diagnostic level includes 14 headache groups. The first four of these are classified as primary headaches, groups 5-12 as secondary headaches, cranial neuralgia, central and primary facial pain and other headaches for the last two groups.
The ICHD-2 classification defines migraines, tension-types headaches, cluster headache and other trigeminal autonomic headache as the main types of primary headaches. Also, according to the same classification, stabbing headaches and headaches due to cough, exertion and sexual activity (sexual headache) are classified as primary headaches. The daily-persistent headaches along with the hypnic headache and thunderclap headaches are considered primary headaches as well.
Secondary headaches are classified based on their cause and not on their symptoms. According to the ICHD-2 classification, the main types of secondary headaches include those that are due to head or neck trauma such as whiplash injury, intracranial hematoma, post craniotomy or other head or neck injury. Headaches caused by cranial or cervical vascular disorders such as ischemic stroke and transient ischemic attack, non-traumatic intracranial hemorrhage, vascular malformations or arteritis are also defined as secondary headaches. This type of headaches may also be caused by cerebral venous thrombosis or different intracranial vascular disorders. Other secondary headaches are those due to intracranial disorders that are not vascular such as low or high pressure of the cerebrospinal fluid pressure, non-infectious inflammatory disease, intracranial neoplasm, epileptic seizure or other types of disorders or diseases that are intracranial but that are not associated with the vasculature of the central nervous system.
ICHD-2 classifies headaches that are caused by the ingestion of a certain substance or by its withdrawal as secondary headaches as well. This type of headache may result from the overuse of some medications or by exposure to some substances. HIV/AIDS, intracranial infections and systemic infections may also cause secondary headaches. The ICHD-2 system of classification includes the headaches associated with homeostasis disorders in the category of secondary headaches. This means that headaches caused by dialysis, high blood pressure, hypothyroidism, and cephalalgia and even fasting are considered secondary headaches. Secondary headaches, according to the same classification system, can also be due to the injury of any of the facial structures including teeth, jaws, or temporomandibular joint. Headaches caused by psychiatric disorders such as somatization or psychotic disorders are also classified as secondary headaches.
The ICHD-2 classification puts cranial neuralgias and other types of neuralgia in a different category. According to this system, there are 19 types of neuralgias and headaches due to different central causes of facial pain. Moreover, the ICHD-2 includes a category that contains all the headaches that cannot be classified.
Although the ICHD-2 is the most complete headache classification there is and it includes frequency in the diagnostic criteria of some types of headaches (primarily primary headaches), it does not specifically code frequency or severity which are left at the discretion of the examiner.
The NIH classification consists of brief definitions of a limited number of headaches.
The NIH system of classification is more succinct and only describes five categories of headaches. In this case, primary headaches are those that do not show organic or structural cause. According to this classification, primary headaches can only be vascular, myogenic, cervicogenic, traction and inflammatory.
Primary headache syndromes have many different possible treatments. In those with chronic headaches the long term use of opioids appears to result in greater harm than benefit.
Migraine can be somewhat improved by lifestyle changes, but most people require medicines to control their symptoms. Medications are either to prevent getting migraines, or to reduce symptoms once a migraine starts.
Preventive medications are generally recommended when people have more than four attacks of migraine per month, headaches last longer than 12 hours or the headaches are very disabling. Possible therapies include beta blockers, antidepressants, anticonvulsants and NSAIDs. The type of preventive medicine is usually chosen based on the other symptoms the person has. For example, if the person also has depression, an antidepressant is a good choice.
Abortive therapies for migraines may be oral, if the migraine is mild to moderate, or may require stronger medicine given intravenously or intramuscularly. Mild to moderate headaches should first be treated with acetaminophen (paracetamol) or NSAIDs, like ibuprofen. If accompanied by nausea or vomiting, an antiemetic such as metoclopramide (Reglan) can be given orally or rectally. Moderate to severe attacks should be treated first with an oral triptan, a medication that mimics serotonin (an agonist) and causes mild vasoconstriction. If accompanied by nausea and vomiting, parenteral (through a needle in the skin) triptans and antiemetics can be given.
