After studying this chapter, the student should be able to:
Recognize and indicate treatment for the main primary headache disorders, including migraine with and without aura, tension-type headache, and trigeminal autonomic cephalgias.
Recognize and indicate treatment for the main secondary headache disorders, including medication overuse headache, medication/caffeine withdrawal headache, idiopathic intracranial hypertension (pseudotumor cerebri), and spontaneous intracranial hypotension.
Recognize the diagnostic “red flags” that warrant imaging and further workup.
Identify the major neurologic pain syndromes, including fibromyalgia, complex regional pain syndrome, postherpetic neuralgia, trigeminal neuralgia, phantom limb pain, and central pain syndrome.
Headache is perhaps the most common neurologic syndrome. About half the world’s population experiences headache at least once each year, and up to three-quarters of people will have a headache at some point in their lives. The most common type of headache is tension-type headache, followed by migraine. The 1-year prevalence of migraine in the United States is 12%, with a female predominance. Migraine prevalence is highest during some of the peak productive years of life (age 30 to 39 years), and 1 of every 4 migraineurs misses at least 1 day of work every 3 months. Migraine is among the top 10 causes of disability worldwide and accounts for the most years lived with disability of any neurologic disorder.
EVALUATION OF HEADACHE DISORDERS
The workup of a headache is guided by several factors in the history and exam (Figure 26–1). The more common primary headache disorders, namely migraine and tension-type headache, are diagnosed based on a thorough history and physical exam. Neuroimaging is not required unless the patient has an abnormal neurologic exam or the history is concerning. However, secondary headaches could masquerade as trigeminal autonomic cephalgias and some of the headaches classified under other primary headache disorders; therefore, further workup is often warranted. There are a number of potential “red flags” in the history that may suggest the need for further workup (Table 26–1).
Headache algorithm. It is important to understand new-onset versus chronic headache and then tease out warning signs for potential secondary headache from a patient’s history and physical exam. CNS, central nervous system; GCA, giant-cell arteritis; TMJ, temporomandibular joint. (Reproduced with permission from Henderson MC, Tierney LM, Smetana GW: The Patient History: Evidence-Based Approach to Differential Diagnosis. 2nd ed. New York, NY: McGraw Hill; 2012.)
TABLE 26–1Warning signs in the history that raise concern. ||Download (.pdf) TABLE 26–1 Warning signs in the history that raise concern.
Change or progression in pattern (increasing frequency or severity)
The first and/or worst headache of a person’s life
New headache in an individual >40 years old
New headache in a patient with cancer, immunosuppression, or pregnancy
Sudden and abrupt onset of attacks (thunderclap), including awakenings from sleep
Headaches triggered by exertion, sexual activity, or Valsalva maneuvers (bearing down, coughing, or sneezing)
Neurologic symptoms lasting >1 hour
Associated alteration of consciousness
Indications of systemic illness (fever, rash, weight loss, meningismus)
History of head trauma
PRIMARY HEADACHE SYNDROMES
Migraine can present in childhood, but generally begins around puberty during adolescence or young adulthood. The pathophysiology of migraine is likely secondary to genetic predisposition and environmental factors leading to the phenotypic presentation of migraine. Three genetic mutations have been identified in familial hemiplegic migraine. These are the CACNA1A gene on chromosome 19, which encodes a P/Q type calcium channel subunit and increases presynaptic calcium; the SCN1A gene on chromosome 2, which encodes a sodium channel subunit and causes persistent sodium influx; and the ATP1A2 gene on chromosome 1, which encodes a subunit of the sodium-potassium ATPase and decreases potassium and glutamate clearance. Mutations in the PRRT2 gene, which is not an ion channel gene but encodes for synaptosomal-associated protein 25 (SNAP25), may also cause hemiplegic migraine. The genetics behind the more common types of migraine are likely multifactorial and still under study. It is thought that patients with migraine have cortical neuronal hyperexcitability and likely abnormal brainstem function.
Abortive treatment: Treatments given at the onset of symptoms to reduce the severity of a headache.
Aura: Sensation that typically occurs shortly before a migraine headache begins. Auras are most commonly visual but can involve motor or other sensory changes as well.
Cephalgia: Synonym for headache.
Neuromediators: Also known as neuromodulators, chemical substances released in the central nervous system or in the periphery that can regulate a broad population of neurons.
Phonophobia: Discomfort associated with sensitivity to sound/noise.
Photophobia: Discomfort associated with light sensitivity.
Preventative treatment: Treatments used on a daily basis to reduce the frequency of headaches.
Primary headaches: Those in which headache is the primary problem, such as tension or migraine headaches.
Secondary headaches: Those due to another condition, such as sinusitis or intracerebral hemorrhage.
Trigger: A stimulus that can set off a migraine, for example, stress or a particular food.
The initiating mechanism of a migraine headache is thought to be secondary to cortical spreading depression (Figure 26–2). This is a wave of increased cortical neuronal activity, followed by neuronal suppression. Cortical spreading depression propagates at a velocity of 2 to 3 mm per minute. The aura spreads at a similar speed, and therefore, it has been attributed to cortical spreading depression. When the cortical spreading depression initiates in the occipital lobes, a visual aura ensues. Migraine without aura may result from cortical spreading depression in a clinically silent area of cortex. Cortical spreading depression (via an unknown mechanism) is thought to activate the trigeminal vascular system and release of substances involved in pain pathways including calcitonin gene-related peptide and glutamate. The trigeminal vascular system and neuromediators cause the headache and likely lead to neurogenic inflammation and peripheral sensitization. If the headache persists, central sensitization and allodynia can occur in a pattern similar to that which arises with chronic pain in other parts of the body (Figure 26–3).
Cortical spreading depression. Cortical spreading depression is a wave of increased cortical neuronal activity, followed by neuronal suppression that propagates at a velocity of 2 to 3 mm per minute. It is thought to be the initiating mechanism in migraine. (Reproduced with permission from Simon RP, Aminoff MJ, Greemberg DA: Clinical Neurology, 10th ed. New York, NY: McGraw Hill; 2018.)
