Harrison's Internal Medicine > Chapter 15. Headache Headache: IntroductionHeadache is among the most common reasons that patients seek medical attention. Diagnosis and management is based on a careful clinical approach that is augmented by an understanding of the anatomy, physiology, and pharmacology of the nervous system pathways that mediate the various headache syndromes.General PrinciplesA classification system developed by the International Headache Society characterizes headache as primary or secondary (Table 15-1). Primary headaches are those in which headache and its associated features are the disorder in itself, whereas secondary headaches are those caused by exogenous disorders. Primary headache often results in considerable disability and a decrease in the patient's quality of life. Mild secondary headache, such as that seen in association with upper respiratory tract infections, is common but rarely worrisome. Life-threatening headache is relatively uncommon, but vigilance is required in order to recognize and appropriately treat patients with this category of head pain.Table 15-1 Common Causes of Headache
Source: After J Olesen et al: The Headaches. Philadelphia, Lippincott, Williams & Wilkins, 2005Anatomy and Physiology of HeadachePain usually occurs when peripheral nociceptors are stimulated in response to tissue injury, visceral distension, or other factors (Chap. 12). In such situations, pain perception is a normal physiologic response mediated by a healthy nervous system. Pain can also result when pain-producing pathways of the peripheral or central nervous system (CNS) are damaged or activated inappropriately. Headache may originate from either or both mechanisms. Relatively few cranial structures are pain-producing; these include the scalp, middle meningeal artery, dural sinuses, falx cerebri, and proximal segments of the large pial arteries. The ventricular ependyma, choroid plexus, pial veins, and much of the brain parenchyma are not pain-producing.The key structures involved in primary headache appear to be
the large intracranial vessels and dura mater the peripheral terminals of the trigeminal nerve that innervate these structures the caudal portion of the trigeminal nucleus, which extends into the dorsal horns of the upper cervical spinal cord and receives input from the first and second cervical nerve roots (the trigeminocervical complex) the pain modulatory systems in the brain that receive input from trigeminal nociceptorsThe innervation of the large intracranial vessels and dura mater by the trigeminal nerve is known as the trigeminovascular system. Autonomic symptoms, such as lacrimation and nasal congestion, are prominent in the trigeminal autonomic cephalalgias, including cluster headache and paroxysmal hemicrania, and may also be seen in migraine. These autonomic symptoms reflect activation of cranial parasympathetic pathways, and functional imaging studies indicate that vascular changes in migraine and cluster headache, when present, are similarly driven by these cranial autonomic systems. Migraine and other primary headache types are not "vascular headaches"; these disorders do not reliably manifest vascular changes, and treatment outcomes cannot be predicted by vascular effects.Clinical Evaluation of Acute, New-Onset HeadacheThe patient who presents with a new, severe headache has a differential diagnosis that is quite different from the patient with recurrent headaches over many years. In new-onset and severe headache, the probability of finding a potentially serious cause is considerably greater than in recurrent headache. Patients with recent onset of pain require prompt evaluation and often treatment. Serious causes to be considered include meningitis, subarachnoid hemorrhage, epidural or subdural hematoma, glaucoma, and purulent sinusitis. When worrisome symptoms and signs are present (Table 15-2), rapid diagnosis and management is critical. Table 15-2 Headache Symptoms that Suggest a Serious Underlying Disorder| "Worst" headache ever |
| First severe headache |
| Subacute worsening over days or weeks |
| Abnormal neurologic examination |
| Fever or unexplained systemic signs |
| Vomiting that precedes headache |
| Pain induced by bending, lifting, cough |
| Pain that disturbs sleep or presents immediately upon awakening |
| Known systemic illness |
| Onset after age 55 |
| Pain associated with local tenderness, e.g., region of temporal artery |
| Symptom | Patients Affected, % |
| Nausea | 87 |
| Photophobia | 82 |
| Lightheadedness | 72 |
| Scalp tenderness | 65 |
| Vomiting | 56 |
| Visual disturbances | 36 |
| Photopsia | 26 |
| Fortification spectra | 10 |
| Paresthesias | 33 |
| Vertigo | 33 |
| Alteration of consciousness | 18 |
| Syncope | 10 |
| Seizure | 4 |
| Confusional state | 4 |
| Diarrhea | 16 |
Brainstem pathways that modulate sensory input. The key pathway for pain in migraine is the trigeminovascular input from the meningeal vessels, which passes through the trigeminal ganglion and synapses on second-order neurons in the trigeminocervical complex. These neurons in turn project in the quintothalamic tract and, after decussating in the brainstem, synapse on neurons in the thalamus. Important modulation of the trigeminovascular nociceptive input comes from the dorsal raphe nucleus, locus coeruleus, and nucleus raphe magnus.Activation of cells in the trigeminal nucleus results in the release of vasoactive neuropeptides, particularly calcitonin gene-related peptide (CGRP), at vascular terminations of the trigeminal nerve. Recently, antagonists of CGRP have shown some early promise in the therapy of migraine. Centrally, the second-order trigeminal neurons cross the midline and project to ventrobasal and posterior nuclei of the thalamus for further processing. Additionally, there are projections to the periaqueductal gray and hypothalamus, from which reciprocal descending