Sphenopalatine ganglion block (SPG block, also known nasal ganglion block or pterygopalatine ganglion blocks) can abort and prevent migraines, tension headaches and cluster headaches. It was originally described by American ENT surgeon Greenfield Sluder in 1908. Both blocks and neurostimulation have been studied as treatment for headaches.
Several complementary and alternative strategies can help with migraines. The American Academy of Neurology guidelines for migraine treatment in 2000 stated relaxation training, electromyographic feedback and cognitive behavioral therapy may be considered for migraine treatment, along with medications.
Tension-type headaches can usually be managed with NSAIDs (ibuprofen, naproxen, aspirin), or acetaminophen. Triptans are not helpful in tension-type headaches unless the person also has migraines. For chronic tension type headaches, amitriptyline is the only medication proven to help. Amitriptyline is a medication which treats depression and also independently treats pain. It works by blocking the reuptake of serotonin and norepinephrine, and also reduces muscle tenderness by a separate mechanism. Studies evaluating acupuncture for tension-type headaches have been mixed. Overall, they show that acupuncture is probably not helpful for tension-type headaches.
Abortive therapy for cluster headaches includes subcutaneous sumatriptan (injected under the skin) and triptan nasal sprays. High flow oxygen therapy also helps with relief.
For people with extended periods of cluster headaches, preventive therapy can be necessary. Verapamil is recommended as first line treatment. Lithium can also be useful. For people with shorter bouts, a short course of prednisone (10 days) can be helpful. Ergotamine is useful if given 1–2 hours before an attack.
Treatment of secondary headaches involves treating the underlying cause. For example, a person with meningitis will require antibiotics. A person with a brain tumor may require surgery, chemotherapy or brain radiation.
Literature reviews find that approximately 64–77% of adults have had a headache at some point in their lives. During each year, on average, 46–53% of people have headaches. However, the prevalence of headache varies widely depending on how the survey was conducted, with studies finding lifetime prevalence of as low as 8% to as high as 96%. Most of these headaches are not dangerous. Only approximately 1–5% of people who seek emergency treatment for headaches have a serious underlying cause.
More than 90% of headaches are primary headaches. Most of these primary headaches are tension headaches. Most people with tension headaches have "episodic" tension headaches that come and go. Only 3.3% of adults have chronic tension headaches, with headaches for more than 15 days in a month.
Approximately 12–18% of people in the world have migraines. More women than men experience migraines. In Europe and North America, 5–9% of men experience migraines, while 12–25% of women experience migraines.
Cluster headaches are relatively uncommon. They affect only 1–3 per thousand people in the world. Cluster headaches affect approximately three times as many men as women.
The first recorded classification system was published by Aretaeus of Cappadocia, a medical scholar of Greco-Roman antiquity. He made a distinction between three different types of headache: i) cephalalgia, by which he indicates a shortlasting, mild headache; ii) cephalea, referring to a chronic type of headache; and iii) heterocrania, a paroxysmal headache on one side of the head. Another classification system that resembles the modern ones was published by Thomas Willis, in De Cephalalgia in 1672. In 1787 Christian Baur generally divided headaches into idiopathic (primary headaches) and symptomatic (secondary ones), and defined 84 categories.
In general, children suffer from the same types of headaches as adults do, but their symptoms may be slightly different. The diagnostic approach to headache in children is similar to that of adults. However, young children may not be able to verbalize pain well. If a young child is fussy, they may have a headache.