Allodynia. Central sensitization and allodynia can occur in patients with refractory headache. It is similar to other types of chronic pain. This phenomenon is thought to be mediated by neuromodulators such as calcitonin gene-related peptide (CGRP) and glutamate (Glu). ATP, adenosine triphosphate; GABA, γ-aminobutyric acid; GRP, gastrin-releasing peptide; IL, interleukin; KLK, kallikrein; MMP, matrix metalloprotease; NGF, nerve growth factor; PGs, prostaglandins; PGE2, prostaglandin E2; SP, substance P; TNF, tumor necrosis factor. (Reproduced with permission from Goldsmith LA, Katz SI, Gilchrest BA, et al: Fitzpatrick’s Dermatology in General Medicine, 8th ed. New York, NY: McGraw Hill; 2012.)
A migraine attack can be divided into 4 phases: (1) the premonitory phase, which occurs hours to days before the onset of head pain and includes various symptoms ranging from euphoria to fatigue; (2) the aura phase, when neurologic symptoms occur just before or during the headache onset; (3) the headache phase, which includes the associated migrainous symptoms; and (4) the postdrome. Migraine is a recurrent headache disorder that is diagnosed clinically based on diagnostic criteria. Neuroimaging is not indicated unless historical warning signs (see Table 26–1) are present or the neurologic exam is abnormal, but may reveal small subcortical hyperintensities that are not periventricular or in the corpus callosum.
Migraine headache can be episodic or chronic, and chronic migraine is defined as a headache on at least 15 days per month with a minimum of 8 days meeting criteria for migraine. Migraine can be further characterized as migraine with or without aura. Based on diagnostic criteria, an untreated migraine attack lasts 4 to 72 hours in adults but can be of shorter duration in children. It has at least 2 of the following 4 characteristics: (1) unilateral location (Figure 26–4), (2) pulsating quality, (3) moderate to severe pain intensity, and (4) aggravation by or causing avoidance of routine physical activity. During the headache, the patient must have 1 of the following features: (1) nausea and/or vomiting or (2) phonophobia and photophobia.
Migraine. The pain pattern in migraine is most often severe unilateral frontal and/or temporal throbbing that can radiate to involve the retro- or supraorbital region. (Reproduced with permission from Simon RP, Aminoff MJ, Greemberg DA: Clinical Neurology, 10th ed. New York, NY: McGraw Hill; 2018.)
Migraine aura has ≥1 visual, sensory, speech and/or language, motor, brainstem, or retinal symptoms that are fully reversible, with at least 2 of the following 4 characteristics: (1) aura spreads gradually over >5 minutes and/or symptoms occur in succession; (2) each individual aura symptom lasts 5 to 60 minutes; (3) at least 1 aura symptom is unilateral; or (4) the aura is accompanied or followed within 60 minutes by headache. Each individual aura can last up to 1 hour, so if a patient has multiple aura symptoms in succession, the total aura time will be longer than 60 minutes.
Migraine with aura has several different variants; these include migraine with typical aura, migraine with brainstem aura, hemiplegic migraine, and retinal migraine. In migraine with typical aura, the aura consists of visual, sensory, and/or speech and language symptoms. However, it excludes motor, brainstem, and retinal symptoms. The typical visual aura is described as a scintillating scotoma with a zig-zag “fortification spectra,” which slowly enlarges at a speed similar to that of cortical spreading depression (Figure 26–5). Migraine with brainstem aura requires at least 2 of the following brainstem symptoms: (1) dysarthria, (2) vertigo, (3) tinnitus, (4) hypoacusis (hearing impairment), (5) diplopia, (6) ataxia, and (7) decreased level of consciousness. Hemiplegic migraine is a subtype of migraine with aura in which the aura is a syndrome of fully reversible motor weakness and fully reversible visual, sensory, and/or speech or language symptoms. Retinal aura is distinguished from the typical visual aura because it is a monocular positive or negative visual phenomenon. This is confirmed by clinical visual examination during an attack or the patient’s drawing of a monocular field defect.
Visual aura in migraine. The typical visual aura associated with migraine headache is described as a scintillating scotoma, which spreads at about 2 to 3 mm per minute. (Reproduced with permission from Simon RP, Aminoff MJ, Greemberg DA: Clinical Neurology, 10th ed. New York, NY: McGraw Hill; 2018.)
Migraine Treatment: Preventive
The treatment of migraine headaches hinges on both preventive and abortive therapies. All patients who suffer from migraine headaches should be counseled on lifestyle modifications, such as regular sleep and meals, healthy diet and exercise, and avoidance of triggers, as part of their preventive therapy. Common triggers for migraine headache include stress, hormonal changes, skipping meals, weather changes, sleep disturbances, strong odors (eg, perfume, gasoline, smoke), lights, alcohol, food (eg, tyramine in aged meat/cheese and ripe bananas, aspartame), and heat. Some migraine triggers cannot be avoided. Migraine patients should be offered prescription preventive migraine therapy if they have >3 migraine days without disability per month or >2 migraine days with disability per month.
For optimal prevention of migraine headaches, it is important to involve patients in their care. Consider comorbidities, and when possible, choose a single medication to treat multiple diseases. With women of childbearing age, discuss contraception and the potential risk of medication use during pregnancy. Each preventive medication should be started at a low dose and slowly titrated up. It is important to give each preventive medication an adequate trial. Generally, once at a therapeutic dose, a preventive medication should be continued for at least 6 weeks before reevaluating. The use of headache calendars before and after initiation of migraine preventive therapy can give objective data on the efficacy of the drug in that patient.
