INTRODUCTION
Headache is an almost universal human experience and is one of the most common complaints encountered in medicine and neurology. Ancient references to headache can be found in the Ebers papyrus (1200 bce ) and the discovery of trepination of 9000-year-old Neolithic skulls has provided evidence of the earliest headache treatment. Hippocrates described visual symptoms associated with a headache, and Aretaeus of Cappadocia crafted the earliest classification of headache in the second century ad . The evaluation of this condition may be straightforward or challenging, and, though often benign, headache may prove to be an ominous symptom. In this chapter we discuss the diagnosis and classification of headache disorders and principles of management, with a focus on migraine, tension-type headache, trigeminal autonomic cephalalgias, and various types of daily headache. The direct and indirect socioeconomic costs of headache to society are estimated at 14 billion dollars per year. All primary care providers will encounter the clinical problem of headache on a regular basis; early and accurate diagnosis and appropriate treatment will help to reduce pain and suffering and the economic burden.
EPIDEMIOLOGY
Almost everyone has experienced headache at one time or another. For migraine, the lifetime prevalence is about 30% of the population, with a female predominance. Depending on the methodology used, tension-type headache is even more common. At any one time, approximately 40% of the global population is experiencing tension-type headache, and for migraine the prevalence is about 10%. Migraine occurs most commonly between the ages of 25 and 55 years and is three times more common in females. Despite the fact that it causes significant disability, migraine remains underdiagnosed and undertreated.
Trigeminal autonomic cephalalgias are rare compared with migraine and tension-type headache. The most common trigeminal autonomic cephalalgia is cluster headache, with a population prevalence of 0.1% and a male-to-female ratio that has fallen over the years and is now thought to be about 2:1.
Chronic daily or near-daily headache, lasting for months to years, is widely reported in the literature but is not an official diagnosis in the most widely used classification system, the International Classification of Headache Disorders (ICHD). Chronic daily headaches of long duration include chronic migraine, chronic tension-type headache, hemicrania continua, and new daily persistent headache. Worldwide prevalence of chronic daily headache has been consistent at 3%–5%, most of which likely represents chronic migraine.
CLASSIFICATION
First published in 1988, the ICHD underwent its most recent revision in 2013. The classification, freely available online at https://www.ichd-3.org/ , contains explicit criteria based on phenomenology for the diagnosis of many types of headache. By convention, headache classification is based on the characteristics of the individual headache in the prior year, not the individual with the headache, though features specific to individuals may be used in helping to differentiate between two close diagnostic matches. The ICHD continues to evolve with an appendix system that allows for the introduction of proposed new headache types or new criteria for old headache types and for eventual removal of outmoded or unhelpful criteria.
PRIMARY VERSUS SECONDARY HEADACHE
The major division in the ICHD is between primary and secondary headache. A primary headache has no known underlying cause. The most common primary headaches include migraine, tension-type headache, and cluster headache.
Secondary headache is the result of another condition causing traction on or inflammation of pain-sensitive structures, resulting in headache. Headache due to psychiatric disease is also considered secondary. Headaches related to infection, vascular disease, and trauma are examples of more common secondary headaches. Studies have shown that only 2%–12% of patients with brain tumor will have headache as the sole presenting complaint. Most patients who present to their primary care provider for an evaluation have a primary headache disorder.
EVALUATION
Patient History and Evaluation
The first step in diagnosis is to obtain a detailed history of the patient’s headache. This is of paramount importance in making the correct diagnosis. In fact, if diagnostic confusion remains, repeating the history intake is more important than any diagnostic study. Information gathered in the history is compared with the diagnostic criteria to create the best diagnostic match. The history records details about the headache, such as frequency, duration, character, severity, location, quality, and triggering, and aggravating and alleviating features. Age of onset is extremely important, and a family history of headache, often present in migraine, should be explored. Lifestyle features including diet, caffeine use, sleep habits, work, and personal stress are important to obtain. Finally, details of any comorbid conditions, such as an associated sleep disorder, depression, anxiety, and an underlying medical disorder are also useful to record.
The examination in headache is based on the general neurologic examination. A funduscopic examination should be performed in every patient presenting for evaluation of headache. Additional features include examination of the superficial scalp vessels and neck vessels, dentition and bite, temporomandibular joints, and cervical and shoulder musculature. The ICHD classification considers pericranial muscle tenderness to be an important physical finding in the diagnosis of tension-type headache.
