Headache and Other Craniofacial Pain

Tumors

The estimated prevalence of headache in patients with brain tumors (see Chapter 74, Chapter 76 ) varies from 50% to 70%. The likelihood of developing headache is probably mediated by the tumor size, type, and location, and on patient age and personal history of a preceding headache disorder ( ; ). Infratentorial tumors and intraventricular tumors might be more likely to cause headache than supratentorial tumors. In gliomas, specifically, infratentorial and right-sided tumors are more frequently associated with headache presence at onset ( ). Progressive headaches (i.e., those with increases in intensity, frequency, and duration of pain) can be due to worsening of cerebral edema, the presence of midline shift, and hydrocephalus. Factors that increase the risk of brain tumor–related headaches include a personal history of a primary headache disorder and younger age at diagnosis ( ).

Although headache is typically not an isolated symptom at the time of brain tumor diagnosis, not uncommonly it can be the first and most severe symptom that the patient experiences ( ). In a prospective study of 211 patients with brain tumors, headache was the most frequent initial manifestation of the tumors (22% of the patients) and headache was the sole presenting symptom in 19% ( ). In a series of 527 adults with glioma, 12.5% indicated headache as a presenting symptom of their disease ( ).

There is wide variation in the characteristics of headaches attributed to intracranial tumors. Most commonly, such headaches are considered “nonclassifiable,” meaning that their phenotype does not meet the phenotypic characteristics of a primary headache disorder such as migraine or tension-type headache ( ). A headache phenotype that is “nonclassifiable” is followed in frequency by headaches that resemble tension-type headache and then migraine ( ). Specifically in gliomas, however, tension-type headache was the most common phenotype (47% of cases) in a recent series ( ). Most brain tumor headaches are felt bilaterally and are described as causing a pressure sensation. There is substantial variability in the frequency, duration, and specific location of pain. The location of headache pain does not reliably predict the location of the underlying brain tumor ( ).

Rapidly growing tumors are more likely to produce headache than indolent lesions, but slowly enlarging lesions can eventually produce pain by compromising the ventricular system or exerting direct pressure on a pain-sensitive structure. When the CSF circulation is partially obstructed, resulting in high intracranial pressure (ICP), headache is often worse when supine, aggravated by coughing, straining, and Valsalva, and is often associated with nausea and vomiting. When tumors interfere with CSF flow and cause periodic increases in ICP, the periods of elevated ICP may correlate with increasing headache severity, vomiting, decreased consciousness, or a change in respiration.

Tumors growing in the ventricular system are rare, but they can manifest dramatically. The classic presentation of a colloid cyst of the third ventricle is a sudden headache of great severity, rapidly accompanied by nausea and vomiting and sometimes by loss of consciousness. Intraventricular meningiomas, choroid plexus papillomas, and other intraventricular tumors can present in this manner if they suddenly obstruct the ventricular outflow pathways. A positional change may precipitate such an event; similarly, adoption of a different posture may rapidly relieve the headache and other symptoms. Colloid cysts of the third ventricle generally lead to slowly enlarging hydrocephalus that may result in a generalized and constant headache with superimposed episodes of catastrophic increases in headache intensity. Headaches that have a rapid onset and/or are associated with loss of consciousness should lead the examiner to seek a secondary cause.

Infiltrating tumors such as gliomas can reach considerable size without causing pain, because they may not deform or stretch the pain-sensitive vessels and nerves. Such lesions are more likely to present with focal neurological symptoms or with seizures rather than headache. Sudden worsening of the neurological state due to hemorrhage into the tumor may present with sudden headache. Infarction of a tumor can cause edema and swelling that result in a similar dramatic onset of head pain and neurological deficit.