systems have established anti-nociceptive effects. Other brainstem regions likely to be involved in descending modulation of trigeminal pain include the nucleus locus coeruleus in the pons and the rostroventromedial medulla.Pharmacologic and other data point to the involvement of the neurotransmitter 5-hydroxytryptamine (5-HT; also known as serotonin) in migraine. Approximately 50 years ago, methysergide was found to antagonize certain peripheral actions of 5-HT and was introduced as the first drug capable of preventing migraine attacks. The triptans are designed to selectively stimulate subpopulations of 5-HT receptors; at least 14 different 5-HT receptors exist in humans. The triptans are potent agonists of 5-HT1B, 5-HT1D, and 5-HT1F receptors and are less potent at the 5-HT1A receptor. A growing body of data indicates that the antimigraine efficacy of the triptans relates to their ability to stimulate 5-HT1B/1D receptors, which are located on both blood vessels and nerve terminals.Data also support a role for dopamine in the pathophysiology of certain subtypes of migraine. Most migraine symptoms can be induced by dopaminergic stimulation. Moreover, there is dopamine receptor hypersensitivity in migraineurs, as demonstrated by the induction of yawning, nausea, vomiting, hypotension, and other symptoms of a migraine attack by dopaminergic agonists at doses that do not affect nonmigraineurs. Dopamine receptor antagonists are effective therapeutic agents in migraine, especially when given parenterally or concurrently with other antimigraine agents. Migraine genes identified by studying families with familial hemiplegic migraine (FHM) reveal involvement of ion channels, suggesting that alterations in membrane excitability can predispose to migraine. Mutations involving the Cav2.1 (P/Q) type voltage-gated calcium channel CACNA1A gene are now known to cause FHM 1; this mutation is responsible for about 50% of FHM. Mutations in the Na+-K+ATPase ATP1A2 gene, designated FHM 2, are responsible for about 20% of FHM. Mutations in the neuronal voltage-gated sodium channel SCN1A cause FHM 3. Functional neuroimaging has suggested that brainstem regions in migraine (Fig. 15-2) and the posterior hypothalamic gray matter region close to the human circadian pacemaker cells of the suprachiasmatic nucleus in cluster headache (Fig. 15-3) are good candidates for specific involvement in primary headache.
Patients with acephalgic migraine experience recurrent neurologic symptoms, often with nausea or vomiting, but with little or no headache. Vertigo can be prominent; it has been estimated that one-third of patients referred for vertigo or dizziness have a primary diagnosis of migraine.Migraine Headaches: TreatmentOnce a diagnosis of migraine has been established, it is important to assess the extent of a patient's disease and disability. The Migraine Disability Assessment Score (MIDAS) is a well-validated, easy-to-use tool (Fig. 15-4).
aNot all drugs are specifically indicated by the FDA for migraine. Local regulations and guidelines should be consulted.Note: Antiemetics (e.g., domperidone 10 mg or ondansetron) or prokinetics (e.g., metoclopramide 10 mg) are sometimes useful adjuncts.Abbreviations: NSAIDs, nonsteroidal anti-inflammatory drugs; 5-HT, 5-hydroxytryptamine.
In general, an adequate dose of whichever agent is chosen should be used as soon as possible after the onset of an attack. If additional medication is required within 60 min because symptoms return or have not abated, the initial dose should be increased for subsequent attacks. Migraine therapy must be individualized; a standard approach for all patients is not possible. A therapeutic regimen may need to be constantly refined until one is identified that provides the patient with rapid, complete, and consistent relief with minimal side effects (Table 15-6).Table 15-6 Clinical Stratification of Acute Specific Migraine Treatments
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)Both the severity and duration of a migraine attack can be reduced significantly by anti-inflammatory agents (Table 15-5). Indeed, many undiagnosed migraineurs are self-treated with nonprescription NSAIDs. A general consensus is that NSAIDs are most effective when taken early in the migraine attack. However, the effectiveness of anti-inflammatory agents in migraine is usually less than optimal in moderate or severe migraine attacks. The combination of acetaminophen, aspirin, and caffeine has been approved for use by the U.S. Food and Drug Administration (FDA) for the treatment of mild to moderate migraine. The combination of aspirin and metoclopramide has been shown to be equivalent to a single dose of sumatriptan. Important side effects of NSAIDs include dyspepsia and gastrointestinal irritation.5-HT1 AgonistsOralStimulation of 5-HT1B/1D receptors can stop an acute migraine attack. Ergotamine and dihydroergotamine are nonselective receptor agonists, while the triptans are selective 5-HT1B/1D receptor agonists. A variety of triptans (e.g., naratriptan, rizatriptan, eletriptan, sumatriptan, zolmitriptan, almotriptan, frovatriptan) are now available for the treatment of migraine.Each drug in the triptan class has similar pharmacologic properties but varies slightly in terms of clinical efficacy. Rizatriptan and eletriptan are the most efficacious of the triptans currently available in the United States. Sumatriptan and zolmitriptan have similar rates of efficacy as well as time to onset, whereas naratriptan and frovatriptan are the slowest-acting and least efficacious. Clinical efficacy appears to be related more to the tmax (time to peak plasma level) than to the potency, half-life, or bioavailability. This observation is consistent with a large body of data indicating that faster-acting analgesics are more effective than slower-acting agents.Unfortunately, monotherapy with a selective oral 5-HT1B/1D