Approximately 1% of emergency department visits for children are for headache. Most of these headaches are not dangerous. The most common type of headache seen in pediatric emergency rooms is headache caused by a cold (28.5%). Other headaches diagnosed in the emergency department include post-traumatic headache (20%), headache related to a problem with a ventriculoperitoneal shunt (a device put into the brain to remove excess CSF and reduce pressure in the brain) (11.5%) and migraine (8.5%). The most common serious headaches found in children include brain bleeds (subdural hematoma, epidural hematoma), brain abscesses, meningitis and ventriculoperitoneal shunt malfunction. Only 4–6.9% of kids with a headache have a serious cause.
Just as in adults, most headaches are benign, but when head pain is accompanied with other symptoms such as speech problems, muscle weakness, and loss of vision, a more serious underlying cause may exist: hydrocephalus, meningitis, encephalitis, abscess, hemorrhage, tumor, blood clots, or head trauma. In these cases, the headache evaluation may include CT scan or MRI in order to look for possible structural disorders of the central nervous system. If a child with a recurrent headache has a normal physical exam, neuroimaging is not recommended. Guidelines state children with abnormal neurologic exams, confusion, seizures and recent onset of worst headache of life, change in headache type or anything suggesting neurologic problems should receive neuroimaging.
When children complain of headaches, many parents are concerned about a brain tumor. Generally, headaches caused by brain masses are incapacitating and accompanied by vomiting. One study found characteristics associated with brain tumor in children are: headache for greater than 6 months, headache related to sleep, vomiting, confusion, no visual symptoms, no family history of migraine and abnormal neurologic exam.
Some measures can help prevent headaches in children. Drinking plenty of water throughout the day, avoiding caffeine, getting enough and regular sleep, eating balanced meals at the proper times, and reducing stress and excess of activities may prevent headaches. Treatments for children are similar to those for adults, however certain medications such as narcotics should not be given to children.
Children who have headaches will not necessarily have headaches as adults. In one study of 100 children with headache, eight years later 44% of those with tension headache and 28% of those with migraines were headache free. In another study of people with chronic daily headache, 75% did not have chronic daily headaches two years later, and 88% did not have chronic daily headaches eight years later.
- "Headache disorders Fact sheet N°277". October 2012. Archived from the original on 16 February 2016. Retrieved 15 February 2016.
- "Headache Causes". Mayo Clinic. Retrieved 21 October 2019.
- Global Burden of Disease Study 2013, Collaborators (22 August 2015). "Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013". Lancet. 386 (9995): 743–800. doi:10.1016/s0140-6736(15)60692-4. PMC 4561509. PMID 26063472.
- Scottish Intercollegiaine Network (November 2008). Diagnosis and management of headache in adults. Edinburgh: NHS Quality Improvement Scotland. ISBN 978-1-905813-39-1. Archived from the original on 19 April 2011. Retrieved 14 July 2010.
- Cecilia B Young (3 January 2012). "The Johns Hopkins Headache Center - Primary Exertion Headache". hopkinsmedicine.org. Archived from the original on 3 May 2014.
- Goadsby PJ, Raskin NH. Chapter 14. Headache. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 18e. New York, NY: McGraw-Hill; 2012.
- Clinch C. Chapter 28. Evaluation & Management of Headache - CURRENT Diagnosis & Treatment in Family Medicine, Third Edition (Lange Current Series): Jeannette E. South-Paul, Samuel C. Matheny, Evelyn L. Lewis. McGraw-Hill. 2011. ISBN 9780071624367.
- Detsky ME, McDonald DR, Baerlocher MO, Tomlinson GA, McCrory DC, Booth CM (September 2006). "Does this patient with headache have a migraine or need neuroimaging?". JAMA. 296 (10): 1274–83. doi:10.1001/jama.296.10.1274. PMID 16968852.
- "Headaches". nhs.uk. 8 January 2018.
- Lionetti E, Francavilla R, Pavone P, Pavone L, Francavilla T, Pulvirenti A, et al. (2010). "The neurology of coeliac disease in childhood: what is the evidence? A systematic review and meta-analysis". Dev Med Child Neurol (Systematic review and meta-analysis). 52 (8): 700–7. doi:10.1111/j.1469-8749.2010.03647.x. PMID 20345955. S2CID 205611320.
