Headache

Overview of Headaches

Headache is one of the most common reasons for consulting a physician and is one of the top three reasons for lost work days. Rather than a disease, headache is a symptom, frequently providing a valuable warning of hidden pathology.

Physicians treating patients for headache must decide whether the headache represents a primary or secondary headache syndrome. Primary headaches are most common and include disorders such as migraine, tension-type headache, and trigeminal autonomic cephalalgias. The patient with primary headaches may have severe and incapacitating pain, but there is no identifiable cause leading to activation of nociception. In contrast, secondary headaches are symptomatic of a cranial or extracranial pathology, such as a brain tumor, ruptured aneurysm, meningitis, or hematoma. Headache diagnosis depends on a thorough history and neurologic and medical examinations. The history should seek information on premonitory symptoms, timing of onset (gradual vs. sudden) and duration, pain quality, and severity, location of pain, provoking factors, any associated symptoms, clinical circumstances, and details of previous investigations and treatments. A past medical history, family history, trauma history, social history, current medications, drug allergies, and review of systems are also indispensable. If a new headache is unlike any headache the patient has had in the past, it requires very expeditious evaluation, which may include ancillary laboratory and neuroradiologic imaging.

Secondary headaches, and possibly primary headaches, are thought to occur when primary afferent nociceptive neurons arising from either the trigeminal ganglion or upper cervical spinal ganglia (C1-3) are depolarized. These neurons innervate both extracranial and intracranial pain-sensitive structures. The first and second trigeminal nerve divisions provide sensory innervation for the anterior head and upper face. The trigeminal nerve innervates pain-sensitive dural structures, including the dural sinuses and tentorium cerebelli as well as many arteries, including the middle meningeal, temporal, proximal portions of the anterior and posterior cerebrals, and the internal/external carotid. The cervical spinal nerves (C1-3) provide innervation to the dural structures of the posterior fossa, the basilar and vertebral arteries, and to muscular structures in the upper neck and posterior portion of the head.

The cause of prolonged head pain is usually apparent when a secondary headache develops related to a tumor or other intracranial lesion producing ongoing traction upon a dural or vascular structure. However, patients with a primary headache disorder do not have a clearly discernible source for ongoing activation of nociceptive neurons. Therefore pathophysiologic mechanisms leading to a persistent primary headache are less clear. It is likely that the neurons within the trigeminal-cervical pain system are more than passive conduits for depolarization; however, because they also seem to play a role in pain sensitization. Sensitization is a process where, after repeated activation, neurons become increasingly responsive to painful and nonpainful stimulation. Peripheral sensitization (in the primary afferent neurons) and central sensitization (within second-order neurons in the trigeminal nucleus caudalis and higher-order neurons within the central nervous system [CNS]) may play a role in prolonging headaches and may contribute to the transformation of episodic migraine to the chronic form of migraine.

The evidence of peripheral sensitization of the primary afferents comes from both animal and human studies. In animal models, stimulation of the trigeminal system leads to increased concentrations of the vasoactive peptides, including substance P (SP), neurokinin A (NKA), and calcitonin gene–related protein (CGRP) in sagittal sinus blood. Similarly in humans, internal jugular CGRP levels reportedly rise during migraine attacks. Release of these neuropeptides is a marker for neuronal activation in primary afferents. Primary afferent neurons exposed to activating stimuli show increased spontaneous firing and lowered activation thresholds.

There is also evidence that initial activation of the primary afferent neurons leads to sensitization of second and possibly higher-order neurons. Chemical irritation of the meninges in animal models (peripheral nociceptors) causes sensitization of both trigeminovascular fibers innervating dura and central trigeminal neurons receiving convergent input from dura mater and skin. After sensitizing activation of the meninges, central trigeminal neurons respond to low-intensity mechanical and thermal stimuli from skin that previously induced minimal or no response. This change in activation threshold for central neurons receiving input from skin (which was not directly irritated) strongly implicates sensitization of second-order neurons within the central nervous system.

Migraine Pathophysiology

Migraine pathophysiology is not well understood. At present, migraine is viewed as a complex, often genetically based disorder that confers a susceptibility to the initiation of a cascade of events within the central nervous system (CNS), resulting in a clinical migraine attack.

Until the 1980s, the accepted explanation for migraine attacks was the vascular theory of migraine, which suggested that migraine headache was caused by the dilation of cranial blood vessels, while the aura of migraine resulted from vasoconstriction. The vascular theory was based on four observations: (1) the only effective treatment of acute migraine at the time, ergotamine, was a potent vasoconstrictor; (2) nitroglycerin, a vasodilating agent, caused headaches; (3) the classic observation that branches of the external carotid arteries often became distended and pulsated during a migraine attack; and (4) finding that stimulation of intracranial vascular structures (but not the brain) in awake patients undergoing surgical procedures caused headache. However, this vascular theory did not appear to account for all of the elements of migraine pathophysiology.