Tumors that are intracranial but extraparenchymal (e.g., meningioma, acoustic neuroma, pinealoma, craniopharyngioma) and pituitary tumors can all produce headaches, but the clinician must carefully consider whether the headaches and these tumors are causally related or coincidental. When headaches are truly associated with these tumors, there are no specific headache patterns. Headaches can be near the lesion, referred to a more distant site in the cranium, or generalized when ICP increases. A family history of primary headaches and cavernous sinus invasion appear to be risk factors for headaches associated with pituitary nonfunctioning adenomas ( ). Meningiomas and meningeal sarcomas can invade the skull and even cause a mass externally by direct tumor spread or by overlying hyperostosis. Such tumors are often associated with localized head pain. Meningeal carcinomatosis (carcinomatous meningitis) produces a headache in most subjects, but the associated cranial nerve involvement and other neurological symptoms are generally more striking.

The headache associated with other intracranial mass lesions such as cerebral abscess and intracranial granuloma is no more specific than that due to a cerebral neoplasm.

Features that should serve as warnings that a patient’s headaches may not be of benign origin and that raise the possibility of an intracranial mass lesion are: subacute and progressive; new onset in adults; change in pattern; associated with nausea or vomiting; nocturnal or upon awakening in the morning; precipitated or worsened by changes in posture or Valsalva maneuver; associated with confusion, seizures, weakness, and/or abnormal neurological examination.

Syndrome of Transient Headache and Neurological Deficits With Cerebrospinal Fluid Lymphocytosis

Although originally termed “migrainous syndrome with CSF pleocytosis,” several later reports used various terms, including headache with neurological deficits, CSF lymphocytosis, and pseudomigraine with temporary neurological symptoms and lymphocytic pleocytosis. This self-limited syndrome consists of one to several episodes of variable neurological deficits accompanied by moderate to severe headache and sometimes fever. Each episode lasts hours, with total duration of the syndrome being from 1 to 70 days. CSF abnormalities have included a lymphocytic pleocytosis varying from 10 to more than 700 cells/mm, elevation of CSF protein, and in some patients, elevated opening pressure. MRI and CT are normal in the vast majority of reported cases. Some patients may have evidence of gray-matter swelling or hemispheric hypoperfusion ( ; ). Results of microbiological studies are usually negative. The cause of the syndrome is unclear, although an immune response to a viral infection is speculated. No treatment alters the self-limited course of this disorder. In contrast to this syndrome, episodes of Mollaret meningitis (see Chapter 103, Chapter 76 ) are separated by months to years and are typically not accompanied by focal neurological symptoms.

Idiopathic Intracranial Hypertension

Idiopathic intracranial hypertension (IIH) is a condition of increased intracranial pressure which typically manifests with papilledema and headaches and has no identifiable cause.

Aneurysms and Arteriovenous Malformations

Intracranial aneurysms are rarely responsible for headache unless they rupture or rapidly enlarge. Large aneurysms may produce pain by exerting pressure upon cranial nerves or other pain-sensitive structures. Such pain is most commonly associated with aneurysms of the internal carotid and posterior communicating arteries. Enlargement of an aneurysm may occur shortly before rupture, and the pain is therefore an important clinical sign.

Parenchymal arteriovenous malformations (AVMs) should be considered in a patient presenting with a cranial bruit or the classic triad of migraine, seizures, and focal neurological deficits. Headache may be a presenting symptom in about 16% of patients and is often ipsilateral to the AVM. Similar to aneurysms, the pain may increase in intensity and frequency before hemorrhage. Though photophobia and phonophobia are uncommon, large AVMs can be associated with ipsilateral or bilateral throbbing cephalgia, resembling migraine. Occipital AVMs may frequently have migraine characteristics, and it is thought that the occipital location may be linked with cortical spreading depression, causing secondary migraine headaches. The visual disturbances associated with occipital AVMs may resemble migrainous aura. MR or CT angiography can usually exclude the presence of clinically significant aneurysms and AVMs.

Both aneurysms and AVMs can produce mild subarachnoid hemorrhages that result in sentinel headaches. Such headaches may be abrupt, mild, and short-lived. More catastrophic subarachnoid hemorrhages classically present as the worst headache the patient has ever had, all the more worrisome when associated with neck stiffness or pain, transient neurological symptoms (e.g., extraocular nerve palsy), or fever. Patients having any suggestion of a sentinel bleeding episode or who describe a recent thunderclap-like headache (see thunderclap headache discussion below) require emergent examination and CT to detect the presence of subarachnoid blood. If the CT is normal, perform a LP, looking for blood or xanthochromia.

