Author: Soma Sahai, MD, Director of Neurology Ambulatory Clinics, LAC and USC Medical Center; Assistant Professor, Department of Neurology, University of Southern California

Coauthor(s): David Y Ko, MD, Associate Professor, Laboratory Director, Department of Neurology, University of Southern California Medical Center

Editors: Joseph Carcione Jr, DO, MBA, Consultant in Neurology and Medical Acupuncture, Medical Management and Organizational Consulting, Central Westchester Neuromuscular Care, PC; Medical Director, Oxford Health Plans; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; James H Halsey, MD, Professor, Department of Neurology, University of Alabama Medical Center; Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital; Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants

Author and Editor Disclosure

Synonyms and related keywords: cluster headache, chronic daily headache, daily chronic headache, tension-type headache, analgesic abuse, rebound headache, analgesic-abuse headache, secondary headache, vascular headache, migraine variants, migraines, cluster headache, tension headache, medication-overuse headache, MOH, migraine with aura, migraine without aura, migrainous aura, migraine transformation, familial hemiplegic migraine, ophthalmoplegic migraine, migraine equivalent, classic aura, late-life migrainous accompaniments, retinal migraine, ocular migraine, abdominal migraine, complicated migraine, vertebrobasilar migraine, status migrainosus, histamine cephalalgia, Horton neuralgia, erythromelalgia

Headache is a pervasive symptom and the most common problem neurologists encounter in their clinical practices. It affects an estimated 60-80% of Americans at any time. The history of headache can be traced almost to the beginning of the history of humankind. The first description of headache dates back to the third millennium BCE. Headache has been written about extensively since the time of the Babylonian civilization. Migraine headache and hemicrania are discussed in the Bible. Some famous historical figures (eg, Napoleon) are known to have had terrible headaches.

Much debate exists among headache specialists regarding the evolutionary mechanisms; however, all agree on the paucity of literature related to this topic. This lack most likely exists because headache is a subjective symptom, because no objective measures or standardizations are available, and because species studies are limited to humans. Two common evolutionary mechanisms of disease production have been described. The first is a protective mechanism in response to what the body perceives as an external environmental stress. The second, and simpler, mechanism is pathogen-mediated disease production (eg, disease due to infections caused by bacteria, viruses, or other pathogens). The first seems most likely to apply to headache.

Several observations give credence to the theory that the evolution of headache may be an internal protective response developed against environmental stressors. When exposed to extremes of temperature, humans can develop the classic vascular headache. The same is true for people who have had a sudden lack of sleep or food.

Common triggers of vascular headaches are stress, heat, or a lack of sleep or food. People with a predisposition to headache may have a lower threshold of response to these external stressors than other people. Patients with migraine may have inherited the predisposition for this lowered threshold. Therefore, some experts have theorized that headache is a slow, adaptive response. Most primary headaches develop slowly over minutes, if not hours. The pain associated with headache is transmitted by the slowest of all unmyelinated nerves.

For clinical purposes, the International Headache Society (IHS) (which revised the classification of headaches in 2004 [IHS-2]) divides headaches into 2 broad categories: primary headaches and secondary headaches. Primary headaches, which are headaches with no organic or structural etiology, include vascular (migraine) headache, trigeminal autonomic cephalalgias (which includes cluster headache), tension headache, and other secondary headaches (ie, hemicrania continua, new daily persistent headache, exertional headache, hypnic headache, thunderclap headache). Secondary headaches are those due to an underlying structural or organic disease and include 9 subcategories.

For related information, see Medscape's Headache Resource Center. 

Two main schools of thought exist to explain the pathophysiology of migraine. The first is older and is based purely on a vascular theory; it has fallen out of favor and has been replaced by the neurovascular theory. What is now clear is that migraine is a chronic disorder of the CNS and the vascular changes that occur are more of an epiphenomenon.

Vascular Theory

In the 1940s and 1950s, the vascular theory was proposed to explain the pathophysiology of migraine headache. Wolff et al believed that intracranial vasoconstriction is responsible for the aura of migraine and that the subsequent rebound vasodilatation and activation of perivascular nociceptive nerves resulted in headache. This theory was based on the observations that (1) extracranial vessels become distended and pulsatile during a migraine attack; (2) stimulation of intracranial vessels in an awake person induces headache; and (3) vasoconstrictors (eg, ergots) improve the headache, whereas vasodilators (eg, nitroglycerin) provoke an attack. However, this theory has been challenged for several reasons, including the theories described below.

Neurovascular Theory

The current view is that a complex series of neural and vascular events initiates migraine. This view is now called the neurovascular theory, the key features of which are described in detail below.

At baseline, a migraineur who is not having any headache has a state of neuronal hyperexcitability in the cerebral cortex, especially in the occipital cortex. This finding has been demonstrated in studies of transcranial magnetic stimulation and with functional MRI. This observation explains the special susceptibility of the migrainous brain to headaches. One can draw a parallel with the patient with epilepsy who similarly has interictal neuronal irritability.

The best data for such an excitability come from studying aura. Aura is initiated by cortical spreading depression (CSD), which is a migraine trigger.