- Aziz I, Hadjivassiliou M, Sanders DS (Sep 2015). "The spectrum of noncoeliac gluten sensitivity". Nat Rev Gastroenterol Hepatol (Review). 12 (9): 516–26. doi:10.1038/nrgastro.2015.107. PMID 26122473. S2CID 2867448.
- Cámara-Lemarroy CR, Rodriguez-Gutierrez R, Monreal-Robles R, Marfil-Rivera A (2016). "Gastrointestinal disorders associated with migraine: A comprehensive review". World J Gastroenterol (Review). 22 (36): 8149–60. doi:10.3748/wjg.v22.i36.8149. PMC 5037083. PMID 27688656.
- Hasler, William L.; Levinthal, David J.; Tarbell, Sally E.; Adams, Kathleen A.; Li, B. U. K.; Issenman, Robert M.; Sarosiek, Irene; Jaradeh, Safwan S.; Sharaf, Ravi N.; Sultan, Shahnaz; Venkatesan, Thangam (June 2019). "Cyclic vomiting syndrome: Pathophysiology, comorbidities, and future research directions". Neurogastroenterology and Motility. 31 Suppl 2: e13607. doi:10.1111/nmo.13607. ISSN 1365-2982. PMC 6899706. PMID 31241816.
- Edlow, J.A.; Panagos, P.D.; Godwin, S.A.; Thomas, T.L.; Decker, W.W. (October 2008). "Clinical policy: Critical issues in the evaluation and management of adult patients presenting to the emergency department with acute headache". Annals of Emergency Medicine. 52 (4): 407–36. doi:10.1016/j.annemergmed.2008.07.001. PMID 18809105.
- Greenberg D, Aminoff M, Simon R (6 May 2012). Clinical Neurology 8/E:Chapter 6. Headache & Facial Pain. McGraw Hill Professional. ISBN 978-0-07-175905-2.
- Dubin, Adrienne E.; Patapoutian, Ardem (November 2010). "Nociceptors: the sensors of the pain pathway". The Journal of Clinical Investigation. 120 (11): 3760–3772. doi:10.1172/JCI42843. ISSN 1558-8238. PMC 2964977. PMID 21041958.
- Cutrer, FM, Bajwa A, Sabhat M. Pathophysiology, clinical manifestations and diagnosis of migraine in adults. In: UpToDate, Post TW (Ed), UpToDate, San Francisco, CA. (Accessed on 23 April 2014.)
- Goadsby, P.J. (January 2009). "The vascular theory of migraine--A great story wrecked by the facts". Brain. 132 (Pt 1): 6–7. doi:10.1093/brain/awn321. PMID 19098031.
- Charles A (2013). "Vasodilation out of the picture as a cause of migraine headache". Lancet Neurol. 12 (5): 419–420. doi:10.1016/s1474-4422(13)70051-6. PMID 23578774. S2CID 42240966.
- Amin FM, Asghar MS, Hougaard A, Hansen AE, Larsen VA, de Koning PJ, Larsson HB, Olesen J, Ashina M (May 2013). "Magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura: a cross-sectional study". Lancet Neurol. 12 (5): 454–61. doi:10.1016/S1474-4422(13)70067-X. PMID 23578775. S2CID 25553357.
- Hadjikhani N, Sanchez Del Rio M, Wu O, Schwartz D, Bakker D, Fischl B, Kwong KK, Cutrer FM, Rosen BR, Tootell RB, Sorensen AG, Moskowitz MA (April 2001). "Mechanisms of migraine aura revealed by functional MRI in human visual cortex". Proc. Natl. Acad. Sci. U.S.A. 98 (8): 4687–92. Bibcode:2001PNAS...98.4687H. doi:10.1073/pnas.071582498. PMC 31895. PMID 11287655.