Medications with established efficacy (level A evidence) for the prevention of migraine include antiepileptic agents (divalproex sodium, topiramate) and β-blockers (metoprolol, propranolol). Divalproex sodium should be considered in someone with concomitant mood disorders and requires monitoring for weight gain, hyponatremia, and hepatitis. Topiramate might be helpful in an overweight patient, as it can cause weight loss. It is contraindicated in patients with renal calculi and glaucoma. Patients need to be monitored for cognitive complaints and should be warned about tingling and changes in taste (carbonated drinks taste “flat”), which are common side effects. Other antiepileptics that can be beneficial in the treatment of headaches include gabapentin, levetiracetam, zonisamide, and lacosamide. Propranolol should be considered in someone with concomitant hypertension or anxiety. It should be avoided in individuals with asthma or diabetes. Patients on an antihypertensive need to be monitored for signs and symptoms of hypotension and bradycardia. Other antihypertensives that can be considered in the preventive treatment of migraine are verapamil and candesartan.
Medications that are probably effective (level B evidence) for the prophylaxis of migraine headaches include antidepressants (amitriptyline, venlafaxine). Amitriptyline should be considered in someone with insomnia or mild depression. It should be used with caution in patients with cardiovascular disease because it can lead to arrhythmia, and an electrocardiogram is warranted prior to initiation in this population of patients. The main side effect is sedation, although it has the potential to cause other anticholinergic side effects including xerostomia, dizziness, blurred vision, constipation, and urinary retention (especially in the elderly). Patients should also be monitored for suicidal ideation. Alternative tricyclic antidepressants that can be used for the prevention of migraine include nortriptyline and protriptyline. Venlafaxine might be useful in a migraine patient who suffers from moderate depression. It requires routine laboratory monitoring of renal function and lipids. Patients should also be monitored for hypertension and, as with many of the antidepressants, suicidal ideation.
If medications in the anticonvulsant, antihypertensive, and antidepressant categories are ineffective or contraindicated, memantine (category B in pregnancy) should be considered in the prevention of migraine headaches. Supraorbital nerve stimulation has also been shown to be an effective preventive therapy. In addition, in a patient who meets criteria for chronic migraine, injection of botulinum toxin in the face, occiput, neck, and shoulders following the chronic migraine paradigm is effective at decreasing the intensity and frequency of migraine attacks. The calcitonin gene-related peptide (CGRP) receptor antagonists are a newer class of preventive treatments made specifically for migraine. CGRP antagonists appear to have good efficacy with a low side effect profile, though their long term effects are unknown.
These treatments can be used in conjunction with progressive relaxation techniques and cognitive behavioral therapy. There is evidence for the use of herbal supplements such coenzyme Q10, magnesium, riboflavin, and feverfew. Although Petasites hybridus extract has strong evidence in the preventive treatment of migraine, its use is currently not recommended because of safety concerns given potential liver toxicity and carcinogenic/teratogenic properties of formulations that are not free of pyrrolizine alkaloids. Trigeminal and occipital distribution nerve and sphenopalatine ganglion blocks, as well as trigger point injections using local anesthetic, may also be beneficial as adjunctive therapy for both the prophylaxis and acute treatment of migraine.
If a patient has predictable migraine headaches during menses, she may qualify for a “mini-prophylaxis.” Instead of taking a daily preventive medication, she would use therapy the week of her expected migraine headache, which can be calculated fairly accurately in someone with regular menstrual cycles. Although the traditional preventive migraine medications can be used during the week of prophylaxis, using frovatriptan has been found to be effective (level A evidence) for this purpose. Aside from this setting, medications in the triptan category are traditionally used for migraine abortive treatment, especially because of their potential to cause medication overuse headache.
Migraine Treatment: Abortive
As an adjunct strategy to preventive therapies in the treatment of migraine, patients should be offered abortive agents. Migraine-specific medications include ergot derivatives and triptans. These medications act as serotonin (5-HT) receptor agonists. Triptans are more selective 5-HT receptor agonists than ergotamine and dihydroergotamine, acting on 5-HT 1B/1D receptors. Triptans are the abortive treatment of choice in migraine headache (level A evidence). Contraindications to triptans include untreated arterial hypertension, coronary artery disease, history of ischemic stroke, administration of an ergot compound within 24 hours of triptan use, severe renal or hepatic disease, peripheral vascular disease, Raynaud disease, age >65 years, and migraine with brainstem aura or hemiplegic migraine.
Originally, migraine was thought to be a vascular disorder, and brainstem symptoms were thought to be secondary to basilar artery vasoconstriction. Because triptans induce vasoconstriction, migraine with brainstem aura was excluded from triptan clinical trials due to concerns of increasing the risk of brain infarction and is thus not a formal indication for triptan therapy. However, it is now clearer that aura is primarily a neuronal process related to cortical spreading depression, and more recent literature suggests that treating these patients with triptans may actually be beneficial without increased risk for ischemic vascular events.
A variety of triptans are approved for migraine treatment (Figure 26–6). Sumatriptan was the first triptan introduced for acute migraine treatment. It has the fastest time to peak levels but also the shortest half-life. Sumatriptan and zolmitriptan are both available in oral and nonoral formulations. Rizatriptan is available in an oral tablet, as well as an oral disintegrating tablet. Almotriptan, eletriptan, frovatriptan, and naratriptan are only available in an oral tablet formulation. Frovatriptan and naratriptan have a slower onset and lower potency but also a lower headache reoccurrence rate because they are longer lasting. Frovatriptan has the longest half-life of the triptans.
The chemical structure of triptans. Sumatriptan was the first triptan introduced for acute migraine treatment. It has the fastest time to peak levels, but also the fastest half-life. Because of a variation in chemical structure, frovatriptan has a slower onset and lower potency, but also the longest half-life of this class of medications.
When choosing a triptan, it is important to consider how quickly the headache climaxes, as well as associated symptoms of nausea and vomiting. Gastroparesis is common during migraine. Although a patient might be able to tolerate oral medications without symptoms of nausea, vomiting, or bloating, the absorption of medications may be delayed. Therefore, nonoral triptans should be considered early, especially if gastrointestinal symptoms are present. Unlike preventive therapy where one would “start low and go slow,” symptomatic therapy should be prescribed at the dose most likely to be effective within the prescribing range. If a lower dose formulation is partially effective, the patient should be instructed to redose, and the practitioner should prescribe the equivalent higher dose formulation in the future.
