#90214: Diagnosing and Managing Headaches

The above sample list of questions may seem daunting, especially in the context of a brief office visit. However, it is critical that a detailed history be obtained. It may be more efficient to have a questionnaire available for patients to fill out while they are waiting, or even prior to the office visit.

Upon further questioning, Mrs. T denies any fever, nausea, or vomiting. She denies depression or weight loss. She has not had visual disturbances. She does not recall any environmental exposures. Her current medications include metformin, lisinopril, simvastatin, and celecoxib. She remarks that her job is going quite well, and she does not feel particularly stressed from work. She works as a senior account manager at a consulting firm.

She has not had any change in medications and does not use any herbs or supplements. She drinks two cups of coffee a day, and there has been no recent change in her coffee consumption. There is neither family history of headaches nor family history of cancer. Both parents died of heart disease. She does note that she recently tripped and fell outside (almost a month ago) while playing with her grandson but denies any serious consequences from the fall other than a sore left wrist. She denies any residual weakness. She notes that she does not feel "quite 100%" but does not feel confused or "in a fog."

Many different factors work to trigger migraines. These factors vary greatly from one individual to another and often no precipitating events can be clearly identified. Trigger factors increase the probability of a migraine attack in the short term (i.e., usually in less than 48 hours) in a person with migraine. Some of the more common triggers include stress, sleep disturbances, depression, low barometric pressure, food, hormonal variations, and caffeine withdrawal. Some trigger factors have been reasonably well studied epidemiologically (e.g., menstruation) or in clinical trials (e.g., chocolate, aspartame); however, causal attribution in individual patients may be difficult[43].

For individuals who are not certain of what triggers their headaches, it may be helpful to recommend keeping a headache diary. This diary allows individuals to chronicle their headaches and document details, such as warning signs, time duration of headache, location of pain, intensity of pain, and treatment attempts/effects, along with details of their diet, sleep patterns, medications, stress, and menstrual cycle (if applicable). This is a useful tool in elucidating the relationship between events, environment, and migraines. The headache diary has been shown to improve diagnostic accuracy and allow a more precise judgment of medication consumption. It may also help in judging the quantity of two or more different headache types or subtypes, and it teaches the patient how to distinguish between different headaches.

The Institute for Clinical Systems Improvement asserts that migraines occurring in association with menses and not responsive to standard cyclic prophylaxis may respond to hormonal prophylaxis with use of estradiol patches, creams, or estrogen-containing contraceptives.

(https://www.icsi.org/wp-content/uploads/2019/01/HeadacheES.pdf Last Accessed: August 15, 2023)

Level of Evidence: Expert Opinion/Consensus Statement

Migraine headaches in premenopausal women often correlate with menses, when estrogen and progesterone levels precipitously drop. These same women, when on birth control pills, develop a similar headache pattern with initiation of their placebo pills, when estrogen and progesterone levels are low. It has been suggested that altering the schedule of birth control pills may significantly reduce the number and severity of the headaches; however, women who experience migraine with aura should not use a combined oral contraceptive pill [11,47]. Despite the increased prevalence of headache and migraine in premenopausal women, migraine is underdiagnosed in this population [48].

Approximately two-thirds of women with migraines experience headache improvement during pregnancy [49]. Usually, symptoms during the first trimester determine whether pregnant patients will experience relief—if symptoms resolve during the first trimester, patients usually remain headache-free throughout the pregnancy; if symptoms persist during first the trimester, they usually remain throughout the pregnancy [13]. In evaluating new-onset headache in a pregnant patient, clinicians should bear in mind that although migraine or tension headaches are common during pregnancy, secondary causes should be ruled out.

People who are prone to migraines also find that caffeine, which can acutely help with headaches, may work to precipitate headaches if it is withdrawn after a period of continuous daily use. Many different foods contain chemicals that may act to initiate the headache cascade (Table 4).

In addition to determining what may trigger a headache, it is important to have an understanding of the impact of a headache on an individual's quality of life and productivity. One way to get a fast yet effective understanding is with the use of the validated questionnaire called the Migraine Disability Assessment Scale (MIDAS) (Table 5) [50]. The MIDAS was developed to measure headache-related disability and improve communication between patient and physician about the functional consequences of migraine. Scores on the MIDAS have been highly correlated with physician judgments about the severity of illness and need for treatment. It may play a role in improving the care of patients with migraine and other types of headache [51].

The goals of both pharmacologic and nonpharmacologic long-term migraine treatment are to [52,53]:

Behavioral and physical interventions are used for preventing migraine episodes rather than for alleviating symptoms after an attack has begun. Although these modalities may be effective as monotherapy, they are more commonly used in conjunction with pharmacologic management [52].

The cornerstone of nonpharmacologic therapy for treating migraine headaches involves empowering patients with knowledge. Educating patients about their diagnosis allows them to have a better understanding of what is occurring and what factors may be contributing to their headaches. Patients should be involved in formulating a management plan. Regular re-evaluation of therapy is also important [38,54].

Migraine is a chronic neurologic disorder that may require patients to undergo some level of lifestyle change. Lifestyle modification is one of the most important aspects of nonpharmacologic therapy. Lifestyle modification includes dietary changes, stress management techniques, establishment of regular sleeping and eating habits, and moderate exercise. These may help ease both the severity and frequency of migraine headaches. After the early signs of headaches are identified, additional attempts may be made to further reduce symptoms.

As noted, patients' headaches are often precipitated by food triggers. Patient education includes teaching patients to recognize these triggers and then avoid them, which may help patients to become headache-free. A headache diary, as discussed previously, may help patients to identify these food triggers [20,38]. Consultation with a nutritionist may help patients find alternative foods. In addition, patients should be counseled to maintain a regular diet and avoid skipping meals. Moreover, they should consume at least eight 8-ounce glasses of water daily [56].

It has been estimated that more than 85% of headache patients use complementary and alternative medicine (CAM) therapies. Some CAM techniques have been shown to be beneficial and effective in preventing migraine. Behavioral interventions (e.g., biofeedback, stress management, psychotherapy) should be part of the standard of care for a difficult migraine patient, especially when stress is a major trigger or when analgesics are being overused [13,38]. Stress management techniques, including biofeedback and acupuncture, have been successful for some patients and have been recommended to help patients reduce the frequency and severity of migraine headache [11,23]. These techniques are most successful with a motivated patient, especially one who is trying to avoid pharmacologic therapy. It should be considered, particularly for pregnant patients and those not easily treated with pharmacologic agents. However, it is time-consuming and requires a commitment on the part of the patient [20].

Acupuncture is another therapy with which some patients have found success. It may be used as preventive management in patients with migraine and tension headache but should be used with caution in patients with severe bleeding disorders, who are pregnant, or who wear a cardiac pacemaker [11,23]. Available studies have suggested that acupuncture is at least as effective as, or possibly more effective than, prophylactic drug treatment, with fewer adverse effects [57]. It can be a valuable nonpharmacologic tool and should be considered a treatment option for patients willing to undergo this treatment [58,59,60].

Sleep disturbances are a well-known cause of headaches [61]. Insomnia has been identified as a risk factor for tension-type headache, and sleep problems have been reported as a trigger of headaches [62]. Therefore, it is important for patients to maintain regular sleep habits. This involves going to sleep and awaking at about the same time every day. It also includes avoiding stimulants around bedtime and trying to receive at least six to eight hours of sleep daily [13,56]. Patients should avoid sleep fragmentation, if possible. Interestingly, patients with a family history of hypersomnia may also experience headache [63].

Moderate exercise has also been found to be helpful in decreasing headache frequency and intensity for some migraine patients [56,64]. Exercise that decreases stress and concurrently improves cardiovascular fitness seems to be the most effective. Simply walking 30 minutes per day during a lunch hour or after work can make quite a difference in terms of decreasing headache frequency. Other migraine patients have found some relief with regular yoga classes, especially those that focus on breathing and relaxation. At a minimum, patients should be encouraged to engage in an exercise program, especially because exercise improves overall health. Ideally, patients should exercise 30 to 60 minutes, at moderate intensity, at least three times per week.

All patients who smoke should be encouraged to quit smoking. Nicotine is a well-known vasoconstrictor, and carbon monoxide is a vasodilator. Combined they can trigger the migraine process. Therefore, current smokers should be counseled to quit.

Often, a multidisciplinary approach can be effective for some patients and may lead to a decrease in migraine pain, frequency, and intensity; improved overall health status and quality of life; and improved functional status [65]. Treatment choices should be based on the severity and frequency of the headache as well as on associated symptoms and comorbidities [24].

Unfortunately, even if a patient has some success with nonpharmacologic options, many will still need medications. Some data have suggested an enhanced effect with a combination of treatments [66].

The pharmacologic options for migraine headache fall into two main categories: acute attack treatment (also known as abortive treatment) and preventive therapies.

Acute Attack Treatments

The U.S. Headache Consortium has identified goals for the successful treatment of acute attacks of migraine [53]:

To meet these goals, the Consortium has recommended that clinicians [52,53,54]:

The goal of acute attack treatment should be for the patient to be pain-free within two to four hours. The patient should be able to return to full function after this time. In addition, the headache should not return within 24 hours of being pain-free. A stepwise approach is typically recommended[38]. This approach suggests that patients are to be treated with the safest, least expensive medication during the first migraine attack, and subsequently progress to more expensive medications for subsequent attacks, if the initial ones are not effective[53,67]. As a general rule, medications used to alleviate the pain of a migraine attack should be taken early after onset, when the headache is still mild, if possible.

