Tumors

Approximately 50% of patients with brain tumors report headaches; in one-third to one-half of these patients, headache is the primary complaint. In a prospective study of over 200 patients with intracranial tumors, 47.6% had headache at the time of presentation (Valentinis et al., 2009). Generalized headache is usual, but in approximately a third of patients, it overlies the tumor and is referred to the scalp near the lesion. 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, headache often becomes generalized and worse in the occipitonuchal area. This type of headache, which is a manifestation of raised intracranial pressure (ICP), is often worse on awakening, aggravated by coughing and straining, and often associated with nausea and vomiting. A prospective study showed that only 5.1% of patients presented with this pattern of headache; in most cases, the headache pattern was nonspecific (Valentinis et al., 2009). In children particularly, the vomiting may be precipitate and without nausea (projectile vomiting).

Large parenchymal tumors and small tumors that interfere with the CSF pathways can be associated with periodic increases in ICP. Monitoring reveals periods of increased pressure (plateau waves of Lundberg), the beginning of which may be associated with increasing headache severity and the peak of which may be associated with vomiting, decreased consciousness, or a change in respiration.

Supratentorial masses generally produce frontal or temporal head pain because of the trigeminal nerve supply to the anterior and middle cranial fossae. The superior surface of the tentorium cerebelli is supplied by the meningeal branches of the first division of the trigeminal cranial nerve, so an occipital lesion can cause pain referred to the fronto-orbital region. A posterior fossa mass generally causes occipitonuchal pain, because the meningeal nerve supply is largely through the upper cervical nerves which also supply the occipital and cervical dermatomes. CNs VII, IX, and X also provide sensory innervation of the posterior fossa, and therefore pain referral can be more widespread. Posterior fossa tumors result in headache earlier than their supratentorial counterparts, because the greater likelihood of compromise of the ventricular system leads to rapidly developing hydrocephalus and raised ICP (Edmeads, 1997).

Pituitary tumors and tumors near the optic chiasm commonly cause a frontotemporal headache, but they may cause referred pain near the vertex. However, patients with tumors of the sellar and parasellar regions do not often present with headache as the initial symptom, because the visual and endocrine symptoms are typically noted first (Edmeads, 1997).

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 rather constant headache, superimposed on which there may be episodes of catastrophic increases in headache. Obstruction of egress of CSF from the ventricular system rapidly leads to increased ICP, which can exceed the capillary perfusion pressure of the brain and lead to loss of consciousness due to cerebral ischemia. Headaches that have a rapid onset and are associated with loss of consciousness, amaurosis, or vomiting are serious and should lead the examiner to seek a secondary cause.

Headache (especially in the occipital region) precipitated by sudden Valsalva maneuvers (e.g., coughing, sneezing, lifting) or exertion may be due to a posterior fossa lesion such as a cerebellar tumor or Chiari malformation. In many patients with cough or exertional headache, however, no underlying lesion is found.

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 as focal neurological deficits or with seizures rather than headache. Sudden worsening of the neurological state due to hemorrhage into the tumor mass may present with sudden headache. The headache may initially appear in the part of the skull overlying the tumor and then become generalized if ICP rises. 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) can all produce headaches, but as with parenchymal lesions, 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. 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 raise the possibility of an intracranial mass lesion are (Purdy, 2001): 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.

Arachnoid Cysts

Cystic spaces bounded by arachnoid membranes found with computed tomography (CT) or magnetic resonance imaging (MRI) during the investigation of headaches are rarely responsible for head pain. Rarely, an arachnoid cyst has a one-way valvelike structure in its wall, so that arterially induced pulsations of the CSF gradually pressurize the cyst and cause it to enlarge. Compression of cranial nerves, such as the trigeminal nerve, or distortion of the midline structures may cause either generalized or localized headaches. If serial CT or MRI studies reveal the cyst to be increasing in size, this finding, depending on the clinical circumstances, may lead to operative intervention. Enlargement of normal subarachnoid spaces such as the cisterna magna and cisterna ambiens is not a cause for headache and should not lead to shunting or other surgical approaches.

Abnormalities of Cerebrospinal Fluid Circulation

Whether raised ICP in the absence of a shift of intracranial structures results in headache is uncertain. The rate at which the ICP increases and the duration of the increase are probably factors that determine pain production.

Obstruction of the Cerebrospinal Fluid Pathways

Lesions that prevent free egress of CSF from the ventricular system result in obstructive hydrocephalus. If this occurs before closure of the cranial sutures, enlargement of the skull occurs, usually without producing headache. Ventricular obstruction after closure of the sutures leads to raised ICP and often to headache. The pain is often worse on awakening, occipital in distribution, and associated with neck stiffness. Vomiting, blurred vision, and transitory obscuration of vision due to papilledema may follow, as well as failing vision due to optic atrophy.

Rapidly developing obstruction due to a posterior fossa mass lesion or a ball-valve tumor, such as a third ventricular colloid cyst, can lead to a rapidly increasing headache followed by vomiting, impaired consciousness, and increasing neurological deterioration. Slowly developing hydrocephalus may result in massively dilated ventricles and may be associated with little or no headache.

Congenital obstruction of the foramina of Luschka and Magendie (the Dandy-Walker syndrome) can lead to ballooning of the fourth ventricle and deformity of the cerebellum. Minor degrees of this malformation can remain asymptomatic until later in life and then manifest with obstructive hydrocephalus and headache. Similarly, the Chiari malformation in its various forms can obstruct the free circulation of CSF and lead to hydrocephalus and headache (Taylor and Larkins, 2002). This malformation can result in an occipital-suboccipital headache worsened or even initiated by a Valsalva maneuver during lifting, straining, or coughing. Thus, the Chiari malformation is one of the causes of an exertional or Valsalva maneuver–induced headache.

In communicating hydrocephalus, free communication exists between the ventricular system and the subarachnoid space, but CSF circulation or absorption is impaired. Obstruction in the basal cisterns or at the arachnoid granulations may follow subarachnoid hemorrhage and meningitis. Venous sinus occlusion can impair absorption of CSF. Headache may be a prominent symptom of both obstructive and communicating hydrocephalus, except in the case of normal-pressure hydrocephalus, which is generally painless (see Chapter 59).

Low–Cerebrospinal Fluid Pressure Headache

The headache of lowered CSF pressure characteristically develops with the patient in the upright position and is rapidly relieved by recumbency. It most commonly occurs after a lumbar puncture. Loss of CSF volume due to the removal of CSF for diagnostic purposes and to leakage through the hole in the arachnoid and dural layers results in headache. The brain normally floats in the intracranial CSF, loss of which allows the brain to sink and thereby exert traction on structures such as bridging veins and sensory nerves. Recumbency removes the effect of gravity, and the traction headache is relieved. The headache that occurs after a spinal tap usually resolves in a few days if the patient remains in bed with good hydration, but occasionally it is prolonged. Relief can usually be obtained by the application of a blood patch, in which 10 to 20 mL of the patient’s own blood is injected into the epidural space close to the site of the original lumbar puncture. Compression of the thecal space for the first 3 hours and a presumed elevation of subarachnoid pressure presumably explains the rapid resolution of the headache. However, compression of the thecal sac is not sustained; maintenance of the therapeutic effect is likely due to the presence of the clot eliminating the CSF leak. The injection of blood is associated with a small risk for cauda equina compression or subarachnoid hemorrhage, but this is unlikely if the blood volume is small and injected gently.