- Buzzi, M.G.; Moskowitz, M (2005). "The pathophysiology of migraine: year 2005". J Headache Pain. 6 (3): 105–11. doi:10.1007/s10194-005-0165-2. PMC 3451639. PMID 16355290.
- "Chapter 159. Headache and Facial Pain". Denny CJ, Schull MJ. Chapter 159. Headache and Facial Pain. In: Tintinalli JE, Stapczynski J, Ma O, Cline DM, Cydulka RK, Meckler GD, T. eds. Tintinalli's Emergency Medicine: A Comprehensive Study Guide, 7e. New York, NY: McGraw-Hill; 2011. mhmedical.com. The McGraw-Hill Companies. 2011. Archived from the original on 31 May 2015. Retrieved 30 May 2015.
- "Migraine Without Headache". Neurobalance. Archived from the original on 8 January 2015. Retrieved 16 July 2014.
- Loder E, Rizzoli P; Rizzoli (2008). "Tension-type headache". BMJ. 336 (7635): 88–92. doi:10.1136/bmj.39412.705868.ad. PMC 2190284. PMID 18187725.
- Leroux E, Ducros A; Ducros (2008). "Cluster headache". Orphanet J Rare Dis. 3 (1): 20. doi:10.1186/1750-1172-3-20. PMC 2517059. PMID 18651939.
- "Using the triptans to treat: Migraine headaches: Comparing effectiveness, safety, and price" (PDF). Consumer Reports Best Buy Drugs: 8. March 2013. Archived (PDF) from the original on 20 March 2013. Retrieved 18 March 2013.
- Gronseth, G.S.; Greenberg, M.K. (July 1995). "The utility of the electroencephalogram in the evaluation of patients presenting with headache: A review of the literature". Neurology. 45 (7): 1263–7. doi:10.1212/WNL.45.7.1263. PMID 7617180. S2CID 26022438.
- Smetana GW. Chapter 9. "Headache." In: Henderson MC, Tierney LM, Jr., Smetana GW. eds. The Patient History: An Evidence-Based Approach to Differential Diagnosis. New York, NY: McGraw-Hill; 2012 Archived 31 May 2015 at the Wayback Machine
- Abrams, BM (2013). "Factors that cause concern". Med Clin N Am. 97 (2): 225–242. doi:10.1016/j.mcna.2012.11.002. PMID 23419623.
- American College of Emergency Physicians (2002). "Clinical policy: critical issues in the evaluation and management of patients presenting to the emergency department with acute headache". Ann Emerg Med. 39 (1): 108–122. doi:10.1067/mem.2002.120125. PMID 11782746.
- Hainer BL, Matheson EM; Matheson (2013). "Approach to acute headache in adults". American Family Physician. 87 (10): 682–687. PMID 23939446.
- Gilmore, Benjamin; Michael, Magdalena (February 2011). "Treatment of Acute Migraine Headache". American Family Physician. 83 (3): 271–280. PMID 21302868. Retrieved 15 September 2021.
- Smetana GW (2000). "The diagnostic value of historical features in primary headache syndromes. A comprehensive review". Arch Intern Med. 160 (18): 2729–2737. doi:10.1001/archinte.160.18.2729. PMID 11025782.
- Harrison's Principles of Internal Medicine (19th ed.). McGraw-Hill Education. 8 April 2015. pp. 2594–2595. ISBN 9780071802154.
- Hundert AS, Huguet A, McGrath PJ, Stinson JN, Wheaton M (August 2014). "Commercially available mobile phone headache diary apps: a systematic review". JMIR mHealth and uHealth. 2 (3): e36. doi:10.2196/mhealth.3452. PMC 4147710. PMID 25138438.