The American Headache Society (AHS), in cooperation with the American Academy of Neurology (AAN), publishes a periodic Consensus Statement designed to offer clinicians updated guidance in the use of established and approved therapies for the acute and preventive treatment of migraine [173,198]. AHS updates, which are based on the expanded evidence base and emerging expert consensus concerning post-approval usage, provide practical recommendations but do not constitute formal practice guidelines [198]. AHS assessments published in 2015 are used in Table 6, referencing individual pharmacotherapies for acute attack treatment [173]. Assessments were based on a review of clinical trials reported between 1998 and 2013, comparing the efficacy of various acute attack treatments versus placebo, but not the comparative efficacy of individual therapies. Where no new studies for a particular drug were found, classifications were based on previous AAN guidelines.

Acute attack pharmacologic options are used at the onset of the attack. They can be divided into nonspecific and specific drugs. The nonspecific therapies are single or combination analgesics. Routes of administration include oral, nasal, parenteral, and rectal. Appropriate situations for use, including potential side/adverse effects, drug-drug interactions, and patient-specific contraindications, should be addressed. Opioids are generally avoided, if possible, due to concerns about tolerance and dependence [54,173].

The more common analgesics used include acetaminophen, NSAIDs (e.g., aspirin, ibuprofen, naproxen sodium), and narcotics (e.g., oxycodone, morphine sulfate) [38]. Acetaminophen-aspirin-caffeine combination may also be used to treat migraines. The evidence for efficacy is most consistent for aspirin, ibuprofen, naproxen sodium, and the acetaminophen-aspirin-caffeine combination. Acetaminophen alone has been found to be ineffective [53,66,173].

In the 2000 AAN guidelines, the NSAID diclofenac was considered "probably effective" for the acute treatment of migraine. Class I studies conducted since that time resulted in the agent being reassessed by the AHS as "effective" (Level A) [14,176,177].

The nonspecific therapeutic drugs may be used to relieve the pain through many different mechanisms, although most typically work by dulling pain receptors. These are usually considered first-line therapeutic options for many individuals who find these adequate in obliterating headaches [54]. In order to increase the likelihood of efficacy it is important that these are taken as early as possible in the headache cycle [38]. In addition, a large single dose tends to be more effective than repeated smaller doses. When any of these medications are used, many clinicians add an antiemetic or pro-motility agent to increase the chance of absorption, especially during an attack when nausea is a major component [53].

Over-the-counter analgesics are often effective in treating migraine. In an observational study of the impact of over-the-counter analgesics for migraines on a patient's quality of life, nearly 100 patients who used over-the-counter medications, such as acetaminophen-aspirin-caffeine combination, and who also received educational migraine materials over a four-month period completed a general health status questionnaire. At the end of the study, patients reported significant improvements in several quality-of-life measures and increased frequency of relief [69].

Ergotamines

The specific therapies include ergotamines and triptans. The ergotamines and triptans both work as vasoconstrictors. Ergotamine derivatives, although less expensive, are more nonspecific and tend to increase the likelihood of rebound headaches after their use [53,67].

The U.S. Headache Consortium reviewed the results from 23 controlled trials of ergotamine tartrate, ergotamine-containing compounds, and ergostine-containing compounds and has recommended the following regarding the use of ergot alkaloids and derivatives, all of which are supported by the recent AHS evidence assessment of migraine pharmacotherapies [53,173]:

Triptans

The triptans are serotonin 5-HT1B/1D receptor agonists and act through three possible mechanisms: vasoconstriction of intracranial vessels, inhibition of neuropeptide release from the trigeminal nerve, and inhibition of central pain transmitters. The newer triptans have fewer side effects and are much less likely to cause rebound headaches as compared to their predecessors.

Although many of the serotonin 5-HT1B/1D receptors are located in the brain, some 5-HT1B receptors are located in the heart, as determined by anatomical studies using selective antibodies [70]. Triptans have been shown to constrict coronary arteries and prevent the release of pro-inflammatory neuropeptides [71]. In rarer circumstances, they may cause myocardial infarction [72]. Because of this, it is contraindicated to use these drugs in the setting of ischemic heart disease, uncontrolled hypertension, pregnancy, and cerebrovascular disease, such as ischemic stroke [36,38,53,73]. They should also be avoided in the treatment of FHM and basilar migraine. Triptans should not be prescribed to patients who are also taking monoamine oxidase inhibitors (MAOIs), nor should they be given within 24 hours of use of ergotamines [73]. No evidence has supported the use of triptans during the aura phase of a migraine attack [53].

Several triptan drugs are available. The drugs may be taken orally as tablets or capsules, sublingually as quick-dissolving wafers, or intranasally as a spray. Sumatriptan is also available in subcutaneous injection form [71,74].

The U.S. Headache Consortium has found that triptans are effective and relatively safe for the acute treatment of migraine headaches. They are an appropriate initial treatment choice in patients with moderate-to-severe migraine who have no contraindications for their use [52]. Patient-reported satisfaction with triptans is modest [75]. It is advisable to switch from one oral triptan to another if three migraine attacks have been treated without success [192].

Almotriptan: Almotriptan is available in oral form. It has the highest oral bioavailability of the triptans, with approximately 70% of the dose absorbed within the first hour [73,76]. A meta-analysis of 53 randomized controlled trials demonstrated almotriptan 12.5 mg to be of comparable efficacy to sumatriptan 50 mg or 100 mg [77]. Side effects include dizziness, dry mouth, paresthesia, nausea, and somnolence [53,73].

Eletriptan: Eletriptan is available in oral form. It has been suggested as one possible therapy for those patients who have a poor response to NSAIDs. In an open-label treatment study, 113 patients who suffered from migraines and did not experience a satisfactory response to NSAIDs were given eletriptan 40 mg for one migraine attack [78]. Headache, pain-free response, absence of associated symptoms, and functional response were assessed at 1, 2, 4, and 24 hours after receiving the medication. By four hours post-dose, the pain-free response rate was greater than 40% and relief of baseline symptoms was 82%. By 24 hours post-dose, only 24% of patients had headache recurrence. In a randomized double-blind study comparing eletriptan 40 mg to naratriptan 2.5 mg and placebo, 548 patients with migraines were evaluated [79]. At four hours post-dose, 67% of patients taking naratriptan experienced headache relief versus 80% for patients taking eletriptan and 44% for placebo. Patients taking eletriptan also used fewer rescue medications. Side effects include asthenia, dizziness, dysphagia, abdominal pain/discomfort, and chest tightness [53,73]. Diagnosis should be re-evaluated if the first dose is ineffective.

Frovatriptan: Frovatriptan, available in oral form, appears to have the highest potency of the triptans and may be cerebro-selective [76]. It has one of the lowest rates of headache recurrence after use. In a review of three randomized placebo-controlled trials involving almost 2,700 patients, patients using frovatriptan 2.5 mg experienced greater headache relief than placebo [80]. Side effects include fatigue, dizziness, flushing, dyspepsia, skeletal pain, and chest tightness [73].

Naratriptan: Naratriptan has the longest half-life of all the triptans. As a result, it may be particularly effective in reducing recurrence headaches in some patients. The use of naratriptan 2.5 mg was compared to naproxen 500 mg in a small, double-blind crossover study [81]. At six hours post-dose, naratriptan was more effective in relieving headache, nausea, and vomiting and did so more quickly than naproxen. Side effects include dizziness, drowsiness, malaise, paresthesias, and throat tightness [73].

Rizatriptan: Rizatriptan is one of the quickest acting oral preparations, typically reaching peak concentration in 1 to 1.5 hours. It is also available as an orally disintegrating wafer [73,76]. In a study comparing rizatriptan 10 mg versus zolmitriptan 2.5 mg versus placebo, both drugs showed improvement in headache relief compared to placebo but there was no significant difference in symptom relief between the two drugs [82]. When taken orally, rizatriptan 10 mg is superior to sumatriptan 100 mg and naratriptan 2.5 mg on some, but not all, efficacy outcomes [71,74]. Compared to sumatriptan 100 mg and naratriptan 2.5 mg, greater proportions of patients taking rizatriptan 10 mg have measurable pain relief one hour after taking medication and/or are completely pain-free after two hours. There is insufficient evidence to determine whether rizatriptan (or any triptan) is superior overall [71,74]. Side effects include asthenia, dry mouth, nausea, paresthesia, dizziness, and chest discomfort. The wafer preparation contains phenylalanine [53,73].

Sumatriptan: Sumatriptan is available in oral, subcutaneous, and intranasal preparations and in combination with naproxen [73]. It was the first triptan on the market and thus has been the most studied. Oral sumatriptan has been found to be significantly more effective than placebo at relieving migraine headache pain within two hours [83]. A systematic review of 61 studies involving 37,250 participants found that oral sumatriptan (100 mg) significantly improved headache relief compared to placebo [83].

Side effects include tingling/flushing, dizziness, fatigue, muscle pain or weakness, and chest discomfort [73]. There may be taste disturbance with the use of the nasal spray [53,73]. Although sumatriptan is the most prescribed treatment for migraine, current formulations may be associated with limitations (e.g., difficulty taking oral medication) that can result in patients' delaying or avoiding treatment. Transdermal patches have proved effective for the delivery of sumatriptan. In 2013, the U.S. Food and Drug Administration (FDA) approved Zecuity, a sumatriptan iontophoretic transdermal system [84,85]. In 2016, the manufacturer of Zecuity suspended sale of the drug pending an FDA evaluation of reports of burns and scars associated with the patch [86]. Additional novel formulations include needle-free injectable sumatriptan [75].