In patients who cannot take triptans, longer acting nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac and naproxen can be used as abortive therapy (level A evidence). These have less of a potential for medication overuse headache. If triptans and NSAIDs cannot be used, then combination medications with isometheptene can be considered. Cyclobenzaprine has a similar chemical structure to amitriptyline and can also be used as an adjunct for symptomatic headache therapy. It is unlikely to cause medication overuse headache. Adding antiemetics, especially in the setting of gastrointestinal symptoms, may also be beneficial. In patients with migraine with aura, transcranial magnetic stimulation at the occipitalis is another option.
The patient should also be counseled on how to use symptomatic medication effectively, using migraine-specific medications when possible at headache onset. Waiting until the headache has built up in intensity may render the symptomatic medication less effective. The goal is to stop the headache, not just to decrease the intensity. The patient should limit all pain medications to 9 days or less per month to avoid medication overuse headache. Note that it is the number of days, not the total number of times during a day, that puts the patient at risk. Therefore, if within prescribing range, the patient should redose or use multiple medications from different categories in an effort to completely abort the headache.
Medication overuse headache only occurs in patients with primary headache disorders. It is defined as a headache occurring ≥15 days per month, with regular overuse for >3 months of ≥1 medication that can be taken for symptomatic relief of headache. The top 3 offenders are caffeine, butalbital, and opioids. However, any symptomatic pain medication or decongestant, whether used for headache or another condition, has the potential to cause medication overuse headache in a patient with a primary headache disorder. Therefore, patients should avoid, if possible: (1) opioids (including butorphanol nasal spray); (2) combination medications containing butalbital, tramadol, or caffeine; and (3) short-acting NSAIDs (eg, ibuprofen). In addition, because many symptomatic medications are available over the counter, it is important to ask patients about nonprescription medication use (type and number of days per week). This is especially important because in the setting of medication overuse headache, preventive and abortive medications are less efficacious.
The prevalence of episodic tension-type headache is high, as it is the most common primary headache disorder in the population. It affects women slightly more than men, with an onset between the second and third decades of life and the highest prevalence between the third and fourth decades of life. Much like migraine, there is a decline in the prevalence of tension-type headache later in life. Because the severity of tension-type headache remains mild to moderate, patients are less likely to seek medical attention unless the headache becomes more frequent and meets criteria for the frequent episodic or chronic tension-type headache subtypes. The pathophysiology of tension-type headache is under investigation. It is thought that peripheral pain mechanisms are involved in episodic tension-type headache, whereas central pain mechanisms are more significant in chronic tension-type headache.
Tension-type headache is further subdivided into the following subtypes: infrequent episodic (once per month; <12 days per year), frequent episodic (<15 days per month; >12 days but <180 days per year), and chronic (>15 days per month; >180 days per year). The headache can last 30 minutes to 7 days in the episodic subtype and hours to days if not unremitting in the chronic tension-type subtype. It requires 2 of the following 4 characteristics: (1) bilateral location (Figure 26–7), (2) pressing or tightening (nonpulsating) quality, (3) mild or moderate intensity, and (4) not aggravated by routine physical activity. Tension-type headache requires no more than 1 symptom of photophobia, phonophobia, or mild nausea and neither of the symptoms of moderate or severe nausea or vomiting.
Tension-type headache. The pain pattern in tension-type headache is most often bilateral and frontal pressure or aching that is mild to moderate in intensity. (Reproduced with permission from Simon RP, Aminoff MJ, Greemberg DA: Clinical Neurology, 10th ed. New York, NY: McGraw Hill; 2018.)
Episodic infrequent tension-type headache can be treated with over-the-counter analgesics including acetaminophen, aspirin, and ibuprofen. There is always the potential for medication overuse headache, and the patient should be instructed to take symptomatic medications 9 days or less per month, or about twice per week. Episodic frequent and chronic tension-type headaches can cause moderate to severe disability and are treated with a treatment strategy similar to migraine headache. Amitriptyline has been shown to be efficacious in the preventive treatment (level I evidence) of tension-type headache; however, given the overlap between migraine and tension-type headache, other migraine prophylactic agents can also be used.
Trigeminal Autonomic Cephalgias
The trigeminal autonomic cephalgias are a group of headache disorders characterized by unilateral headache associated with ipsilateral autonomic features. These include cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks (with 2 forms: short-lasting unilateral neuralgiform headache attacks with conjunctival injection and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms), and hemicrania continua.
Cluster headaches are very severe headaches that occur in bouts, typically every 6 to 24 months. During a bout, patients have a number of cluster attacks (headaches), usually 0.5 to 8 per day when the disorder is active. Although not part of the diagnostic criteria, circadian periodicity is a hallmark of cluster headaches, and the times of attacks are often predictable, frequently occurring at night. The syndrome is relatively rare and male predominant.
Cluster headaches attacks cause unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 180 minutes (Figure 26–8). These headaches are very intense and are often referred to as “suicide headaches” because they pain is so severe it can lead to suicidal ideation or attempt during an attack. Cluster headaches must have either or both of the following: (1) at least 1 ipsilateral autonomic symptom including conjunctival injection, lacrimation, eyelid edema, ptosis, miosis, nasal congestion and/or rhinorrhea, forehead and facial sweating and/or flushing, and/or a sensation of fullness in the ear (Figure 26–9), or (2) a sense of restlessness or agitation during an attack. Unlike migraine patients who prefer to be still during an attack, patients with cluster headache tend to pace and move around during a cluster episode.
Autonomic symptoms in a patient with cluster headache. This patient has severe right-sided headache, mainly involving his eye, that is associated with right-sided ptosis. It is difficult to appreciate other autonomic symptoms such as miosis, flushing, and rhinorrhea that may also be present in this picture. (Reproduced with permission from Simon RP, Aminoff MJ, Greemberg DA: Clinical Neurology, 10th ed. New York, NY: McGraw Hill; 2018.)