A neurogenic theory evolved next, suggesting that the migraine aura was caused by a cortical wave of neuronal and glial depolarization, referred to as cortical spreading depression (CSD). From its cerebral cortical origin, this CSD wave spreads across the cortex at a rate of 3 to 5 mm/min, a rate similar to the estimated speed of visual aura of migraine as it progresses across the primary visual cortex. In experimental CSD, there are characteristic cerebral blood flow changes, with an initial increase in blood flow (hyperemia), followed by a decrease in blood flow (oligemia) and relative tissue hypoxia. Imaging studies using functional magnetic resonance imaging (MRI) seem to corroborate these hemodynamic changes in migraineurs during visual aura. In addition to contributing to aura, CSD may also act as a trigger for the headache pain. Experimental evidence demonstrates that CSDs may result both in activation of nociceptive second-order neurons within the medullary trigeminal nucleus caudalis and in changes within the vessel caliber of dural vessels innervated with pain-sensitive neurons. This mechanism might certainly account for activation of the headache in patients who experience the migraine aura, but would not explain headache in migraine patients without aura. It has been suggested that migraine without aura occurs when CSD takes place in noneloquent brain areas (such as the cerebellum), where depolarization is not consciously perceived; however, there is insufficient evidence to support this possibility at this time.

The headache of migraine likely arises upon activation of nociceptive neurons in the trigeminovascular system (TVS). The TVS consists of small-caliber pseudounipolar sensory neurons arising from the trigeminal ganglion and upper cervical dorsal roots and project to innervate pial vessels, dura mater, large cerebral vessels, and venous sinuses. Once activated, the neurons transmit the nociceptive information to the trigeminal nucleus caudalis of the medulla, where they synapse on second-order neurons.

From the trigeminal nucleus caudalis, neurons that are involved in localization of pain project to the thalamus and then to the sensory cortex, where pain reaches consciousness. Central signals can be modulated by projections from several sources, including the periaqueductal gray, the nucleus raphe magnus in the rostral ventromedial medulla, and by descending cortical inhibitory systems. Other activated second-order neurons within the trigeminal nucleus caudalis project to numerous subcortical nuclei and to limbic areas of the brain involved in the emotional and vegetative responses to pain.

There is ongoing debate as to whether initial activation of primary afferent neurons is necessary for the occurrence of migraine headaches. The fact that increases in measured levels of CGRP, a neuropeptide known to be released by activated first-order neurons, are observed in external jugular venous blood during migraine in humans implicates activation of primary afferents neurons. However, logically, it would seem the abnormal activation or lack of regulating inhibitory tone could result in the propensity of a migraine attack in some individuals.

Migraine Presentation

Migraine is a very common disorder, with a 1-year prevalence of more than 18% of women and almost 7% of men in the United States. It is most common in the third and fourth decades, although it may occur at any time of life from early childhood onward. Migraine is divided into two types based on the presence or absence of transient neurologic symptoms referred to as aura. Migraine without aura (formerly referred to as common migraine ) is more common than migraine with aura (formerly referred to as classic migraine ) and accounts for about three quarters of migraine patients. Both migraine with aura and migraine without aura occur in either an episodic form (<15 headache days per month) or a chronic form (≥15 headache days/mo). Over the course of a lifetime, a migraine sufferer may move back and forth between the chronic and episodic forms. The factors determining susceptibility to the development of the chronic form of migraine are poorly understood.

Although head pain is the most debilitating aspect of migraine, a migraine attack may unfold through a series of four phases: (1) prodrome , (2) aura (when present), (3) headache, and (4) postdrome . Not all individuals experience all phases. The prodrome occurs in up to 60% of migraine patients and consists of vague vegetative or affective symptoms that herald the onset of the attack. These symptoms may include food cravings, constipation, neck stiffness, increased yawning, irritability, euphoria, or depression. With resolution of the prodrome, the aura (when present) occurs generally just before or during the opening minutes of the headache.