An identical low–CSF pressure headache can occur when a tear develops in the spinal theca. This is usually in the midthoracic region and may result from lifting or coughing or, at times, occurs spontaneously. It can also occur with a crush injury to the chest or abdomen and in patients with overdraining CSF shunts. When it occurs, in the absence of a significant history of trauma, it may not be considered as a cause of daily headache. A history of a headache rapidly responding to recumbency suggests a tear. However, in some patients whose headaches are long standing, a persistent headache may be noted and the postural feature of the headache may become less prominent. Nausea or emesis, neck pain, dizziness, horizontal diplopia, changes in hearing, photophobia, upper-limb paresthesias, vision blurring, and dysgeusia may also occur, particularly when the headache first develops. As additional cases have been reported in the literature, the clinical picture of CSF leaks has been found to take many forms (Mokri, 2004).

When a CSF leak is possible, the initial diagnostic test is MRI with gadolinium. MRI has become an invaluable diagnostic tool in this syndrome, with the cardinal features being diffuse pachymeningeal thickening with gadolinium enhancement, subdural collections of fluid, and evidence of brain descent (Figs. 69.1 to 69.3). This evidence includes cerebellar tonsillar descent (resembling a Chiari type I malformation); reduction in size or effacement of the prepontine, perichiasmatic, and subarachnoid cisterns; inferior displacement of the optic chiasm; and descent of the iter (the opening of the aqueduct of Sylvius as seen on a midsagittal MRI scan).

Fig. 69.1 Axial T1-weighted magnetic resonance images with gadolinium in a patient with a spontaneous cerebrospinal fluid leak and orthostatic headache demonstrate diffuse pachymeningeal thickening and enhancement.

Fig. 69.2 Coronal T1-weighted magnetic resonance images with gadolinium of a patient with orthostatic headache secondary to a spontaneous cerebrospinal fluid leak demonstrate subdural fluid collections and pachymeningeal enhancement.

Fig. 69.3 Sagittal T1-weighted magnetic resonance images demonstrate brain descent made evident by low cerebellar tonsils, crowding of the posterior fossa, small prepontine cistern, and inferior displacement of the optic chiasm in a patient with a spontaneous cerebrospinal fluid leak.

If the clinical and MRI findings are typical, determination of the CSF opening pressure may not be necessary. Measurement of the opening pressure is warranted in patients with normal MRI studies. However, in only 50% of patients is the CSF pressure less than 40 mm H₂O. Because the opening pressure may be normal, the term CSF volume depletion best identifies the core of the problem in this disorder (Mokri, 2004). These patients may have a variable pleocytosis with up to 50 or more mononuclear cells/mm and a mild to modest increase in CSF protein (Mokri, 2004).

In patients with the typical clinical and radiographic features of low–CSF pressure headache, treatment may be conservative with bed rest and hydration for 1 to 2 weeks. If this is either impractical or ineffective, options include empirical treatment with a blood patch or further studies to identify the site of the CSF leak. In patients with spontaneous leaks, the leak is often at the level of the thoracic spine or cervicothoracic junction. Myelography with CT of the spine is more sensitive than radioisotope cisternography or MRI of the spine at localization of the source of the leak, but the latter procedures may serve as guides for obtaining multiple CT images at the appropriate levels. MR myelography may also be helpful in some patients to reveal a leak that is not demonstrable on conventional MRI sequences (Katramados et al., 2006). Most leaks are stopped with either conservative therapy or blood patches. Although an epidural blood patch is effective in the majority of patients, most require more than one blood patch, and some require as many as four to six blood patches (Mokri, 2004). For resistant leaks, surgical repair of the dural tear may be necessary. Even after a protracted duration, surgical repair of the causative dural tear can be quite effective (Mokri, 2004).

A similar syndrome of headache due to low pressure occurs uncommonly when the CSF is leaking through the cribriform plate, petrous bones, or any basal skull defect. CSF rhinorrhea and especially CSF otorrhea may not be obvious to the patient, whose complaint may be postoperative or posttraumatic headache. Leakage of CSF from the skull can occur spontaneously when ICP is raised or a tumor erodes through the base of the skull. This occurs most often around the cribriform plate region, where the bone is especially thin. The CSF leak can be identified by radioisotope cisternography. Placing numbered cotton pledgets in the nose next to the ostia of the sinuses detects leakage of CSF through the nasal sinuses. Contamination of the pledgets by radioactivity enables the sinus through which the fluid is leaking to be identified. CSF otorrhea is not easy to identify if the fluid is draining down the eustachian tube when the eardrum is intact. Scanning with a gamma camera after instillation of a radioactive tracer by lumbar puncture may allow the leak to be identified. Treatment is usually surgical repair of the bony and meningeal defect.

Idiopathic Intracranial Hypertension

Headache, transient visual obscuration, pulsatile tinnitus, and diplopia are the most common presenting symptoms of idiopathic intracranial hypertension (pseudotumor cerebri). The headache is rather nonspecific but tends to be worse on awakening and aggravated by activity. The visual obscurations are direct results of raised ICP leading to papilledema. Indeed, if papilledema is not present, the diagnosis is in doubt. Once determining by MRI that there is no intracranial mass, ventricular system obstruction, or thrombosis of a dural venous sinus, the high CSF pressure can be confirmed by lumbar puncture manometry. Removal of CSF to achieve a normal closing pressure relieves the headache and temporarily prevents visual obscurations. A discussion of long-term management of idiopathic intracranial hypertension is in Chapter 59.

Transient Syndrome of Headache with Neurological Deficits and Cerebrospinal Fluid Lymphocytosis

Although originally termed migrainous syndrome with CSF pleocytosis, several later reports used various terms including headache with neurological deficits and CSF lymphocytosis (Berg and Williams, 1995) and pseudomigraine with temporary neurological symptoms and lymphocytic pleocytosis (Gomez-Aranda et al., 1997). 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. A single patient had MRI evidence of gray-matter swelling in addition to right temporal and occipital sulci CSF enhancement and hypoperfusion. Similar findings have been reported in hemiplegic migraine (Yilmaz et al., 2009). Another patient was found to have global hemisphere hypoperfusion on MRI perfusion imaging (Vallet et al., 2010). Results of microbiological studies are usually negative. A single patient was reported to have evidence of recent human herpesvirus-6 infection, but its pathogenic role in the syndrome is unclear (Emond et al., 2009). Accordingly, 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 Chapters 53B and 73) are separated by months to years and are typically not accompanied by focal neurological symptoms.

