Clinical Vignette

A 50-year-old woman is referred to a neurologist because of severe headaches. She first developed headaches during adolescence, and they worsened in the setting of menopause. A typical headache is unilateral and localized to the right frontotemporal and periorbital regions. The pain is described as throbbing and pulsating. When severe, her headaches are associated with nausea, vomiting, photophobia, phonophobia, and visual symptoms. Her headaches had increased in frequency and were occurring a few times a month, lasting for at least 12 hours, and causing her to miss work. Her examination was normal. Blood work and a magnetic resonance imaging (MRI) of the brain were normal.

Headache is one of the most common symptoms in medicine and is often the primary complaint presented to the internist, neurologist, or emergency room physician. Despite this, like many pain syndromes, headaches are underdiagnosed and undertreated. Accurate headache diagnosis is important before specific treatment can be initiated. It can be the presenting symptom in many primary neurologic illnesses and in a number of serious systemic disorders. The preceding vignette is typical of migraines, one of the most common headache syndromes. Distinguishing features of more serious causes, such as brain tumors, ruptured aneurysms, low cerebrospinal pressure syndromes, subdural hematoma, meningitis, and temporal arteritis, are often present but should be deliberately inquired of and must not be overlooked. Assessment of a patient presenting with headache starts with a detailed history. Essential characteristics should be defined: any premonitory symptoms, manner of onset (e.g., precipitous or gradual), diurnal variation, provoking and alleviating factors, location, pain characteristics, duration, medical and psychiatric comorbidities, and degree of disability. Family and social history, current medications, drug allergies, and review of systems are also paramount. A detailed neurologic and general medical examination is essential to the evaluation, particularly with individuals having a recent or precipitous onset or experiencing changes in headache characteristics. Ancillary laboratory and neuroradiologic testing are often indicated.

Headache syndromes must first be classified as primary, without significant underlying neurologic pathology, or secondary due to intracranial pathology. The differentiation between primary and secondary headache is critical; it dictates the diagnostic approach and guides treatment and prognosis.

Primary Headache Disorders

Migraine

Migraine, often underdiagnosed, is the most common type of headache that leads patients to seek medical care. According to the US Headache Consortium, an estimated 6% of men and 15–17% of women in the United States have migraine, but only 3–5% of them receive preventive therapy. First-degree relatives of patients with migraine are at higher risk. Migraine can occur at any age but frequently begins during puberty. It is most prevalent in individuals aged 25–55 years and is one of the leading causes of chronic suffering and disability in this population. They tend to diminish or totally disappear in the older population but have been known to transiently flare up again in women around the time of menopause.

Migraine pathophysiology includes a combination of cortical hyperexcitability and discharge followed by cation and neurotransmitter release with secondary activation of trigeminal pathways, and subsequent release of vasoactive neuropeptides and proinflammatory substances. These promote meningeal blood vessel dilatation and neurogenic inflammation in the primary pain nerve endings of the head lying in the arteries, leptomeninges, and nasal sinuses (Figs. 11-1 and 11-2). In migraine with aura, the pathophysiology of the aura is thought to be related to slow neuronal discharge of the cortex in a sequential pattern or “spreading depression” followed by a concomitant decrease in cerebral blood flow.

Figure 11-1 Pain-Sensitive Structures and Pain Referral.

Figure 11-2 Mechanisms in Migraine.