Cortical spreading depression

In 1944, Leao proposed the theory of CSD to explain the mechanism of migraine with aura. A migraine aura is due to a well-defined wave of neuronal excitation in the cortical gray matter that spreads from its site of origin at the rate of 2-6 mm/min. This spread is followed by a wave of neuronal suppression in the same manner. The blood vessels in this area simultaneously dilate and then constrict. Therefore, migrainous aura is a cortical event with a definite and well-defined neuroelectrical basis.

The neurochemical basis of the CSD is the release of potassium or the excitatory amino acid glutamate from neural tissue. This release depolarizes the adjacent tissue, which, in turn, releases more neurotransmitters, propagating the spreading depression.

Positron emission tomography (PET) scanning demonstrates that blood flow is moderately reduced during a migrainous aura, but the spreading oligemia does not correspond to vascular territories. The oligemia itself is insufficient to impair function. Instead, the flow is reduced because the spreading depression reduces metabolism.

The reason why these neurons are more excitable at a cellular level in certain patients is not entirely clear. Specific groups of patients with migraine have a genetic defect leading to a lowered threshold for CSD, and this is called familial hemiplegic migraine (FHM). However, for the vast majority of patients, a clear metabolic or genetic defect that easily explains this neuronal excitability cannot be determined.

Brainstem activation

PET scanning in patients having an acute migraine headache demonstrates activation of the contralateral pons, even after medications abort the pain. Weiler et al proposed that brainstem activation may be the initiating factor of migraine.

Once the CSD occurs on the surface of the brain, H⁺ and K⁺ ions diffuse to the pia mater and activate C-fiber meningeal nociceptors, which releases a proinflammatory soup of neurochemicals (eg, calcitonin gene–related peptide) and plasma extravasation occurs. Therefore, a sterile, neurogenic inflammation of the trigeminovascular complex is present. Once the trigeminal system is activated, it stimulates the cranial vessels to dilate. The final common pathway to the throbbing headache is the dilatation of blood vessels.

Cutaneous allodynia

Burstein et al described the phenomenon of cutaneous allodynia, in which secondary pain pathways of the trigeminothalamic system become sensitized during a migrainous episode.¹ This observation further demonstrates that sensitization of central pathways in the brain mediates the pain of migraine, in addition to the previously described neurovascular events.

Dopamine Pathway

Some authors have proposed a dopaminergic basis for migraine.² In 1977, Sicuteri postulated that a state of dopaminergic hypersensitivity is present in patients with migraine. Interest in this theory has recently been renewed.

A variety of prodromal symptoms (eg, yawning, irritability, nausea, vomiting) can be attributed to relative dopaminergic stimulation. Dopamine antagonists, such as prochlorperazine, completely relieve almost 75% of acute migraine attacks.

Magnesium Deficiency

Another theory proposes that deficiency of magnesium in the brain triggers a chain of events, starting with platelet aggregation and glutamate release and finally resulting in the release of 5-hydroxytryptamine, which is a vasoconstrictor.

Prevalence

Migraine affects 17% of females and 6% of males in the United States.³ Before puberty, both the prevalence and incidence of migraine are higher in boys than in girls. In individuals older than 12 years, the prevalence increases in both males and females, and the incidence declines in individuals older than 40 years, except for women in perimenopause. The overall prevalence is higher in females than in males. The female-to-male ratio increases from 2.5:1 at puberty to 3.5:1 at age 40 years, after which it declines.

The incidence of migraine with aura peaks in boys at around age 5 years and in girls at around age 12-13 years. The incidence of migraine without aura peaks in boys at age 10-11 years and in girls at age 14-17 years. The incidence of migraine in females of reproductive age has increased over the last 20 years, probably due to more awareness of the condition. In the United States, white women have the highest incidence of migraine, whereas Asian women have the lowest incidence. Moreover, low socioeconomic status is associated with migraine. Currently, 1 of 6 American women has migraine headaches.

Genetics

Approximately 70% of patients have a first-degree relative with a history of migraine. The risk of migraine is increased 4-fold in relatives of people who have migraine with aura. However, no genetic basis has been identified for common migraine, although it generally demonstrates a maternal inheritance pattern.

FHM type 1 is a type of migraine with aura that is preceded or followed by hemiplegia, which typically resolves. In approximately 50% of affected families, FHM is linked to band 19p13 or a mutation in the calcium channel gene (CACNA1A4) at the 1q locus. FHM may be associated with cerebellar ataxia, which is also linked to the 19p locus. Evidence suggests that the 19p locus for FHM may also be involved in patients with nonhemiplegic migraine. FHM type 2 is due to mutation in the sodium channel gene ATP1A2 on chromosome 1.

Migraine occurs with increased frequency in patients with mitochondrial disorders, such as MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes). CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a genetic disorder of the notch 3 gene on chromosome 19 that causes migraine with aura.

Comorbidities of migraine

Migraine is associated epilepsy (eg, benign rolandic epilepsy, benign childhood epilepsy), familial dyslipoproteinemias, hereditary hemorrhagic telangiectasia, Tourette syndrome, hereditary essential tremor, hereditary cerebral amyloid angiopathy, ischemic stroke (migraine with aura is a risk factor, with an odds ratio of 6), depression and anxiety, asthma, patent foramen ovale, and stroke. Epilepsy increases the relative risk of migraine by 2.4.