agonist does not result in rapid, consistent, and complete relief of migraine in all patients. Triptans are not effective in migraine with aura unless given after the aura is completed and the headache initiated. Side effects are common though often mild and transient. Moreover, 5-HT1B/1D agonists are contraindicated in individuals with a history of cardiovascular and cerebrovascular disease. Recurrence of headache is another important limitation of triptan use and occurs at least occasionally in most patients.Ergotamine preparations offer a nonselective means of stimulating 5-HT1 receptors. A nonnauseating dose of ergotamine should be sought since a dose that provokes nausea is too high and may intensify head pain. Except for a sublingual formulation of ergotamine, oral formulations of ergotamine also contain 100 mg caffeine (theoretically to enhance ergotamine absorption and possibly to add additional analgesic activity). The average oral ergotamine dose for a migraine attack is 2 mg. Since the clinical studies demonstrating the efficacy of ergotamine in migraine predated the clinical trial methodologies used with the triptans, it is difficult to assess the clinical efficacy of ergotamine versus the triptans. In general, ergotamine appears to have a much higher incidence of nausea than triptans, but less headache recurrence.NasalThe fastest-acting nonparenteral antimigraine therapies that can be self-administered include nasal formulations of dihydroergotamine (Migranal), zolmitriptan (Zomig nasal), or sumatriptan. The nasal sprays result in substantial blood levels within 30–60 min. Although in theory nasal sprays might provide faster and more effective relief of a migraine attack than oral formulations, their reported efficacy is only approximately 50–60%.ParenteralParenteral administration of drugs such as dihydroergotamine and sumatriptan is approved by the FDA for the rapid relief of a migraine attack. Peak plasma levels of dihydroergotamine are achieved 3 min after intravenous dosing, 30 min after intramuscular dosing, and 45 min after subcutaneous dosing. If an attack has not already peaked, subcutaneous or intramuscular administration of 1 mg dihydroergotamine suffices for about 80–90% of patients. Sumatriptan, 6 mg subcutaneously, is effective in ~70–80% of patients.Dopamine AntagonistsOralOral dopamine antagonists should be considered as adjunctive therapy in migraine. Drug absorption is impaired during migraine because of reduced gastrointestinal motility. Delayed absorption occurs even in the absence of nausea and is related to the severity of the attack and not its duration. Therefore, when oral NSAIDs and/or triptan agents fail, the addition of a dopamine antagonist such as metoclopramide, 10 mg, should be considered to enhance gastric absorption. In addition, dopamine antagonists decrease nausea/vomiting and restore normal gastric motility.ParenteralParenteral dopamine antagonists (e.g., chlorpromazine, prochlorperazine, metoclopramide) can also provide significant acute relief of migraine; they can be used in combination with parenteral 5-HT1B/1D agonists. A common intravenous protocol used for the treatment of severe migraine is the administration over 2 min of a mixture of 5 mg of prochlorperazine and 0.5 mg of dihydroergotamine.Other Medications for Acute MigraineOralThe combination of acetaminophen, dichloralphenazone, and isometheptene, one to two capsules, has been classified by the FDA as "possibly" effective in the treatment of migraine. Since the clinical studies demonstrating the efficacy of this combination analgesic in migraine predated the clinical trial methodologies used with the triptans, it is difficult to compare the efficacy of this sympathomimetic compound to other agents.NasalA nasal preparation of butorphanol is available for the treatment of acute pain. As with all narcotics, the use of nasal butorphanol should be limited to a select group of migraineurs, as described below.ParenteralNarcotics are effective in the acute treatment of migraine. For example, intravenous meperidine (50–100 mg) is given frequently in the emergency room. This regimen "works" in the sense that the pain of migraine is eliminated. However, this regimen is clearly suboptimal for patients with recurrent headache. Narcotics do not treat the underlying headache mechanism; rather, they act to alter the pain sensation. Moreover, in patients taking oral narcotics such as oxycodone or hydrocodone, narcotic addiction can greatly confuse the treatment of migraine. Narcotic craving and/or withdrawal can aggravate and accentuate migraine. Therefore, it is recommended that narcotic use in migraine be limited to patients with severe, but infrequent, headaches that are unresponsive to other pharmacologic approaches.Medication-Overuse Headache Acute attack medications, particularly codeine or barbiturate-containing compound analgesics, have a propensity to aggravate headache frequency and induce a state of refractory daily or near-daily headache called medication-overuse headache. This condition is likely not a separate headache entity but a reaction of the migraine patient to a particular medicine. Migraine patients who have two or more headache days a week should be cautioned about frequent analgesic use (see "Chronic Daily Headache," below).Preventive Treatments for Migraine Patients with an increasing frequency of migraine attacks, or with attacks that are either unresponsive or poorly responsive to abortive treatments, are good candidates for preventive agents. In general, a preventive medication should be considered in the subset of patients with five or more attacks a month. Significant side effects are associated with the use of many of these agents; furthermore, determination of dose can be difficult since the recommended doses have been derived for conditions other than migraine. The mechanism of action of these drugs