Primary and Secondary Headache

Epidemiology

Migraine is the most common type of headache that makes patients seek medical care. Recent epidemiologic studies reveal a worldwide prevalence of 10%–15% with the highest prevalence in South and Central America. Females are affected twice as often as men, and prevalence is especially high in younger females and the urban population. According to the Global Burden of Disease Survey 2010 conducted by the World Health Organization (WHO), migraine ranks as the third most common disease worldwide (after dental caries and tension type headaches), the seventh most disabling disease, and the third most expensive neurologic disease after dementia and stroke. The estimated heritability of migraine is 40%–60% based on family and twin studies; a child with a migraineur parent has about a 50% chance of developing a migraine, and this number rises to 75% if both parents are affected. First migraine attacks often manifest in the teens and early 20s, and 80% of patients have had their first migraine by age 30. Typically, migraines diminish or disappear in the older population and with menopause; one should be particularly cautious in making a new migraine diagnosis in the elderly.

Pathophysiology

Migraine pathophysiology is likely linked to cortical hyperexcitability in genetically susceptible patients, which subsequently activates trigeminal pathways and results in release of vasoactive neuropeptides and proinflammatory substances (including substance P and calcitonin gene-related peptide [CGRP]) in the trigeminal nociceptive nerve endings. These nociceptive nerve endings are located in pial, arachnoid, and dural blood vessels, as well as large cerebral arteries and sinuses; they are carried mostly by V1 and to lesser degree V2 and V3 nerve roots ( Figs. 21.1 and 21.2 ). The release of vasoactive substances promotes meningeal blood vessel dilatation and release of inflammatory cytokines, leads to peripheral trigeminal nerve sensitization as well as central sensitization in the spinal trigeminal nucleus. Ultimately, these changes not only cause a throbbing headache, but via activation of the pulvinar, hypothalamus, and periaqueductal gray in the brainstem result in widespread symptoms of allodynia, malaise, and autonomic responses. The convergence of trigeminal sensory afferents and C1–C3 occipital afferents in the trigeminal nucleus spinalis likely allows for cross sensitization and referred pain in the occipital region and neck (see Fig. 21.1 ). The phenomenon of an aura (i.e., a transient focal neurologic symptom heralding or accompanying a migraine headache) represents a slowly propagating wave (2–6 mm/min) of neuronal and glial depolarization followed by a prolonged inhibition (15–30 min) of cortical activity, termed cortical spreading depression. Because this phenomenon can occur anywhere on the cortex, auras can produce a wide range of symptoms including visual, motor, sensory, and cognitive alterations.

Clinical Symptoms ( Fig. 21.3 )/Diagnostic Criteria

Migraine is a primary headache disorder; however it can and often does coexist with other either primary (e.g., tension type headache) or secondary (medication-overuse headache) headache disorders. Migraine has two major subtypes, based on the presence or absence of an aura; furthermore, migraine frequency distinguishes between episodic and chronic migraines; the latter is characterized by greater than 15 headache days per month for 3 months.

According to the International Headache Society (IHS) classification, migraine headaches are characterized by

• Recurrent headache attacks lasting 4–72 hours AND

• Typical headache characteristics (2 out of 4): unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity, AND

• Association with (1 out of 2) nausea/vomiting or photophobia and phonophobia.

The location of migraine headache is typically frontotemporal, but can involve the entire hemicranium and sometimes the face. Laterality can switch from attack to attack, however typically there is a strong side preference for most attacks. Migraine onset in children can often have a bilateral presentation, and lateralizes typically as they reach adolescence. Symptoms of cutaneous/scalp allodynia as well as more widespread neck muscle tenderness are not uncommon and are likely attributed to sensitization of the trigeminocervical complex.

Patients with migraine often have premonitory symptoms which occur up to 1–2 days before the actual migraine attack. These include fatigue, neck tenderness, thirst, anorexia, fluid retention, food cravings, gastrointestinal symptoms, and emotional or mood disturbances such as irritability, elation, or depression.