The risk of posterior circulation strokes, especially cerebellar, is increased in migraineurs with aura. Female migraineurs, with or without aura, have an increased risk of deep white matter brain lesions. Several studies are currently investigating patent foramen ovale, which is seen in 18-21% of migraine patients.

For related information, see Medscape's Epilepsy and Anxiety Resource Centers.

Diagnosis, description, and triggers of migraine

The diagnosis of migraine is clinical in nature, based on criteria established by the IHS.

Some patients describe a prodromal phase as early as 48 hours before the headache. This phase includes irritability, depression, frequent yawning, or hyperexcitability.

The headache itself is usually described as throbbing or pulsatile. It is usually unilateral, but the side affected in each episode may be different. The headache usually lasts 6-24 hours. During a headache, patients prefer to lie quietly in a dark room. Nausea, vomiting, photophobia, phonophobia, irritability, and malaise are common.

A history of certain triggers can be elicited. Common triggers include certain foods (eg, chocolate, cheese, oranges, tomatoes, onions, monosodium glutamate [MSG], aspartame, red wine, alcohol), hormonal changes (eg, menstruation, ovulation, oral contraceptives, hormone replacement), head trauma, physical exertion, fatigue, medications (eg, nitroglycerin, histamine, reserpine, hydralazine, ranitidine, estrogen), and stress.

Types of migraine

 Migraine variants

Treatment

Successful treatment of migraine involves 5 steps.

Step 1

Step 1 is an accurate clinical diagnosis based on the IHS criteria. A full neurologic examination should be performed during the first visit; the findings are usually normal. Neuroimaging is not necessary in a typical case.

Step 2

Step 2 is a disability assessment. Simple questionnaires, such as the Migraine Disability Assessment Scale (MIDAS), can be used to quantify the extent of disability on the first visit. These questionnaires can also be used for follow-up evaluations.

Step 3

Step 3 is stratified care for the acute treatment of the headache. Patients who have mild symptoms and disability can be adequately treated with acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), propoxyphene, or a combination of these.

Patients with moderate disability need migraine-specific oral medications. The 2 categories of such medications are triptans and ergot alkaloids. The specific triptans are sumatriptan, rizatriptan, zolmitriptan, naratriptan, almotriptan, eletriptan, and frovatriptan. The specific ergot alkaloids are ergotamine and dihydroergotamine. Do not administer vasoconstrictors, such as ergots or triptans, to patients with known complicated migraine; treat their acute attacks with one of the other available agents, such as NSAIDs or prochlorperazine.

The first combination product of a 5HT receptor agonist (ie, sumatriptan) and an NSAID (ie, naproxen sodium), Treximet, was approved by the US Food and Drug Administration in April 2008. Efficacy was demonstrated in 2 randomized, double-blind, multicenter, parallel-group trials comparing the combination product to placebo and each individual active component (ie, sumatriptan and naproxen sodium). The percentage of patients remaining pain free without use of other medications through 24 hours postdose was significantly greater (p<0.01) among patients receiving a single dose of Treximet (25% and 23%) compared with placebo (8% and 7%) or either sumatriptan (16% and 14%) or naproxen sodium (10%) alone.⁴

Patients with severe headaches need subcutaneous, intravenous, or oral formulations of these drugs. Patients with severe nausea and vomiting at the onset of an attack may respond best to intravenous prochlorperazine. These patients may be dehydrated, and adequate hydration is necessary.

Approximately 40% of all attacks do not respond to a given triptan or any other substance. If all else fails, an intractable migraine attack (status migrainosus), or an attack lasting longer than 72 hours, should be addressed in an urgent care or emergency department. In rare cases, patients may need to be hospitalized for a short period.

Step 4

Step 4 is to individualize treatment on the basis of the patient's profile. No 2 patients with migraine are the same. Each patient has a unique psychosocial environment that heavily influences his or her treatment.

Step 5

Step 5 is patient education, which is key to successful long-term management. Migraine is a chronic neurologic disorder that requires a lifestyle change at some level.

Patient education includes teaching the patient to avoid triggers. Patients should avoid factors that precipitate a migraine attack (eg, lack of sleep, fatigue, stress, certain foods, use of vasodilators). Encourage patients to use a daily diary to document the headaches. This is an effective and inexpensive tool to follow the course of the disease.

Changes in hormonal levels, particularly estrogen levels, may exacerbate headaches in women. Women may be advised to modify, change, or discontinue use of their oral contraceptives for a trial period. Leuprolide (Lupron) has been used to simulate menopause to assess the relative role of estrogenic changes as a trigger.

Nonpharmacologic treatment

Americans spend more than $13.7 billion a year on complementary medicine, and more than 70% of patients do not tell their doctors about it. Interest in the use of complementary and alternative medicine (CAM) by headache patients has been increasing. A recent survey showed that more than 85% of headache patients use CAM therapies and 60% felt they provided some relief.⁵

Some CAM techniques have good scientific evidence of benefit and have been proven by studies to be effective in preventing migraine. Biofeedback and behavioral therapy should be part of the standard of care for a difficult migraine patient.

Recently, some good studies have demonstrated the effectiveness of the herb Butterbur (Petasites hybridus) in preventing migraines.⁶ Another herb, Feverfew, is also widely used and some studies have shown it to be safe and possibly effective for migraine prevention.