- Chapter 18. "I Have a Patient with Headache. How Do I Determine the Cause?" In: Stern SC, Cifu AS, Altkorn D. eds. Symptom to Diagnosis: An Evidence-Based Guide, 2e. New York, NY: McGraw-Hill; 2010 Archived 31 May 2015 at the Wayback Machine
- Consortium US Headache: Evidence-based guidelines in the primary care setting: Neuroimaging in patients with nonacute headache, 2000.
- American Headache Society (September 2013). "Five Things Physicians and Patients Should Question". Choosing Wisely. American Headache Society. Archived from the original on 6 December 2013. Retrieved 10 December 2013., which cites
- Lewis, D. W.; Dorbad, D. (2000). "The utility of neuroimaging in the evaluation of children with migraine or chronic daily headache who have normal neurological examinations". Headache. 40 (8): 629–632. doi:10.1046/j.1526-4610.2000.040008629.x. PMID 10971658. S2CID 14443890.
- Silberstein, S. D. (2000). "Practice parameter: Evidence-based guidelines for migraine headache (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology". Neurology. 55 (6): 754–762. doi:10.1212/WNL.55.6.754. PMID 10993991.
- Health Quality, O. (2010). "Neuroimaging for the evaluation of chronic headaches: An evidence-based analysis". Ontario Health Technology Assessment Series. 10 (26): 1–57. PMC 3377587. PMID 23074404.
- Strain JD, Strife JL, Kushner DC, et al. "Headache. American College of Radiology. "ACR appropriateness criteria." Radiology 2000; 215(suppl):855–860.
- IHS Classification ICHD-2 (Online ed.). International Headache Society. Archived from the original on 3 November 2013. Retrieved 18 November 2013.
- Website The International Headache Classification (ICHD-3 Beta). Retrieved 29. August 2016.
- Olesen et al. 2005, pp. 9–11.
- Brown, M.R. (1951). "The classification and treatment of headache". Medical Clinics of North America. 35 (5): 1485–93. doi:10.1016/S0025-7125(16)35236-1. PMID 14862569.
- Ad Hoc Committee on Classification of Headache (1962). "Classification of Headache". JAMA. 179 (9): 717–8. doi:10.1001/jama.1962.03050090045008.
- Olesen, Jes; Goadsby, Peter J.; Ramadan, Nabih M.; Tfelt-Hansen, Peer; Welch, K. Michael A. (2005). The Headaches (3 ed.). Lippincott Williams & Wilkins. ISBN 978-0-7817-5400-2.
- Levin, Morris; Baskin, Steven M.; Bigal, Marcelo E. (2008). Comprehensive Review of Headache Medicine. Oxford University Press. ISBN 978-0-19-536673-0.
- Linn, F.H.H. (2010), "Primary thunderclap headache", Headache, Handbook of Clinical Neurology, 97, Elsevier, pp. 473–481, doi:10.1016/s0072-9752(10)97042-5, ISBN 978-0-444-52139-2, PMID 20816448, retrieved 2021-10-22
- Obermann, Mark; Holle, Dagny (September 2010). "Hypnic headache". Expert Review of Neurotherapeutics. 10 (9): 1391–1397. doi:10.1586/ern.10.112. ISSN 1473-7175. PMID 20839413. S2CID 19141493.
- Levin et al. 2008, p. 60.
- "Headache Information Page | National Institute of Neurological Disorders and Stroke". www.ninds.nih.gov. Retrieved 21 July 2021.
- Franklin, G. M.; American Academy Of, Neurology (29 September 2014). "Opioids for chronic noncancer pain: A position paper of the American Academy of Neurology". Neurology. 83 (14): 1277–1284. doi:10.1212/WNL.0000000000000839. PMID 25267983.
- Bajwa ZH, Sabahat A. Preventive Treatment of Migraine in Adults. In: UptoDate. Swanson JW (Ed), UpToDate, San Francisco, CA. (Accessed on 24 April 2014).