Zolmitriptan: Zolmitriptan is available in oral form, nasal spray, and orally disintegrating wafers [73]. In a randomized controlled trial of nearly 1,200 patients comparing oral zolmitriptan to placebo, zolmitriptan 2.5 mg was found to significantly decrease headache symptoms, resulting in headache relief in the majority of patients [87]. Of note, a dose response effect was observed, with lower doses resulting in fewer adverse events. In a randomized controlled trial comparing the use of zolmitriptan to sumatriptan of nearly 1,500 patients with migraines, there was no significant difference in headache relief [87]. Side effects include asthenia, nausea, paresthesia, dizziness, and chest discomfort. The use of the nasal spray can cause taste disturbances. The wafer preparation contains phenylalanine [53,73].

The triptans are all closely related although they differ slightly in terms of half-life, oral bioavailability, and metabolism. Side effects vary but in general they are mild and include tingling, flushing, dizziness, somnolence, and the sensation of pressure in the head; their safety profiles are all quite similar [36]. Because sumatriptan was the first on the market and the most commonly prescribed, it is often used as a comparison in studies with newer triptans [53].

A comparative review of the safety and efficacy of the triptans has indicated that [71,73,74]:

Note that, like NSAIDs, failure with one triptan does not imply that the patient will not find relief with another triptan. At least two medications in a class should be tried before the class of medications is considered unsuccessful in headache treatment. Ultimately, individuals will need to try the different triptans and determine what works best for them. One might also consider adding an NSAID to a triptan to potentially enhance effectiveness. The first combination product of a triptan and an NSAID (Treximet) was approved by the FDA in 2008. Treximet contains sumatriptan (85 mg) and naproxen sodium (500 mg) and has found to be more effective than placebo or either sumatriptan or naproxen sodium alone [38,74].

Treating pregnant patients with migraines can be particularly challenging. In general, most medications should be avoided, and patients should be treated with behavioral intervention and nonpharmacologic measures. The triptans are considered FDA Pregnancy Risk Category C, which means risk to humans has not been ruled out [73].

Management of Acute Attack in the Emergency Department

Acute migraine attack results in 1.2 million visits to emergency departments in the United States each year [174]. While more than 20 different parenteral medications and combinations of medications are used to treatment acute migraine in U.S. emergency departments, fewer than 25% of patients experience sustained freedom from headache after treatment [175]. The ideal parenteral treatment should offer rapid, sustained freedom from headache, no short- or long-term sequelae, a rapid return to normal activities, and no adverse effects; however, no such treatment exists. This led the AHS to develop a guideline on the management of acute migraine in the emergency department, with the goal of determining which injectable medications should be considered first-line treatment for acute migraine in the emergency setting, and whether parenteral corticosteroids can prevent recurrence of migraine in adults discharged from the emergency department (Table 7) [175].

Other Medications

Although the triptans provide effective relief from migraine for many patients, a substantial number will be unresponsive. Calcitonin gene-related peptide (CGRP), a potent vasodilator widely distributed in the trigeminovascular system, is a signaling molecule that plays an important role in migraine pathogenesis [192]. Clinical studies have established that that migraine attacks develop in patients with migraine when they are exposed to CGRP (and other activating peptides), whereas study participants with no history of migraine report mild or no headache upon exposure [192]. These studies have led to the development of monoclonal antibodies and other small molecules (gepants) targeting the CGRP ligand or its receptor. Two CGRP receptor antagonists (ubrogepant and rimegepant) have proved to be beneficial and have received FDA approval for the treatment of acute migraine. Four CGRP monoclonal antibodies (erenumab, fremanezumab, galcanezumab, and ubrogepant) have been approved for prevention of migraine [192]. CGRP receptor antagonists and monoclonal antibodies have been tested in clinical trials and shown to be beneficial and safe, with an acceptable adverse effect profile[88,89,90,91,199]. At present, high costs and restricted availability limit the use of these agents to patients for whom NSAIDs and triptans are ineffective or have unacceptable side effects [192].

Selective serotonin reuptake inhibitors (SSRIs) block the passage of serotonin, a neurotransmitter, in brain cells and are typically used to treat depression. In view of research suggesting that serotonin may play a role in the genesis of headache pain, SSRIs have been tested for their potential benefit in preventing headaches. Results suggest, however, that SSRIs are no better than placebo for preventing migraine or tension-type headaches[92]. Additionally, the FDA has issued a public health advisory regarding the combined use of 5-hydroxytryptamine receptor agonists (triptans), SSRIs, or selective serotonin/norepinephrine reuptake inhibitors (SNRIs). A life-threatening condition called "serotonin syndrome" may occur when triptans are used together with an SSRI or an SNRI (Table 8). Symptoms may include restlessness, hallucinations, loss of coordination, tachycardia, rapid changes in blood pressure, increased body temperature, overactive reflexes, nausea, vomiting, and diarrhea. Serotonin syndrome may be more likely to occur when starting or increasing the dose of a triptan, SSRI, or SNRI. The FDA has requested that all manufacturers of triptans, SSRIs, and SNRIs update their prescribing information to warn of the possibility of serotonin syndrome when triptans and SSRIs or SNRIs are taken together[93].

In 2019, lasmiditan, a ditan, was approved for the treatment of migraine [73]. Lasmiditan is similar to a triptan but is a high-affinity, highly selective 5-HT1F receptor agonist. The selective targeting of the 5-HT1F receptor is hypothesized to decrease stimulation of the trigeminal system and treat migraine pain without causing vasoconstriction. In a phase 3 study, patients reporting being free of headache after two hours with lasmiditan 200 mg (32.2%) or 100 mg (28.2%) compared with placebo (15.3%). Patients who received lasmiditan were also significantly more likely to report alleviation of their most bothersome symptom compared with placebo [193]. Adverse events were mostly mild or moderate in intensity and included dizziness, fatigue, and sedation. Patients given a prescription for lasmiditan should be cautioned not to drive within eight hours after taking the medication [198].

Botulinum Toxin

Botulinum toxin type A (Botox) injections were discovered as a treatment for migraines after individuals who had injections for cosmetic purposes found that it lessened or obliterated their migraine headaches. These observations subsequently led to a series of clinical research studies designed to assess the value of botulinum toxin type A therapy for headache prevention; however, the results from these studies have been mixed [68,94,95,96,97].

For example, a review of botulinum toxin studies was performed by the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. The Subcommittee examined evidence of the toxin's effectiveness for a variety of conditions, including migraine. According to the Subcommittee's report, the evidence indicated that botulinum toxin may be useful in the treatment of lower back pain but that it is probably not effective against episodic migraine and chronic tension-type headache. The report also stated that the available evidence was not strong or consistent enough to determine botulinum toxin's usefulness in the treatment of chronic daily headache (primarily, transformed migraine) [95,96].

In a double-blind, randomized, placebo-controlled study, researchers compared the number of headache-free days experienced by patients four weeks prior to injections of botulinum toxin type A with the number of such days occurring four to eight weeks after treatment. The number of headache-free days increased for the study's placebo and nonplacebo groups, but the difference in increase between the two groups was not significant. The researchers did find, however, that when compared with the placebo group, the patients who received botulinum toxin type A injections experienced a significant reduction in the duration of their headaches [95]. Additionally, pooled results from two large trials indicated that treatment with up to five cycles of botulinum toxin type A at 12-week intervals was effective in reducing headache symptoms, decreasing headache-related disability, and improving health-related quality of life in patients with chronic migraine [97].

The American Academy of Neurology has stated that botulinum toxin type A injections should be offered as a treatment option to patients with chronic migraine (but not episodic migraine) to increase the number of headache-free days and reduce headache impact on health-related quality of life.

(http://n.neurology.org/content/86/19/1818.full Last Accessed: August 15, 2023)

Strength of Recommendation: A (Established as effective for the given condition in the specified population)

It is generally recommended that use of botulinum toxin type A be restricted to patients who fail to respond to conventional preventative therapy or experience intolerable side effects from such therapy. It is important to note that botulinum toxin type A is not FDA-approved for migraine treatment [73,94]. Because its effects on a developing fetus are unknown, women who are pregnant should not receive botulinum toxin type A [73,94].

The mechanism of action of botulinum toxin type A is thought to be secondary to relieving pressure on certain nerves, such as branches of the trigeminal nerve, and thus reducing the release of neuropeptides. The actual process involves 20 to 30 injections in the forehead, temple, and neck. Side effects may include pain and bleeding at the site, exacerbation of the headache, and ptosis (eyelid droop) [73]. In those patients for whom it works, the effect typically lasts three to six months, at which time the headaches often return. This necessitates repeat injections every three to six months. This treatment is still considered to be experimental. Much more research is needed before this therapy can be considered effective.

In recent years, there has been more research and development of neuromodulation devices for the treatment and prevention of headache disorders. Benefits of this type of device include proven efficacy, non-invasive nature, and very limited side effects. Due to the limited amount of time these devices have been available, ongoing research is needed to determine long-term safety and efficacy for headache disorders.

Cerena

In 2013, the Cerena transcranial magnetic stimulation (TMS) device was approved to treat migraine with aura. Patients use both hands to hold the device against the back of the head, then press a button to release a pulse of magnetic energy to stimulate the occipital cortex in the brain, which may stop or lessen the pain associated with migraine headaches. The maximum recommended dosage is one treatment in 24 hours [38].