Diagnostic Evaluation
The diagnosis of migraine is based almost entirely on the history; there is no diagnostic test for migraine. Further, evidence suggests that, in the specific setting of a history suggesting migraine combined with a normal neurologic examination, imaging is overwhelmingly likely to be unremarkable. There remain, however, appropriate indications for imaging in the evaluation of headache. Imaging should be considered when various “red flags” are present that could indicate the presence of a serious underlying structural explanation for headache ( Box 11.1 ). These red flags include indications, such as fever, night sweats, and weight loss, of an underlying systemic illness; focal neurologic signs or symptoms; sudden or thunderclap onset of headache; or headache onset over the age of 60. Notwithstanding, in practice, many patients, over the course of their years with headache, will end up undergoing imaging at least once, and most of these studies will be negative. On the one hand, negative imaging may be reassuring to the patient; on the other hand, the cost for such imaging can reach one billion dollars per year.
- •
New headache in patients over the age of 60
- •
Abnormal neurologic examination, including papilledema and change in mental status
- •
New change in headache pattern or progressive headache
- •
New headache in the setting of HIV risk factors, cancer, or immunocompromised status
- •
Signs of a systemic illness (e.g., fever, stiff neck, rash)
- •
Triggered by cough, exertion, Valsalva maneuver
- •
Headache in pregnancy and/or postpartum period
- •
First or worst headache
Approach to Treatment
The approach to treatment of secondary headaches is focused on treatment of the suspected cause (e.g., treating the sinus infection). The treatment of some secondary headaches, such as posttraumatic headache, may default to the treatment of migraine because many posttraumatic headaches have the phenotype of migraine. The treatment of migraine and other primary headaches is not uniform but is proportioned to the severity of the symptoms and resulting disability. Mild and infrequent symptoms may be initially treated with lifestyle modification, stress management techniques, and over-the-counter abortive medications. Prescription medications may be added as warranted to help thwart disability and maintain function. A distinction is made between prescription abortive and preventive medication in the management of headaches. Abortive medications are prescribed to treat an individual attack, and preventative medications are used to reduce the frequency and severity of the individual attacks, with the goal of reducing disability.
PRIMARY HEADACHE
Migraine
Migraine is the third most prevalent disorder according to the 2010 Global Burden of Disease Survey and the seventh highest cause of disability worldwide. The main subtypes are migraine with and without aura ( Box 11.2 ). An aura is a fully reversible set of nervous system symptoms, most often visual or sensory symptoms, that typically develops gradually, recedes, and is then followed by headache accompanied by nausea, vomiting, photophobia, and phonophobia. Less common symptoms of aura include speech/language symptoms, motor or brain stem symptoms, or retinal symptoms. If an aura contains multiple features, symptoms usually occur in succession of at least 5 or so minutes each, with a total symptom complex of 5–60 minutes. Thus visual symptoms, both positive, such as scintillations, and negative, such as scotomata, are typically noted at the outset, followed by development of sensory complaints, then a mixed dysarthric/aphasic language disorder, followed by gradual clearing. The headache usually begins within 60 minutes after the resolution of the neurologic symptoms. Some patients will experience an aura, usually visual, without an accompanying headache, referred to as “typical aura without headache.” Hemiplegic migraine is a rare subtype of migraine with aura that is characterized by unilateral weakness and may be familial or sporadic. Aura phenomena are likely linked to a characteristic spreading cortical depression, starting posteriorly and moving slowly across the brain surface, producing this orderly progression of neurologic symptoms.
- A.
At least five headache attacks fulfilling the criteria B–D
- B.
Attacks last 4–72 hours
- C.
With at least two of the following four characteristics:
- 1.
unilateral location
- 2.
pulsating quality
- 3.
moderate or severe pain intensity
- 4.
aggravation by or causing avoidance of routine physical activity
- 1.
- D.
At least one of the following during headache:
- 1.
nausea and/or vomiting
- 2.
photophobia and phonophobia
- 1.
- E.