A variety of other CAM techniques are not bolstered by solid scientific data, but they may be perceived to be of benefit to patients. A few techniques commonly practiced for headache relief include body work (eg, chiropractic, massage), creative arts (eg, dance, music), nutritional/herbal supplements (eg, vitamins, herbs), Eastern medicine (eg, yoga), acupressure and acupuncture⁷, and Ayurveda. Overall, scientific evidence on the efficacy of these studies is lacking, partly due to the poor design and/or poor quality of the studies performed to date.

The advantages of CAM therapies are that many of these remedies have no adverse effects, they advocate a self-help technique that is attractive to patients, and they offer a holistic approach. The practitioners often spend significant time with their patients, and that in itself makes the patient feel as if he or she has been given careful attention.

The disadvantages of CAM therapies are that the method to either the practice or the dispensing of the therapies and techniques is not standardized. In addition, no standard format exists to ensure the practitioners are adequately trained in the techniques they use.

Besides those described, one of the most effective and simple ways to manage migraines includes patient education, including the recognition of and avoidance of factors that precipitate a migraine attack (eg, lack of sleep, fatigue, stress, certain foods, vasodilators). Encouraging the use of a diary to document the headache pattern is a very effective and inexpensive tool to follow the course of the disease.

Migraine Prophylaxis

Indications

Therapy to prevent migraine is indicated if  (1) the patient has more than 2 migraine attacks per month, (2) the patient has single attacks that last longer than 24 hours, (3) the headaches cause major disruptions in the patient's lifestyle, (4) abortive therapy fails or is overused, and (5) the patient has complicated migraine.

The goals of preventive therapy are (1) to reduce attack frequency, severity, and/or duration; (2) to improve responsiveness to acute attacks, and (3) to reduce disability.

Classes of prophylactic drugs

The 3 classes of medications that are effective for migraine prevention are antiepileptics, antidepressants, and antihypertensives. Botulinum toxin A (BOTOX®) may be another effective medication.⁸ Tailor the choice of medication to the patient profile.

Antiepileptics such as topiramate⁹ (Topamax) are indicated for migraine prophylaxis and are well tolerated. The main adverse effects are weight loss and dysesthesia. Valproic acid (Depakote) is also indicated as a migraine prophylactic and is useful as a first-line agent. However, it can cause weight gain, hair loss, and polycystic ovary disease; therefore, it may not be ideal for young female patients who have a tendency to gain weight. It also carries substantial risks in pregnancy, but it may be best suited for women who have had tubal ligation and who cannot tolerate calcium channel blockers because of dizziness. Valproic acid is a good mood stabilizer and can benefit patients with concomitant mood swings. Data for other antiepileptics (eg, gabapentin, lamotrigine, oxcarbazepine) are limited in migraine. 

Tricyclic antidepressants are good second-line alternatives because of their adverse-effect profile and efficacy. Amitriptyline and nortriptyline are most effective, as has been shown in the current data. Although serotonin-selective reuptake inhibitors are widely used, data regarding their efficacy in migraine prevention are lacking.

Antihypertensives such as beta-blockers are approved by the US Food and Drug Administration for migraine prophylaxis, but they should be tailored if the patient is young and anxious. They may not be the ideal choice for elderly patients or patients with depression, thyroid problems, or diabetes. Calcium channel blockers are another possible choice of treatment. ACE inhibitors (eg, lisinopril) and angiotensin-receptor blockers (eg, candesartan) have recently been shown to be effective for migraine prevention.¹⁰
 
Botulinum toxin A (BOTOX®) may be beneficial in patients with intractable migraine headaches that fail to respond to conventional preventive medication. The injections are administered to the scalp and temple. They may reduce the frequency and severity of migraine attacks after 2-3 months of injections. The injections are expensive and must be administered every 2-3 months to maintain their effectiveness. The most appropriate duration of prophylactic therapy has not been determined. In most patients who are receiving prophylaxis, therapy must be continued for at least 3-6 months.

For any of these prophylactic agents, prophylaxis should not be considered a failure until it has been given at the maximum tolerable dose for at least 30 days.

Cluster headache has more than a dozen synonyms, including histamine cephalalgia, Horton neuralgia, or erythromelalgia. It was first described by Horton in 1939. In recent years, some exciting new discoveries have been made with regard to the pathophysiology and treatment of this strange headache. The IHS-2 has recently subclassified cluster headache as a trigeminal autonomic cephalalgia because of the prominent autonomic findings that accompany the headache.

Prevalence

Cluster headaches are rare, with a prevalence of less than 1% (1 in a 1000), and they are more common in white persons. The disease usually appears in persons aged 20-40 years. Men peak in the third decade of life. Women have 2 peaks, in the second and sixth decades of life. The male-to-female ratio is 5-8:1. However, in recent years, the incidence among women is rising, probably because of better understanding of the disorder. Women's cluster headaches are of shorter duration, they have fewer autonomic symptoms, and they have less miosis. Migrainous symptoms are more common.

Episodic cluster headaches occur in 80% of patients. These headaches last 7 days to 1 year, with pain-free periods for up to 14 days. Chronic cluster headaches last 1 year or more without remission or remission that lasts less than 14 days.

Other headaches with a higher male-to-female ratio are short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and exertional headache (including cough and coital headache).