Approval for Cerena was based on a study in which 39% of users were pain-free two hours post-treatment, compared with 22% of the control group. At 24 hours post-treatment, 34% of patients were pain-free, compared with 10% in the control group. However, studies and research on Cerena are limited [38].

Cefaly

In 2014, the first neuromodulation device received approval from the FDA for prevention of episodic migraines and received approval for acute treatment in 2017 [182,183]. The Cefaly is a prescription external trigeminal nerve stimulation (e-TNS) device that is placed on the forehead. A self-adhesive electrode transmits electrical impulses to specific areas of the trigeminal nerve, generating an analgesic effect. The Cefaly device is used 20 minutes daily at a frequency of 60 Hz to prevent migraine or can be used for acute treatment during migraine with or without aura at a frequency of 100 Hz [183].

Results of a trial published in 2019 showed that patients using Cefaly as a preventive treatment for three months experienced a 16.21% reduction in headache days and a 30.81% decrease in acute medication intake compared with a group assigned to a sham device. Minor adverse events included skin irritation under the electrode and headache worsening with vertigo [184]. Another study published in 2019 examined the efficacy in acute treatment of migraine with or without aura. One hour after beginning the Cefaly treatment, 79% of patients achieved significant pain relief and 29% reported being pain free [185]. According to results of these and other studies, the Cefaly device is considered safe and effective for both prevention and acute treatment of migraine. In 2020, Cefaly was made available over the counter without the need for a prescription [194].

gammaCore

In 2017, the gammaCore device was cleared by the FDA for the acute treatment of migraine and cluster headache, and as a preventive treatment for cluster headache. This device is a handheld, non-invasive vagus nerve stimulator (nVNS) that produces mild electrical stimulation to the vagus nerve through the neck, thereby reducing and preventing pain [186]. Stimulation is controlled by the user, and treatment sessions consist of 2 to 3 two-minute stimulations. Patients that have a metallic device (e.g., a stent, bone plate, or bone screw) implanted at or near their neck should not use gammaCore.

A four-week study published in 2018 examined the effects of nVNS using the gammaCore device on episodic migraine headache with or without aura. Researchers found 12.7% of patients were pain free after 30 minutes of initiation of treatment (vs. 4.2% in the sham group) and 21% after 60 minutes (vs. 10%). The only adverse event was vertigo, seen in 1% of patients. Researchers indicate that nVNS is a safe treatment that may possibly decrease the risk of medication overuse in some patients [187].

Another study published in 2018 examined the effects of nVNS on episodic and chronic cluster headache over the course of two weeks. Compared with the sham group, 16.7% of patients with episodic cluster headaches achieved pain-free status at 15 minutes for greater than 50% of their attacks (vs. 6.8%), and 64.3% of patients reported significant improvement (vs. 15.4%). Comparison of patients with chronic cluster headaches were insignificant, with patients reporting free of pain at 8.8% (vs. 6.5% in the sham group) and patients with significant improvement at 29.4% (vs. 12.9%) [188].

Clinical trials for prophylactic treatment of cluster headaches using nVNS showed that there was a significantly greater reduction in the number of cluster attacks per week versus the control (5.9 vs 2.1, respectively). Forty percent of patients reported pain relief of 50% or greater, compared with 8.3% of the control group. nVNS also led to a reduction in the use of abortive medications. There was no change in cluster headache duration or severity of acute attacks reported in this trial [186].

Nerivio Migra

Nerivio Migra received FDA de novo clearance in 2019 for acute treatment of migraine with or without aura. It is a prescription trunk and limb electrical stimulator that is used on the upper arm. Electrical pulses are controlled through a smartphone for 30 to 45 minutes. This device is expected to be available in the United States in late 2019 [189].

A study of the efficacy of Nerivio Migra was published in 2019 and included patients who experience two to eight migraines per month. Two hours post-treatment with active stimulation, Nerivio Migra provided complete pain relief to 37.4% of patients (vs. 18.4% of sham participants), significant pain relief in 66.7% of patients (vs. 38.8%), and relief of most bothersome symptoms in 46.3% of patients (vs. 22.2%). For many, pain relief was sustained 48 hours post-therapy [190].

Relivion

In 2021, the FDA cleared Relivion, a transcutaneous electrical nerve stimulator that can be self-applied at home [195]. This device consists of a headset controlled by a smartphone app and delivers stimualtion to to six branches of the occipital and trigeminal nerves. It is is indicated for the treatment of migraine with or without aura in patients 12 years of age or older.

The initiation of a preventive agent is a decision that can be made only when a variety of factors have been considered. For example, if an individual is using abortive medications more than two times per week with only moderate success, if there are more than two seriously disabling attacks per month, if there is failure of or contraindication to abortive treatments, if there is occurrence of uncommon features, or if there is a pattern being established of medication overuse, physicians should consider the initiation of a preventive medication [38,113]. Additional factors that should be considered include the patient's preference, adverse events associated with treatments for acute migraine attacks, and how much treatment costs for acute attacks and migraine prevention [54]. Most treatment is effective within the first month.

Although the precise mechanism of action is unknown, it is believed that preventive therapies act on the CNS by raising the threshold of a migraine headache, producing "resistance" for the system to develop headaches. They also work by inhibiting the propagation of the migraine process early on.

When considering preventive agents, keep in mind the following points [98,113]:

The proven and/or well-accepted drugs used for prevention of migraines include beta blockers (e.g., propranolol, metoprolol), tricyclic antidepressants, triptans, and antiepileptics (Table 9) [98,113]. When antiepileptic drugs are used to treat or prevent migraine, the dose is typically much lower than the dose used to treat seizures. Also, divalproex sodium and topiramate are the only antiepileptic drugs approved by the FDA for migraine prevention[73]. Antiepileptic drugs have been shown to be effective in reducing the frequency of migraine attacks by 38% to 50% or more with antiepileptics than with an inactive placebo[99,100,101]. It should be noted that, although the drug may be beneficial, the FDA has issued a warning regarding the risk of metabolic acidosis in patients receiving topiramate as well as a warning of increased risk of development of oral clefts in infants born to women treated with the drug during pregnancy[76,102].

Gabapentin has demonstrated some effectiveness in the prevention of migraine; however, more research is needed to determine long-term effectiveness [98,101,103,104]. The preventive treatments are often helpful but will not eradicate headaches altogether. Preventive therapy may reduce the frequency of migraines by 38% or more; such improvement is considered successful [36,99,100,101,105].

Newer mechanism-based therapies for migraine prevention include monoclonal antibodies targeting CGRP or its receptor. In 2018, the FDA approved three once-monthly parenteral agents for preventive treatment—erenumab-aooe, fremanezumab-vfrm, and galcanezumab-gnlm [178,179,180]. These CGRP antagonists are self-administered with an autoinjector. In 2023, the FDA approved atogepant, the only oral CGRP receptor-antagonist approved to prevent both episodic and chronic migraine. In a double-blind 12-week clinical trial, once-daily oral atogepant (60-mg dose) achieved a 61% reduction in the three-month average of migraine days per month, compared with 29% for placebo [200].

Physicians and other clinicians should also be cognizant that migraine sufferers often must try as many as five different medications (both acute and preventive) before they find one that is effective for their symptoms. It is important to be patient and not become frustrated during these trial periods.

The prevalence of migraine among children and adolescents may be as high as 6% to 10% [202]. Adolescents with migraine are reported to have high levels of disability, low health-related quality of life, and a tendency to inferior academic performance as compared with their peers. A longitudinal Canadian health survey, involving 61,000 subjects 12 to 19 years of age, found a strong, persistent association between migraine and perceived mental health in adolescents, including anxiety/mood disorders [202]. The authors recommended screening for symptoms of anxiety and depression in adolescents presenting with migraine. Clinical studies have found that prompt pharmacologic interventions (NSAIDs and/or triptans) for acute attacks plus self-management techniques and biopsychosocial approaches (e.g., biofeedback, relaxation or cognitive-behavioral therapy) constitutes the most effective strategy for managing pediatric/adolescent migraine [203].

In 2019, the AAN and AHS published practice guidelines for treatment of acute migraine in children and adolescents [191]. Ibuprofen oral solution (10 mg/kg) is the initial treatment option recommended to reduce pain and is more likely to be effective when administered early, within one hour of headache onset. The efficacy of triptans is less well established and triptans are less commonly prescribed in children than in adults. Four triptans have been approved by the FDA for treatment of migraine in adolescents (12 to 17 years of age): sumatriptan/naproxen, almotriptan, rizatriptan, and zolmitriptan nasal spray. When response to a triptan is less than satisfactory, ibuprofen or naproxen in combination should be offered to improve migraine relief. It is important to counsel patients and families on the cumulative duration limits of NSAID and triptan use to avoid adverse effects and overuse headache. AAN/AHS guidelines recommend that ibuprofen or acetaminophen use be limited to no more than 14 days per month, and triptan use limited to no more than 9 days per month [201]. Ergots and naproxen for acute migraine have not been studied in children [191].

As the name implies, primary exercise headache (formerly referred to as a primary exertional headache) is a headache that occurs with exertion, is benign in nature, and is unassociated with any structural lesions. On first occurrence of this headache type, it is mandatory to exclude subarachnoid hemorrhage (SAH) and arterial dissection [43,117].