Cluster headache. The pain pattern in cluster headache is most commonly abrupt, excruciating orbital or periorbital pain associated with autonomic symptoms. These include unilateral conjunctival injection, lacrimation, eyelid edema, ptosis, miosis, nasal congestion/rhinorrhea, sweating, and/or flushing on the same side as the headache. (Reproduced with permission from Simon RP, Aminoff MJ, Greemberg DA: Clinical Neurology, 10th ed. New York, NY: McGraw Hill; 2018.)
Prior to diagnosis, secondary disorders that can present like cluster headache, including pituitary tumors, need to be ruled out. Therefore, this patient population needs neuroimaging with magnetic resonance imaging (MRI) of the brain at presentation. If the history is suspicious for vascular etiology, then further vascular imaging of the head and neck may be warranted to look for arterial dissection, aneurysm, or arteriovenous malformations, among other causes. Management of cluster attacks involves counseling against alcohol use during the cluster bout and discussing the use of preventive and abortive therapies.
The drug treatment of choice for a cluster attack is subcutaneous sumatriptan. When available, continuous inhalation of 100% oxygen at 7 to 12 L/min via a non-rebreathing facial mask for 15 to 20 minutes can completely abort a cluster attack. However, a quarter of patients find that oxygen only delays an attack. Preventive medications are used to speed up the time to remission and to decrease the frequency and intensity of cluster attacks during a bout. Except in patients with chronic cluster headache, there is no evidence that continuing prophylactic medications beyond the cluster bout is beneficial. Preventive treatments that can be used include lithium, verapamil, gabapentin, topiramate, valproic acid, corticosteroids, and high-dose melatonin. Greater occipital nerve and sphenopalatine ganglion blocks using local anesthetic in combination with steroid can also be effective.
Hemicrania continua is more common in women and generally presents in adulthood. It is a unilateral, mild to moderate continuous headache with exacerbations of moderate to severe intensity that often has both autonomic and migrainous associated symptoms. The diagnostic criteria require either or both of the following: (1) at least 1 ipsilateral autonomic symptom and/or (2) a sense of restlessness or agitation or aggravation of pain by movement. Hemicrania continua is an indomethacin-responsive headache. The treatment and diagnosis rest on the response to indomethacin, and the dose should be up titrated to at least 50 mg 3 times per day before efficacy is determined. If needed, it can be increased to 75 mg 3 times per day as tolerated. In patients who cannot tolerate indomethacin, Boswellia serrata extract is an herbal supplement with a similar chemical structure that may be beneficial.
Other Primary Headache Disorders
The other primary headache disorders include primary cough headache, primary exercise headache, primary headache associated with sexual activity, primary thunderclap headache, cold-stimulus headache, external-pressure headache, hypnic headache, primary stabbing headache, new daily persistent headache, and nummular headache.
Hypnic headache mainly occurs in the elderly (age >40 to 50 years) and is more common in women. It presents as frequent headaches that are only present during sleep and usually occur around the same time each night. The diagnostic criteria require that the recurrent headache attacks (1) develop only during sleep and cause awakenings; (2) occur on ≥10 days a month; (3) last from 15 minutes to 4 hours after awakening; and (4) have no autonomic symptoms or a sense of restlessness. Other causes of secondary headache that can lead to nocturnal awakenings such as sleep apnea, nocturnal hypertension, subdural hematomas, communicating hydrocephalus, vascular lesions, temporal arteritis, pheochromocytomas, subacute angle-closure glaucoma, and medication overuse or withdrawal headache need to be excluded. Scheduled bedtime caffeine, melatonin, indomethacin, and lithium have been found to be effective in the treatment of hypnic headache.
Primary stabbing headache often occurs in migraine patients and can coexist in those with other primary headache disorders. Among other descriptions, it has been referred to as “jabs and jolts syndrome” and “ice pick headache.” It is characterized by brief and localized stabs of pain that occur in the absence of pathologic damage to underlying structures or cranial nerves. The diagnostic criteria require head pain occurring spontaneously as a single stab or a series of stabs where (1) each stab lasts for up to a few seconds; (2) stabs recur with irregular frequency, from 1 to many per day; and (3) there are no cranial autonomic symptoms. Other causes for similar pain such as meningioma and pituitary tumors, cerebrovascular diseases, cranial or ocular trauma, and herpes zoster need to be ruled out prior to diagnosis. This is usually an indomethacin-responsive headache at total daily doses of 25 to 150 mg. However, if a patient is unable to tolerate indomethacin, success has been reported with high-dose melatonin or the use of gabapentin.
New daily persistent headache is described as development of a daily and unremitting headache in a patient who does not have history of major life stressor, trauma, or illness prior to the onset of headaches. There usually is no history of prior headaches; however, if such history is present, then the patient does not report a crescendo in headache frequency and/or intensity over the time preceding onset of daily headaches. If present, this pattern might suggest medication overuse headache or other types of secondary headache. A patient with new daily persistent headache is able to give a definitive date of when the headache started. The diagnostic criteria necessitate a distinct and clearly remembered onset, with pain becoming continuous and unremitting within 24 hours. Since the diagnosis of new daily persistent headache is one of exclusion, it requires normal neuroimaging, lumbar puncture, and blood work. Preventive medications used for other headache disorders are often tried in new daily persistent headache with variable efficacy.
Nummular headache has a female predominance with a mean age of onset in the fourth decade of life. The root of the word means “resembling a coin,” and the pain usually affects a small, coin-shaped area of the scalp. The character of the pain can differ from one patient to the next and has been described as pressure-like, sharp, achy, throbbing, burning, or itching. There can also be exacerbations in the intensity of pain. The diagnostic criteria require continuous or intermittent head pain felt exclusively in the scalp with the following 4 characteristics: (1) sharply contoured, (2) fixed in size and shape, (3) round or elliptical, and (4) 1 to 6 cm in diameter. Gabapentin, tricyclic antidepressants, and injections of botulinum toxin at the headache site have been found to be effective in the treatment of nummular headache.