Approximately 15% of migraine patients have an aura, characterized by focal, transient neurologic symptoms which typically precede but also can accompany the headache phase. By far the most common aura symptoms (>90%) are of visual character, followed by sensory and speech/language disturbance. Rarer presentations include motor weakness (referred to as hemiplegic migraine) and brainstem symptoms (e.g., vertigo). Aura phenomena are diagnosed according to their time of onset, duration, and relation to the headaches (IHS criteria). Most auras typically spread over 5–20 minutes (e.g., spreading tingling sensation or flashing lights), last 5–60 minutes, are typically unilateral, and are followed by the headache phase within 1 hour of onset. Gradual spreading of symptoms within one modality (tingling starting in the face and gradually involving the arm) or even spreading to other modalities (e.g., flashing lights followed by tingling) is the result of continuous spreading across various cortical areas. Prolonged inhibition after the depolarization wave (spreading depression) results clinically in negative phenomena like a transient scotoma, numbness, or even weakness.

Visual auras can occur in a homonymous or hemifield distribution and include scintillating flashes or stars (phosphenes) and geometric patterns known as fortification spectra (see Fig. 21.3 ), with an absolute or relative transient scotoma. Sensory symptoms typically consist of tingling/pins and needles anywhere in the body (often face or arm), and spread gradually, often leaving behind transient numbness. Less frequent, and often more dramatic, auras include language disturbances (any type of aphasia), brainstem auras (dysarthria, vertigo, tinnitus, hyperacusis, diplopia, ataxia, decreased level of consciousness) and hemiplegic migraine presenting with transient weakness or hemiplegia. Hemiplegic migraine is often familial (familial hemiplegic migraine) and is caused in many cases by various mutations of the voltage-gated calcium channel Ca _V 2.1. Oculomotor nerve palsies are the hallmark of ophthalmoplegic “migraine”; however this might represent a recurrent demyelinating neuropathy rather than a true migraine variant.

Careful neurologic evaluation is critical, and brain MRI is typically obtained for a first-time presentation of an aura. This is especially true if the aura is not followed by a headache (aura without headache), but presents as an isolated focal neurologic deficit.

Special Considerations

Ischemic strokes as well as other cardiovascular events (ischemic hemorrhage, coronary events) have been shown to have a higher prevalence in patients with migraines, especially in migraine with aura. Based on epidemiologic studies, the relative risk for ischemic stroke is double in female migraineurs with aura, and the risk increases with more frequent migraine attacks. However given the low prevalence in this typically young and healthy population, absolute numbers remain very low. In addition, several neuroimaging studies have shown an up to four-fold increased prevalence of white matter hyperintensities especially in the posterior circulation (“white spots”) in people with migraine, as well as an increased risk for white matter lesions with increased attack frequency. Whether the association of migraine and cardiovascular events is causative remains uncertain; rather, there are several known diseases which present with both migraine type headaches as well as increased cardiovascular risk. For example, gene mutation of NOTCH3 causes cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary small-artery disease of the brain that is characterized by multiple ischemic strokes; however in 40% of patients, migraine headaches precede the first stroke by 10–20 years.

Patent foramen ovale (PFO) and migraines have sometimes been linked together; however, two population-based studies showed that the prevalence of a PFO was similar in patients with and without migraine. In addition, three randomized clinical trials did not show significant improvement of migraines other than in small subpopulations 1 year after PFO closure surgery.

Estrogen levels likely play a significant role as a migraine trigger in females. About two-thirds of female migraineurs primarily experience migraines just before or during menses, likely caused by the timing and rate of estrogen withdrawal. In many cases, first time migraine onset occurs around the time of menarche, and frequency often significantly decreases after menopause. In addition, migraines often worsen early in pregnancy but tend to improve during the second and third trimesters, particularly in women with migraine primarily related to their menstrual cycle.

Management and Therapy

Two types of treatment exist for migraine therapy: abortive treatment for acute headaches, and prophylactic treatment to decrease frequency and intensity of future migraine attacks.