Certain personality and physical characteristics, such as a leonine appearance, peau d'orange skin, and coarse features, have been associated with cluster headache. Strong associations with smoking, alcohol use, and previous head and face trauma have been noted. A positive family history is present in 11% of patients. Although no gene has been identified as being causative of cluster headaches, a 14-fold increase in cluster headache incidence is noted in first-degree relatives. A polymorphism of the hypocretin receptor 2 gene (responsible for narcolepsy) has been found to be associated with cluster headache, and the risk increases 5-fold with this finding.^{11, 12} Interestingly, sleep apnea is common in cluster headache patients. Attacks of cluster headache occur 60-90 minutes after falling asleep, during the first rapid eye movement period.

Pathophysiology

In accordance with the vascular theory, cluster headache was previously thought to be due to cavernous sinus venous vasculitis, because this is the only anatomic location in the nervous system where all 3 key elements in question are in close proximity. A venous vasculitis blocks venous drainage and damages the carotid plexus of sympathetic nerve fibers. Angiograms performed on patients during a cluster headache episode have shown vasodilation of the ophthalmic artery. Other findings include increased corneal indentation, intraocular pressure, and skin temperature around the eyes.

With regard to the neurovascular theory, exciting evidence has indicated from PET scanning and functional MRI studies of cluster patients during an episode that the (ipsilateral) hypothalamus is the primary generator of cluster headaches.¹³ A wide range of endocrinological disturbances (eg, low testosterone and melatonin levels) are seen in cluster headache patients. The hypothalamus then activates the superior salivatory nucleus, which stimulates the parasympathetic pathway. The parasympathetic pathway is responsible for tearing, rhinorrhea, and conjunctival redness, among other things. Levels of the neurotransmitter vasoactive intestinal peptide are very high in persons with cluster headache.  

Furthermore, regarding the neurovascular theory, the hypothalamus also activates the trigeminal vascular pathway, which is responsible for the head pain. Pain is mediated by the V1 division of the trigeminal nerve. Ocular sympathetic defects are thought to be due to neurapraxic injury of postganglionic fibers, autonomic dysregulation that originates centrally, or vasodilation and perivascular edema. The sympathetic chain is hypoactivated, resulting in the development of a partial Horner syndrome.

With regard to parasympathetic overactivity, only 7% of patients have no autonomic symptoms. Some patients have only autonomic symptoms but no headache.

During acute cluster episodes, PET studies have shown that the ipsilateral hypothalamus, the anterior cingulate gyrus, and the bilateral insula are activated. Moreover, PET studies have consistently shown increased density of the ipsilateral hypothalamus in cluster headache patients. A magnetic resonance spectroscopy study of hypothalamic metabolism in 26 cluster headache patients performed in Italy showed that N-acetyl aspartase levels were of lower peak in cluster headache patients. Thus, the density of neurons in the hypothalamus is increased with a reduced ratio of N-acetyl aspartase to creatine, which indicates neuronal dysfunction in that area.

Clinical features

No premonitory features are associated with cluster headaches. Cluster pain is described as extremely severe, unilateral, orbital or supraorbital pain associated with ipsilateral facial autonomic symptoms, such as ptosis, tearing, and injection. Of cluster headache patients, 7% may not have autonomic symptoms. The pain also may radiate to the back of the neck, to the suboccipital area, and along the carotid artery. The pain often is boring or piercing in nature and lasts from 15 minutes to 4 hours. The headache typically awakens the patient in the middle of the night. Tenderness of the temporal artery, facial flushing, and elevated skin temperature on the ipsilateral side have been reported.

During an attack, the patient is restless and may find relief in pacing or crying. Clusters start rapidly over a few minutes, and maximum pain is in the distribution of the first or second divisions of the trigeminal nerve. Periodicity is characteristic of the disease; the patient experiences clusters of headaches, each lasting as long as several months, once or twice a year. Attacks are more common during the months with the longest and shortest days of the year. During a cluster period, patients may experience many attacks per day. The use of alcohol, histamine, or nitroglycerin during an attack of cluster headache may worsen the attack.

Treatment of acute attack

Oxygen therapy is safe and effective; thus, it is the treatment of choice. Oxygen delivered through a face mask at a dose of 8 L/min for 10 minutes, early on during an attack, often terminates or diminishes the intensity of the attack. Oxygen is postulated to be a vasoconstrictor and increases synthesis of serotonin in the CNS, which may be the reason for its efficacy.

Subcutaneously administered sumatriptan (6-12 mg) is effective in treating an acute attack of cluster headache. In one study, 74% of patients responded to subcutaneous sumatriptan, compared with 26% who took placebo. Sumatriptan also relieves the autonomic symptoms associated with cluster headaches. Oral agents are less effective and less useful because cluster headache typically lasts for less than 1-2 hours and oral agents may take up to 1 hour to be effective. Oral zolmitriptan (10 mg) and oral sumatriptan have also been used.

Cocainization of the sphenopalatine ganglion has been shown in the past to abort cluster headaches; thus, viscous lidocaine dropped into the ipsilateral nose may work. Intranasal administration of 2% lidocaine (1 mL) with the patient in the supine position is effective in some patients.