The headache is typically described as a diffuse, bilateral pain, throbbing in quality and acute in onset. It is precipitated by strenuous physical exercise. The headache lasts from five minutes to 48 hours and occurs particularly in hot weather or at high altitude [43,117].

Primary exercise headache is believed to be vascular in origin. Strenuous physical activity increases intracranial venous sinus pressure, which leads to an increase in intracranial pressure and decreases blood flow. This results in the occurrence of the headache. Effective treatment includes ergotamines and NSAIDs. Indomethacin has been found effective in most cases [43,117].

Hypnic headaches are relatively brief (15 to 240 minutes), mild-to-moderate (severe pain is reported in 20% of patients), usually dull in quality, and bilateral in about two-thirds of cases. Hypnic headaches occur during sleep and are related to the REM stage. The headaches typically awaken patients from sleep, but there are few other associated symptoms [43]. They usually occur almost every night and may last for months until patients ultimately present for evaluation. These types of headaches primarily affect the elderly [118].

The etiology is considered idiopathic, and thus, the diagnosis is primarily one of exclusion. Other causes of headache associated with sleep, such as sleep apnea and drug withdrawal, should be excluded.

One of the most effective treatments for hypnic headaches includes the use of lithium; however, it is often limited by side effects and interactions and requires monitoring of plasma concentrations to avoid toxicity. Indomethacin, atenolol, prednisone, and caffeine have also been shown to be useful [43,118].

These headaches have been previously referred to as benign sex headaches, coital cephalalgias, benign vascular sexual headaches, or benign orgasmic headaches. They may be provoked by activities besides coitus and not necessarily with orgasm. Headache associated with sexual activity affects men more than women [119,120].

Two subforms (preorgasmic headache and orgasmic headache) were previously described, but further research was unable to clearly delineate the two separate entities [43]. Therefore, headache associated with sexual activity is now a single diagnosis with variable presentation. The condition is characterized by at least two episodes of pain in the head and/or neck brought on by and occurring only during sexual activity [43]. The pain becomes more severe with increasing sexual excitement and/or may be experienced as abrupt explosive intensity just before or with orgasm. The duration of severe pain is from 1 minute to 24 hours; more mild presentations may last up to 72 hours [43].

Diagnosis cannot be made until secondary causes (e.g., SAH or arterial dissection) have been excluded. For most patients, these are self-limited disorders. Patients often can lessen the severity of an impending attack by ceasing the sexual activity. Frequent, recurrent episodes may require preventive strategies, such as propranolol or indomethacin [119].

Epidural hematomas occur between the dura and skull, and thus separate the dura from the skull. In most cases, there is an associated skull fracture. Typically, there is a history of head trauma, although an epidural hematoma occurs in less than 2% of all serious head injuries. Epidural hematomas are not a frequent occurrence in the elderly, partly because as one ages, the dura becomes more firmly attached to the inner part of the skull [121].

Classically, there is a brief period of unconsciousness and then a return to a normal mental status. This is known as the "lucid interval." Roughly 10% to 33% of patients demonstrate the classic presentation of a lucid interval, and alterations in the level of consciousness may have a variable presentation. After a period of hours, the hematoma expands and pushes the dura inward. Signs of rising intracranial pressure manifest as a severe, diffuse, constant headache, which develops within minutes to 24 hours after development of the hematoma [121]. Other symptoms may include papillary dilatation, hemiplegia, and eventually obtundation. Often there is weakness on the side of the body opposite the hematoma [121].

Hemorrhages usually occur in the temporal fossa from middle meningeal artery tears; they may also occur in the posterior fossa as a result of a transverse sinus tear. Posterior fossa epidural hematoma may exhibit a rapid and delayed progression from minimal symptoms to even death within minutes. Overall mortality has been estimated to be as high as 50%, so prompt evaluation and treatment is critical [43].

With respect to diagnosis through neuroimaging, in the acute setting, unenhanced CT scan is more useful than MRI imaging. Epidural hematomas have a characteristic white lenticular shape adjacent to the bone, while focal hypodense or isodense areas on CT indicate active bleeding. Because the temporal fossa is often involved, one must be careful that bony artifacts do not obscure a hemorrhage [121].

As the name implies, subdural hematomas occur between the surface of the brain and the dura. The source of bleeding is the venous system (i.e., bridging veins) as opposed to the arterial system. Because the subdural space is continuous, these types of hemorrhage may have significant mass effect. Subdural hematomas are more common than epidural hematomas. They tend to evolve more slowly based on the slower rate of venous bleeding compared to arterial hemorrhage. As a result, there may be a progression of symptoms over two to four weeks; the rate of progression depends upon the severity of the injury [122].

Patients often present with a mild persistent headache. There may be drowsiness and confusion, although focal neurologic signs are often absent. Symptoms may be followed by a brief lucid interval with subsequent deterioration. Subdural hematomas are seen in approximately 15% of all head traumas. Automobile accidents are a typical cause of subdural hematomas [122].

Different types of subdural hematomas should be differentiated according to their temporal profile. In acute and subacute hematomas, which usually occur after obvious head trauma, headache is frequent (11% to 53% of cases) but commonly overshadowed by focal signs and disorders of consciousness. In chronic subdural hematomas, headache is more frequent still (up to 90%) and, though moderate, may be the leading symptom [122]. The diagnosis can be difficult because the causative head trauma is often trivial and may have been forgotten by the patient [43].

Subdural hematomas are more common in the elderly than epidural hematomas, and patients on anticoagulants are at increased risk of developing a subdural hematoma. Chronic subdural hematoma should always be considered in an elderly patient with a progressive headache, particularly if there is some cognitive impairment and/or mild focal signs [43,122,123].

Patients with suspected subdural hematoma should undergo CT scanning. CT scan findings depend on the age of the hemorrhage but typically demonstrate an abnormality in the entire hemisphere, causing a shift of the midline structures. Early on, there are hyperdense areas demonstrated on CT, followed by isodense areas after a week and hypodense areas after a month [122,123].

Prompt treatment is critical because mortality can reach 60%. Treatment may include diuretics to reduce swelling. Because there is a high frequency of seizures, antiepileptics are frequently used to either control or prevent seizures. For more serious hematomas, surgical evacuation may be necessary. The long-term prognosis is actually worse than that for epidural hematomas [122,123,124].

Upon further history taking, it becomes clear that Mrs. T did experience a significant fall a few weeks ago, even though she minimized it when mentioning it. Sequelae are present. Therefore, a contrast-enhanced CT should be ordered.

The CT scan demonstrated hypodense areas in both hemispheres, consistent with subdural hematoma. There was no evidence of mass effect. The subdural hematoma is likely a result of the fall approximately one month earlier. Mrs. T was admitted to the hospital for observation and given diuretics and anticonvulsants. Her clinical course was good with resolution of the hematoma without the need for surgery.

Typically, headache due to an SAH is described as a sharp pain that usually involves the entire head. Patients classically describe it as the "worst headache of their life." It often radiates into the neck and even into the back. There is usually nausea and vomiting. In general, there are no focal neurologic deficits early on, but as it progresses, there may be loss of consciousness and altered mental state. Seizures during the acute phase occur in 10% to 25% of patients [125].

The course of this headache is abrupt in its onset and maximum intensity at its origin; it is typically incapacitating in its severity. It is exacerbated by neck and head movements. It usually remains severe for several days and then gradually diminishes [43]. An often-overlooked aspect is that the acute headache may be preceded days to weeks earlier by a similar but less severe headache due to slow bleeding. Therefore, a high index of suspicion is necessary for accurate diagnosis [125].

The headache results most often (approximately 80% of cases) from rupture of an aneurysm, although this condition may also result from trauma, arteriovenous malformations, venous thrombosis, blood dyscrasias, cocaine use, amphetamine use, and a variety of metabolic conditions [43,125]. Types of aneurysms include berry aneurysms, fusiform aneurysms, atherosclerotic lesions, and mycotic aneurysms from septic emboli. Approximately 80% of nontraumatic SAHs are due to a ruptured berry aneurysm; rupture of arteriovenous malformations is the second most identifiable cause (10%) [126]. The initial pain is actually produced by tearing and distortion of the blood vessel and its adjacent arachnoid membrane. The incidence of headache in ruptured aneurysms is 90% [122].

The prevalence of SAH increases with age in a linear relationship. The mean age is 50 years [125,126,127]. On physical examination, the patient is typically in severe pain. The pain is sometimes referred to as a "thunderclap" headache [126]. Symptoms of meningeal irritation, such as nuchal rigidity and pain, back pain, and bilateral leg pain, occur in as many as 80% of patients with SAH but may take several hours to manifest [126]. Focal neurologic deficits, such as facial droop or weakness in a specific extremity, are present in 25% of patients. However, if the hemorrhage is associated with ischemic stroke it will likely involve the brain parenchyma, which may lead to hemiparesis, aphasia, or visual field abnormalities. Loss of consciousness is transient [43,125].

Patients with suspected SAH should undergo CT scanning without contrast or MRI (flair sequences) [43,122]. The CT typically demonstrates blood localized to the basal cisterns or extended into the ventricles [122]. Unenhanced CT detects SAH in about 90% of cases; however, sensitivity drops to 80% after three days. As a result, a normal CT does not exclude a small SAH [125].