Subarachnoid Hemorrhage and Thunderclap Headache

The term thunderclap headache describes a severe headache occurring with instantaneous onset (within seconds) and without warning, like a clap of thunder. While multiple processes can present like this, a subarachnoid hemorrhage is the most worrisome. Rupture of an intracranial aneurysm or AVM results in a subarachnoid hemorrhage, with or without extension into the brain parenchyma. The headache of a subarachnoid hemorrhage is characteristically explosive in onset and of overwhelming intensity. Patients may relate that they thought they were hit on the head. The headache rapidly generalizes and may quickly be accompanied by neck and back pain. Loss of consciousness may also occur, but many patients remain alert enough to complain of the excruciating headache. Vomiting often accompanies the headache, which may aggravate the pain. Extension of blood into the ventricles and basal cisterns or distortion of the midline structures can each contribute to the rapid development of hydrocephalus, which frequently worsens the headache.

Suspicion of the diagnosis is easily confirmed by an unenhanced CT scan that reveals blood in the subarachnoid cisterns or within the parenchyma and often early hydrocephalus. When a CT unequivocally shows blood in the subarachnoid spaces it is not necessary or advisable to perform a LP, because the resultant reduction of CSF pressure may cause herniation of the brain or may remotely induce further bleeding from the aneurysm. Demonstration of subarachnoid hemorrhage generally indicates the need for cerebral angiography. The timing of this procedure and the subsequent mode of treatment are detailed elsewhere (see Chapter 65 ). The headache that occurs after a subarachnoid hemorrhage may be persistent, lasting up to 7–10 days. Rarely, a chronic daily headache (CDH) may persist for months to years.

Movement aggravates a subarachnoid hemorrhage headache, and photophobia and phonophobia are often associated. Therefore, these patients require a dark, quiet room, as well as comfort measures that minimize straining with bowel movements, vomiting, and coughing.

Other conditions which can also manifest with thunderclap headache in addition to subarachnoid hemorrhage include cerebral venous sinus thrombosis, cervicocephalic arterial dissection, pituitary apoplexy, acute hypertensive crisis, spontaneous spinal CSF leaks, meningitis, embolic cerebellar infarcts, pheochromocytoma ( ; ), and reversible cerebral vasoconstriction syndromes (RCVS) ( ; ). These entities can be associated with significant neurological morbidity and may not be easily seen on the initial CT image, thus underscoring the need for MRI and magnetic resonance angiography (MRA)/MRV in this group if results of the initial workup are negative. There is also a rarely seen category of thunderclap headache, referred to as primary thunderclap headache, for which there is no underlying cause established (see the section “Other Primary Headaches” later in the chapter).

Subdural Hematoma

Bleeding into the subdural space is generally due to tearing of the bridging veins that cross the subarachnoid space to reach the venous sinuses. Chronic subdural hematomas may cause headache via enlargement of the lesion and may present without serious neurological signs for a considerable time. Midline shift was the most influential factor for headache in one study, which has led some to consider that the likely cause of headache may be stretching or twisting of the pain-sensitive meninges and meningeal arteries or veins ( ). Changes in personality, alterations in cognitive abilities, subacute dementia, and nonspecific symptoms such as dizziness and excessive sleepiness may be present for weeks or months. Focal seizures, focal weakness, sensory changes, and ultimately, decreasing levels of consciousness may occur. Symptoms of chronic subdural hematoma, including headache and focal neurological symptoms, may fluctuate and occur intermittently, thereby mimicking transient ischemic attacks (TIAs). Headache is the single most common symptom of subdural hematoma and often presents as a severe bitemporal pain. Headache due to subdural hematoma is more common in young people; the cerebral atrophy seen in many elderly patients may be protective in the setting of any space-occupying intracranial lesion. Subdural hematoma should be considered in an elderly person with recent onset of headaches, especially in the context of a traumatic injury of even mild severity. Once suspected, exclude the presence of a subdural hematoma with CT or MRI. Treatment of subdural hematomas is discussed in Chapter 60 . Headaches tend to resolve after resolution of the bleed.