is unclear; it seems likely that the brain sensitivity that underlies migraine is modified. Patients are usually started on a low dose of a chosen treatment; the dose is then gradually increased, up to a reasonable maximum to achieve clinical benefit. Drugs that have the capacity to stabilize migraine are listed in Table 15-7. Drugs must be taken daily, and there is usually a lag of at least 2–12 weeks before an effect is seen. The drugs that have been approved by the FDA for the prophylactic treatment of migraine include propranolol, timolol, sodium valproate, topiramate, and methysergide (not available in the United States). In addition, a number of other drugs appear to display prophylactic efficacy. This group includes amitriptyline, nortriptyline, flunarizine, phenelzine, gabapentin, topiramate, and cyproheptadine. Phenelzine and methysergide are usually reserved for recalcitrant cases because of their serious potential side effects. Phenelzine is a monoamine oxidase inhibitor (MAOI); therefore, tyramine-containing foods, decongestants, and meperidine are contraindicated. Methysergide may cause retroperitoneal or cardiac valvular fibrosis when it is used for >6 months, and thus monitoring is required for patients using this drug; the risk of fibrosis is about 1:1500 and is likely to reverse after the drug is stopped.Table 15-7 Preventive Treatments in Migrainea
bNot available in the United States.The probability of success with any one of the antimigraine drugs is 50–75%. Many patients are managed adequately with low-dose amitriptyline, propranolol, topiramate, gabapentin, or valproate. If these agents fail or lead to unacceptable side effects, second-line agents such as methysergide or phenelzine can be used. Once effective stabilization is achieved, the drug is continued for 5–6 months and then slowly tapered to assess the continued need. Many patients are able to discontinue medication and experience fewer and milder attacks for long periods, suggesting that these drugs may alter the natural history of migraine.
Tension-Type HeadacheClinical FeaturesThe term tension-type headache (TTH) is commonly used to describe a chronic head-pain syndrome characterized by bilateral tight, bandlike discomfort. The pain typically builds slowly, fluctuates in severity, and may persist more or less continuously for many days. The headache may be episodic or chronic (present >15 days per month). A useful clinical approach is to diagnose TTH in patients whose headaches are completely without accompanying features such as nausea, vomiting, photophobia, phonophobia, osmophobia, throbbing, and aggravation with movement. Such an approach neatly separates migraine, which has one or more of these features and is the main differential diagnosis, from TTH. However, the International Headache Society's definition of TTH allows an admixture of nausea, photophobia, or phonophobia in various combinations, illustrating the difficulties in distinguishing these two clinical entities. Patients whose headaches fit the TTH phenotype and who have migraine at other times, along with a family history of migraine, migrainous illnesses of childhood, or typical migraine triggers to their migraine attacks, may be biologically different from those who have TTH headache with none of the features.PathophysiologyThe pathophysiology of TTH is incompletely understood. It seems likely that TTH is due to a primary disorder of CNS pain modulation alone, unlike migraine, which involves a more generalized disturbance of sensory modulation. Data suggest a genetic contribution to TTH, but this may not be a valid finding: given the current diagnostic criteria, the studies undoubtedly included many migraine patients. The name tension-type headache implies that pain is a product of nervous tension, but there is no clear evidence for tension as an etiology. Muscle contraction has been considered to be a feature that distinguishes TTH from migraine, but there appear to be no differences in contraction between the two headache types.Tension-Type Headache: TreatmentThe pain of TTH can generally be managed with simple analgesics such as acetaminophen, aspirin, or NSAIDs. Behavioral approaches including relaxation can also be effective. Clinical studies have demonstrated that triptans in pure TTH are not helpful, although triptans are effective in TTH when the patient also has migraine. For chronic TTH, amitriptyline is the only proven treatment (Table 15-7); other tricyclics, selective serotonin reuptake inhibitors, and the benzodiazepines have not been shown to be effective. There is no evidence for the efficacy of acupuncture. Placebo controlled trials of botulinum toxin type A in chronic TTH have not shown benefit.Trigeminal Autonomic Cephalalgias, Including Cluster HeadacheThe trigeminal autonomic cephalalgias (TACs) are a group of primary headaches that includes cluster headache, paroxysmal hemicrania, and SUNCT (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing). TACs are characterized by relatively short-lasting attacks of head pain associated with cranial autonomic symptoms, such as lacrimation, conjunctival injection, or nasal congestion (Table 15-8). Pain is usually severe and may occur more than once a day. Because of the associated nasal congestion or rhinorrhea, patients are often misdiagnosed with "sinus headache" and treated with decongestants, which are ineffective. Table 15-8 Clinical Features of the Trigeminal Autonomic Cephalalgias
| Cluster Headache | Paroxysmal Hemicrania | SUNCT | |
| Gender | M>F | F=M | F~M |
| Pain | |||
| Type | Stabbing, boring | Throbbing, boring, stabbing | Burning, stabbing, sharp |
| Severity | Excruciating | Excruciating | Severe to excruciating |
| Site | Orbit, temple | Orbit, temple | Periorbital |
| Attack frequency | 1/alternate day– 8/d | 1–40/d (>5/d for more than half the time) | 3–200/d |