- Láinez, Miguel JA; García-Casado, Ana; Gascón, Francisco (11 October 2013). "Optimal management of severe nausea and vomiting in migraine: improving patient outcomes". Patient Related Outcome Measures. 4: 61–73. doi:10.2147/PROM.S31392. ISSN 1179-271X. PMC 3798203. PMID 24143125.
- Ho, KWD; Przkora, R; Kumar, S (28 December 2017). "Sphenopalatine ganglion: block, radiofrequency ablation and neurostimulation - a systematic review". The Journal of Headache and Pain. 18 (1): 118. doi:10.1186/s10194-017-0826-y. PMC 5745368. PMID 29285576.
- Silberstein SD (2000). "Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology". Neurology. 55 (6): 754–62. doi:10.1212/wnl.55.6.754. PMID 10993991.
- Taylor R. Tension type headaches in adults: Preventive treatment. In: UpToDate. Swanson JW (Ed). UpToDate, San Francisco, CA. Accessed on 24 April 2014
- Jackson JL, Shimeall W, Sessums L, Dezee KJ, Becher D, Diemer M, Berbano E, O'Malley PG (October 2010). "Tricyclic antidepressants and headaches: systematic review and meta-analysis". BMJ. 341: c5222. doi:10.1136/bmj.c5222. PMC 2958257. PMID 20961988.
- Davis MA, Kononowech RW, Rolin SA, Spierings EL (August 2008). "Acupuncture for tension-type headache: a meta-analysis of randomized, controlled trials". J Pain. 9 (8): 667–77. doi:10.1016/j.jpain.2008.03.011. PMID 18499526.
- Linde K, Allais G, Brinkhaus B, et al. Acupuncture for tension-type headache. Cochrane Database Syst Rev 2009; :CD007587.
- Hao XA, Xue CC, Dong L, Zheng Z (April 2013). "Factors associated with conflicting findings on acupuncture for tension-type headache: qualitative and quantitative analyses". J Altern Complement Med. 19 (4): 285–97. doi:10.1089/act.2013.19608. PMID 23075410.
- Melchart D, Streng A, Hoppe A, Brinkhaus B, Becker-Witt C, Hammes M, Irnich D, Hummelsberger J, Willich SN, Linde K (December 2005). "The acupuncture randomised trial (ART) for tension-type headache--details of the treatment". Acupunct Med. 23 (4): 157–65. doi:10.1136/aim.23.4.157. PMID 16430123. S2CID 23437975.
- Melchart D, Streng A, Hoppe A, et al. (2005). "Acupuncture in patients with tension-type headache: randomised controlled trial". BMJ. 331 (7513): 376–382. doi:10.1136/bmj.38512.405440.8f. PMC 1184247. PMID 16055451.
- Reed, KL (January 2013). "Peripheral neuromodulation and headaches: history, clinical approach, and considerations on underlying mechanisms". Current Pain and Headache Reports. 17 (1): 305. doi:10.1007/s11916-012-0305-8. PMC 3548086. PMID 23274677.
- Manzoni, G C; Stovner, L J (2010). Epidemiology of headache. Handbook of Clinical Neurology. 97. pp. 3–22. doi:10.1016/s0072-9752(10)97001-2. ISBN 978-0-444-52139-2. PMID 20816407.
[T]he prevalence [of headache within the last year] was on average 46% based on 35 different studies from all over the world, but the variation was immense, between 1% and 87%. The lifetime prevalence was much as expected – 64%, varying between 8% and 96% in 14 studies. For current chronic headache, the average of 10 studies was 3.4%, varying between 1.7% and 7.3%.
- Stovner, LJ; Andree, C (2010). "Prevalence of headache in Europe: a review for the Eurolight project". Journal of Headache Pain. 11 (4): 289–299. doi:10.1007/s10194-010-0217-0. PMC 2917556. PMID 20473702.