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. 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 50B. Headaches tend to resolve after resolution of the bleed.

Posttraumatic Headache

Since head and neck trauma frequently occur together, take care not to overlook cervical spine injuries or instability. Cervical spine radiographs with odontoid views are important, especially when patients present with an altered level of consciousness or when other factors prevent a more thorough neurological evaluation. In some cases, such as in the presence of focal neurological abnormalities, CT or MRI may be necessary for additional evaluation of cervical spine pathology.

Headaches, dizziness, difficulty concentrating, irritability, decreased libido, and fatigue are common complaints after head injury (Keidel and Ramadan, 2005). Many studies suggest that milder injuries are more frequently associated with posttraumatic headache then more severe injuries (Packard, 2005). This counterintuitive observation may result from the fact that seriously injured patients may have other symptoms of such severity that headache may be overshadowed by their other complaints; however, there is no definitive evidence as of yet to support this assumption. In civilian populations, the phenotypical appearance of headache attributed to traumatic brain injuries is most consistent with tension-type headache. In military populations, however, posttraumatic headache more commonly meets criteria for migraine. The underlying mechanisms behind this discrepancy are unclear. The variable latencies between injury and the onset of headache observed in combat veterans suggests the need to revise the diagnostic criteria for posttraumatic headaches; the currently accepted window of 7 days may not adequately capture the number of true cases (Vargas, 2009). Brain imaging rarely reveals abnormalities in the absence of an abnormal neurological examination, although unexpected subdural hematomas are occasionally found. MRI examination tends to be more sensitive for the detection of small occult extracerebral hematomas, cortical contusions, and indeterminate changes in the cerebral parenchyma. Treatment of posttraumatic syndrome and posttraumatic headache is difficult. Encouragement, patience, and a sympathetic attitude on the part of the physician are essential. Undoubtedly, a thorough physical examination and evaluation of appropriate imaging studies are important to reassure the patient that more sinister underlying disorders have been ruled out. As successful treatment can be challenging, reasonable expectations should be established. All the treatments useful for tension-type headaches, migraine, occipital neuralgia, and neck sprains may be needed. Physical therapy, biofeedback, and psychotherapy each have a place in treatment. Drug treatment may include analgesics (nonopioid), nonsteroidal antiinflammatory drugs (NSAIDs), and antidepressants. The tricyclic antidepressants and gabapentin can be particularly helpful.

Recovery from posttraumatic syndrome, including the headache, may be significantly delayed. Most patients who continue to have headaches for more than 2 months after the trauma continue to have them for 1 to 2 years (Ramadan and Láinez, 2005). If the history included a period of unconsciousness or if there is a simple skull fracture, a limited period of bed rest followed by a graduated return to full activity should be advised.

Posttraumatic dysautonomic cephalalgia is rare and usually follows a neck injury. Posttraumatic overactivity of the cervical sympathetic system may be the cause. The throbbing unilateral headache, ipsilateral mydriasis, and facial sweating respond to treatment with propranolol.

Aneurysms and Arteriovenous Malformations and Thunderclap Headache

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) rarely cause pain before rupture. Very large lesions can be associated with ipsilateral or bilateral throbbing cephalalgia, but they rarely cause a migraine-like headache. The presence of a cranial bruit or the classic triad of migraine, seizures, and focal neurological deficits may indicate an AVM. Numerous case reports and retrospective studies suggest migraine may be more prevalent in patients harboring AVMs versus the general population. Among these, the headache frequently occurs ipsilateral to the AVM, highlighting the need for cautious evaluation of patients with side-locked headaches (Monteiro et al., 1993). 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” headache require emergent examination and CT to detect the presence of subarachnoid blood. If the CT is normal, perform lumbar puncture looking for blood or xanthochromia.

The term thunderclap headache describes a severe headache of instantaneous onset (within seconds) and without warning, like a clap of thunder. Other conditions can also manifest with thunderclap headache: cerebral venous sinus thrombosis, cervicocephalic arterial dissection, pituitary apoplexy, acute hypertensive crisis, spontaneous intracranial hypotension, meningitis, embolic cerebellar infarcts, and reversible cerebral vasoconstriction syndromes (Calabrese et al., 2007; Schwedt et al., 2006). These entities are associated with significant neurological morbidity and not easily seen on the initial CT image, thus underscoring the frequent need for MRI and MRA/magnetic resonance venography (MRV) in this group if results of the initial workup are negative. Finally, for one category of primary thunderclap headache, no underlying cause is established.

Whether an unruptured cerebral aneurysm can cause a thunderclap headache is debated (Schwedt et al., 2006).

Subarachnoid Hemorrhage

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. Subjects who survive 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 CT unequivocally shows blood in the subarachnoid spaces, it is not necessary or advisable to perform a lumbar puncture, 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 in Chapter 51C. The headache that occurs after a subarachnoid hemorrhage may be persistent, lasting up to 7 to 10 days. Rarely, a chronic daily headache may persist for months to years.

Movement aggravates the headache of subarachnoid hemorrhage, and photophobia and phonophobia are often associated. Therefore, these patients require a dark, quiet room and comfort measures which minimize straining at stool, vomiting, and coughing.

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 51B).

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 infarction, whether embolic or thrombotic, may cause head pain. The location of the pain is a poor predictor of the vascular territory involved. Some studies indicate that cortical infarction is more likely to be associated with headache than deep cerebral hemisphere infarctions. The headache may be either steady or throbbing and is rarely as explosive or as severe as the headache of subarachnoid hemorrhage. Cerebral infarctions and transient ischemic attacks may be associated with transient head pain in up to 40% of patients. Some reports indicate that carotid-distribution ischemia most commonly leads to frontotemporal head pain, whereas vertebrobasilar ischemia tends to lead to occipital headache.

Approximately 10% of patients note the development of a new or different headache in the weeks and months before onset of ischemic stroke.

If a large cerebral or cerebellar infarct produces a significant mass effect as a result of edema, 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 by straining or by the head-low position. As the infarct decreases in size and the phase of hyperemia subsides, headache generally eases. Hemorrhagic transformation of an ischemic infarct may be associated with worsening of 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, which are typically unrecognizable in the dark or with the eyes closed; 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 migrainous 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 Occlusion and Dissection

Occlusion or dissection of the cervical portion of the carotid artery can result in headache and may be associated with an ipsilateral Horner syndrome. 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. The combination of headache, ipsilateral Horner syndrome, and contralateral hemiparesis is a common presentation of carotid occlusion or dissection.