| Duration of attack | 15–180 min | 2–30 min | 5–240 s |
| Autonomic features | Yes | Yes | Yes (prominent conjunctival injection and lacrimation)a |
| Migrainous featuresb | Yes | Yes | Yes |
| Alcohol trigger | Yes | No | No |
| Cutaneous triggers | No | No | Yes |
| Indomethacin effect | — | Yesc | — |
| Abortive treatment | Sumatriptan injection or nasal sprayOxygen | No effective treatment | Lidocaine (IV) |
| Prophylactic treatment | VerapamilMethysergideLithium | Indomethacin | LamotrigineTopiramateGabapentin |
Many experts favor verapamil as the first-line preventive treatment for patients with chronic cluster headache or prolonged bouts. While verapamil compares favorably with lithium in practice, some patients require verapamil doses far in excess of those administered for cardiac disorders. The initial dose range is 40–80 mg twice daily; effective doses may be as high as 960 mg/d. Side effects such as constipation and leg swelling can be problematic. Of paramount concern, however, is the cardiovascular safety of verapamil, particularly at high doses. Verapamil can cause heart block by slowing conduction in the atrioventricular node, a condition that can be monitored by following the PR interval on a standard EKG. Approximately 20% of patients treated with verapamil develop EKG abnormalities, which can be observed with doses as low as 240 mg/d; these abnormalities can worsen over time in patients on stable doses. A baseline EKG is recommended for all patients. The EKG is repeated 10 days after a dose change in those patients whose dose is being increased above 240 mg daily. Dose increases are usually made in 80-mg increments. For patients on long-term verapamil, EKG monitoring every 6 months is advised.Neurostimulation TherapyWhen medical therapies fail in chronic cluster headache, neurostimulation therapy strategies can be employed. Deep-brain stimulation of the region of the posterior hypothalamic gray matter has proven successful in a substantial proportion of patients. Favorable results have also been reported with the less-invasive approach of occipital nerve stimulation.Paroxysmal HemicraniaParoxysmal hemicrania (PH) is characterized by frequent unilateral, severe, short-lasting episodes of headache. Like cluster headache, the pain tends to be retroorbital but may be experienced all over the head and is associated with autonomic phenomena such as lacrimation and nasal congestion. Patients with remissions are said to have episodic PH, while those with the nonremitting form are said to have chronic PH. The essential features of PH are: unilateral, very severe pain; short-lasting attacks (2–45 min); very frequent attacks (usually more than five a day); marked autonomic features ipsilateral to the pain; rapid course (<72 h); and excellent response to indomethacin. In contrast to cluster headache, which predominantly affects males, the male:female ratio in PH is close to 1:1.Indomethacin (25–75 mg tid), which can completely suppress attacks of PH, is the treatment of choice. Although therapy may be complicated by indomethacin-induced gastrointestinal side effects, currently there are no consistently effective alternatives. Topiramate is helpful in some cases. Piroxicam has been used, although it is not as effective as indomethacin. Verapamil, an effective treatment for cluster headache, does not appear to be useful for PH. In occasional patients, PH can coexist with trigeminal neuralgia (PH-tic syndrome); similar to cluster-tic syndrome, each component may require separate treatment. Secondary PH has been reported with lesions in the region of the sella turcica, including arteriovenous malformation, cavernous sinus meningioma, and epidermoid tumors. Secondary PH is more likely if the patient requires high doses (>200 mg/d) of indomethacin. In patients with apparent bilateral PH, raised CSF pressure should be suspected. It is important to note that indomethacin reduces CSF pressure. When a diagnosis of PH is considered, MRI is indicated to exclude a pituitary lesion.SUNCT/SUNASUNCT is a rare primary headache syndrome characterized by severe, unilateral orbital or temporal pain that is stabbing or throbbing in quality. Diagnosis requires at least 20 attacks, lasting for 5–240 s; ipsilateral conjunctival injection and lacrimation should be present. In some patients conjunctival injection or lacrimation are missing, and the diagnosis of SUNA (short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms) has been suggested.DiagnosisThe pain of SUNCT/SUNA is unilateral and may be located anywhere in the head. Three basic patterns can be seen: single stabs, which are usually short-lived; groups of stabs; or a longer attack comprising many stabs between which the pain does not completely resolve, thus giving a "saw-tooth" phenomenon with attacks lasting many minutes. Each pattern may be seen in the context of an underlying continuous head pain. Characteristics that lead to a suspected diagnosis of SUNCT are the cutaneous (or other) triggerability of attacks, a lack of refractory period to triggering between attacks, and the lack of a response to indomethacin. Apart from trigeminal sensory disturbance, the neurologic examination is normal in primary SUNCT.The diagnosis of SUNCT is often confused with trigeminal neuralgia (TN) particularly in first-division TN (Chap. 371). Minimal or no cranial autonomic symptoms and a clear refractory period to triggering indicate a diagnosis of TN.Secondary (Symptomatic) SUNCTSUNCT can be seen with posterior fossa or pituitary lesions. All patients with SUNCT/SUNA should be evaluated with pituitary function tests and a brain MRI with pituitary views.SUNCT/SUNA: TreatmentAbortive TherapyTherapy of acute attacks is not a useful concept in SUNCT/SUNA since the attacks are of such short duration. However, intravenous lidocaine, which arrests the symptoms, can be used in hospitalized patients.Preventive TherapyLong-term