Transitional prophylaxis with nightly administration of oral or suppository  ergotamine (2 mg) can also be used. Relief is reported in more than 50% of patients when ergotamine is given early during the attack. The inhaled form of ergotamine is given in the dose of 0.5 mg, with a maximum total dose of 2.16 mg delivered in as many as 6 puffs. The sublingual dose is 2 mg every half hour, with a maximum of 8 mg/d.

Dihydroergotamine is as effective as ergotamine, but it has the disadvantage of self-administration during an attack. The dose is 0.5-1 mg given intravenously or intramuscularly.

Prophylactic therapy

Prophylactic therapy should be initiated early, during the beginning of a cluster period, and discontinued only after the patient has an attack-free period of 2 weeks. Therapy should typically be started at the lowest dose and gradually increased to the maximum effective and tolerated dose. The adverse-effect profile determines the choice of medication. Medication doses should be tapered and not abruptly withdrawn at the end of a cluster period.

Calcium channel blockers are the first-choice agents for the prophylactic treatment of cluster headaches. Verapamil is the most effective calcium channel blocker; the dose is 120 mg in 3-4 divided doses. Adverse effects include constipation and water retention.

Prednisone is dramatically effective in some patients and should be tried if other therapies fail. The dose is 30-75 mg/d for the first few days, followed by a quick taper, or maintenance at a dose of 5-10 mg for the duration of the cluster headache.

The dose of ergotamine is 2 mg orally given twice a day.

Dihydroergotamine can be given for severe, recurrent attacks. The dose is 0.5-1 mg given intravenously every 8 hours for 72 hours.

For methysergide maleate, the dose is 2 mg/d, with a daily 2-mg increase to a maximum of 8 mg/d. Adverse effects include nausea, vomiting, abdominal cramps, leg cramps, skin swelling and discoloration, and fibrotic reactions in peritoneal, pleural, cardiac, and pulmonary tissue. Contraindications include peripheral vascular disease, chronic pulmonary disease, hypertension, deep vein thrombosis, and active peptic ulcer.

The dose for lithium is 600-900 mg/d in divided doses. Adverse effects include hypothyroidism, renal complications, and adverse neurological effects (eg, tremor, slurred speech, blurred vision, confusion, nystagmus, ataxia, extrapyramidal effects, seizures).

Adverse effects of indomethacin include gastric irritation, mental confusion, and psychosis in some patients with cluster headaches.

Steroid injections into the occipital nerve are another option. Methylprednisolone acetate at 120 mg in polyethylene glycol with lidocaine is injected into the ipsilateral greater occipital nerve, resulting in remission of the attack.

For valproic acid, the dose is 250 mg given twice a day. The dosage can be increased to 1000 mg/d as tolerated.

Newer treatment modalities

Somatostatin inhibits the release of calcitonin gene–related peptide and vasoactive intestinal peptide. The chief source is the hypothalamus. Octreotide is a somatostatin analog. It has a peripheral mode of action. Matharu et al reported on a study of 57 patients given octreotide (46 provided efficacy data) and 45 given placebo. The headache response rate with 100 mcg of octreotide subcutaneously was 52%, and the headache response rate was 36% for those given placebo. GI upset was the main adverse effect reported.¹⁴ 

Surgical treatment for patients with intractable disease

Ipsilateral hypothalamic stimulation has now been used on more than 12 patients as a treatment for intractable cluster headache, especially for those with chronic disease. The hypothesis is that the hypothalamus is the clock-pulse generator. Constant depolarization discontinues the biological clock like an impulse from a distant trigeminal anatomic execution. Leone et al reported the results over 4 years in 20 patients, the first procedure being in 2000. Thirteen of 16 patients did extremely well. Only transient diplopia was noted as an adverse effect. However, the stimulator takes several weeks to work.¹⁵

Chronic daily headache is defined as a headache that is present for more than 15 d/mo. The 3 main types discussed are (1) chronic tension-type headache, (2) chronic migraine, and (3) hemicrania continua.
 
The pathogenesis of chronic daily headache is not well understood, and some believe that it is due to a central mechanism involving an alteration in serotonergic and monoaminergic pathways to the brainstem and hypothalamus.

Only 1% of patients with chronic headache and normal neurologic examination findings have abnormal neuroimaging study findings. Neuroimaging is recommended only if the headache has atypical features.

Chronic daily headaches have been associated with an increased frequency of comorbid conditions, including depression, anxiety, bipolar disorders, panic attacks, oromandibular dysfunction, stress, and drug overuse.

Chronic Tension-type Headache

The IHS-2 criteria are at least 10 episodes of the following:

Patients report almost constant daily headache of mild-to-moderate intensity. The headache is described as a tightness or pressure that is not worsened with activity. Patients with chronic tension-type headache can perform their daily activities with the headache. Nausea and photophobia may be present, but the patient usually has no vomiting. A subset of patients may have tenderness of the pericranial and neck muscles, with or without electromyographic changes.

Treatment

Patients whose headaches are unresponsive to previous treatment and patients with comorbid conditions, such as depression and stress, may be candidates for psychological treatments.

Biofeedback

Electromyographic biofeedback has been applied successfully in patients with tension headache to teach them how to relax their tense muscles. Thermal biofeedback, in which patients are taught to increase their body temperatures to improve their headaches, has also been successful. Neurofeedback with real-time EEG technology has been used for both migraine and posttraumatic headache. The precise mechanism of biofeedback responses is unknown. Other unconventional treatments, such as relaxation training and stress-coping training, may be helpful in the long term.