If the CT is negative, equivocal, or technically inadequate, a lumbar puncture should be performed [43]. Most cases not detected on CT are identified on lumbar puncture by red blood cells (RBCs) that do not clear in three samples of CSF. A decrease in RBCs from the first to the last tube represents an artificially bloody tap, whereas an increase count in RBCs suggests SAH. The fluid is then centrifuged and examined for xanthochromia. Xanthochromia is often characterized as a yellow-tinged supernatant, although it may also be pink or orange. It represents enzymatically derived breakdown products, oxyhemoglobin, methemoglobin, and bilirubin, of in vivo red blood cells. It is always seen within 12 hours of SAH but is absent after a traumatic tap. Its presence may be helpful in the diagnosis [43]. Of note, blood in the CSF after a traumatic tap will also result in an artificial increase in white blood cells (WBCs). WBCs will increase by one for every 500 to 1,000 RBCs in the CSF. This assumes a normal WBC count, which is typically the case in SAH [126]. Ultimately, angiography may be necessary to determine aneurysm size and location, as well as to determine surgical or medical management. Treatment options include a surgical clip, management of hypertension, and volume expansion [124,126]. In 2013, the FDA approved a new oral nimodipine solution for the treatment of patients with SAH from ruptured intracranial berry aneurysms. The solution is administered enterally (e.g., oral, nasogastric tube, gastric tube route) within 96 hours of the SAH at a starting dose of 20 mL every four hours for 21 consecutive days [73,128].

SAH is a serious condition. Prompt diagnosis of SAH is critical because 50% of patients die following SAH, often before arriving at hospital, and 50% of survivors are left disabled [43,125].

Giant cell (temporal) arteritis is systemic large and medium-sized vessel vasculitis. Most often, it involves the external carotid arteries [43,129]. This headache typically begins as an intermittent soreness or burning discomfort and steadily escalates over several weeks or months to become a constant, well-localized pain. On rare occasions, it can be explosive. Many patients report that the pain is worse at night. Although the pain is usually unilateral, it may also be bilateral. Pain is classically confined to the temples. Between 70% to 90% of patients with giant cell (temporal) arteritis complain of headache [53,129].

The typical presentation is a new-onset headache in patients older than 50 years of age. Incidence is higher in females than males (ratio 3.7:1), as well as in persons of northern European descent. It represents the most common vasculitis in adults. Nearly 50% of patients with polymyalgia rheumatica also have giant cell arteritis [129].

On exam, the affected scalp artery is sometimes prominent. It may be tender and is often pulseless. The scalp itself is usually tender as well. Depending upon the progression, visual field defects and decreased acuity may be noted, although the patient does not usually exhibit focal neurologic deficits. Typically, the headache occurs in someone who is febrile, has malaise, and feels aches in the back and shoulders. Jaw claudication (pain on chewing food) occurs commonly and is virtually pathognomonic for this condition when present during talking or chewing [129].

Giant cell arteritis involves not only the arteries of the scalp causing headache, but also other vessels, including those supplying the eye and occasionally the brain. Nearly half of patients with giant cell arteritis develop blindness, if untreated, due to ischemia of the optic nerve or retina. Because blindness can be prevented by immediate steroid treatment, prompt and accurate diagnosis is critical [43,129].

Laboratory studies often show patients to have an elevated erythrocyte sedimentation rate (ESR), typically >80 mm/hour. (In general, a normal rate would be less than or equal to the patient's age, divided by two.) Given the lack of sensitivity and specificity of this test, however, a normal ESR does not exclude the diagnosis [129]. Platelets may also be elevated, as well as liver function tests (especially alkaline phosphatase). These are nonspecific but may provide more information to make a clinical diagnosis [129].

Diagnosis is confirmed by biopsy of the temporal artery, which should be performed as an outpatient procedure within one week after the initiation of corticosteroid therapy [129]. The biopsy demonstrates skip lesions, which are due to the disease's segmental process. When ocular symptoms exist, emergency medical treatment is necessary. High-dose corticosteroids are an effective treatment. Headache usually resolves or greatly improves within three days of high-dose steroid treatment [43,129]. A maintenance dose of prednisone may be required to be administered for one to two years in some patients [129].

Arterial dissection may cause headache. Dissection of the cervical carotid or vertebral artery typically causes sudden, nonthrobbing pain around the eye, piercing pain in the neck, and a "pounding" one-sided headache. Headache with or without neck pain may be the only manifestation of cervical artery dissection. It is by far the most frequent symptom (55% to 100% of cases), and it is also the most frequent inaugural symptom (33% to 86% of cases). Headache and facial and neck pain are usually unilateral, severe, and persistent, averaging four days in duration. However, it has no constant specific pattern and may sometimes be misleading [43]. The headache is often mistaken to be due to migraine or tension. However, the time, course, and associated symptoms are considerably different.

The cause of arterial dissection is multifactorial and may involve some sudden neck movement, causing hyperextension or significant pressure in the area. This may be a result of trauma; however, cases of dissection have been reported after patients cough or sneeze, undergo spinal manipulation, shave a beard, or place their necks in the sink at beauty salons. Underlying arteriopathies, alone or in combination with the mechanical forces, account for most of the pathophysiology [130]. Therefore, it is important to determine what a patient was doing when the headache occurred.

The dissection may begin when the rotation/hyperextension of the neck causes a small lesion in the lining of an artery. This causes bleeding, which then leads to the formation of a clot. Over time, the clot expands restricting blood flow to the brain [130].

Dissection is more common in patients younger than 50 years of age. It accounts for nearly a quarter of all strokes in that age range [130]. Diagnosis is confirmed by Duplex scanning, MRI, MRA, and/or helical CT and, ultimately, arteriography. Several of these investigations are commonly needed as any of them may be normal. Once detected, the majority of patients survive, and most dissections heal without surgery. Treatment includes the use of anticoagulants (heparin followed by warfarin for three to six months), stenting, and bypass surgery on rare occasion [43].

Headache, migraine, and stroke are common and can be temporally related, but a direct causal association has not been definitively proven in clinical studies. Headache may be coincidental with stroke (also referred to as cerebrovascular accident or stroke syndrome), including both ischemic and hemorrhagic stroke, or it may be a consequence of stroke. Headache or migraine may increase the risk of stroke [131]. Results of the Women's Health Study, presented at the 2013 International Headache Congress, reported that migraine with aura is a strong risk factor for any type of stroke [132,133,134]. Headaches associated with stroke are typically reported as dull but diffuse (35%) [135]. They are not localized to a particular side. In addition, headache presentation of a stroke is more common in patients younger than 40 years of age [135]. Headache is more likely to occur in combination with other signs and symptoms of stroke [132]. Depending upon the type of stroke, there may be a focal neurologic deficit, such as aphasia or dysarthria. Young patients should be evaluated carefully to avoid misclassification of stroke as a complicated migraine [135].

Diagnostic work-up necessitates a CT scan or MRI to identify the location of the stroke. Treatment focuses on preventing further ischemia and bleeding [132,135]. For ischemic strokes, recombinant tissue plasminogen activator may be given within 3 to 4.5 hours of symptoms. Aspirin and other antiplatelet medications are also frequently used. For hemorrhagic stroke, most care is supportive, unless there is a large hematoma, in which case surgery may be necessary [124].

Meningitis is an inflammation of the meninges. The etiology of the meningitis may be bacterial, viral, or fungal.

Bacterial meningitis causes an abrupt diffuse headache associated with a high fever, altered consciousness (most commonly lethargy), focal neurologic deficits, and nuchal rigidity [43]. The severity of the headache and the acuteness of the infection are directly proportional. Focal neurologic deficits and papilledema are uncommon. Classically, a patient would show Kernig sign (i.e., resistance to knee extension following flexion of hips and knees) and Brudzinski sign (i.e., rapid flexion of the neck elicits involuntary flexing of the knees in a supine patient). However, a prospective study of 297 adults with suspected meningitis documented very low sensitivities for these signs (5% for Kernig sign; 5% for Brudzinski sign) indicating that their absence should not defer the performance of lumbar puncture [138]. In general, whenever the diagnosis of meningitis is strongly considered, a lumbar puncture should be promptly performed [139]. Laboratory studies reveal a CSF with more than 100 WBCs per mL and a protein level >100 mg/dL. CSF cell counts above 2,000/mL, a protein above 100 mg/dL, and a CSF-serum glucose ratio of <0.40 are all 99% specific for bacterial meningitis [139]. Treatment with antibiotics is usually empiric but may be modified by gram stain results. Typical organisms are Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae.

Viral meningitis causes a less severe headache that may develop over several days with a low-grade fever. The headache is usually frontal or retro-orbital. Other symptoms may include fever, irritability, nausea, vomiting, stiff neck, rash, or fatigue within the previous 18 to 36 hours. Meticulous history taking is essential and should include evaluation of exposure to ill contacts; mosquitoes, or ticks; outdoor activity in areas of endemic Lyme disease; travel history; history of medication use, including intravenous drug use; and risk of sexually transmitted disease [140]. Diagnosis may be made with the assistance of a CSF viral culture or the absence of a positive bacterial culture. Most cases of viral meningitis are caused by enteroviruses, such as coxsackieviruses and echoviruses. Herpes viruses and human immunodeficiency virus (HIV) may also cause viral meningitis. Therapy consists of bed rest, analgesics, fluids, and other conservative treatment [140].