Prophylaxis is indicated if migraine attacks are frequent and/or disabling despite use of abortive medications overuse/misuse of abortive medication occurs; auras are frequent and disabling, or for specific migraine conditions (e.g., hemiplegic migraine). Prophylactic treatment can be preemptive, short term, or continuous. If defined migraine triggers exist, preemptive treatment 30–60 minutes before the anticipated trigger is useful (e.g., indomethacin before exercise-induced headache). Time-limited exposure to a provoking factor can be treated with short-term daily prophylaxis, such as daily nonsteroidal antiinflammatory drug (NSAID) intake a few days prior and into menstruation for menstrual-related migraines. Continuous, daily prophylactic medication is necessary if trigger factors are unpredictable, unknown, or absent. Most commonly used daily prophylactic drug classes include tricyclic antidepressants, β-blockers, calcium channel blockers, antiepileptics, and gabapentinoids. Of these, certain β-blockers (especially propranolol and metoprolol), divalproex sodium, and topiramate have the best evidence. Other antiepileptics, including gabapentin, pregabalin, carbamazepine, oxcarbazepine, lamotrigine, levetiracetam, vigabatrin, and zonisamide, do not have high-quality evidence to support their use; however they might be worth trying in otherwise refractory patients. Given the similar efficacy of first-line preventatives in studies, the initial choice of medication is often based on comorbidities, side-effect profile, medication interaction, patient and prescriber preference, medication cost, and insurance coverage. For instance, difficulty with sleep may prompt prescribing of medications that are more sedating like amitriptyline. Topiramate may be preferable over valproic acid or tricyclics for those in whom weight gain is a concern. A concomitant mood disorder may prompt the use of antidepressants or medications with mood-stabilizing properties. β-blockers may help in controlling coexisting hypertension in some patients but should be avoided in those with reactive-airway disease or preexisting depression. To improve efficacy and to lower side effects, combination therapy of two different class agents is often advisable, such as the combination of β-blockers and a tricyclic, or the addition of topiramate. The empirical approach to find the right medication or medication combination can often be frustrating for patient and provider alike.

“Natural” treatments might sometimes be preferable due to their very favorable side-effect profile or patient preference, and substances with some evidence include riboflavin 400 mg daily, coenzyme Q10 300 mg daily, magnesium 400–600 mg daily, and a combination of simvastatin with vitamin D3. Nonpharmacologic prophylactic treatments are also advisable, and may include avoiding certain foods (typically caffeine overuse, chocolate, alcohol, cheese, processed meat containing nitrates) and environmental triggers, regular sleep, physical activity, regular meals, and appropriate hydration.

Interventional headache treatments should be considered if oral medications of different classes fail to control migraine attacks, or if use is limited due to side effects, comorbidities, or allergies. Occipital nerve blocks with or without steroids can be effective in reducing migraines for 1–3 months. The administration of 155 units of onabotulinumtoxin A every 12 weeks is FDA approved and has been shown in two large randomized controlled trials to be a safe and effective way to reduce migraine frequency and improve quality of life. The likely mechanism of action is inhibition of release of pronociceptive substances like substance P and CGRP from peripheral nociceptive trigeminal terminals, as well as (via retrograde axonal transport) decreasing central sensitization at the trigeminal spinal nucleus. Neurostimulation represents yet another modality, and daily supraorbital transcutaneous neurostimulation using the Cefaly device has been FDA approved for reduction of migraine frequency in episodic migraines. There might also be a modest effect from occipital nerve stimulation implant for chronic migraine prevention; however complication rate and surgical risk must be carefully weighed against potential benefit.

Regarding abortive therapy, mild to moderately intense migraines are best treated with oral NSAIDs, acetylsalicylic acid (aspirin), or acetaminophen. Opiates should be avoided as should butalbital-containing medications due to their association with medication overuse headache (MOH) and tendency to cause dependency. While many different NSAIDs are used for acute treatment, the soluble powder formulation of diclofenac potassium (Cambia in the United States, Voltfast in Europe) is the only FDA-approved NSAID for migraine. Caffeine may enhance the effect of these various medications or can be helpful by itself. Antiemetics such as prochlorperazine, metoclopramide, or ondansetron are often useful in conjunction with analgesics.

For more severe migraine attacks, serotonin 1B/1D receptor agonist (“triptan”) preparations are the medications of choice. Their success is attributed to several sites of action on the migraine cascade, including peripheral mechanisms (vasoconstriction, nociceptor inhibition, inhibition of peripheral release of vasoactive peptides) as well as likely central mechanisms (decreasing neurotransmitter release at central nociceptive terminals, decreasing neuronal excitability) (see Fig. 21.2 ). Seven different triptans are available, which differ by their available route of administration (oral, quick-dissolve sublingual, injectable, or intranasal) as well as their bioavailability, plasma half-life, and lipophilicity, all of which does not translate into meaningful increased efficacy or decreased headache recurrence. The rapidly acting triptans include almotriptan, eletriptan, rizatriptan, sumatriptan, and zolmitriptan. The slower acting/longer acting triptans include naratriptan and frovatriptan. Sumatriptan is the only triptan available as subcutaneous injectable, which results in ultra-fast absorption and a quick onset of migraine relief. There are marked interindividual differences for both effect and side effects for different triptans, and changing triptans on a trial-and-error basis often results in better migraine control. Varying the administration route (e.g., from oral to subcutaneous in patients with severe nausea or the concomitant intake of an anti-nausea medication like metoclopramide) can increase the efficacy by improving triptan absorption. Despite the limited evidence for cardiovascular events caused by triptan use, it is still recommended that triptans be avoided in patients with hemiplegic migraine, basilar migraine, ischemic stroke, ischemic heart disease, Prinzmetal's angina, uncontrolled hypertension, and pregnancy.