Of note, new daily persistent headache is a new classification under the IHS-2. This is simply chronic tension-type headache for which the patient can recall the exact onset of the headache.

Other Uncommon Chronic Headaches

Hemicrania continua and chronic paroxysmal hemicrania

Hemicrania continua is an exclusively 1-sided constant headache, which, like chronic paroxysmal hemicrania, is exquisitely responsive to indomethacin. Because indomethacin is often poorly tolerated, it is also available in a suppository. Importantly, patients treated with this medication must be monitored for tarry stools and GI upset.

Chronic paroxysmal hemicrania is a unilateral severe chronic headache, similar to cluster headache, with a male predominance. The headaches are paroxysmal, with pain in the temporo-orbital region, and last 20-30 minutes. The pain may be associated with conjunctival redness, rhinorrhea, and Horner syndrome. The paroxysms occur several times a day. The headache is named after its chronicity and can last several years. Treatment with indomethacin results in a dramatic response.

Other Primary Headaches

Hypnic headache

Hypnic headache is an exclusively nocturnal headache that occurs in elderly persons. They are frequent, often occurring 4 or more nights per week, and of relatively short duration, lasing less than 2 hours. These headaches typically lack migrainous or autonomic qualities. The headaches can be worsened by lying down. Treatment options include indomethacin, lithium, and caffeine.

Secondary headaches are secondary to organic or structural etiologies. In the IHS-2, they are subdivided  into the following 8 categories:

Headaches attributed to head and neck trauma

Headache can be part of the postconcussion syndrome, which results in a wide spectrum of symptoms. Patients may report vague headaches, fatigue, memory problems, and irritability for months or years after the traumatic event. Treatment is difficult. Reassurance with treatment of the patient's underlying anxiety are the mainstays of therapy. Tricyclic agents can be effective in treating posttraumatic headache.

Headache attributed to cranial or cervical vascular disorders

Subarachnoid hemorrhage is a neurologic emergency when the patient presents with a sudden, worst-ever headache. The bleeding may be associated with abnormal neurologic examination findings, with signs of raised intracranial pressure (eg, papilledema, nausea, vomiting, cranial nerve palsies) or with palsy of the third cranial nerve. A subarachnoid hemorrhage is typically due to a ruptured berry aneurysm at the branching site of an intracranial blood vessel.

Immediate CT scanning of the head reveals the blood. Patients with negative CT scanning findings may require lumbar puncture to show breakdown of blood products in the cerebrospinal fluid (CSF), termed xanthochromia. Consultation with a neurosurgeon and conventional angiography are the next steps in diagnosis. Other causes in this subcategory include giant cell arteritis, CNS vasculitis, and dissection (which is a migraine comorbidity)

Headache due to temporal arteritis

First described by Hutchinson in 1890, this is an inflammatory arteritis of the temporal artery or other branches of the carotid system. The headache is generally localized to the affected side and is exacerbated by chewing. The pain is due to the inflamed vessels of the scalp, which are thickened, tender, and often pulseless. The diagnosis is confirmed by the presence of a high erythrocyte sedimentation rate and findings on temporal artery biopsy. The mainstay of treatment is steroids. Many clinicians titrate prednisone to the falling erythrocyte sedimentation rate response rather than to symptoms.

Headache attributed to nonvascular intracranial disorders

The headaches in this category are due to either high CSF pressure (eg, idiopathic, secondary to tumors) or low CSF pressure. Headaches associated with intracranial tumors are, in the classic description, initially paroxysmal, waking the patient from sleep at night, and are associated with projectile vomiting. However, this classic presentation is rare, and any new headache should be viewed as potentially lesional in origin. With time, the headaches may become continuous and intensify with activities that increase intracranial pressure (eg, Valsalva maneuver, coughing, sneezing).

Tumors of the posterior fossa often are localized to the occipital region and radiate to the neck. Tumors of the foramen magnum manifest as an occipital headache that worsens if the patient is in a supine position and is relieved by standing up. Headaches related to chronic hydrocephalus are diffuse and can radiate down the neck. Adults with a brain tumor present with headache in 40-60% cases. Headache is a more common presentation in children with tumors, possibly because posterior fossa tumors are common in children.

Headache due to idiopathic intracranial hypertension (benign intracranial hypertension, pseudotumor cerebri)

This is a disorder due to increased intracranial pressure in the absence of any structural CNS abnormality or obstruction of the flow of CSF. Initially, patients report chronic headache followed by visual symptoms and diplopia. Neurologic examination findings differentiate it from primary headaches. Patients have papilledema and loss of visual acuity, and they may have cranial nerve VI palsy. Lumbar puncture confirms the diagnosis. Treatment includes repeated lumbar punctures, steroid therapy, acetazolamide, weight reduction, and, if all else fails, surgical therapy (lumboperitoneal shunt or optic fenestration).

Headache due to lumbar puncture

Persistently low CSF pressure after lumbar puncture can cause a headache that is exacerbated by sitting up from the lying down position. This headache is probably secondary to the shift and traction on intracranial vessels because of decreased intracranial tension. It is usually self-limiting and resolves with hydration. If the condition persists beyond 24 hours, caffeine or a blood patch may be required.