Parenchymal Hemorrhage

A hemorrhage into the cerebral or cerebellar tissue is a potent source of headache of rapid onset and increasing severity. The intraparenchymal mass causes headache by deforming and shifting the pain-sensitive vascular, meningeal, and neural structures. As the hematoma enlarges, it may obstruct the normal circulation of CSF and lead to increases in ICP. Initially, the pain of a cerebral hemorrhage is often ipsilateral, but it may generalize in the presence of hydrocephalus and elevated ICP. Rupture of the hematoma into the subarachnoid space or leakage of the blood into the basal cisterns through the CSF pathways may cause the headache to intensify and may also be associated with neck stiffness and other signs of meningeal irritation. Disorders leading to cerebral and cerebellar hemorrhages are more thoroughly discussed elsewhere (see Chapter 64 ).

Cerebellar hemorrhages account for about 10% of all intraparenchymal bleeds and are neurological emergencies with potentially fatal outcomes. An enlarging hematoma in the cerebellum rapidly compresses vital brainstem structures and obstructs the outflow of CSF from the ventricular system. This leads to occipital headache followed rapidly by vomiting, impaired consciousness, and various combinations of brainstem, cerebellar, and cranial nerve dysfunction.

Cerebral Ischemia

Cerebral infarctions and TIAs may be associated with transient head pain in up to 40% of patients. The headache may be either steady or throbbing and is rarely explosive or severe ( ). The location of the pain is a poor predictor of the vascular territory involved, though unilateral headaches tend to be ipsilateral to the infarct. Cerebral ischemia-related headache is more common in younger patients and patients who are female. It is also more common in patients with larger infarcts and infarcts in the posterior cerebral and vertebrobasilar arterial distributions ( ). A recent MRI voxel-based symptom lesion-mapping study suggests headache phenotypes may be related to specific ischemic lesion patterns ( ). In this study, pulsatile headache occurred with widespread cortical/subcortical strokes, noise sensitivity was associated with cerebellar lesions, nausea was associated with posterior circulation territory infarcts, and cranial-autonomic symptoms were related to parietal lobe, somatosensory cortex, and middle temporal cortical lesions ( ).

If a large cerebral or cerebellar infarct produces significant mass effect as a result of edema, the associated headache may worsen. Obstruction of the ventricular system frequently results in hydrocephalus and further aggravation of the pain. The pain may be pulsatile and may worsen with straining or the head-low position. Hemorrhagic transformation of an ischemic infarct may be associated with worsening of headache. As the infarct decreases in size and the phase of hyperemia subsides, headache generally eases, although in some, headache following stroke becomes chronic and often resembles tension-type headache ( ).

Paroxysmal visual and sensory disturbances commonly associated with migraine aura may mimic symptoms of cerebrovascular disease, occasionally making the differentiation between the two a challenge. The visual aura of migraine is typically a positive phenomenon, perceived with the eyes open or closed. Visual disturbances due to ischemic lesions of the visual pathway or retina are usually associated with negative phenomena such as vision loss or a negative scotoma; however, emboli to the retinal artery can result in showers of bright flashes, and calcarine ischemia can occasionally produce scintillating scotoma. While visual disturbances associated with stroke and TIA are usually abrupt and fixed, the migraine aura tends to march across the visual field over the course of a few minutes and is generally followed by headache after a latent interval. The headache associated with stroke and TIA typically has a more variable relationship to the visual disturbances.