SECONDARY HEADACHE SYNDROMES
It is important to know the warning signs that need to be worked up in order to distinguish primary from secondary headache disorders. Historical “red flags” or an abnormal neurologic exam needs to be expeditiously investigated. Despite being aware of these warning signs, some secondary headaches can be missed if the practitioner does not have a high level of suspicion, and these include medication overuse headaches and medication or caffeine withdrawal headaches. Further, the presence of these headaches can have a great impact on the efficacy of preventive and abortive headache treatments. Medication overuse headache was described earlier in the migraine section to emphasize the most common offending agents and stress the importance of limiting symptomatic migraine therapy to ≤9 days per month.
Medication withdrawal headache requires daily intake of a substance for >3 months that has been interrupted. Evidence of causation is demonstrated by both of the following: (1) the headache has developed in close temporal relation to withdrawal from the substance, and (2) the headache has resolved within 3 months after total withdrawal from the substance. Caffeine withdrawal headache requires caffeine consumption of >200 mg/d (∼2 cups of coffee) for >2 weeks, which has been interrupted or delayed. There is also evidence of causation demonstrated by development of the headache within 24 hours of last caffeine intake and either headache relief within 1 hour of taking 100 mg of caffeine or resolution within 7 days of total caffeine withdrawal.
Medication overuse and withdrawal are probably the most common causes of intractability in migraine patients. These causes can be missed by a practitioner because patients often do not include over-the-counter analgesics, decongestants, and herbal supplements in their medication list. In addition, caffeine intake is generally not part of a routine social history and can be overlooked. Some patients are also embarrassed about medication misuse, and therefore, it is essential to take a detailed medication history focusing on both prescription and over-the-counter medications, including vitamins, herbs, and natural products. Excessive use of symptomatic agents and caffeine overuse (on average more than once a day) can cause intractable migraine, and vitamin A or D overuse may lead to headaches. When stopping or tapering the offending agent, the patient may have an initial worsening of the headache before there is improvement. This worsening can be bridged with relaxation therapy and outpatient pharmacologic treatment using long-acting NSAIDs, muscle relaxers, or steroids, but may require inpatient admission for detoxification from an offending agent if the patient has daily use of potent opioids and/or barbiturates or has failed outpatient attempts.
High- and low-pressure headaches can also be tricky to diagnose. The historical warning signs (see Table 26–1) and neurologic exam can raise the clinician’s level of suspicion, but it can sometimes be difficult to distinguish between the 2 conditions.
Idiopathic Intracranial Hypertension
Idiopathic intracranial hypertension, also known as pseudotumor cerebri, most commonly occurs in obese women of childbearing age. The disease is most prevalent in the second and third decades of life. The majority of patients present with headache that is worse with lying down and Valsalva maneuvers. It is accompanied by symptoms of increased intracranial pressure including transient episodes of visual loss and visual obscurations, pulse-synchronous tinnitus, diplopia due to cranial nerve VI palsy, and papilledema (Figure 26–10), which is the hallmark of idiopathic intracranial hypertension, with associated visual loss.
Papilledema. Optic disk swelling caused by raised intracranial pressure. (Reproduced with permission from Kasper D, Fauci A, Hauser S, et al: Harrison’s Principles of Internal Medicine, 19th ed. New York, NY: McGraw Hill; 2015.)
Idiopathic intracranial hypertension is characterized by increased cerebrospinal fluid opening pressure (>250 mm H2O) without evidence of ventriculomegaly. It is thought to be secondary to decreased absorption of cerebrospinal fluid, although increased production may also play a role. Neurodiagnostic studies reveal no ventricular obstruction, abnormal enhancement, or intracranial lesion to explain the increased pressure. MRI of the brain can show signs of increased intracranial pressure including flattening of the posterior sclera and a partial empty sella turcica. Potential intracranial lesions include scarring secondary to previous inflammation (eg, meningitis, subarachnoid hemorrhage) leading to decreased flow through the arachnoid granulations and venous sinus thrombosis causing obstruction of venous flow. Arteriovenous malformations and dural shunts are also associated with intracranial hypertension. Other potential secondary causes of intracranial hypertension include corticosteroid withdrawal, increased vitamin A, and the use of isotretinoin and tetracycline. The differential also includes obstructive sleep apnea and orthostatic edema (abnormal systemic retention of sodium and/or water).
Most patients with idiopathic intracranial hypertension and papilledema have visual loss, and perimetry to assess visual field defects is the main measure used to determine the course of therapy. The management of idiopathic intracranial hypertension is divided into symptomatic treatment of headaches and treatment of increased intracranial pressure. Medications used in prophylaxis of migraine can be effective in symptomatic treatment of headaches; however, agents that cause weight gain should be avoided or monitored closely. Topiramate can be used for the treatment of headache, but it is a weak carbonic anhydrase inhibitor, and therefore, it should not be used alone to decrease intracranial hypertension.
Patients should be counseled on weight loss (about 10% of the patient’s body weight) as an effective treatment of intracranial hypertension. A low-sodium diet and avoiding excessive fluid intake can also help in the management of idiopathic intracranial hypertension. Acetazolamide is effective at lowering intracranial pressure because it is a carbonic anhydrase inhibitor that reduces production of cerebrospinal fluid. It can cause changes in taste, paresthesias, and drowsiness. Furosemide is a second-line agent that is efficacious in the treatment of idiopathic intracranial hypertension either alone or in combination with acetazolamide. It is thought to work both by decreasing sodium transport to the brain and increasing urine production. However, potassium supplementation is required. If the patient is refractory to medical treatment and has progressive visual loss, optic nerve sheath fenestration is indicated. Ultimately, if other therapies have failed and vision loss continues, lumboperitoneal or ventriculoperitoneal shunting should be considered. Surgical procedures should not be used if refractory headache is the only symptom.