Fungal meningitis gives a more chronic picture and may not be associated with fever or fever may be below normal. The headache is temporal, frontal, or retro-orbital. It becomes more frequent and severe over time and may be accompanied by irritability, nausea, vomiting, stiff neck, and hallucinations. Diagnosis is made by CSF analysis (fungal stain and culture, increased CSF pressure, elevated protein, decreased glucose [45% of blood glucose], and leukocytosis [40–400/mm3—mostly mononuclear cells]). The most common organism is Cryptococcus neoformans [139]. Blastomyces and Coccidioides may also cause fungal meningitis. The most common treatment is with amphotericin B, an intravenous therapy. Rarely, treatment may also consist of oral antifungal drug therapy [141].

Encephalitis is an inflammation of the brain parenchyma. Encephalitis may be due to either infectious or noninfectious causes. Noninfectious causes include toxins, tumors, and connective tissue disorders.

Viral encephalitis is the most common infectious type. Examples include herpes, arboviruses, HIV, and cytomegalovirus. Typically, there is acute onset of low-grade fever, altered consciousness, vomiting, and sometimes seizures. There is often disorientation and some speech disturbances. Encephalitis may occur as a secondary complication after the administration of certain vaccines or during the course of an acute illness, such as measles. Dull, diffuse headache may also be present, although it is neither common nor prominent as a symptom. When present, the headache typically does not radiate. Headache is not as common a symptom as in meningitis [142].

Most cases of encephalitis are mild and benign in nature, with symptoms resolving over one to two weeks. When neurologic symptoms are present, it may take up to two months for symptoms to completely resolve. If associated with HIV, such infections may be life-threatening.

CSF examination is critical to establish the diagnosis and reveals moderate monocytosis and erythrocytosis with a variably elevated protein level. EEG is sensitive but not specific, and contrast CT is only 60% sensitive. It may be used, however, to evaluate acute disease progression and to follow up on complications. MRI is more sensitive than CT scan [142]. MRI with gadolinium enhancement is the preferred imaging study. One should keep in mind certain seasonal and geographic issues when differentiating specific etiologic agents.

Depending upon the etiology, treatment is mostly supportive (e.g., rest, fluid, electrolyte balance). For some conditions, antiretrovirals are available [142].

Although the term "sinus headache" is widely used, sinus headaches are uncommon. Sinusitis causes headache or facial pain when mucosal swelling and purulent inflammatory debris obstruct the sinus ostium, interrupting drainage and raising pressure within the sinus cavity. This occurs most often in two clinical settings: acute bacterial superinfection (purulent sinusitis) complicating conditions that impede sinus drainage (e.g., viral upper respiratory infection, nasal allergy, polyps, deviated septum); recurring chronic sinusitis complicated by fixed mucosal damage, inadequate mucociliary transport, and retained secretions/inflammatory debris.

The paranasal frontal, ethmoid, and sphenoid sinuses are contiguous with the intracranial vault. Congestion or inflammation combined with inadequate drainage in any one of these sinuses may cause headache. The location and character of headache pain is determined by the sinus involved. The floor of the frontal sinus forms a portion of the roof of the orbit; frontal sinusitis causes pain (headache) above the eye over the region of the skull, accompanied by local tenderness and occasionally slight edema of the eyelid. This headache often occurs mid-morning and is aggravated by bending forward. The ethmoid sinus air cells are variable in number and occupy the bony area between the nasal cavity and the medial wall of the orbit. Headache associated with anterior ethmoid sinusitis is referred to the parietal region of the head, while posterior ethmoiditis causes pain in the mastoid and occipital regions. The sphenoid sinus is located behind the orbit, where the roof of the sphenoid sinus forms the pituitary fossa at the base of the brain. Sphenoid sinusitis produces a deep retro-orbital pain and coronal headache that can be severe and unremitting.

The cardinal clinical features of acute rhinosinusitis are nasal congestion/obstruction, purulent nasal discharge, and pain (regional facial pain and/or headache), Patients may exhibit low-grade fever, though this is more common in children [43]. Regional pain is often described as a deep, dull, heavy sensation of pressure or fullness that sometimes may be throbbing. Bending forward, shaking or flexion of the head, coughing, and sneezing exacerbate the pain. Sinus headache is seldom associated with nausea and, except for sphenoiditis, does not reach the same pain intensity of cluster headache or migraine. The diagnosis of sinusitis is most often made by careful clinical assessment, including sinus transillumination for suspected frontal or maxillary disease. In select cases, plain radiographs of the face ("sinus views") are helpful, as they may show clouding or air-fluid levels in the involved sinus [144]. Diagnosis may be facilitated by Gram stain and culture of purulent discharge directly from the sinuses; however, this technique is not commonly performed in the primary care office setting. Neuroimaging is usually reserved for evaluation of persistent, recurrent, or complicated cases. A CT scan is highly sensitive and is the neuroimaging modality of choice in evaluating sinusitis, particularly cases of chronic sinus disease [144]. MRI is generally preferred for the evaluation of sphenoid sinus disease, and for suspected intracranial extension of infection (e.g., orbital cellulitis, abscess).

Treatment of sinusitis is designed to promote drainage, relieve pain, and treat suspected bacterial infection. A systemic and/or topical decongestant should be administered. The most common offending bacterial pathogens are streptococcal species (group A and S. pneumoniae) and Hemophilus influenzae; therefore, a common choice is amoxicillin or amoxicillin/clavulanate for 10 to 14 days. The use of local corticosteroids may offer the allergic individual added relief when nasal symptoms are prominent [145].

It is important to note that more than 90% of self- or physician-diagnosed sinus headaches meet the IHS criteria for migraine or probable migraine [145,146]. In those patients with migraine, the most common reasons for misdiagnosis include headache triggers, pain location, and associated features commonly attributed to sinus headache. The clinician should be aware of these unique presentations of migraine so that a correct diagnosis can be made, and effective treatment instituted [145]. Additionally, a portion of patients with self-diagnosed sinus headache suffer from a headache type that is unclassifiable by the IHS criteria. These headaches are characterized by bilateral maxillary pressure, mild-to-moderate pain intensity, cranial autonomic symptoms, and the complete absence of migraine features [145].

Brain abscesses are quite uncommon; however, when they do occur, they are life-threatening. They may originate from a contiguous site of infection (e.g., sinusitis, dental infections, otitis media), hematogenous spread, or trauma. In at least 15% of cases, the source of the infection is unknown [43,146,147]. They occur usually in the first three decades of life. They are also more prevalent in immunocompromised patients [146].

A moderate-to-severe headache, frequently hemicranial, is a common complaint (70%) [147]. The level of pain remains constant and may be aggravated by straining [43]. Often, there is nuchal rigidity. Frontal lobe abscesses tend to present with headache more often than other regions. In more than half of the cases, patients present with fever, altered mental status, nausea, and vomiting. There may also be papilledema and seizures [146,147].

The time course of an abscess is reflected in the symptoms and usually progresses over one to two weeks [147]. Diagnosis is aided by CT, MRI, and nuclear medicine studies. In general, MRI provides better brain parenchymal differentiation than CT and shows the edema from the abscess in better detail [147]. The abscess is also better demonstrated because the routine brain MRI generally is multiplanar, as opposed to the routine CT, which is usually axial. However, MRI may not be useful in an acutely ill patient [146]. MR spectroscopy and some nuclear medicine studies may also be helpful to differentiate abscess from brain tumor [146]. Diffusion weighted MR may also give early indication of an infarction because this may be part of the sequelae of the abscess. Lumbar puncture is contraindicated due to its poor diagnostic yield and possible risk of herniation of the cerebellar tonsils [146,147].

The typical treatment is evacuation/drainage and an antibiotic regimen based on cultures. The most common organisms are Staphylococcus aureus, Streptococcus, Bacteroides species, and Enterobacter. Occasionally, intracranial tuberculosis or fungal infections may present as an abscess. Therefore, cultures for acid-fast bacilli and fungi should be done in all cases [43,146].

High blood pressure is an infrequent cause of headaches. In general, it does not become a cause of headaches until diastolic blood pressure exceeds 120 mm Hg [43,148]. The association between blood pressure and headache is most clearly manifested in patients with systolic blood pressure greater than 200 mm Hg [148]. Whether moderate hypertension predisposes to headache at all remains controversial, but there is some evidence that it does [43].

Headaches associated with high blood pressure usually appear in the morning. Typically, the headache eases as the patient gets up and about [43,148]. It is usually dull, although sometimes throbbing, and is either diffuse or bioccipital in location. Infrequently, it is bifrontal in location. As blood pressure increases, there is often nausea, vomiting, and visual disturbances. As elevation of blood pressure progresses further, seizures and confusion may develop.

Malignant hypertension occurs when there is evidence of end-organ damage. On funduscopy, one will see papilledema and retinal hemorrhages. A diagnosis of malignant hypertension is based on the association of severely elevated blood pressure (e.g., >130 mm Hg) with severe hypertensive retinopathy [149]. The average age at diagnosis is 40 years, although a wide range of ages has been observed. Men are affected more often than women and Black individuals more often than White individuals [150,151]. Despite progress in the overall management of hypertension, the prevalence of malignant hypertension has remained stable over the past 30 to 40 years [149].

Routine screening consists of a chest radiograph, which is useful for assessment of cardiac enlargement, pulmonary edema, or involvement of other thoracic structures. Other tests (e.g., head CT scan, transesophageal echocardiogram, renal angiography) may be indicated if directed by the initial workup. An EKG is an essential part of the evaluation to screen for ischemia, infarct, or evidence of electrolyte abnormalities or drug overdose [151]. Treatment consists of slowly reducing pressure. Too rapid a decline may cause cerebral hypoperfusion and coronary insufficiency. Recommendations advise reduction of mean arterial pressure by 25% over the first 24 to 48 hours [151]. Nitroprusside has been the drug of choice [151].