The migraine headache is usually (but not always) unilateral. In fact, the term migraine is derived from the ancient Greek word, hemikranos, which means “half head.” A migraine headache tends to have a throbbing or pulsatile quality that at times is superimposed on a constant pressure-like sensation. As the attack severity increases over the course of one to several hours, patients may experience nausea and sometimes vomiting. Most individuals report abnormal sensitivity to light ( photophobia ) and/or sound ( phonophobia ) during attacks. Individuals may also report cutaneous allodynia over the face or scalp on the same side as the headache. Allodynia is a tenderness or hypersensitivity in the context of which even a light touch may be perceived as painful. In adults, an untreated migraine headache will attain at least a moderate level of pain intensity that can persist from 4 hours to 3 days. Many attacks resolve with sleep that can occur as a part of the natural course of the migraine attack or as the result of treatment of the headache with sedating medications.

As the headache is resolving, many patients experience a postdromal phase in which they feel drained or exhausted, although some report a feeling of mild elation or euphoria. During the postdromal phase, sudden head movement may cause transient pain in the location of the recently resolved spontaneous throbbing of the headache.

Frequently cited precipitating factors (triggers) of migraine headache include stress, fasting, sleep disturbances, weather changes, bright light or glare, ingestion of alcohol, strong odors, smoke, nitroglycerin or other vasodilating drugs, nasal congestion, withdrawal from caffeine or ergotamine-containing medicines, exercise, intercourse, and certain food substances, such as chocolates, sharp cheese, processed meats, and hot dogs. There are reports that migraine headaches frequently begin in the morning on arising and may have a predisposition to occur on a Saturday or after a prolonged or intense period of work or study. For most patients, migraine attacks occur unpredictably.

One of the most potent and frequent triggers of migraine in women is the monthly fluctuation in gonadal hormones that underlies the menstrual cycle. Typically, the headaches appear 1 to 2 days before or the first day of menstrual flow, although they may also appear during the menstrual cycle itself. Some women also experience migraine headaches at midcycle with ovulation. The headaches can be quite severe and are usually without aura, although women can also have headaches preceded by aura at other times of the month.

Migraine Aura

Migraine aura consists of transient focal neurologic symptoms that tend to last for 5 minutes to 1 hour and may occur before or during the headache phase. There are four types of migraine aura: visual, sensory, language, and motor. Patients may have one or more types, and auras may occur even in the absence of headache. The most common aura type, visual aura, may consist of positive visual symptoms (shimmering, sparkling, flashes of light) or negative symptoms (blurred vision or loss of vision) in both eyes. The most classic visual aura is a scintillating scotoma that starts as a small shimmering or blurred spot just lateral to the point of visual fixation. This spot expands over 5 minutes to 1 hour to involve a quadrant or half of the visual field. It often assumes a curved or sickle shape with a zigzagging or serrated border, sometimes multicolored or sparkling in appearance. This jagged edge has also been referred to as a fortification spectra based on its resemblance to the top of a medieval fortress. Over time, the positive visual phenomena tend to move toward the periphery leaving a blind spot, that is, scotoma, in their wake.

When sensory aura accompanies visual aura, it tends to follow visual aura within minutes. This aura typically begins as unilateral paresthesias in a limb or one side of the face. From their origin, the paresthesias may gradually march down the limb or face, often with a subsequent feeling of numbness that may last as long as an hour. The sensory aura may also expand to involve the inside of the mouth, affecting the inside of one cheek and half the tongue. The slow spread of positive symptoms (the scintillations or the tingling) followed by negative symptoms (scotoma or numbness) is very suggestive of migraine aura and contrasts significantly with an ischemic event, such as a transient ischemic attack, wherein all symptoms begin concomitantly.

A language aura occurs much less commonly than the visual and sensory type auras. This consists of transient language problems that may range from mild word-finding difficulties to frank dysphasia with paraphasic errors.

The least common aura type, motor aura, involves unilateral weakness in the limbs and possibly the face. Most patients with motor aura also report sensory symptoms, and many also have other attacks, including visual, sensory, or language aura. When one considers diagnosing a motor aura, it is most important to distinguish true motor weakness from clumsiness based on proprioceptive loss caused by sensory aura. To date, research studies have linked motor aura to three separate genetic mutations. As a result, motor aura is classified separately from the other forms of migraine aura, and is referred to as hemiplegic migraine. Hemiplegic migraine can be further classified as either familial or sporadic. Familial hemiplegic migraine patients have at least one first- or second-degree relative with the same disorder. Sporadic hemiplegic migraine (SHM) is thought to be the result of a new mutation, and a patient with SHM may or may not carry one of the three gene variants already linked to the familial form.

Migraine Management

The medical management of migraine involves two types of therapy: acute or abortive treatments taken at the time of an attack to truncate it, and prophylactic treatments taken on a daily basis to decrease the intensity and frequency of the migraine headaches.