Carotid and Vertebral Artery Dissection

Dissection of the cervical portion of the carotid or vertebral arteries is associated with headache, neck pain, or face pain in approximately 80% of patients. The headache may be isolated or associated with an ipsilateral Horner syndrome or stroke symptoms. An ipsilateral Horner syndrome is more common in carotid than vertebral dissections, and the sympathetic hypofunction may be due to interference with the sympathetic fibers around the internal carotid artery as they ascend from the superior cervical ganglion to the intracranial structures. In internal carotid artery dissections, the headache is typically unilateral and ipsilateral to dissection. Facial pain is common and ipsilateral cranial nerve palsies, especially of lower cranial nerves, are not infrequent. Cerebral or retinal ischemic symptoms are the initial manifestations in a minority of patients. Vertebral artery dissections present most often with headache with or without neck pain, followed by a delay of focal CNS ischemic symptoms. In uncomplicated intracranial vertebral artery dissection, the headache usually is acute in onset with a persistent and temporal feature and in many cases the pain appears to be throbbing and severe in the ipsilateral and occipitonuchal area. Additionally, the headache often is aggravated by head flexion/ rotation and relieved by head extension and being supine ( ).

Cervicocephalic arterial dissections can result from intrinsic factors that predispose the vessel to dissection, including fibromuscular dysplasia, cystic medial necrosis, and other connective tissue disorders such as Marfan syndrome or Ehlers-Danlos syndrome. Extrinsic factors such as trivial trauma may play a pathogenic role when superimposed on structurally abnormal arteries. Severe head and neck trauma may occasionally be the proximate cause of dissection. Importantly, in patients >60 years old, pain and mechanical triggers may be absent, making the diagnosis of cervical artery dissection more challenging in these older patients ( ). MRI or MRA usually confirms the diagnosis of arterial dissection. At the level of involvement, the lumen of the artery typically appears as a dark circle of flow void of smaller caliber than the original vessel, and the intramural clot appears as a hyperintense and bright crescent or circle (in both T1- and T2-weighted images) surrounding the flow void ( eFig. 102.4 ). Catheter angiography is rarely required. The pain associated with cervicocephalic dissections is of variable duration and may require treatment with potent analgesics. Patients with evidence of distal embolization are usually treated with either antiplatelet agents or anticoagulation. FLOAT NOT FOUND

Giant-Cell Arteritis

Giant-cell arteritis is a vasculitis of elderly persons and is one of the most ominous causes of headache in this population. When unrecognized and untreated, it may lead to permanent blindness. Patients with this disorder most commonly see neurologists for new headaches of unknown cause.

Pathology

The histopathological features of arterial lesions include intimal proliferation with consequent luminal stenosis, disruption of the internal elastic membrane by a mononuclear cell infiltrate, invasion and necrosis of the media progressing to panarteritic involvement by mononuclear cells, giant-cell formation with granulomata within the mononuclear cell infiltrate, and (variably) intravascular thrombosis ( eFig. 102.5 ). Involvement of an affected artery is patchy, with long segments of the normal unaffected artery flanked by vasculitic foci known as skip lesions , which may begin to normalize within days after treatment. For these reasons, biopsy specimens of the superficial temporal artery should be generous (4- to 6-cm-long specimens), multiple histological sections should be taken, and bilateral biopsy considered. Employing these strategies may increase the diagnostic yield of temporal artery biopsy up to 86%. FLOAT NOT FOUND

Ocular Causes of Headache

In the absence of injection of the conjunctiva or other obvious signs of eye disease, headache and eye pain rarely have an ophthalmic cause. The maxim is that a white eye is rarely the cause of a monosymptomatic painful eye. Acute angle-closure glaucoma is a rare but often dramatic event. The patient may present with extreme eye and frontal head pain with associated vomiting. The sclera is injected, the cornea is cloudy, the globe is stony hard, and unlike cluster headache, the pupil is fixed in mid-position.

Refractive errors, imbalance of external eye muscles, amblyopia, and “eyestrain” are not causes of headache in most instances. In children and teenagers, however, refractive errors, especially hyperopia, can produce dull frontal and orbital headaches from straining to achieve accommodation at school. Myopic children are unaffected. Trochleitis may produce a periorbital headache and be either idiopathic or secondary to an autoimmune disorder. The headache is characteristically aggravated by vertical ductions of the eye, as the tendon of the superior oblique muscle runs through this structure. Cluster headache, migraine, and other primary headaches, as well as carotid artery dissection, can cause orbital and retro-orbital pain. Each is discussed elsewhere in this chapter.