Cervicocephalic arterial dissections can result from intrinsic factors that predispose the aneurysm to dissection, including fibromuscular dysplasia, cystic medial necrosis, and association with 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. In most patients, the initial manifestation of internal carotid dissection is pain described as headache, facial pain, or neck pain. The pain associated with carotid dissection is typically ipsilateral but infrequently is present bilaterally. Cerebral or retinal ischemic symptoms are the initial manifestations in a minority of patients. The common clinical syndromes associated with carotid dissection include (1) hemicranial pain plus ipsilateral oculosympathetic palsy, (2) hemicranial pain and delayed focal cerebral ischemic symptoms, or (3) lower cranial nerve palsies, usually with ipsilateral headache or facial pain.

The most common symptoms of vertebral dissection are headache and neck pain. The syndrome seen most often consists of headache with or without neck pain, followed after a delay by focal CNS ischemic symptoms.

MRI or MRA usually confirm 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 intracranial clot appears as a hyperintense and bright crescent or circle (in both T1- and T2-weighted images) surrounding the flow void (Fig. 69.4). Catheter angiography is rarely required (Mokri, 2002). 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.

Fig. 69.4 Magnetic resonance images of a patient with right internal carotid artery (ICA) dissection. Large arrow in each figure points to right ICA, which has a smaller flow void than left ICA (small arrows), reflecting narrowed vessel lumen. Region of flow void is surrounded by a hyperintense crescent representing the intramural hematoma.

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 headache 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 (Fig. 69.5). 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 increases the diagnostic yield of temporal artery biopsy up to 86%.

Fig. 69.5 Transverse section of temporal artery showing narrowed lumen (arrowhead) and giant cells (double arrows) in relation to the elastic lamina (hematoxylin-eosin stain, ×100).

(Micrograph courtesy R. Jean Campbell, MBChB.)

Up to one-third of patients have clinically significant large-artery disease. The most common causes of vasculitis-related death are cerebral and myocardial infarction. In fatal occurrences, vertebral, ophthalmic, and posterior ciliary arteries are involved as often and as severely as the superficial temporal arteries. Rupture of the aorta is rare. In patients with peripheral neuropathic syndromes, ischemic infarction of peripheral nerves due to vasculitis are demonstrable. Intracranial vascular involvement is rare.

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 and may be in the early stage of shock. The sclera is injected, the cornea is cloudy, the pupil is fixed in midposition, and the globe is stony hard. It is a true ophthalmological emergency.

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.

Soon after initiation of miotic preparations such as pilocarpine, some patients with glaucoma complain of eye and frontal discomfort due to ciliary muscle spasm. This subsides with continued use of the drops. 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. Currently there is insufficient evidence to suggest that chronic rhinosinusitis is a cause for headache or facial pain unless associated with a relapse into an acute phase. Frontal sinusitis that spreads through the posterior wall of the sinus to produce an epidural abscess is a serious cause of local head pain. If neglected, the abscess may pass through the meningeal layers to produce meningitis or a brain abscess. Similarly, an acute infection involving the sphenoid sinus can be dangerous because of its close proximity to the cavernous sinus.

The occurrence of so-called sinus headaches without an underlying infection remains unsubstantiated. Commonly, migraine headaches are erroneously diagnosed as sinus headaches, because they are associated with cranial autonomic symptoms, have prominent facial involvement, 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 (Cady et al., 2005).

Rarely, patients may suffer from mucosal contact point headaches in which pain localizes to the periorbital, medial canthal, or temporozygomatic regions. Nasal endoscopy or CT imaging must reveal evidence of mucosal contact points to support this diagnosis.

Malignant tumors of the sinuses and nasopharynx can produce deep-seated facial and head pain before involving cranial nerves or otherwise becoming obvious. MRI scanning is the optimal technique for detecting these cryptic lesions. Consider osteomyelitis, multiple myeloma, and Paget disease in particular when bony invasion is present on MRI.

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. Articles in the popular press and diagnoses by dentists have led many patients to believe that TMJ disorders are the most common cause of headache. 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.

For the neurologist evaluating head or facial pain, the criteria for identification and localization of TMJ disorders listed in Table 69.2 should be helpful. 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 criteria listed in Table 69.2, 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, antiinflammatory 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.

Table 69.2 Criteria for Identification and Localization of Temporomandibular Joint Disorders

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.

Definition and Classification

The term migraine derives from the ancient Greek word, hemikranios, which means “half head,” underscoring the unilateral distribution of head pain in many sufferers. Box 69.2 shows the classification of migraine (Headache Classification Committee, 2004).

Clinical Aspects

Although migraine can begin at any age, the initial attack occurs most commonly during adolescence. By the age of 40, 90% of those with the condition have had their first attack. View migraine with suspicion when attacks begin de novo in older patients, because the incidence of serious intracranial disorders that may mimic primary headaches is greater. After puberty, migraine is more common in females, whereas in children there is a small preponderance of males. A family history of migraine is present in up to 90% of patients. In Europe and the United States, the prevalence of migraine is approximately 18% in women and 6% in men (Lipton et al., 2001). Migraine tends to recur with varying frequency throughout life, and attacks tend to get milder and less frequent in later years, although this certainly is not a universal finding.

Although migraine attacks are separable into those with and without aura, the two types are not mutually exclusive, and many patients have attacks of each type. The headache is similar in both types and typically consists of episodic unilateral throbbing head pain of moderate to severe intensity that if untreated persists from 4 hours up to 3 days and tends to worsen with routine physical exertion. Migraine attacks tend to be accompanied by nausea, vomiting, and light or sound sensitivity, although not every patient experiences all of these symptoms (Headache Classification Committee, 2004). Variability exists in the intensity, frequency, and details of the headache from patient to patient and from attack to attack in the same patient.

Migraine without Aura

Migraine without aura (common migraine) occurs episodically and is not preceded or accompanied by any identifiable neurological symptoms that are due to focal cerebral or brainstem disturbances. Many patients with migraine report that a prodromal phase precedes the headache, consisting of alterations in mood or energy level (either euphoria or depression), excessive yawning, thirst, or food cravings. After these, the headache may occur within hours or during the next day. The attack may awaken the subject during the night, but more commonly, the patient awakens near to the normal time to find that the attack has already started. At this stage, the pain may be unilateral and is usually supraorbital, but it may be holocephalic. An initially unilateral headache may progress to generalized head pain, or it may switch to the contralateral side during the course of the attack. Headache arising frontally can radiate or migrate posteriorly or vice versa. Patients with migraine may have “lower-half” attacks that primarily affect the cheek, ear, nose, or neck and may be accompanied by nausea, vomiting, and photophobia.

The quality of the pain of migraine is often throbbing (pulsatile), although in some patients the throbbing only occurs with more severe attacks. Many patients, however, describe the pain as steady while they remain still. It tends to pulsate or throb at the heart rate with exertion, after a Valsalva maneuver, or during the head-low position; however, a description of throbbing pain during migraine attacks is not mandatory for a diagnosis. In general during acute attacks, migraineurs wish to remain as still as possible and prefer a dark quiet room, although with milder attacks some patients may be able to function at a reduced capacity.