prevention to minimize disability and hospitalization is the goal of treatment. The most effective treatment for prevention is lamotrigine, 200–400 mg/d. Topiramate and gabapentin may also be effective. Carbamazepine, 400–500 mg/d, has been reported by patients to offer modest benefit. Surgical approaches such as microvascular decompression or destructive trigeminal procedures are seldom useful and often produce long-term complications. Greater occipital nerve injection has produced limited benefit in some patients. Mixed success with occipital nerve stimulation has been observed. Complete control with deep-brain stimulation of the posterior hypothalamic region was reported in a single patient. For intractable cases, short-term prevention with intravenous lidocaine can be effective.Chronic Daily HeadacheThe broad diagnosis of chronic daily headache (CDH) can be applied when a patient experiences headache on 15 days or more per month. CDH is not a single entity; it encompasses a number of different headache syndromes, including chronic TTH as well as headache secondary to trauma, inflammation, infection, medication overuse, and other causes (Table 15-10). Population-based estimates suggest that about 4% of adults have daily or near-daily headache. Daily headache may be primary or secondary, an important consideration in guiding management of this complaint. Table 15-10 Classification of Chronic Daily Headache
| Primary | ||
| >4 h Daily | <4 h Daily | Secondary |
| Chronic migrainea | Chronic cluster headacheb | Posttraumatic |
| Head injury | ||
| Iatrogenic | ||
| Postinfectious | ||
| Chronic tension-type headachea | Chronic paroxysmal hemicrania | Inflammatory, such as |
| Giant cell arteritis | ||
| Sarcoidosis | ||
| Behçet's syndrome | ||
| Hemicrania continuaa | SUNCT/SUNA | Chronic CNS infection |
| New daily persistent headachea | Hypnic headache | Medication-overuse headachea |
| Primary | Secondary |
| Migrainous-type | Subarachnoid hemorrhage |
| Featureless (tension-type) | Low CSF volume headache |
| Raised CSF pressure headache | |
| Posttraumatic headachea | |
| Chronic meningitis |
Magnetic resonance image showing diffuse meningeal enhancement after gadolinium administration in a patient with low CSF volume headache.Initial treatment for low CSF volume headache is bed rest. For patients with persistent pain, intravenous caffeine (500 mg in 500 mL saline administered over 2 h) is often very effective. An EKG to screen for arrhythmia should be performed before administration. It is reasonable to administer at least two infusions of caffeine before embarking on additional tests to identify the source of the CSF leak. Since intravenous caffeine is safe and can be curative, it spares many patients the need for further investigations. If unsuccessful, an abdominal binder may be helpful. If a leak can be identified, an autologous blood patch is usually curative. A blood patch is also effective for post-LP headache; in this setting the location is empirically determined to be the site of the LP. In patients with intractable pain, oral theophylline is a useful alternative; however, its effect is less rapid than caffeine.Raised CSF Pressure HeadacheRaised CSF pressure is well recognized as a cause of headache. Brain imaging can often reveal the cause, such as a space-occupying lesion. NDPH due to raised CSF pressure can be the presenting symptom for patients with idiopathic intracranial hypertension (pseudotumor cerebri) without visual problems, particularly when the fundi are normal. Persistently raised intracranial pressure can trigger chronic migraine. These patients typically present with a history of generalized headache that is present on waking and improves as the day goes on. It is generally worse with recumbency. Visual obscurations are frequent. The diagnosis is relatively straightforward when papilledema is present, but the possibility must be considered even in patients without fundoscopic changes. Formal visual-field testing should be performed even in the absence of overt ophthalmic involvement. Headache on rising in the morning or nocturnal headache is also characteristic of obstructive sleep apnea or poorly controlled hypertension.Evaluation of patients suspected to have raised CSF pressure requires brain imaging. It is most efficient to obtain an MRI, including an MR venogram as the initial study. If there are no contraindications, the CSF pressure should be measured by LP; this should be done when the patient is symptomatic so that both the pressure and the response to removal of 20–30 mL of CSF can be determined. An elevated opening pressure and improvement in headache following removal of CSF is diagnostic. Initial treatment is with acetazolamide (250–500 mg bid); the headache may improve within weeks. If ineffective, topiramate is the next treatment of choice; it has many actions that may be useful in this setting, including carbonic anhydrase inhibition, weight loss, and neuronal membrane stabilization, likely mediated via effects on phosphorylation pathways. Severely disabled patients who do not respond to medical treatment require intracranial pressure monitoring and may require shunting. Post-Traumatic HeadacheA traumatic event can trigger a headache process that lasts for many months or years after the event. The term trauma is used in a very broad sense: headache can develop following an injury to the head, but it can also develop after an infectious episode, typically viral meningitis, a flulike illness, or a parasitic infection. Complaints of dizziness, vertigo, and impaired memory can accompany the headache. Symptoms may remit after several weeks or persist for months and even years after the injury. Typically the neurologic examination is normal and CT or MRI studies are unrevealing. Chronic subdural hematoma may on occasion mimic this disorder. In one series, one-third of patients