Nasal Causes of Headache and Facial Pain

Acute purulent rhinosinusitis causes local and referred pain. The distribution of the pain depends on the sinuses involved. Maxillary sinusitis causes pain and tenderness over the cheek. Frontal sinus disease produces frontal pain; sphenoid and ethmoidal sinusitis causes pain behind and between the eyes, and the pain may refer to the vertex. Acute rhinosinusitis is commonly associated with fever, purulent nasal discharge, and other constitutional symptoms. The pain is worse when the patient bends forward and is often relieved as soon as the infected material drains from the sinus. Chronic rhinosinusitis is considered to be a risk factor for CDH, where the headache most often resembles chronic tension-type headache in features ( ). Intracranial infections may occur as a complication of untreated sinusitis. Acute infection involving the sphenoid sinus can be especially dangerous because of its close proximity to the cavernous sinus.

Commonly, migraine headaches are erroneously diagnosed as sinus headaches, because they are associated with cranial autonomic symptoms, have prominent facial involvement, and/or are triggered (e.g., by a change in altitude/weather, an exposure to pollens, or a seasonal predilection). Most patients with a diagnosis of “sinus headaches” have migraine headaches ( ).

Malignant tumors of the sinuses and nasopharynx can produce deep-seated facial and head pain before involving cranial nerves or otherwise becoming obvious. Trigeminal sensory loss is an important neurological sign which is associated with neurological involvement, often by perineural spread. MRI scanning is the optimal technique for detecting these cryptic lesions.

Temporomandibular Joint Disorders

In 1934, Costen first drew attention to the temporomandibular joint (TMJ) as a cause of facial and head pain. Until recently, Costen syndrome was a rare diagnosis. During the past 2 decades, however, interest in disorders of the TMJ, the muscles of mastication, and the bite as they relate to headaches has been increasing. Painful temporomandibular dysfunction is most common between the ages of 35 and 45, after which spontaneous resolution is often seen. Mechanical disorders of the joint, alterations in the way the upper and lower teeth relate, and congenital and acquired deformities of the jaw and mandible can all produce head and facial pain and are very occasionally responsible for the episodic and chronic pain syndromes seen by neurologists.

The neurologist evaluating head or facial pain should be familiar with the criteria for identification and localization of TMJ disorders. Temporomandibular joint pain should relate directly to jaw movements and mastication and commonly associates with tenderness in the masticatory muscles or over the TMJ on palpation. Anesthetic blocking of tender structures should confirm presence and location of the pain source. A sudden change in occlusal relationship of the teeth, restriction of mandibular movement, and interference with mandibular movement (clicking, incoordination, and crepitus) are all symptoms and signs suggestive of TMJ dysfunction.

Bruxism, teeth clenching, and chronic gum chewing are important in the production of pain in the masseter and temporalis muscles. Arthritis and degenerative changes in the TMJ, loss of teeth, ill-fitting dentures or lack of dentures, and other dental conditions can all lead to the TMJ or myofascial pain dysfunction syndrome, which manifests as facial and masticatory muscle pain. Head pain and facial pain, even when associated with the above-discussed criteria, require full evaluation, which should include a detailed history and examination, appropriate radiographs, and laboratory studies to exclude other more serious causes. If TMJ dysfunction is thought to be the source of pain, further evaluation and treatment are in the province of the appropriate dental specialist. Even when TMJ dysfunction is believed to be responsible for facial or head pain, conservative management with analgesics, anti-inflammatory agents, application of local heat, and nonsurgical techniques to adjust the bite generally provide relief. Before using surgical modalities on the TMJ or mandibles, the diagnosis must be secure and other causes of head and facial pain excluded by appropriate investigations.