Other symptoms are often associated with the pain of migraine. Photophobia and phonophobia are common, and osmophobia (sensitivity to smells) also occurs. The onset of nausea and vomiting in migraine can occur almost as soon as the pain develops, but more commonly delays until the attack has been in progress for 1 hour or longer. The gastrointestinal symptoms can include diarrhea. Blurred vision is a common complaint during all types of migraine. Lightheadedness is also common and may progress to syncope in a small percentage of patients. Although fever, tachycardia, and paroxysmal atrial tachycardia are rare migraine-related symptoms, their presence requires investigation of other possible causes for headache, such as infection or intracranial hemorrhage. The pain of a migraine attack tends to build up to a peak over 30 minutes to several hours. Rarely is the onset described as explosive. The attack generally lasts several hours to a full day. Severe episodes can continue for days and, if associated with vomiting, can lead to prostration and dehydration. Very prolonged severe attacks lasting longer than 72 hours (status migrainosus) may warrant admission to the hospital for pain relief and correction of fluid and electrolyte imbalance. More commonly, the attack subsides within a day or after a night’s sleep. The day after the intense pain, the patient feels tired and listless. The head is still heavy, and transitory pain can occur with sudden movement, bending over, or a Valsalva maneuver.

Recurrence of attacks one to four times per month is common, and attacks in relation to the menstrual cycle are a common pattern in women during the reproductive years. Attacks at less than weekly intervals are common in patients who attend neurology clinics and may indicate that a chronic daily headache pattern is evolving.

Migraine with Aura

In migraine with aura, an aura precedes or accompanies the periodic headaches. The aura consists of transitory visual, sensory, or language disturbance or other focal cerebral or brainstem symptoms. Unilateral motor symptoms may also occur in the context of a migraine attack, although they are now classified separately as hemiplegic migraine. Aura occurs in about 20% to 25% of migraineurs and generally does not occur in every attack. Although each of the aura types may occur alone in a given attack, in some individuals they can occur sequentially. Classically, sensory symptoms follow the visual disturbance, and then in turn by language symptoms. When this occurs, the headache may overlap one or more of the later-appearing aura symptoms. The head pain is identical to that of migraine without aura but is unilateral in a higher percentage of patients. Alterations in mood and other premonitory symptoms may precede the aura.

The most common aura is the disturbance of vision known as a scintillating scotoma (teichopsia). This generally begins as a shimmering arc of white or colored lights in the left or right visual field homonymously. The arc of light gradually enlarges. It may have a definite zigzag pattern. It may be a single band of light or may have a much more complex pattern. It has a shimmering or flickering quality similar to that seen when a fluorescent light fixture is close to failure, or a strobe light is just short of the flicker fusion frequency. Gradually, over the course of a few minutes, the scintillating pattern expands from the point just lateral to fixation to involve a quadrant or hemifield of vision in both eyes. Commonly, the positive scotoma is followed by a spreading zone of vision loss (negative scotoma).The disturbance of vision makes it difficult to read or drive. The scotoma originates in the calcarine cortex of one cerebral hemisphere, and an essentially congruent homonymous field defect is expected; however, sometimes it is only seen in one eye or is worse on one side than the other. Patients often describe the visual disturbance in vague terms such as “blurry vision,” “double vision,” or “jumpy vision.” Close questioning or showing the patient an artist’s representation of a scintillating scotoma generally clarifies the complaint.

There are many variations of migrainous teichopsia (subjective visual images). The zigzag appearance may be so pronounced as to justify the term fortification spectrum because of a fanciful resemblance to the ground plan of a fort. Occasionally the scotoma is less complex and simply described as a ball of light in the center of the visual fields. It may obscure vision to a significant degree. This type of teichopsia may represent a bilateral calcarine disturbance. The scintillating and positive (bright) scotomata can still be seen with the eyes closed or while in the dark. This is not a feature of the negative scotomata (areas of darkness), which disappear in the dark.

The teichopsia of migraine may be more complex and formed than the usual lines and geometric patterns. Very rarely, a complex scene is visible to the migraineur; it may be recognizable as an image from the patient’s past experience, or it may be an unknown scene. Disturbances of this complex type may be due to posterior temporal lobe dysfunction. Changes in the perception of the shape of viewed objects (metamorphopsia) can lead to frightening and bizarre visual hallucinations. Visual disturbances due to retinal dysfunction are uncommon in migraine and may take the form of unilateral flashes of light (photopsia), scattered areas of vision loss, altitudinal defects, or transient unilateral vision loss. When headache follows such monocular visual disturbances, the term retinal migraine is appropriate. When the photopsia, teichopsia, and other disturbances occur in both visual fields simultaneously, they probably originate from the calcarine cortex. A homonymous visual aura is generally followed by a headache on the contralateral side of the head, but exceptions are not uncommon. In such patients, the headache is ipsilateral to the visual disturbance, or it is bilateral.

Sensory aura, the second most common aura type, is, like the visual aura, characterized by positive symptoms (paresthesias) followed by negative symptoms (numbness), which slowly spread or migrate. Paresthesias can occur alone or in conjunction with one of the previously described visual symptoms. Numbness or tingling may be experienced in almost any distribution, from a hemisensory disturbance to one that involves all four limbs or a much more restricted area such as the lips, face, and tongue. The paresthesias usually last from 5 minutes to 20 to 30 minutes. The paresthesias of migraine aura seem to have a predilection for the face and hands. This may be due to the large representation of these structures in the sensory cortex or thalamus. The term cheiro-oral migraine is sometimes applied to instances involving a sensory disturbance of the fingers, lips, and tongue during the aura phase.

The rate of spread of a sensory aura is important to help distinguish it from a sensory seizure and the sensory disturbance of a TIA. Just as a visual aura spreads across the visual field slowly, taking as long as 20 minutes to reach maximum, the paresthesias may take 10 to 20 minutes to spread from the point at which they are first felt to reach their maximal distribution. This is slower than the spread or march of a sensory seizure and much slower than the spread of sensory symptoms of a TIA. A migrainous sensory aura generally resolves over the course of 20 to 60 minutes. After the aura, there is usually a latent period of a few minutes before the onset of the headache. In some subjects, the aura and the headache merge.

After sensory aura, the next most common type is the language aura. Aphasia can occur as the aura of migraine; usually mild and transitory, it can be either an expressive or a receptive type. Alexia and agraphia can also occur and can be associated with mild confusion and difficulty concentrating.

Weakness of the limbs or facial muscles on one side of the body occurs only rarely as a motor aura in migraine, now classified as hemiplegic migraine (Headache Classification Committee, 2004). When it occurs, it usually affects the upper limb and is sometimes accompanied by mild dysphasia if the dominant hemisphere is involved (see Complications of Migraine, later).