Patients with migraine often have prodromal symptoms that herald the oncoming headache. These include fatigue, thirst, anorexia, fluid retention, food cravings, gastrointestinal symptoms, and emotional or mood disturbances such as irritability, elation or depression. Approximately 15% of migraine patients have an aura preceding the pain phase. This presentation known presently as migraine with aura (formerly classic migraine) comprises focal neurologic symptoms, most commonly visual (>95% of all auras), that typically evolve and then regress over minutes before headache onset. These visual phenomena can occur in a homonymous or hemifield distribution. Typical migraine scotomata include scintillating flashes or stars (phosphenes) and geometric patterns known as fortification spectra (Fig. 11-3). Auras may also involve sensory, motor or rarely higher cortical pathways, including language. Most auras develop slowly over several to 20 minutes, last less than 1 hour, and may spread over different anatomic areas. For example, the patient may initially experience numbness in the fingers that gradually spreads up the arm to the face and sometimes even down the leg. In some individuals, the auras may not be necessarily followed by the headache phase. Less commonly, the aura phase consists of complex symptomatology with a more abrupt onset. For example, in basilar artery migraine, symptoms may include dysarthria, vertigo, ataxia, diplopia, hearing deficits, and even altered mentation or loss of consciousness. In confusional migraine, cognitive deficits are more prominent. Ocular nerve palsies are the hallmark of ophthalmoplegic migraine. Hemiplegic migraine is associated with variable but prominent unilateral weakness, and there is often a family history with an inherited voltage-dependent calcium channelopathy.

Figure 11-3 Migraine.

Careful neurologic evaluation is mandatory before migraine can be safely diagnosed in individuals with a focal aura, and it is usually a diagnosis of exclusion. Although auras are thought to typify migraine and help differentiate it from other headaches, most migraine patients never experience an aura.

The pain phase and its associated symptoms support the clinical classification of headaches as migraine. The most widely used headache classification system was developed in 1988 by the Headache Classification Committee of the International Headache Society, and it was revised in 2004. Recurrent headaches may be classified as migraines, if they last 4–72 hours (either untreated or unsuccessfully treated) and are associated with one of the two features: nausea and/or vomiting, or photophobia and phonophobia. The headaches are characterized by two of the following four symptom characteristics: unilateral location, pulsating quality, moderate to severe intensity, and aggravation by routine physical activity. It remains crucial, however, for the physician to ensure that specific secondary causes are excluded before confirming a diagnosis of migraine. Therefore, careful evaluation of the patient presenting with new-onset headaches is essential. Similarly, any change in the character of previously experienced headaches warrants a fresh investigation of any potential underlying mechanism.

Special Considerations

Two thirds of women with migraine primarily experience them just before or during menses. These headaches are often associated with other premenstrual dysphoric symptoms. Estrogen withdrawal most likely influences this common migraine subgroup.

Migraine may worsen early in pregnancy but tends to improve during the second and third trimesters, particularly in women with migraine primarily related to their menstrual cycle. Women with migraines that begin earlier in life generally experience a significant decrease in episode frequency after menopause.

Great care must be used in the evaluation and treatment of “migraine” headache in the elderly. The incidence of headaches as a manifestation of other illnesses significantly increases with age. In addition, the use of migraine medication may be more hazardous in the elderly.

Management and Therapy

There are two primary steps in the care of migraine patients: treatment of the acute headache and prevention of subsequent events. The initial goal is prompt pain relief without recurrence and minimal, if any, adverse effects. For mild to moderately severe nondisabling pain, oral nonsteroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid (aspirin) or acetaminophen, are recommended for short-term treatment. Caffeine may enhance the effect of these various medications. If needed, antiemetics are often useful in conjunction with analgesics.

However, in patients with more severe disabling migraines, oral, injectable, intranasal, or quick-dissolve sublingual serotonin 1B/1D receptor agonist (“triptan”) preparations are the medications of choice. Their success is attributed to the multiple sites of action triptans have on the migraine cascade that include decreasing cortical hyperexcitability, decreasing tissue leakage of neuropeptides and blocking their dural neurovascular effects, tempering trigeminal afferent input, suppressing or down-regulating brainstem activation, gating thalamic pain response, and finally countering progressive vasodilation (Fig. 11-4). The rapidly acting triptans include almotriptan, eletriptan, rizatriptan, sumatriptan, and zolmitriptan. The longer acting triptans include naratriptan and frovatriptan. These preparations are also recommended for patients with milder migraines that are not initially disabling but are refractory to simple analgesics. Butalbital, ergotamine, and isometheptene/dichloralphenazone preparations are also commonly used for abortive therapy. When the above-mentioned therapeutic options are ineffective in patients with the most severe migraines or if those treatments are contraindicated, nonnarcotic treatments, such as ketorolac and antiemetics, are attempted. When these fail, opiate-category medications are often used, primarily in the emergency room. However, the possibility of sedation and, more importantly, subsequent overuse and dependence must be considered.