Other Dental Causes of Craniofacial Pain

Pulpitis and root abscess generally produce dental pain that a patient can localize. The cracked tooth syndrome results from an incomplete tooth fracture, most commonly involving a lower molar. The initial pain is usually sharp and well localized, but thereafter the pain is often diffuse and hard to locate. After a fracture, the tooth is sensitive to cold. Pain may be felt in the head and face ipsilateral to the damaged tooth. With time, infection develops in the pulp, leading to extreme and well-localized pain. Confirmation of the diagnosis and treatment of the cracked tooth require the expertise of a dentist.

Medication Overuse Headache

Overuse of acute medications by patients with frequent headache may lead to a daily headache syndrome, now known as medication overuse headache (MOH) . Previously referred to as rebound or medication-induced headache, this syndrome is induced and maintained by the very medications used to relieve the pain. Diagnostic criteria according to ICHD-3 are designed to improve sensitivity, requiring only the presence of chronic daily headache (CDH) in the setting of exposure to an overused analgesic ( ). The risk for development of medication overuse headache varies with individual substances. Opioids, butalbital-containing compounds, and some combination analgesics appear to have the highest risk; triptans carry moderate risk, and nonsteroidal antiinflammatory drugs (NSAIDs) the lowest risk. In fact, migraine prevention guidelines include recommendations for daily NSAID exposure in the preventive treatment of migraine ( ). Further, there is longitudinal epidemiological evidence that NSAID use among individuals with <10 headache days per month is associated with a dose-dependent reduction in the development of chronic migraine ( ).

The population prevalence of CDH associated with acute medication overuse has been estimated to be 1.4% ( ). The proportion of patients in the population with CDH who overuse acute medications ranges from 18% to 33%, indicating that medication overuse is not necessary for the development of CDH, nor is the overuse of acute medication synonymous with MOH. In other words, tapering and discontinuing the overused medication does not always return the patient to an episodic pattern of headache.

The most frequently overused acute medications include analgesics, opioids, butalbital-containing products, ergotamine, and triptans, alone or in combination. The delay between the frequent intake of these medications and the development of CDH appears to be shortest for triptans (1.7 years), longer for ergots (2.7 years), and longest for analgesics (4.8 years). The duration of withdrawal symptoms after discontinuation and the recidivism rate are also shortest/lowest for triptans and longest/highest for analgesics.

The pathogenesis of MOH is unclear. A leading hypothesis suggests facilitation of central trigeminal sensitization caused by a medication-induced impairment of descending inhibition of nociceptive trafficking. In rats, chronic morphine exposure increases the pain, facilitating “on” cell activation in the rostral ventromedial medulla (RVM) that may alter the balance between the descending inhibition from the nucleus reticularis dorsalis (NRD) and the facilitation from the RVM in favor of a pro-nociceptive increased descending facilitation from the RVM ( ; ). Similar neural adaptations may contribute to opiate-induced MOH in humans by increasing the responsiveness of the nociceptive system, as well as increasing the transmission of pain signals at the medullary dorsal horn ( ). Animal studies have found that sustained or repeated administration of triptans can also induce pro-nociceptive neural adaptations, enhance responses to established triggers of migraine headache, and lower cortical spreading depression threshold, the latter of which can increase the activation of the trigeminal nucleus caudalis ( ; ). Some individuals may possess a genetically determined liability to medication overuse. A FDG-PET study in patients with chronic analgesic overuse in migraine sufferers demonstrated persistent hypometabolism of the orbitofrontal cortex (especially in patients overusing combination analgesics) even after withdrawal of the overused medication. Persistent orbitofrontal hypofunction is known to occur in substance abuse ( ).

Treatment of MOH is challenging and requires aggressive nonpharmacological and appropriate acute and preventive headache treatment. Rigorous controlled data are lacking, with current evidence supporting preventive therapy alone, withdrawal of overuse analgesics alone, and the combination of the two. It is generally considered that lifestyle modifications such as limiting or eliminating caffeine consumption, exercise, and establishing regular mealtimes and sleep schedules can be beneficial for some patients. Depression, anxiety, and sleep disturbances occur in more than half of patients and must be addressed. Training in relaxation techniques and biofeedback may be helpful, especially if stress or anxiety is a frequent provocative trigger. Patients should always be provided with support and close follow-up, particularly during the first 8 weeks after treatment is initiated.