Episodes of transient abdominal symptoms, periods of disturbed mentation, déjà vu experiences, and other bizarre symptoms have been thought to be a migraine aura at various times, although the nature of these experiences remains unclear compared to the more common visual, sensory, language, and motor auras already described.

Migraine Aura without Headache

When a visual, sensory, motor, or psychic disturbance characteristic of migraine aura is not followed by a headache, the episode is termed migraine aura without headache, a migraine equivalent, or acephalgic migraine. Most commonly encountered in patients who have a past history of migraine with aura, the episodes can begin de novo, usually after 40 years of age, but they can occur at almost any age.

Migraine equivalents are easily recognizable when the attacks occur on a background of migraine with aura. In the absence of such a history, the transitory disturbance may be difficult to distinguish from an episode of transient cerebral or brainstem ischemia. MRI/MRA, cerebral angiography, echocardiography, and tests of hemostasis may be necessary to exclude the more serious causes. The typical scintillating scotoma with its slow spread and zigzag appearance in both visual fields is almost invariably migrainous, whether or not headache follows. Under these circumstances, it is rarely necessary to perform invasive investigations. A contrast-enhanced CT or MRI scan is a reasonable compromise when there is doubt about the migrainous nature of the event.

Acute episodes of confusion can occur with migraine, usually representing the aura stage. An acute confusional state occurs most often in children or adolescents, but it can occur later in life. In the absence of a long history of migraine with aura, the episodes are rarely suspected of being migrainous. In an elderly patient, consider the diagnosis only after exclusion of more serious conditions, including transient ischemic events. As a migraine equivalent, the acute confusional state may be unaccompanied by headache. The migrainous nature may be suspected from the past history of more typical migraine with aura.

Basilar-Type Migraine

Basilar-type migraine is usually first encountered during childhood or adolescence. It appears to occur in men almost as commonly as in women (Peatfield and Welch, 2000). Basilar migraine is recognizable only in the classic form, because only the dramatic constellation of brainstem symptoms allows its recognition. The headache is usually occipital and severe. The aura, which lasts 10 to 45 minutes, usually begins with typical migrainous disturbances of vision such as teichopsia, graying of vision, or actual temporary blindness. The visual symptoms are bilateral. Numbness and tingling of the lips, hands, and feet often occur bilaterally. Ataxia of gait and ataxic speech, vertigo, dysarthria, and tinnitus are also features of basilar migraine.

Involvement of the brainstem reticular formation can lead to impairment of consciousness, especially in childhood and adolescence. This often occurs as the other symptoms of the aura are subsiding. The level of depressed consciousness is never profound and can resemble sleep from which the patient can be temporarily aroused. Recovery usually coincides with onset of the severe throbbing occipital headache. The pain may generalize to the whole head and may be associated with prolonged vomiting. After sleep, the headache usually resolves. A basilar migraine equivalent occurs in which teenagers have the basilar symptoms without the headache. This clinical picture can be difficult to recognize. Certain investigations provide reassurance. MRI scans and an electroencephalogram (EEG) usually suffice. Rarely, patients with otherwise typical basilar migraine can have seizures with the attacks of headache, with epileptiform EEG abnormalities recorded.

With increasing maturity of the nervous system, attacks of basilar migraine become less common and generally replaced by migraine without aura. Basilar migraine can occur in later life, but view later onset with suspicion because arteriosclerotic vertebrobasilar artery insufficiency is more common and can produce almost identical symptoms.

Ophthalmoplegic Migraine

Ophthalmoplegic migraine is a very uncommon condition that almost always has its onset in childhood. Recurrent attacks are stereotypical. Each episode begins with a unilateral orbital and retro-orbital headache, often accompanied by vomiting, that lasts 1 to 4 days. During the painful stage or as the headache is subsiding, ipsilateral ptosis occurs and within a few hours progresses to a complete paralysis of cranial nerve III. Rarely, cranial nerves IV or VI may be involved. The neural deficit can last from hours to several months. In the past, the focal nature of the deficit often led to major investigations including angiography to rule out the presence of an internal carotid or posterior communicating artery aneurysm. Usually, no abnormality is found. MRI scans have shown thickening and contrast enhancement of the nerve as it exits the midbrain, which may persist after the third nerve palsy has disappeared (Daroff, 2002). Lance and Zagami (2001) speculated that this represents a recurrent demyelinating/inflammatory neuropathy, although pathological evidence has not been available for confirmation. Whether cases with no identifiable cause (or cranial nerve enhancement on MRI) and spontaneously remitting episodes represent a form of migraine or not remains to be determined (Friedman, 2009). In any case, this disorder is probably a cranial neuropathy. The prognosis is favorable for recovery unless attacks occur very often.

Complications of Migraine

Attacks of migraine with associated hemiparesis can occur sporadically or (rarely) as a familial condition. Either form can occur singly or recurrently. Consider the diagnosis only if the patient has a convincing history of migraine with aura. The attack usually begins with a motor aura involving the limbs on one side, and facial involvement may be present. Unlike the common aura, however, this motor aura may involve quite profound weakness that persists throughout the headache phase and for a variable period thereafter. Muscle weakness may last for hours, days, or even weeks in rare patients. Recovery is usually complete, except in patients in whom a dense hemiplegia develops and a CT or MRI scan demonstrates an area of infarction. CSF pleocytosis can occur with hemiplegic migraine. The increased cell count is transient and believed to occur in response to clinical or subclinical cerebral infarction. The sporadic form of hemiplegic migraine, if it is recurrent, can alternate sides. In the familial form, the involved side tends to be the same with each attack. Inheritance of this condition may be a dominant trait and is discussed further under Migraine Genetics.

A facioplegic form of complicated migraine with recurrent episodes of upper and lower motor neuron facial palsy also occurs. Whether this state is separate from hemiplegic migraine is unclear.

Usually on a background of migraine with visual aura, an occasional patient reports the persistence of visual symptoms for long periods or even indefinitely. Most such patients have a field defect. It can be congruous and due to a cerebral lesion, or rarely it can be monocular and due to a retinal abnormality. CT images have shown small infarcts in the occipital lobes or along the course of the central visual pathways in some patients. In those with retinal involvement, occlusion or spasm of the retinal arteries has been observed. A negative scotoma can persist, and scintillating scotomata can persist for long periods. The association between migraine and stroke is also discussed in Chapter 51A.

Physical Findings

Between attacks, the migraineur generally has a normal physical examination. During an attack of migraine, the scalp vessels may be distended and tender. The blood pressure is likely to be elevated due to the pain. Many patients are pale and clammy during the attack, especially if nauseated. The patient is likely to object to the lights of the examination room and try to avoid the glare of the ophthalmoscope during the eye examination. Occasionally there is some inequality of the pupils, with the one ipsilateral to the headache generally being larger. A fully developed “ophthalmoplegic migraine” reveals various degrees of a CN III deficit with ptosis, a dilated pupil, and impaired medial and upward movement of the involved eye. Involvement of CN VI impairs lateral deviation of the globe. Demonstration of impaired vision during the visual aura is difficult.