Figure 11-4 Pathophysiology of Migraine and Triptan Site of Action.

Prophylactic treatment, the other aspect of migraine therapeutics, is indicated for patients with frequent headache. Other indications for preventive therapies include poor response or adverse effects to abortive treatments, frequent need for medications with potential for abuse and dependency, or patient preference when even infrequent migraines significantly interfere with daily activities or responsibilities. Tricyclic antidepressants, β-blockers, calcium channel blockers, sodium valproate, gabapentin, and topiramate are the most frequently used migraine prophylactic medications. Experimentation with different agents may be needed to determine which medication is the most effective for any individual patient. The initial choice may be directed by existing comorbidities or considerations. For instance, difficulty with sleep may prompt prescribing medications that are more sedating and help sleep initiation. Topiramate may be preferable over valproic acid for those in whom weight gain is a concern. A concomitant mood disorder may prompt the use of antidepressants or medications with mood-stabilizing properties. β-Blockers may help in controlling coexisting hypertension in some patients but should be avoided in those with reactive-airway disease or in athletes. Elucidating and avoiding potential dietary and environmental triggers is an important part of nonpharmacological migraine prevention. Sleep deprivation, dehydration, and erratic meals are strong triggers, and proper general health habits should be encouraged.

Future Directions

Half of migraine patients report dissatisfaction with therapy, despite the above options. A comprehensive approach to treatment of migraine headache is important, and must also address contributing factors such as hypertension or other medical problems, mood and sleep disorders, psychosocial stressors, and excessive use of caffeine, alcohol, and nicotine. Avoidance of rebound headache from overuse of analgesics is essential. Adjunct treatment with certain vitamins and supplements (riboflavin or vitamin B₂ and magnesium sulfate), exercise, biofeedback, cognitive–behavioral management training, and acupuncture can also be beneficial. Botulinum toxin type A is showing promise for migraine prevention as are clonazepam and some of the newer antiepileptic medications.

Cluster Headache

Clinical Vignette

A 34-year-old man presents to his internist for evaluation of severe pain above and behind his right eye. The pain began a few days ago and is intermittent. It occurs several times a day, usually lasting for 30–60 minutes, and often awakens him at night. The pain is associated with ipsilateral tearing, conjunctival injection, and nasal congestion. Alcohol triggers or exacerbates the pain. His wife reports that he has been irritable and agitated. On exam, he has right-sided periorbital edema and mild ptosis. He reports having similar symptoms 2 years ago and is concerned because that episode lasted for several weeks.

Cluster headaches are much less common than migraines, to which they are unrelated, affecting only 0.1% of adults. However, they are usually more severe and debilitating and have been referred to as the “suicide headache.” Although cluster headaches are very distinctive and stereotyped, they tend to be underdiagnosed. Cluster headaches usually respond well to the appropriate therapy and, therefore, a very careful history that aids in making the correct diagnosis is important. They usually first occur in the third decade, affecting men more often than women, although the ratio has decreased over the past several years (male-to-female ratio is 2–4 : 1).

The distinctive clinical features, as summarized in the clinical vignette, assist in diagnosing cluster headaches (Fig. 11-5). The underlying pathophysiology is related to activation of the trigeminal vascular and parasympathetic systems. The first two divisions of the trigeminal pathway are more commonly involved. Recent positron emission tomographic scan studies by Goadsby and colleagues revealed activation of the medial hypothalamic gray matter, an area involved in the control of circadian rhythms. It is felt that dysfunction of neurons in this area leads to activation of a trigeminal-autonomic loop in the brainstem. These pathophysiologic mechanisms would explain the cardinal symptoms of cluster headache that include the episodic/circadian nature of the attacks, the distribution and quality of pain, and associated autonomic symptoms.