with NDPH reported headache beginning after a transient flulike illness characterized by fever, neck stiffness, photophobia, and marked malaise. Evaluation reveals no apparent cause for the headache. There is no convincing evidence that persistent Epstein-Barr infection plays a role in this syndrome. A complicating factor is that many patients undergo LP during the acute illness; iatrogenic low CSF volume headache must be considered in these cases. Post-traumatic headache may also be seen after carotid dissection and subarachnoid hemorrhage, and following intracranial surgery. The underlying theme appears to be that a traumatic event involving the pain-producing meninges can trigger a headache process that lasts for many years.Treatment is largely empirical. Tricyclic antidepressants, notably amitriptyline, and anticonvulsants such as topiramate, valproate, and gabapentin, have been used with reported benefit. The MAOI phenelzine may also be useful in carefully selected patients. The headache usually resolves within 3–5 years, but it can be quite disabling.Primary NDPHPrimary NDPH occurs in both males and females. It can be of the migrainous type, with features of migraine, or it can be featureless, appearing as new-onset TTH (Table 15-11). Migrainous features are common and include unilateral headache and throbbing pain; each feature is present in about one-third of patients. Nausea, photophobia, and/or phonophobia occur in about half of patients. Some patients have a previous history of migraine; however, the proportion of NDPH sufferers with preexisting migraine is no greater than the frequency of migraine in the general population. At 24 months, ~86% of patients are headache-free. Treatment of migrainous-type primary NDPH consists of using the preventive therapies effective in migraine (Table 15-7). Featureless NDPH is one of the primary headache forms most refractory to treatment. Standard preventive therapies can be offered but are often ineffective.Other Primary HeadachesHemicrania ContinuaThe essential features of hemicrania continua are moderate and continuous unilateral pain associated with fluctuations of severe pain; complete resolution of pain with indomethacin; and exacerbations that may be associated with autonomic features, including conjunctival injection, lacrimation, and photophobia on the affected side. The age of onset ranges from 11 to 58 years; women are affected twice as often as men. The cause is unknown. Hemicrania Continua: TreatmentTreatment consists of indomethacin; other NSAIDs appear to be of little or no benefit. The intramuscular injection of 100 mg indomethacin has been proposed as a diagnostic tool; administration with a placebo injection has been recommended. Alternatively, a trial of oral indomethacin, starting with 25 mg tid, then 50 mg tid, and then 75 mg tid, can be given. Up to 2 weeks may be necessary to assess whether a dose has a useful effect. Topiramate can be helpful in some patients. Occipital nerve stimulation may have a role in patients with hemicrania continua who are unable to tolerate indomethacin.Primary Stabbing HeadacheThe essential features of primary stabbing headache are stabbing pain confined to the head or, rarely, the face, lasting from 1 to many seconds or minutes and occurring as a single stab or a series of stabs; absence of associated cranial autonomic features; absence of cutaneous triggering of attacks; and a pattern of recurrence at irregular intervals (hours to days). The pains have been variously described as "ice-pick pains" or "jabs and jolts." They are more common in patients with other primary headaches, such as migraine, the TACs, and hemicrania continua. Primary Stabbing Headache: TreatmentThe response of primary stabbing headache to indomethacin (25–50 mg two to three times daily) is usually excellent. As a general rule the symptoms wax and wane, and after a period of control on indomethacin, it is appropriate to withdraw treatment and observe the outcome.Primary Cough HeadachePrimary cough headache is a generalized headache that begins suddenly, lasts for several minutes, and is precipitated by coughing; it is preventable by avoiding coughing or other precipitating events, which can include sneezing, straining, laughing, or stooping. In all patients with this syndrome serious etiologies must be excluded before a diagnosis of "benign" primary cough headache can be established. A Chiari malformation or any lesion causing obstruction of CSF pathways or displacing cerebral structures can be the cause of the head pain. Other conditions that can present with cough or exertional headache as the initial symptom include cerebral aneurysm, carotid stenosis, and vertebrobasilar disease. Benign cough headache can resemble benign exertional headache (below), but patients with the former condition are typically older.Primary Cough Headache: TreatmentIndomethacin 25–50 mg two to three times daily is the treatment of choice. Some patients with cough headache obtain pain relief with LP; this is a simple option when compared to prolonged use of indomethacin, and it is effective in about one-third of patients. The mechanism of this response is unclear.Primary Exertional HeadachePrimary exertional headache has features resembling both cough headache and migraine. It may be precipitated by any form of exercise; it often has the pulsatile quality of migraine. The pain, which can last from 5 min to 24 h, is bilateral and throbbing at onset; migrainous features may develop in patients susceptible to migraine. Primary exertional headache can be prevented by avoiding excessive exertion, particularly in hot weather or at high altitude.The mechanism of primary exertional headache is unclear. Acute venous distension likely explains one syndrome, the acute onset of headache with straining and breath holding, as in weightlifter's headache. As exertion can result in headache in a