Not better accounted for by another ICHD-3 diagnosis
The overall clinical picture of migraine may be divided into four phases: prodrome, aura, headache phase, and postdrome. The prodrome, which is present in up to 60% of patients, may precede development of the headache by hours to days and can consist of a multitude of symptoms, including depression, hyperactivity, cognitive changes, frequent urination, irritability, euphoria, neck stiffness and/or pain, and fatigue. Food cravings, such as for chocolate, may be present and result in these foods being blamed for triggering the attack when in fact the craving was simply part of the prodrome. A subset of patients will then experience an aura but not necessarily with each and every attack. The headache in migraine is typically, approximately 60%, described as unilateral and of moderate to severe intensity. Though an individual’s headache attacks tend to be fairly stereotyped, many variations can be present. Finally, the headache may be followed by a postdrome, often referred to as a “headache hangover,” characterized by impaired concentration and fatigue or feeling “washed out.” Some patients alternatively report feeling refreshed and rejuvenated after an attack.
From a pathophysiologic standpoint, migraine is considered a genetically induced hypersensitivity of the brain to both internal and external homeostatic changes that can act as headache triggers. These triggers influence the trigeminovascular system, which contains both peripheral and central nervous system components. Stimulation of the trigeminovascular system results in release of neuropeptides and other substances that cause both local inflammation and distant amplification of neural circuitry in the brain stem, trigeminal nucleus caudalis, thalamus, and cortex, leading to central sensitization and symptom worsening along with reduced activity in central descending inhibitory systems and reduced ability to control or extinguish the headache attack.
Chronic migraine, defined as headache on more than 15 days per month for a period of more than 3 months, shows a persistent prevalence of approximately 3% of the population and forms up to 70%–80% of cases seen in a tertiary headache center. Implicit in the diagnosis is a process of transformation from a prior pattern of episodic migraine that can occur over months to years. Though the resulting headache pattern may lose many of its distinguishing features, typical migraine features on 8 days per month are required for the diagnosis ( Box 11.3 ). Risk factors associated with transformation to chronic migraine include coexisting noncephalic sites of pain, mood and anxiety disorders, medication overuse, obesity, female sex, and lower educational status. It is, however, not possible to predict who will transform and whether aggressively treating a pattern of increasing-frequency migraine can reliably prevent transformation to chronic migraine.
- A.
Headache (tension-type-like and/or migraine-like) on 15 days per month for >3 months and fulfilling criteria B and C
- B.
Occurring in a patient who has had at least five attacks fulfilling criteria B–D for 1.1 migraine without aura and/or criteria B and C for 1.2 migraine with aura
- C.
On 8 days per month for >3 months, fulfilling any of the following:
- 1.
criteria C and D for 1.1 migraine without aura
- 2.
criteria B and C for 1.2 migraine with aura
- 3.
believed by the patient to be migraine at onset and relieved by a triptan or ergot derivative
- 1.
- D.
Not better accounted for by another ICHD-3 diagnosis
Treatment Principles
Treatment of migraine has traditionally been divided between abortive management, designed to reduce or resolve an individual headache event, and preventive management, used to reduce the overall headache activity. Treatment early in the attack produces the best results. Features of the headache, including severity, speed of onset, and early associated nausea/vomiting, may influence the choice of agent. Efficacy is based on the treatment’s ability to reduce symptoms and restore function.
Abortive medications include nonsteroidal antiinflammatory agents, combination analgesics, antiemetic medications, and corticosteroids. Opioid medications and butalbital compound are generally discouraged because of the risk of overuse and potential for rebound. More specific antimigraine agents include the selective 5-HT1B/D serotonin agonists, the triptans ( Table 11.1 ), and ergotamine-containing preparations, such as intravenous/intranasal dihydroergotamine. Randomized controlled trials have revealed that standard dose triptans provide freedom from pain at 2 hours in 18%–50% of patients and pain relief in 42%–76%. Combining the triptan with a nonsteroidal antiinflammatory drug enhances the effectiveness of the triptan.
| Name (Brand) | Formulation | Half-life (h) |
|---|---|---|
| Sumatriptan (Imitrex) | PO (25, 50, 100 mg), SC (4, 6 mg), | |
| Nasal spray/powder | 2.5 | |
| PO (85/500 mg) | 2/19 |
| Rizatriptan (Maxalt) | PO and ODT (5, 10 mg) | 2–3 |
| Naratriptan (Amerge) | PO (2.5 mg) | 5–8 |
| Eletriptan (Relpax) a | PO (20, 40 mg) | 4 |
| Almotriptan (Axert) | PO (6.25, 12.5 mg) | 3–4 |
| Frovatriptan (Frova) | PO (2.5 mg) | 26 |
| Zolmitriptan (Zomig) | PO and ODT (2.5, 5 mg) | 3 |
Preventive medication is considered if the patient is suffering from headaches for more than 6 days, impaired for 4 days, or completely disabled for 3 days each month despite abortive treatment. In initiating preventive management, it is important to begin at a low dose, increase the dose slowly to help minimize adverse side effects, and continue for an adequate trial length of time, usually 3 months, so as not to miss a slowly developing therapeutic effect ( Table 11.2 ). The management of chronic migraine can be challenging, and preventive agents used in combination may be of benefit. There are data to support the combination of topiramate and nortriptyline. Onabotulinumtoxin A administered every 3 months has demonstrated efficacy in reducing the number of headache days per month and is a US Food and Drug Administration–approved treatment.