When migraine attacks occur infrequently (3 days or fewer per month) and are not associated with prolonged neurologic symptoms, abortive treatments are probably sufficient. However, daily prophylactic treatment should be considered if (1) headaches are usually disabling to the patient for 4 or more days per month, (2) the severity of the attacks, or even the dread of an attack, negatively impacts the patient's ability to carry out normal activities of daily living between attacks, (3) headaches are associated with neurologic deficits that persist beyond the duration of the headache phase of the attack, (4) there is a history of migraine-associated cerebral infarction, or (5) the patient obtains only incomplete relief from all tolerated abortive treatments.

Acute migraine treatment mainstays are the nonsteroidal anti-inflammatory drugs (NSAIDs), such as naproxen sodium or ketoprofen, and serotonin agonists, including the ergotamine derivative, dihydroergotamine (DHE) and the 5-hydroxtryptamine (5-HT) 1B and 5-HT 1D selective serotonin agonists, so-called “triptan” medications (sumatriptan, zolmitriptan, naratriptan, rizatriptan, almotriptan, eletriptan, and frovatriptan). DHE is available in intravenous and intranasal formulations. The “triptans” are available in subcutaneous injectable, oral, and intranasal formulations. The preferred route of delivery may vary from patient to patient or may vary based the characteristics of a given attack.

For example, attacks that awaken the patient from sleep at a fully developed stage or that very rapidly escalate may require subcutaneous injection, Attacks that start while the patient is awake and gradually increase in intensity may respond well to an oral formulation. An NSAID combined with a triptan may provide better relief than a triptan alone.

The addition of an antiemetic, such as prochlorperazine or promethazine, may further increase the effectiveness of acute treatment. Although the use of nonspecific analgesic medications containing opiates or butalbital is sometimes necessary in patients with known contraindications for the use NSAIDS or serotonin agonists, caution is advised. The use of these medications more than 2 days per week may contribute to an increasing frequency and severity of headaches over time.

When prophylactic or preventive treatment is necessary, as noted above, several general principles should be remembered. To minimize side effects, prophylactic medications need to be started at a low dose and gradually increased over a period of a few weeks to a therapeutic target dose. Once the therapeutic dose is attained, the patient needs to be on the medication for at least 4 to 6 additional weeks to reliably assess effectiveness. Early discontinuation may deprive the patient of a potentially effective therapy. If drugs are not completely effective but are well-tolerated as monotherapies, then a combination of two agents, each from a different class, may be tried, despite the greater risk of side effects. Unfortunately, whether there is additional benefit to be gained from the use of combination therapy has not been examined thoroughly in a prospective evidence-based fashion. To be considered successful, the prophylactic treatment should reduce the number of headache–days per month by at least 50%.

Migraine preventive treatments come from at least six classes of medications, including beta-adrenergic blockers (atenolol, metoprolol, nadolol, propranolol, and timolol), tricyclic antidepressants (amitriptyline or nortriptyline), NSAIDs (naproxen sodium), calcium channel blockers (verapamil), anticonvulsants (divalproex sodium, topiramate, and gabapentin), and nutritional supplements (riboflavin, feverfew, and butterbur). Recently, the injection of botulinum toxin A has been shown to be an effective migraine prophylactic strategy in patients with chronic migraine headaches more than 15 days per month. Individual patients may find that one preventative agent is more effective than another. Unfortunately, at present, there is no method for drug selection other than trial and error. For some individuals, nonpharmacologic treatments, such as cognitive-behavioral therapy and biofeedback, play an important role in migraine management as well.

Trigeminal Autonomic Cephalalgias

The trigeminal autonomic cephalalgias (TACs) are a category of primary headache disorders distinguished by one-sided pain in the trigeminal distribution that is present in combination with ipsilateral cranial autonomic signs and symptoms including

• Ipsilateral conjunctival injection and/or lacrimation

• Ipsilateral nasal congestion and/or rhinorrhea

• Ipsilateral forehead and facial sweating or flushing

• Ipsilateral eyelid edema

• Ptosis and/or miosis (less common)

The TAC disorders include (1) cluster headache, (2) paroxysmal hemicrania, (3) short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), and (4) short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA). Although sharing several features, the TACs differ in attack duration and frequency, as well as in their therapeutic response (see Plate 13-7 ). Cluster headache (CH) has the longest attack length and a relatively low-attack frequency. Paroxysmal hemicrania (PH) has an intermediate attack length and an intermediate attack frequency. SUNCT/SUNA headache attacks have the shortest attack length and the highest attack frequency. Most importantly, underlying structural brain lesions can mimic these disorders. Therefore brain magnetic resonance imaging/magnetic resonance angiography (MRI/MRA) is indicated when a TAC diagnosis is considered.