Spontaneous Intracranial Hypotension
The presentation of spontaneous intracranial hypotension is analogous to that caused iatrogenically in post–lumbar puncture headache. Spontaneous intracranial hypotension is often preceded by trivial trauma (eg, lifting boxes, falls, coughing, roller coaster rides, exercise). Patients who are hyperflexible or have a history of connective tissue disorders seem to be predisposed to developing spontaneous intracranial hypotension. It is thought to be caused by cryptogenic cerebrospinal fluid leaks via dural fistulas adjacent to the spinal roots. Tears in the arachnoid and dural layers can also lead to chronic cerebrospinal fluid leaks. The majority of the leaks in this condition are in the thoracic spine or near the cervicothoracic junction. Cranial nerve abnormalities are thought to be secondary to downward traction caused by decreased pressure.
Spontaneous intracranial hypotension presents as a postural headache that is worse when upright and better lying down, and it tends to be worse toward the end of the day. The character and location of headaches in spontaneous intracranial hypotension can be variable, but most often, they are either holocephalic or in the bilateral frontal, occipital, or occipitofrontal regions. Neck stiffness or pain, nausea, and tinnitus tend to be more common, and other associated symptoms of interscapular pain, upper extremity radicular pain, vomiting, auditory muffling, dizziness, diplopia, or visual blurring may also be present. In extreme cases, intracranial hypotension can cause alterations in consciousness. Physical exam can be normal, but often the patient’s headache improves or resolves after being placed in the Trendelenburg position for about 5 minutes.
Neuroimaging can show pachymeningeal gadolinium enhancement (Figure 26–11) and cerebellar tonsillar descent. Sometimes, subdural hematomas can be present, although in roughly 25% of cases, MRI of the brain with contrast is normal. On lumbar puncture, opening pressure is low or unobtainable; otherwise, cerebrospinal fluid studies are normal. Patients can improve with caffeine and hydration; however, often treatment with an epidural blood patch is warranted. In this procedure, approximately 20 mL of the patient’s blood is drawn and then injected into the epidural space, and clotting factors in the blood help seal the leak. Computed tomography and MRI myelography may be necessary to confirm and locate the leak for directed high-volume epidural blood patching or fibrin glue, among other options if initial treatments fail.
Pachymeningeal gadolinium enhancement on magnetic resonance imaging of the brain with contrast can be seen in patients with spontaneous intracranial hypotension, as is demonstrated on this coronal cut. Another clue to this diagnosis is cerebellar tonsillar descent (not shown); however, 25% of imaging in patient suffering from this condition can also be normal. (Reproduced with permission from Ropper AH, Samuels MA, Klein JP: Adams and Victor’s Principles of Neurology, 11th ed. New York, NY: McGraw Hill; 2019.)
NEUROLOGIC PAIN SYNDROMES
Fibromyalgia is often a comorbid condition in patients with chronic headaches. It is more common in women, with a prevalence of 2% to 3% worldwide that is similar across different socioeconomic classes. It manifests as chronic widespread musculoskeletal pain and tenderness. The pathophysiology is likely multifactorial, and associated genes are linked to pathways controlling pain sensitivity and the stress response. There are theories that chronic fibromyalgia can elicit the same central sensitization that is seen in chronic migraine, likely through similar neuropeptide cascades (eg, calcitonin gene-related peptide and substance P). The term fibromyalgia is something of a misnomer, and there is no evidence of inflammation or lesions of the fibrous tissues of the muscles, fascia, and aponeuroses.
The diagnosis is based on clinical symptoms of widespread pain and neuropsychological symptoms. Tenderness to palpation (4 kg of digital pressure) of predefined sites in the occiput, trapezius, supraspinatus, gluteal region, greater trochanter, low cervical region, second rib, lateral epicondyle, and knee bilaterally on exam can help with diagnosis (Figure 26–12). Management of patients with fibromyalgia revolves around counseling on improvement of quality of life rather than abolition of pain. Physical therapy, relaxation techniques, and cognitive behavioral therapies are used in conjunction with pharmacologic treatments such as antidepressants (amitriptyline, duloxetine, milnacipran) and anticonvulsants (gabapentin, pregabalin).
Tender points in fibromyalgia. Shown are the predetermined tender points in the body that are associated with a diagnosis of fibromyalgia. There are 18 total points, 9 on each side. (Data from Wolfe F, Clauw DJ, Fitzcharles MA, et al: The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity, Arthritis Care Res (Hoboken). 2010 May;62(5):600-610.)
Complex Regional Pain Syndrome
Complex regional pain syndrome is a neurogenic pain syndrome. Complex regional pain syndrome type I develops spontaneously and was formerly known as reflex sympathetic dystrophy. Complex regional pain syndrome type II is more common and occurs after nerve injury including trauma or immobilization of a limb and was formerly known as causalgia. The pathophysiology underlying complex regional pain syndrome is under investigation. It was initially postulated that the pain was related to short-circuiting of impulses; however, it is now thought that the abnormal cross-excitation is chemical (secondary to neurotransmitters) rather than electrical. Studies are underway to define the molecular changes that occur in the nervous system with this type of chronic pain.
In both types of complex regional pain syndrome, there is persistent disabling regional neuropathic pain in the absence of recognizable pathology to adjacent nerves. There is also associated regional autonomic dysfunction, and patients can present with limb edema, skin discoloration, altered temperature/sweating, allodynia, and hyperalgesia. Medications used to treat neuropathic pain disorders that are similar to those used as preventive therapy in migraine should be used. Early mobilization of the limb also helps. Overall, current treatment options are unsatisfactory.
Herpes zoster, commonly known as shingles, is a relatively common condition affecting older individuals and those who are immunocompromised. The herpes virus primarily lies dormant in the spinal ganglia, especially in the unilateral thoracic or lumbar segments. In a significant minority of patients, the cranial ganglia, especially the ophthalmic division of the trigeminal ganglion, can be involved (Figure 26–13). When the virus reactivates, neuralgic pain or dysesthesia is the presenting symptom. This is followed in about 4 days by cutaneous erythema and vesicular eruption in the area supplied by the affected roots. The vesicular eruption scabs over in about 10 to 14 days. Postherpetic neuralgia can persist for ≥3 months in a significant minority of patients. Diagnosis is based on history and clinical exam; however, if necessary, the vesicular fluid can be cultured for varicella-zoster virus.