Calculating the mean of all the studies comprising more than 205,000 adult participants, current headache [i.e. headache within the last year] occurred in 53% of adults (61% among women and 45% among men).... The total lifetime prevalence of headache among adults was as expected higher than that of current headache (77%).
- Stovner, Lj; Hagen, K.; Jensen, R.; Katsarava, Z.; Lipton, Rb; Scher, Ai; Steiner, Tj; Zwart, J.-A. (2007). "The global burden of headache: a documentation of headache prevalence and disability worldwide". Cephalalgia: An International Journal of Headache. 27 (3): 193–210. doi:10.1111/j.1468-2982.2007.01288.x. ISSN 0333-1024. PMID 17381554. S2CID 23927368.
- Mattu, Amal; Goyal, Deepi; Barrett, Jeffrey W.; Broder, Joshua; DeAngelis, Michael; Deblieux, Peter; Garmel, Gus M.; Harrigan, Richard; Karras, David; L'Italien, Anita; Manthey, David (2007). Emergency medicine: Avoiding the pitfalls and improving the outcomes. Malden, MA: Blackwell / BMJ Books. p. 39. ISBN 978-1-4051-4166-6.
- Kunkel, Robert S. (1 August 2010). "Headache". Disease Management Project: Publications. Cleveland Clinic. Archived from the original on 4 May 2013. Retrieved 6 August 2010.
- Rothner, AD (Jun 1995). "The evaluation of headaches in children and adolescents". Seminars in Pediatric Neurology. 2 (2): 109–18. doi:10.1016/s1071-9091(05)80021-x. PMID 9422238.
- Schultz BE, Macias CG (2011). "130: Headaches in Children". In Tintinalli JE, Stapczynski J, Ma O, Cline DM, Cydulka RK, Meckler GD (eds.). Tintinalli's Emergency Medicine: A Comprehensive Study Guide (7th ed.). New York, NY: McGraw-Hill. Archived from the original on 23 December 2016.
- Scagni P, Pagliero R; Pagliero (Apr 2008). "Headache in an Italian pediatric emergency department". J Headache Pain. 9 (83): 83–7. doi:10.1007/s10194-008-0014-1. PMC 3476181. PMID 18250964.
- Kan L, Nagelberg J, Maytal J (January 2000). "Headaches in a pediatric emergency department: etiology, imaging, and treatment". Headache. 40 (1): 25–9. doi:10.1046/j.1526-4610.2000.00004.x. PMID 10759899. S2CID 39115552.
- Burton LJ, Quinn B, Pratt-Cheney JL, et al. (1997). "Headache etiology in a pediatric emergency department". Pediatr Emerg Care. 13 (1): 1–4. doi:10.1097/00006565-199702000-00001. PMID 9061724. S2CID 33965477.
- "What Causes Headaches in Children and Adolescents?". WebMD. Archived from the original on 7 May 2013. Retrieved 30 June 2010.
- Medina LS, Kuntz KM, Pomeroy S (August 2001). "Children with headache suspected of having a brain tumor: a cost-effectiveness analysis of diagnostic strategies". Pediatrics. 108 (2): 255–63. doi:10.1542/peds.108.2.255. PMID 11483785.
- "Headaches in Children". achenet.org. Archived from the original on 16 May 2008. Retrieved 30 June 2010.
- Guidetti V, Galli F, Fabrizi P, Giannantoni AS, Napoli L, Bruni O, Trillo S (September 1998). "Headache and psychiatric comorbidity: clinical aspects and outcome in an 8-year follow-up study". Cephalalgia. 18 (7): 455–62. doi:10.1046/j.1468-2982.1998.1807455.x. PMID 9793697.
- Wang SJ, Fuh JL, Lu SR (August 2009). "Chronic daily headache in adolescents: an 8-year follow-up study". Neurology. 73 (6): 416–22. doi:10.1212/WNL.0b013e3181ae2377. PMID 19605771. S2CID 32419124.