Butalbital, isometheptene/dichloralphenazone, and oral opioids are rarely recommended abortive therapies, as they have a higher risk of sedation, overuse, and dependence.

The alpha-adrenergic blocker and serotonin 1B/1D receptor agonist dihydroergotamine (DHE) is available as intravenous, intramuscular, subcutaneous, and intranasal formulations, and is often used in the emergency room setting in combination with an antiemetic for acute migraine attacks and status migrainosus. Intravenous ketorolac or opioids are other options for emergency treatment in the most refractory cases.

Future Directions

Of the new therapeutic targets for migraine treatment, CGRP has been the most extensively investigated. The release of CGRP after activation of the trigeminal system plays a key role in inducing meningeal vasodilation, inflammation, and nociceptive transmission to the trigeminal spinal nucleus. Monoclonal antibodies to either the CGRP receptor or CGRP ligand itself have shown promising efficacy as preventative treatment in episodic and chronic migraine in several randomized controlled trials, with only minimal side effects. Single dose, subcutaneous administration monthly or quarterly, makes them an attractive alternative to daily preventative medications or botulinum toxin injection.

Cluster Headache

Clinical presentation

The distinctive clinical features, as summarized in the clinical vignette, assist in diagnosing cluster headaches ( Fig. 21.4 ). The first two divisions of the trigeminal nerve are more commonly involved as opposed to trigeminal neuralgia which primarily involves the second and third divisions.

According to the International Headache Society's revised classification of cluster headache, there must be recurrent attacks of at least severe unilateral pain lasting 15–180 minutes. The pain must be orbital, supraorbital, and/or temporal. The headaches must be accompanied by at least one of the following: restlessness or agitation, ipsilateral conjunctival injection and/or lacrimation, nasal congestion and/or rhinorrhea, eyelid edema, forehead and facial sweating, ipsilateral miosis, and/or ptosis. Attacks have a frequency of one every other day to eight a day. Finally, other causes must be ruled out.

Paroxysmal Hemicranias

These are unusual primary headaches—unilateral and short-lived (2–30 minutes), which occur in a chronic or episodic manner. They are localized to the orbital, supraorbital, and/or temporal region. Typically, the pain has a severe throbbing or boring quality and often recurs several times throughout the day. These headaches are associated with ipsilateral cranial autonomic dysfunction but, unlike cluster headaches, occur more often in women than in men. Furthermore, these headaches have daily recurrences and tend not to conglomerate over a few days such as in cluster headaches. They usually respond well to 25–50 mg indomethacin 2–3 times daily for at least 48 hours. Therefore these headaches by definition are “indomethacin responsive,” and a trial is always warranted if there are no medical contraindications to its use (see Fig. 21.4 ). Agents proven effective for prophylactic treatment include lamotrigine, topiramate, and acetylsalicylic acid.

Short-Lasting Unilateral Neuralgiform Headache Attacks

Two subtypes of short-lasting unilateral neuralgiform headache attacks are recognized in the 3rd edition of the International Classification of Headache Disorders: short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA). They are syndromes of strictly unilateral headache attacks with the pain confined to the orbital/periorbital area. Most episodes are moderate to severe in intensity with a burning, stabbing, or electrical quality. The duration of the paroxysms usually ranges from 10–120 seconds distinguishing them from longer lasting headache syndromes. Prominent, ipsilateral conjunctival injection and lacrimation are present. Nasal congestion or rhinorrhea and ipsilateral forehead perspiration may also be present. In contrast to paroxysmal hemicranias, this headache syndrome predominates in middle-aged men and is not responsive to indomethacin. In fact, treatment efforts with numerous medications have been frustrating, with little or inconsistent responses. Antiepileptic drugs including lamotrigine, gabapentin, and topiramate may improve symptoms. At present, the drug of choice for SUNCT is lamotrigine whereas SUNA may respond better to gabapentin. Methylprednisolone therapy and intravenous lidocaine may be of benefit in severe cases. A few SUNCT patients who have undergone deep brain hypothalamic stimulation have had substantial and persistent relief.