| Name | Daily Dose (mg) | Comments |
|---|---|---|
| Established Efficacy | ||
| Candesartan | 4–16 | |
| Metoprolol | 50–150 | Question avoid in migraine with aura |
| Propranolol | 80–240 | Question avoid in migraine with aura |
| Topiramate | 25–150 | Avoid in pregnancy |
| Valproate sodium | 250–1500 | Avoid in pregnancy |
| Probably Effective | ||
| Amitriptyline | 10–100 | Strong clinical impression of efficacy |
| Nortriptyline | 10–100 | |
| Atenolol | 50–150 | |
| Lisinopril | 10–20 | |
| Memantine | 10–20 | Generally well tolerated |
| Venlafaxine | 37.5–150 | Well tolerated and nonsedating |
| Others | ||
| Cyproheptadine | 2–8 | Used in the pediatric population |
| Gabapentin | 300–1800 | Favorable AE profile |
| Verapamil | 80–480 | Migraine with prolonged aura, vestibular migraine |
Specific Treatments
Lasmiditan
Lasmiditan is a 5-HT1F receptor agonist that has been shown to block neurogenic inflammation and c-Fos expression in neural tissue but, unlike the triptans, without evidence of vasoconstriction in vascular tissue models in vitro. It has been FDA approved since 2019 for the acute treatment of migraine with or without aura at doses of 50, 100, and 200 mg. Lasmiditan works both centrally and peripherally on 5-HT1F receptors, and this likely explains central nervous system (CNS) adverse effects, including dizziness, fatigue, and somnolence. Based on these AEs, the FDA approval came with a warning against driving for 8 hours after each dose, the first time such a driving restriction has been included in an approval.
Calcitonin Gene–Related Peptide Antibodies
Extensive research has demonstrated that calcitonin gene–related peptide (CGRP) plays an important role in the development of migraine pain through the activation of the trigeminovascular system. Serum CGRP levels are elevated during migraine attacks, and intravenous administration of CGRP will trigger a migraine-like headache. CGRP antagonists are a class of drugs that work by blocking the activity of CGRP, thereby reducing the severity and frequency of migraines. CGRP monoclonal antibodies are administered via injection and are generally well tolerated with minimal side effects.
There are two types of CGRP antagonists: monoclonal antibodies and small molecules. Monoclonal antibodies are large proteins that are administered via injection and work by binding to CGRP, preventing it from interacting with its receptors. Small molecules are orally active drugs that are able to penetrate the blood-brain barrier and directly inhibit the activity of CGRP receptors.The first CGRP antagonist to receive FDA approval for migraine prevention was erenumab, a monoclonal antibody that is administered via subcutaneous injection once per month, targets and blocks the CGRP receptor. Other CGRP monoclonal antibodies that have been approved for the prevention of migraine include fremanezumab, galcanezumab, and eptinezumab; they act by binding to the CGRP ligand. Small molecule CGRP antagonists that have been approved for the abortive treatment of migraine include ubrogepant and rimegepant, both of which are administered orally. Studies revealed pain freedom at 2 hours in approximately 20% of patients and pain relief in 61%. Zavegepant nasal spray for the acute treatment of migraine has been demonstrated to effect freedom from pain in about 23% of patients. Rimegepant taken every other day has also been approved for migraine prevention. Atogepant taken daily has proven to be extremely effective in reducing the frequency of migraine attacks. Clinical trials have shown that CGRP antagonists are effective at reducing the frequency and severity of migraine episodes and may have a lower risk of side effects compared to traditional migraine medications such as triptans. However, as with any medication, there may be potential risks and side effects associated with CGRP antagonists, and they may not be effective for all patients. The most common side effects are constipation and nausea ( Table 11.3 ).
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