Pharmacological treatment involves tapering or discontinuing the overused medication. Abrupt drug withdrawal is the treatment of choice except with barbiturates, benzodiazepines, and opioids. Typical withdrawal symptoms last 2–10 days (mean 3.5 days) but may persist for 2–4 weeks. In most patients, the withdrawal can be managed on an outpatient basis. Patients with coexistent medical or psychiatric illnesses and overuse of agents containing opioids, benzodiazepines, and barbiturates may need hospitalization or withdrawal in a controlled environment. Prednisone 60 mg daily for 5 days as a transitional and short-term treatment during the withdrawal phase to reduce withdrawal symptoms can be considered and may decrease the need for acute treatment during this time ( ; ). Preventive medication aimed at the underlying primary headache disorder should be started from the outset while initiating the taper of the overused substance.

Studies have indicated a high rate of relapse following withdrawal of acute headache medications in patients with presumed MOH. One prospective study reported a relapse rate of 41% in the first year and 45% after 4 years ( ). In another report with 4 years of follow-up, only one-third of patients initially treated for CDH and analgesic overuse were successful in refraining from chronic overuse of medication.

To avoid MOH relapse, in general, it is best to avoid the use of opioids and/or butalbital for the regular management of primary headache disorders. To prevent relapse, limit NSAIDs, aspirin, or acetaminophen use to ≤14 days/month and limit combination analgesics, triptans, ergot derivatives, or opioids to ≤9 days/month. Although data are limited, the effectiveness of headache preventive medications may be decreased by overuse of acute medications ( ).

Definition and Classification

The term migraine derives from the ancient Greek word hemikranios , which means “half head,” underscoring the unilateral distribution of head pain that is present in about 60%–75% of people with migraine ( ; ). Although not all people with migraine experience all potential phases of a migraine attack, the migraine attack can consist of up to four phases: the premonitory phase, aura, headache phase, and postdrome. In addition to head pain, the “headache phase” consists of a combination of photophobia, phonophobia, osmophobia, cutaneous allodynia, nausea, and vomiting. Although osmophobia is not part of the formal diagnostic criteria for migraine, when present, is considered to be highly specific for the disorder ( ). Box 102.2 shows the classification of different encountered forms of migraine, including episodic migraine with aura, episodic migraine without aura, and chronic migraine ( ).

Epidemiology

A survey of a sample of 20,000 households estimated 27.9 million migraine patients in the United States. More than 90% of patients report an impaired ability to function during migraine attacks, and 53% report severe disability requiring bed rest. Approximately 31% of patients with migraine missed at least 1 day from work or school in the preceding 3 months due to migraine ( ). Indirect costs of migraine related to decreased productivity and lost days of work have been calculated to be $13 billion per year; estimates are that the equivalent of 112 million bedridden days per year are due to migraine ( ). The World Health Organization has declared migraine to be among the most disabling medical conditions experienced worldwide.

Migraine has a 1-year prevalence of 12% in the general population, including 18% of women and 6% of men ( ; ). Migraine afflicts prepubescent boys and girls with a similar frequency. At puberty, the incidence of migraine increases sharply in both boys and girls, but preferentially so in girls. Peak migraine prevalence for both sexes occurs in the fourth decade of life, during which time approximately 24% of women and 7% of men have migraine ( ). Migraine tends to manifest with fluctuating frequencies of attacks throughout one’s life, with a typical trend towards milder and less frequent migraines late in life. The lifetime prevalence of migraine is about 33% in women and 13% in men ( ).

Due to headache and other migraine symptoms, migraine causes substantial pain and disability. During a migraine attack, the vast majority of migraineurs have at least mild disability and about half have severe disability, often requiring rest in a dark and quiet room ( ). Overall, migraineurs have lower physical, emotional, and social quality of life.

There is a genetic predisposition for developing migraine. Compared to the general population, first-degree relatives of people who have migraine without aura are about twice as likely to develop migraine without aura, while first-degree relatives of people who have migraine with aura are about four times more likely to have migraine with aura ( ).