Headache attributed to infection

Headaches can occur due to either CNS or systemic infection. Meningitis, especially the chronic forms (eg, tuberculous, fungal), can irritate the meninges and result in chronic headaches. The headache is often diffuse and due to displacement and traction of the blood vessels traversing through the meninges. Triptans can relieve the pain of any headache with a neurovascular component, including those due to subarachnoid hemorrhage and meningitis. Therefore, triptans should never be used as a diagnostic tool.

Headache attributed to disorders of the cranium, neck, eyes, ears, nose, sinuses, teeth, mouth, or other facial or cranial structures

Headache may be a form of referred pain from the neighboring structures. Dental disease can manifest as chronic headache. Upper cervical spinal diseases, such as cervical disk disease, degenerative arthritis, or spondylosis, may result in occipital headache radiating to the neck. Chronic sinusitis and temporomandibular joint syndrome may also cause vague chronic headaches.

Headache attributed to disorders of homeostasis

The headaches in this category include those due to diving, high altitude, hypoxia, hypercapnia, dialysis, arterial hypertension, hypothyroidism, fasting, and cardiac cephalalgia

Headache attributed to a substance or its withdrawal

This category includes headaches due to acute substance use (eg, nitric oxide, phosphodiesterase-inhibitors, alcohol, food additives, cocaine, cannabis, histamine, calcitonin gene–related peptide).  It also includes medication overuse headache (eg, from triptans, ergots, analgesics, opioids, combination overuse). Substance withdrawal can also cause headaches (eg, from caffeine, opioids, estrogen).

Medication overuse headache

Some authorities have used the term migraine transformation to describe the evolution of intermittent migraine to daily migraine due to medication overuse. However, the term transformed migraine has been removed from the IHS-2. Medication overuse headache has been described as a secondary headache category to be associated with analgesic, narcotic, or ergotamine abuse.

Some investigators have reported a decreased platelet count and decreased whole blood 5-hydroxytryptamine levels in patients with analgesic-induced headache.

For detoxification drug treatment, initial discontinuation of all analgesics and headache-related medications is best achieved in an inpatient setting under the guidance of a headache specialist experienced in the protocols. A patch containing clonidine (0.1 mg) can be used to decrease withdrawal symptoms in patients dependent on codeine or morphine-based medications. Preventative medications should be started in anticipation of or in conjunction with the detoxification protocol. Various agents are used for preventative measures, including beta-adrenergic blockers, antiepileptic agents, tricyclic antidepressants, and calcium channel blockers, among others, and are discussed below.

Beta-adrenergic blockers seem to be effective in the prophylaxis of chronic daily headache, as in migraine. Beta-blockers include nadolol at 20 mg/d or twice a day, which can be increased to 120-1160 mg as tolerated; propranolol at 40 mg/d, which can be increased to 3-4 times per as tolerated; and long-acting propranolol at 80 mg twice a day, which can be increased to 160 mg twice a day as tolerated.

Among the antiepileptic agents, valproic acid and topiramate, and possibly other drugs, are effective for prophylaxis. Valproic acid has the advantage of an intravenous formulation, which can be administered to achieve therapeutic levels upon admission for detoxification. The loading dose of valproic acid is 10 mg/kg given intravenously, followed by 500 mg at bedtime. Topiramate should be titrated up to 50 mg twice a day over 1 month.

Tricyclic antidepressants are effective for chronic daily headaches. They include amitriptyline at 25-150 mg/d given at bedtime and nortriptyline at 25-75 mg. Monoamine oxidase inhibitors, such as phenelzine, may be administered at 15 mg alone or in combination with a tricyclic antidepressant 3-4 times per day. These drugs should not be first-line medications because of their drug-interaction and adverse-effect profiles.

Calcium channel blockers, such as verapamil, diltiazem, and nifedipine, are effective in some cases. Methysergide and ergonovine maleate are other options. Finally, alpha-adrenergic blocking agents are useful, especially for withdrawal from benzodiazepines or narcotics.

Headache due to psychiatric conditions

The IHS added this category in 2004. A variety of psychiatric conditions, including depression, anxiety disorders, somatization disorders, and conversion disorders, can result in headache. A reasonable attempt should be made to exclude common causes of headache before giving this diagnosis. The goal of treatment is to address the underlying psychiatric condition

Headache due to cranial neuralgias

The trigeminal and the hypoglossal cranial nerves have a propensity to cause neuropathic pain in the structures they supply. Both trigeminal and glossopharyngeal neuralgias are usually idiopathic. The diagnosis is based on the patient's history of typical neuropathic pain in the distribution of one of these cranial nerves. The neuropathic pain is sharp, short lasting, and lancinating and may be associated with allodynia.

First-line treatment is an anticonvulsant (eg, carbamazepine, oxcarbamazepine). Tricyclic antidepressants are second-line treatment. In intractable pain cases, surgical decompression of the nerve from an overlying small blood vessel is usually effective. Uncommon cranial neuralgias include occipital neuralgia, which is neuropathic pain in the distribution of the greater and/or lesser occipital nerve in the back and in one half of the scalp. Occipital nerve blocks can be effective treatment.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Robert Paul Cowan, MD, to the development and writing of this article.