Mild weakness, especially of the upper limbs, may occur during a motor aura, and various degrees of weakness, including hemiplegia, may occur in complicated migraine.

Laboratory Findings

No special investigations are useful for the clinical diagnosis of migraine. Visual evoked potentials and EEG are of little use clinically. CT scans can reveal large areas of decreased attenuation over the hemisphere ipsilateral to the headache, especially if it is severe and prolonged. These changes, which are temporary and resolve in a few days, probably represent edema of the affected region. Complicated migraine, especially associated with a permanent deficit such as a hemiparesis or a visual-field defect, shows an appropriate area of cerebral infarction. The relationship of antiphospholipid antibodies to migrainous infarction is unclear.

Case series extending back to the early 1990s have reported an increased occurrence of small areas of increased MRI T2 signal within the subcortical white matter. A meta-analysis of seven MRI-based case-control series by Swartz and Kern (2004) indicated a significantly increased risk for asymptomatic white-matter lesions in migraineurs, with an odds ratio (OR) of 3.9 (95% confidence interval [CI], 2.26-6.72). The clinical significance of the findings is unknown. A recent population-based cross-sectional MR study comparing 295 migraineurs (161 with aura, 134 without aura) and 140 nonmigraineurs (Kruit et al., 2004), which controlled for vascular risk factors, found that female migraineurs both with and without aura had an increased number of deep white-matter lesions compared with nonmigraine controls. In addition, this study reported that migraineurs carried an increased risk for subclinical infarct-like lesions within the cerebellum. The occurrence of these lesions positively correlates with attack frequency and the presence of aura (Kruit et al., 2004). We emphasize that the findings were subclinical, that the study was cross-sectional rather than longitudinal, and that at this time assessment for unexplained cerebellar infarcts is not a reliable diagnostic tool in migraine.

CT and MRI scans are useful in the investigation of migraine to exclude other causes of recurrent headaches. If there is a question about whether a vascular lesion such as an aneurysm or AVM is present, MRA is often used as a screening tool, although standard angiography may in some instances be necessary when the diagnosis of migraine is doubtful and a vascular lesion is strongly suspected on clinical grounds.

Migraine Genetics

The prevalence of a family history of migraine was recognized in the 17th century. Although prior familial migraine studies have shown no clear Mendelian inheritance patterns, recent genetic epidemiological surveys and large national registry–based twin studies strongly support the hypothesis of a genetic contribution. Perhaps the most striking evidence of a genetic basis for migraine has come to us over the past decade from investigation of familial hemiplegic migraine.

Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura in which, in the context of otherwise typical migraine attacks, patients experience hemiplegia. The hemiparesis of FHM in many patients extends beyond the customary time limit of 1 hour usually associated with migraine aura. Ataxia, nystagmus, and coma occur in the context of FHM. In 1993, FHM was mapped to chromosome 19p13 in linkage studies that were inspired by the clinical association with migraine and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). About 50% of tested families have mutations in CACNA1A, a gene located on chromosome 19p13 that codes for the α₁-subunit of a brain-specific voltage-gated P/Q-type calcium channel (Ophoff et al., 1996). Mutations in the same gene occur in some pedigrees with hereditary paroxysmal cerebellar ataxia, indicating that these two disorders that share several features are allelic channelopathies (see Chapter 64). Gardner et al. (1997) reported another locus for FHM on chromosome 1q31 in a 39-member four-generation pedigree showing a clear FHM phenotype. This region on chromosome 1 contains a neuronal calcium channel α_1E-subunit gene. Recent reports (Terwindt et al., 2001) not only implicate CACNA1A in FHM, but it may be overrepresented in patients with migraine without hemiplegia. Subsequent studies in other families have found two additional mutations linked to FHM. One that mapped to chromosome 1q21-q23 (De Fusco et al., 2003) is located in a gene coding for a subunit of a sodium/potassium pump (ATP1A2). Another mutation identified on chromosome 2q24 is located in a gene that encodes a sodium channel subunit (Dichgans et al., 2005). Although FHM is a rare genetic subtype of migraine with aura, the clinical similarities (with typical migraine, with and without aura) suggest at least the possibility of a shared pathophysiology. The discovery of a genetic locus for FHM has generated considerable interest and prompted a large effort in the field of molecular genetics to find the fundamental defect in the more common forms of migraine. However, studies testing the 19p13 region for linkage to typical migraine have produced conflicting results. One study implicated chromosome 19 mutations, either in the CACNL1A4 gene or in a closely linked gene in some pedigrees with familial typical migraine, and concluded that the disorder is genetically heterogeneous (Nyholt et al., 1998). The numerous sites reporting linkage to migraine underscores the likelihood of genetic heterogeneity in the common form of migraine. Published association sites include 1p13.3 (Kusumi et al., 2003), 4q31.2 (Tzourio et al., 2001), 9q34 (Lea et al., 2000), 11p15 (Mochi et al., 2003), 11q23 (Del Zompo et al., 1998; Peroutka et al., 1997, 1998), 17 q11.1-q12 (Ogilvie et al., 1998), 19p13.3/2 (McCarthy et al., 2001), and 22q11.2 (Emin Erdal et al., 2001).

A recent study based on a genome-wide screen of 50 multigenerational clinically well-defined Finnish families showing intergenerational transmission of migraine with visual aura yielded significant evidence of linkage between the migraine with aura phenotype and marker D4S1647 located on chromosome 4q24 (Wessman et al., 2002). Genomic and proteomic techniques will likely lead to further unraveling of the precise molecular defects that underlie migraine.

Pathophysiology

Treatment and Management

The nature of the disorder should be explained to the patient and reassurance given that it is a painful but generally benign condition that can usually be controlled or alleviated. Explain that a cure for migraine is lacking, but management is available. It is important that patients feel the physician understands that their headaches represent a medical problem and does not consider them to arise from psychological factors. A normal CT or MRI scan may offer considerable reassurance. Some patients are more interested in knowing that they do not have a brain tumor or other potentially lethal condition than they are in obtaining relief from the pain.

Avoidance of trigger factors is important in the management of migraine, but simply advising a patient to avoid stress and relax more is usually meaningless. Advice to reduce excessive caffeine intake, stop smoking, and reduce alcohol intake may be more useful. Medication use should be reviewed and modified if necessary. The use of drugs known to cause headaches (e.g., reserpine, indomethacin, nifedipine, theophylline derivatives, caffeine, vasodilators [including long-acting nitrates], alcohol) should be discontinued, or substituted to other agents if possible. Use of estrogens and oral contraceptives should be discontinued if they are suspected of contributing to the headaches, although in some patients this may not be possible. Exercise programs to promote well-being, correction of dietary excesses, and avoidance of prolonged fasts and irregular sleeping habits can be helpful.