Divisions of the trigeminal nerve. There are 3 division of the trigeminal nerve. V1 is the ophthalmic division, V2 is the maxillary division, and V3 is the mandibular division. In a minority of patients, the herpes virus can lie dormant in the cranial ganglia. If this happens, the ophthalmic division of the trigeminal ganglion is most commonly involved. (Reproduced with permission from Simon RP, Aminoff MJ, Greemberg DA: Clinical Neurology, 10th ed. New York, NY: McGraw Hill; 2018.)
The zoster vaccine is recommended as preventive treatment in all patients age 60 or older. Antiviral therapy with acyclovir is the treatment of choice for acute herpes zoster, but valacyclovir and famciclovir can also be used and may be more successful at decreasing healing time and the duration of postherpetic neuralgia. The prompt administration of antivirals within the first 72 hours of varicella-zoster virus reactivation may decrease the duration of postherpetic neuralgia. Amitriptyline and other tricyclic antidepressants, as well as antiepileptic medications including carbamazepine, gabapentin, and phenytoin, can be effective, although postherpetic neuralgia is often refractory to medical treatments.
Trigeminal neuralgia is also known as tic douloureux and is the most common of all neuralgias. Idiopathic trigeminal neuralgia presents in middle age and later in life. It is characterized by severe, paroxysmal, sharp and stabbing facial pain without numbness or objective findings in the distribution of the fifth cranial nerve. The second and third divisions of the trigeminal nerve are more commonly affected (Figure 26–14). The cause of trigeminal neuralgia is unknown. Theories based on patients’ response to treatments suggest that it may be related to excessive firing within the fifth cranial nerve nucleus with concomitant peripheral excitation and abnormal neuronal chemical discharges. The diagnostic criteria require attacks of unilateral facial pain in 1 or more divisions of the trigeminal nerve (without radiation outside of the nerve) with at least 3 of the following 4 characteristics: (1) recurring in paroxysmal attacks lasting from a fraction of a second to 2 minutes; (2) severe intensity; (3) electric shock–like, shooting, stabbing, or sharp pain; and (4) precipitated by innocuous stimuli to the affected side of the face. Although some attacks can be spontaneous, patients report minimal stimulation provoked by chewing, facial movements, touch, or temperature (even a breeze) can trigger an attack.
Trigeminal neuralgia. The second (maxillary) and third (mandibular) divisions of the trigeminal nerve are most commonly affected in trigeminal neuralgia. These patients have severe, paroxysmal, sharp or stabbing pain in this distribution of the face. (Reproduced with permission from Simon RP, Aminoff MJ, Greemberg DA: Clinical Neurology, 10th ed. New York, NY: McGraw Hill; 2018.)
Trigeminal neuralgia can be symptomatic due to underlying neurologic lesions and therefore is a diagnosis of exclusion that requires imaging of the brain and arterial vasculature to look for compression of the trigeminal nerve, basilar artery aneurysm, tumor in the cerebellopontine angle, or multiple sclerosis among the potential causes. Trigeminal neuralgia in a young female, especially if bilateral, should raise the suspicion for multiple sclerosis. The most effective treatment for trigeminal neuralgia is carbamazepine, which can cause drowsiness, dizziness, and ataxia. Blood work should be monitored for renal toxicity, hepatotoxicity, pancytopenia, and hyponatremia. Other antiepileptic medications such as phenytoin, valproic acid, gabapentin, and pregabalin can help as well. Baclofen is also effective, especially as adjunctive therapy to an anticonvulsant. If the pain is refractory, the patient may be a candidate for botulinum toxin injections to the affected trigeminal division or surgical procedures including microvascular decompression, radiofrequency ablation, chemical gangliolysis, and rhizotomy.
The incidence of phantom limb pain in patients requiring amputations is high, and factors such as the site of amputation and the presence of preamputation pain are associated with the risk of developing phantom limb pain. Phantom limb pain is the sensation that pain is coming from a body part that no longer exists, although it does not necessarily need to be a limb (eg, tongue). The pain is likely generated secondary to peripheral and central mechanisms. Although the mechanism is poorly understood, symptoms are likely secondary to a combination of neuroma hypersensitivity in the periphery, spinal cord sensitization, and cortical reorganization. Tricyclic antidepressants; anticonvulsants such as carbamazepine, oxcarbazepine, gabapentin, and pregabalin; and memantine are agents used in the treatment of phantom limb pain. Transcutaneous nerve stimulation, mirror therapy, biofeedback, and cognitive-behavioral therapy can also be beneficial. Nerve blocks and surgical procedures can be considered if conservative therapies fail.
Central pain syndrome is also known as thalamic pain syndrome and Dejerine-Roussy syndrome. Patients with this syndrome have continuous moderate to severe pain (with variable characterization: tingling, aching, stabbing, burning, pressure-like) secondary to a lesion in the central nervous system (brain, brainstem, and spinal cord) that can be exacerbated by trivial cold or hot stimuli, emotional disturbances, and loud noises. Despite this, the patient has a higher pain threshold to objective testing in the affected hemibody. The syndrome was first described secondary to stroke in the ventral posteromedial and ventral posterolateral nuclei of the thalamus (posterior cerebral artery–penetrating branches). Classically, there is initial hemisensory loss that is followed by hemibody pain. In this instance, the pain is thought to be secondary to partial recovery of the thalamus. Acute but incomplete lesions (eg, vascular insult, multiple sclerosis, tumors, epilepsy) affecting the central nervous system can also produce central pain syndrome. Lesions causing central pain syndrome have been reported in the thalamus, parietal lobe, medial lemniscus, and posterior columns of the spinal cord. Stress reduction in conjunction with tricyclic antidepressants or anticonvulsants, including gabapentin, can help in the treatment of central pain syndrome.