It is important not to misdiagnose the normal reactive hypertension that follows an ischemic stroke as hypertensive encephalopathy. In addition, a sudden increase in blood pressure may be the result of illicit drugs, such as cocaine or methamphetamine; this sudden increase may cause a headache [151]. Patients using MAOIs who ingest tyramine may also exhibit a precipitous rise in blood pressure that will cause a headache.

Idiopathic intracranial hypertension (IIH) (formerly referred to as pseudotumor cerebri or benign intracranial hypertension) is characterized by increased intracranial pressure without evidence of a tumor, obstruction, infection, or encephalopathy [43,152]. The etiology is unknown [153]. Although benign, it is not without morbidity.

Most patients present with papilledema (although IIH without papilledema has been observed), progressive visual loss, sixth-nerve palsies (10% to 40%), and headache [43,152]. Headache is the most common symptom and is usually pulsatile and of mild severity. It is usually chronic in duration and can either be bilateral or unilateral; the most common presentation is bifrontotemporal. Overall, the patient appears in relatively reasonable health, although there may be some gastrointestinal upset [153,154].

Incidence is greatest in young obese females. Risk factors include corticosteroid use, pregnancy, large doses of vitamin A, adrenal and parathyroid disease, and venous sinus thrombosis [43,153].

The diagnosis is one of exclusion. Brain MRI with gadolinium enhancement is the study of choice for most patients with IIH because it provides sensitive screening for hydrocephalus, intracerebral masses, meningeal infiltrative or inflammatory disease, and dural venous sinus thrombosis. MR venography may be useful for patients who are at greater risk for dural venous sinus thrombosis. Brain CT scan is less expensive than MRI and is adequate to rule out larger tumors or lesions, but it is not as sensitive as MRI for meningeal infiltration and/or dural venous sinus thrombosis. On lumbar puncture, CSF pressure is elevated with a low protein level [153].

This condition may resolve spontaneously, although it may take several months to a year to completely resolve. Analgesics typically are given for the headache. Acetazolamide, or other diuretics, may be considered as well as serial lumbar punctures to drain fluid. Corticosteroids are sometimes used if there is impending visual loss. In rare circumstances, surgery consisting of lumboperitoneal shunting may be performed when the condition is refractory [153].

Numerous toxins may cause headache as a sequela. Carbon monoxide is one of the more common causes of poisoning and represents the most frequent cause of toxin-induced death. This poisoning most commonly occurs when there is inadequate or faulty ventilation. Examples of sources include car exhausts, propane heaters, and gasoline-powered generators [153,155,156,157].

Patients typically present with headache, altered mental status (most commonly confusion), nausea, chest pain, and dizziness. Cherry-red discoloration of the skin and lips has been described but is a rare manifestation. The acuity and time of exposure determine the degree of symptoms [43]. High levels may cause loss of consciousness and death [153,155,156].

High clinical suspicion is necessary as this condition mimics other illnesses with nonspecific symptoms, including significant myocardial damage. A complete blood count and arterial blood gas analysis are helpful in aiding the diagnosis. Often, there is a metabolic acidosis with an anion gap; in addition, there may be neutrophilia. Diagnosis is made through measuring venous or arterial carboxyhemoglobin, which will be elevated (>2% nonsmokers, >9% smokers). Treatment involves 100% oxygen. Some patients may need to undergo hyperbaric treatment. In severe cases of poisoning, there may be residual brain damage [158].

Lead poisoning is uncommon in adults. In general, it takes years of exposure before symptoms become apparent. Whereas children usually become exposed due to lead-based paint in old homes, adults can develop lead poisoning through occupational exposures [159].

Symptoms include headache, which generally is diffuse and nonspecific, irritability, confusion, mood disorders, and sleep problems. As levels become toxic, patients develop ataxia and convulsions [159].

Diagnosis is based on symptoms and blood or urine tests for lead. Treatment involves chelation therapy in severe cases, as well as removal of the source of exposure [159].

Syringomyelia is an uncommon presentation of headache. It is a condition in which a cyst forms within the spinal cord, either congenitally or due to trauma, malignancy, infection, or hemorrhage. In most cases, the disorder is related to a congenital abnormality of the brain called a Chiari malformation. This malformation occurs during the development of the fetus and causes the lower part of the cerebellum to protrude from its normal location in the back of the cranium into the cervical portion of the spinal canal [160].

The cyst, or syrinx, gradually expands and elongates over time, eventually resulting in destruction of the cord's center. As a result, patients may present with a variety of symptoms, although they typically present with headache, back pain and stiffness, and numbness of the extremities [160]. Symptoms usually begin between 25 and 40 years of age; they are more common in men than women and may worsen with straining (e.g., heavy lifting) or any activity that causes CSF pressure to fluctuate [160].

Signs of the disorder tend to develop slowly, although sudden onset may occur with coughing or straining. In addition, there are often long periods of stability. The preferred imaging modality is MRI, which shows dilation of the central canal and may reveal contributing factors (e.g., a tumor). The usual treatment when significant symptoms are present is surgery, which involves drainage of the syrinx. If not treated surgically, syringomyelia may lead to progressive weakness in the arms and legs, loss of hand sensation, and chronic, severe pain [160].

In the absence of symptoms, syringomyelia is usually followed by observation over time. Patients are advised to avoid activities that involve straining [160].

There may be times when referral to a dentist is appropriate for headache management. Disorders of the teeth usually cause toothache and/or facial pain; those causing headache are rare. Pain from the teeth may be referred, however, and cause diffuse headache. The most common cause of headache is periodontitis or pericoronitis as the result of infection or traumatic irritation around a partially erupted lower wisdom tooth [43].

Myofascial pain dysfunction (MPD) syndrome (formerly called temporomandibular joint or TMJ syndrome) originates in the muscles that move the jaw. Symptoms include dull, aching pain in and around the ear, which may radiate to the side of the scalp, back of the head, or down into the neck. Usually, the source of pain is an overuse of the masticatory musculature through parafunction. The most common dental parafunctional habits are bruxism and clenching. The patient is often unaware of the habit, which may take place while asleep [161].

Initial therapy is directed at relief of muscle spasms and involves use of heat, massage, a soft and non-chewy diet, muscle relaxing, and pain-reducing medications. For many patients, one or two weeks of such treatment is sufficient to eliminate the symptoms. Early treatment is important to prevent shifting of the jaw and arthritic changes in the jaw joint [161].

Cervicogenic headache is often a sequela of head or neck injury but may also occur in the absence of trauma [162]. With this type of headache, the pain is perceived to be in the head but is actually referred from the cervical spine. Typically, the pain may be characterized as insidious in nature and unilateral in position [163]. The parietal and occipital areas are most commonly affected. The pain is usually constant and may last for days to weeks. It is aggravated by neck movements. On exam, there is usually cervical paraspinal tenderness. The source of pain is usually the cervical ligaments or intervertebral discs [162].

The mean age of patients with this condition is 43 years, and it is four times more prevalent in women than in men [162,163]. Diagnostic criteria have been established, but the presenting characteristics of cervicogenic headache are often difficult to distinguish from primary headaches disorders, such as tension-type headache [43,162]. Additionally, there are significant differences, especially with respect to quality of life. In a study comparing responses on a medical outcomes questionnaire for patients with cervicogenic headache, episodic tension-type headache, and patients with migraine without aura, domain scores for physical functioning for patients with cervicogenic headache were lower than the tension-type and migraine groups [164].

Diagnostic imaging cannot confirm the diagnosis of cervicogenic headache but may lend support to its diagnosis. Successful treatment requires a multifaceted approach, including using pharmacologic, nonpharmacologic, manipulative, anesthetic, and occasionally surgical interventions. Medications alone have proven to be ineffective or, at best, to provide only modest benefit [162,163].

Medication overuse headache, also known as rebound headache, results from misuse of drugs, most notably over-the-counter analgesics or migraine medications. It is most common in patients with frequent migraine attacks or tension-type headaches [165]. Chronic tension-type headache is less often associated with medication overuse; however, episodic tension-type headache has commonly become a chronic headache through overuse of analgesics [43]. The headache is caused by frequent use of anti-headache medications for more than 15 days per month. Evidence suggests that this occurs sooner with triptan overuse than with ergotamine overuse [43,166]. The mean period of time that elapses before this type of headache evolves ranges from one to two years for the triptans, three to five years for ergotamines, and up to 5 to 10 years for over-the-counter analgesics [167]. The pathophysiology of this syndrome remains unknown.

The diagnosis of medication-overuse headache is clinically extremely important because patients rarely respond to preventative medications while overusing acute medications [43]. Treatment is withdrawal from the medication. If tapered, this may take more than two weeks, depending on the medication. Improvement should occur within two months after cessation of overuse in order for the diagnosis to be definite [43]. This is followed by prophylactic treatment of the primary headache [165,166].

It is important to consider the use of herbal medications as a possible cause of headaches. Approximately 38% of adults in the United States use at least one herbal medicine [168]. Many patients do not admit use to physicians, either because they do not consider them to be a "medication," because they do not need a prescription to obtain them, or because they are embarrassed to admit they use a medication that most physicians do not consider scientific. Herbal medications that have been reported to cause headaches include valerian root, ginkgo biloba, and ginseng [169].