The topic of dietary factors in migraine is difficult. Radical alterations in the diet are rarely justified and seldom effective. Avoidance of foods containing nitrites (e.g., hot dogs, preserved cold cuts) and prepared foods containing monosodium glutamate can be helpful. Avoiding monosodium glutamate can be difficult because it is a constituent of many canned and prepared foods and is widely used in restaurants, especially in the preparation of Chinese dishes. Ripened cheeses, fermented food items, red wine, chocolate, chicken liver, pork, and many other foods have been suspected of precipitating headaches. These foods mostly contain tyramine, phenylethylamine, and octopamine. An occasional patient identifies an offending foodstuff, but in our experience, dietary precipitation of migraine is uncommon. Other headache authorities disagree. In some migraineurs, strong odors, especially of the perfume or aromatic type, precipitate attacks. Avoiding the use of strong-smelling soaps, shampoos, perfumes, and other substances can be helpful for some individuals.

Persons with migraine may note that stress is a trigger for attacks, but helping them deal with or avoid stress is difficult. Long-term stress management may require the help of a psychologist or other appropriately trained professional. Useful techniques include biofeedback, relaxation training, hypnosis, and cognitive behavioral training (Campbell et al., 2000).

Hormones and Migraine

Migraine occurs equally in both sexes before puberty, but it becomes three times more common in women after menarche. Approximately 25% of women have migraine during their reproductive years. The changing hormonal environment throughout a woman’s life cycle, including menarche, menstruation, oral contraceptive use, pregnancy, menopause, and hormone replacement therapy (HRT), can have a profound effect on the course of migraine.

Menstrual Migraine

Migraine attacks are associated with menses in one of three ways. The attacks may occur exclusively during menstruation and at no other time during the cycle. This association is referred to as true menstrual migraine (TMM), and it has been proposed that TMM be defined as attacks that occur between days −2 and +3 of the menstrual cycle (MacGregor, 1996). The prevalence of TMM according to this definition is about 7%. More commonly, migraine attacks occur throughout the cycle but increase in frequency or intensity at the time of menstruation. This association occurs in up to 60% of female migraineurs. Finally, premenstrual migraine can occur between days −7 and −3 before menstruation as part of premenstrual syndrome or late luteal phase dysphoric disorder. A cluster of symptoms in the luteal phase—depression, irritability, fatigue, appetite changes, bloating, backache, breast tenderness, and nausea—characterize the disorder. These different relationships between migraine and the menstrual cycle can be determined by reviewing headache diaries, and their distinction is important because pathophysiology may differ, as would the therapeutic approach.

Numerous mechanisms have been proposed to explain the pathogenesis of menstrual migraine. There is abundant clinical and experimental evidence to support the theory that estrogen withdrawal before menstruation is a trigger for migraine in some women. Estrogen withdrawal may modulate hypothalamic β-endorphin, dopamine, β-adrenergic, and serotonin receptors. This complex relationship causes significant downstream effects such as a reduction in central opioid tone, dopamine receptor hypersensitivity, increased trigeminal mechanoreceptor receptor fields, and increased cerebrovascular reactivity to serotonin. These changes, which occur during the luteal phase of the cycle, may be germane to the pathogenesis of menstrual migraine.

Several lines of investigation have implicated both prostaglandins and melatonin in the pathogenesis of menstrual migraine. Prostaglandins and melatonin are important mediators of nociception and analgesia, respectively, in the CNS. The concentrations of prostaglandin F₂ and nocturnal melatonin secretion increase and decrease, respectively, during menstruation in female migraineurs. These observations are the basis for the clinical use of NSAIDs and melatonin for menstrual migraine prophylaxis.

Management of Menstrual Migraine

To establish a direct link between menstruation and headache attacks, ask the patient to keep a diary of migraine attacks and menstrual periods for at least 3 consecutive months. The nature of this relationship determines subsequent therapy. For example, for patients who have both menstrual and nonmenstrual attacks (menstrual-associated migraine), a standard prophylactic medication might be used throughout the cycle rather than the perimenstrual use of a prophylactic agent. Clearly outline the goals of therapy in addition to the dosages, benefits, and side-effect profile of each recommended medication. Ideally, the headache diary can help identify other nonhormonal triggers. Biofeedback and relaxation therapy can be helpful in selected patients and should be used whenever possible.

Acute Menstrual Migraine Therapy

The goal of acute menstrual migraine therapy is to decrease the severity and duration of pain as well as the associated symptoms of an individual migraine attack, including nausea, vomiting, photophobia, and phonophobia. Some women may control attacks of menstrual migraine quite adequately with abortive therapy only (Fig. 69.6).

Fig. 69.6 Algorithm for acute treatment of menstrual migraine. ASA, Acetylsalicylic acid; DHE, dihydroergotamine; NSAID, nonsteroidal antiinflammatory drug.

The acute management of menstrual migraine does not differ from the treatment of migraine unassociated with menstruation. Mild attacks (which are relatively rare) can be managed with acetaminophen or NSAIDs. Moderate to severe attacks can be treated with an oral triptan. If there is significant nausea and vomiting, however, an alternate route of administration is necessary. In this setting, parenteral therapy with sumatriptan, DHE, ketorolac, or a neuroleptic such as prochlorperazine is appropriate. Alternatively, sumatriptan, zolmitriptan, and DHE are available in a nasal formulation and can be helpful in patients with significant gastrointestinal upset. The combination of an antiemetic with any of these medications may not only alleviate nausea and vomiting but also potentiate the efficacy of these compounds.

Prophylactic Menstrual Migraine Therapy

Prophylaxis may either be perimenstrual (cyclic) or continuous (noncyclic) (Box 69.3). Many of the regimens suggested for perimenstrual migraine prophylaxis depend on regular menstruation. Perimenstrual prophylaxis commences a few days before the period is expected and continues until the end of menstruation. In women whose cycles are difficult to predict, continuous prophylaxis with standard migraine prophylactic agents such as tricyclic antidepressants and beta-blockers can be quite effective if taken continuously.

Box 69.3 Nonhormonal Prophylaxis for Menstrual Migraine

Cyclic (Perimenstrual) Days −3 Though +3

Nonsteroidal antiinflammatory drugs:

Naproxen sodium, 550 mg bid

Mefenamic acid, 250 mg tid

Ketoprofen, 75 mg tid

Triptans and ergots:

Sumatriptan, 25 mg tid

Naratriptan, 1 mg tid or 2.5 mg bid

Frovatriptan, 2.5 mg once daily

Zolmitriptan, 2.5 mg bid

Ergotamine tartrate + caffeine (Wigraine), 1 mg qhs or bid

Dihydroergotamine, 0.5-1 mg (subcutaneous, intramuscular, or intranasal) bid