number of serious underlying conditions, these must be considered in patients with exertional headache. Pain from angina may be referred to the head, probably by central connections of vagal afferents, and may present as exertional headache (cardiac cephalgia). The link to exercise is the main clinical clue that headache is of cardiac origin. Pheochromocytoma may occasionally cause exertional headache. Intracranial lesions and stenosis of the carotid arteries are other possible etiologies.Primary Exertional Headache: TreatmentExercise regimens should begin modestly and progress gradually to higher levels of intensity. Indomethacin at daily doses from 25 to 150 mg is generally effective in benign exertional headache. Indomethacin (50 mg), ergotamine (1 mg orally), dihydroergotamine (2 mg by nasal spray), or methysergide (1–2 mg orally given 30–45 min before exercise) are useful prophylactic measures.Primary Sex HeadacheSex headache is precipitated by sexual excitement. The pain usually begins as a dull bilateral headache which suddenly becomes intense at orgasm. The headache can be prevented or eased by ceasing sexual activity before orgasm. Three types of sex headache are reported: a dull ache in the head and neck that intensifies as sexual excitement increases; a sudden, severe, explosive headache occurring at orgasm; and a postural headache developing after coitus that resembles the headache of low CSF pressure. The latter arises from vigorous sexual activity and is a form of low CSF pressure headache. Headaches developing at the time of orgasm are not always benign; 5–12% of cases of subarachnoid hemorrhage are precipitated by sexual intercourse. Sex headache is reported by men more often than women and may occur at any time during the years of sexual activity. It may develop on several occasions in succession and then not trouble the patient again, even without an obvious change in sexual activity. In patients who stop sexual activity when headache is first noticed, the pain may subside within a period of 5 min to 2 h. In about half of patients, sex headache will subside within 6 months. About half of patients with sex headache have a history of exertional headaches, but there is no excess of cough headache. Migraine is probably more common in patients with sex headache.Primary Sex Headache: TreatmentBenign sex headaches recur irregularly and infrequently. Management can often be limited to reassurance and advice about ceasing sexual activity if a mild, warning headache develops. Propranolol can be used to prevent headache that recurs regularly or frequently, but the dosage required varies from 40 to 200 mg/d. An alternative is the calcium channel-blocking agent diltiazem, 60 mg tid. Ergotamine (1 mg) or indomethacin (25–50 mg) taken about 30–45 min prior to sexual activity can also be helpful. Primary Thunderclap HeadacheSudden onset of severe headache may occur in the absence of any known provocation. The differential diagnosis includes the sentinel bleed of an intracranial aneurysm, cervicocephalic arterial dissection, and cerebral venous thrombosis. Headaches of explosive onset may also be caused by the ingestion of sympathomimetic drugs or of tyramine-containing foods in a patient who is taking MAOIs, or they may be a symptom of pheochromocytoma. Whether thunderclap headache can be the presentation of an unruptured cerebral aneurysm is uncertain. When neuroimaging studies and LP exclude subarachnoid hemorrhage, patients with thunderclap headache usually do very well over the long term. In one study of patients whose CT scans and CSF findings were negative, ~15% had recurrent episodes of thunderclap headache, and nearly half subsequently developed migraine or tension-type headache.The first presentation of any sudden-onset severe headache should be vigorously investigated with neuroimaging (CT or, when possible, MRI with MR angiography) and CSF examination. Formal cerebral angiography should be reserved for those cases in which no primary diagnosis is forthcoming and for clinical situations that are particularly suggestive of intracranial aneurysm. Reversible segmental cerebral vasoconstriction may be seen in primary thunderclap headache without an intracranial aneurysm. In the presence of posterior leukoencephalopathy, the differential diagnosis includes cerebral angiitis, drug toxicity (cyclosporine, intrathecal methotrexate/cytarabine, pseudoephedrine, or cocaine), posttransfusion effects, and postpartum angiopathy. Treatment with nimodipine may be helpful, although by definition the vasoconstriction of primary thunderclap headache resolves spontaneously.Hypnic HeadacheThis headache syndrome typically begins a few hours after sleep onset. The headaches last from 15 to 30 min and are typically moderately severe and generalized, although they may be unilateral and can be throbbing. Patients may report falling back to sleep only to be awakened by a further attack a few hours later; up to three repetitions of this pattern occur through the night. Daytime naps can also precipitate head pain. Most patients are female, and the onset is usually after age 60. Headaches are bilateral in most, but may be unilateral. Photophobia or phonophobia and nausea are usually absent. The major secondary consideration in this headache type is poorly controlled hypertension; 24-h blood pressure monitoring is recommended to detect this treatable condition.Hypnic Headache: TreatmentPatients with hypnic headache generally respond to a bedtime dose of lithium carbonate (200–600 mg). For those intolerant of lithium, verapamil (160 mg) or methysergide (1–4 mg at bedtime) may be alternative strategies. One to two cups of coffee or caffeine, 60 mg orally, at bedtime may be effective in approximately one-third of patients. Case reports suggest that flunarizine, 5 mg nightly, can be effective.
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