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Neurologic Management of Headache in Women

Linda M. Selwa, MD

Headache disorders are a frequent cause of morbidity and disability. The most common types of headache are tension headache, migraine without aura, migraine with aura, and cluster headaches. Migraine headaches have a prevalence of 6% in men, compared with 18% in women.1 More than 60% of migraineurs suffer a severe attack at least once a month. Headaches generally affect patients in the prime of productivity, between the ages of 25 and 55 years, with recent estimates of lost income exceeding $13 billion per year.2,3

There are many other less frequent but well-recognized headache syndromes with varying degrees of disability and patterns of prevalence. Idiopathic intracranial hypertension (pseudotumor cerebri) is more common in women, whereas cluster headaches have a higher incidence in men. Different types of headaches can be managed by a wide variety of primary and secondary clinicians. This paper presents the neurologist’s perspective on headache management, with special attention to reproductive and hormonal considerations in women with headaches.

PATHOPHYSIOLOGY

Head pain is generally transmitted via the trigeminovascular system through innervation of the dura, venous sinuses, and medium-to-large sized vessels. In addition to pain, other associated symptoms can occur with migraine and other headache types. In cluster headaches, unilateral lacrimation and rhinorrhea are pathognomonic, while migraines are defined by concurrent nausea, photophobia, and unusual positive visual scintillations (auras).

A number of models have been proposed to explain the diverse symptoms of migraine, but the pathophysiology remains unclear. Wolff’s⁴ early hypothesis was that the aura and pain were purely vascular, with spontaneous vasoconstriction in the meningeal vessels and accompanying symptoms of ischemia (particularly in the occipital lobes) followed by a rebound vasodilatory phase resulting in dural pain. Several years later, a model of spreading cortical depression emerged to explain the relatively positive components of the aura, wherein a wave of cortical depolarization triggered late vascular changes.⁵

More recently, a neurovascular model has been developed to combine these two hypotheses and include specific neurotransmitters involved in mediating pain through the brainstem and trigeminal nerve. The proximate cause of migraine is still elusive, and seems to require both central hyperexcitability and local neurotransmitter activity. Positron emission tomography studies have demonstrated excessive excitability of brainstem structures,⁶ which may include the raphe nuclei and the locus coeruleus.

Magnetoencephalography studies have also documented excessive excitability in the occipital cortex in migraineurs.⁷ Experimental evidence has clearly linked alterations in systemic and local serotonin metabolism to migraine, although the vascular effects of the many serotonin receptor subtypes are diverse and complex.⁸ There have also been convincing reports of links between local glutamate and nitric oxide,⁹ as well as fluctuating dopamine concentrations¹⁰ during early migraine symptoms. Other agents that have been more indirectly implicated in the generation of migraine include magnesium, adenosine, histamine, and bradykinin.^11-14

The pathogeneses of cluster headaches, pseudotumor cerebri, and chronic daily tension headache are even less clearly delineated. In idiopathic intracranial hypertension, investigations have indicated the possibility of reduced resorption of cerebrospinal fluid (CSF) over the arachnoid villi,¹⁵ or even chronic venous insufficiency.¹⁶ Associated features include obesity and obstructive sleep apnea, but the roles of these co-morbid factors are not well understood.¹⁷ In cluster headache, there is even more prominent evidence implicating obstructive sleep apnea, pointing to hypoxemia during rapid-eye-movement sleep in addition to the neurovascular mechanisms of migraine.¹⁸

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ACUTE HEADACHE AND CENTRAL NERVOUS SYSTEM DISORDERS

When headache is an acute symptom with no history of similar events, or the headache is substantially worse or different in character from previous headaches, emergent causes of head pain must be considered. This is particularly relevant if the headaches are associated with abnormalities in the neurologic findings. With or without neurologic signs, these conditions require cerebral imaging by computed tomography (CT) or magnetic resonance imaging and a lumbar puncture (LP). Structural imaging and careful examination of the fundi will limit any potential risk from performing the lumbar puncture, but if there is any question of acute infection (ie, fever, elevated white blood cell count), empiric treatment with antibiotics is indicated even prior to LP. Penicillin is a reasonable choice for otherwise healthy women, with third-generation cephalosporins and antivirals reserved for immunocompromised patients.

The most common acute causes of severe headache include meningoencephalitis, subarachnoid hemorrhage, intraparenchymal cerebral hemorrhage, and venous thrombosis. In pregnant women, special attention should be given to possible eclampsia or venous sinus thrombosis. Venous sinus thrombosis requires urgent anticoagulation with intravenous (IV) heparin, plus consideration of low-dose subcutaneous heparin treatment for the remainder of the pregnancy.

Careful measurement of CSF opening pressure with the patient in lateral decubitus position will help exclude idiopathic intracranial hypertension. If the pressure is high and papilledema is present, acetazolamide or diuretics should be administered. If CT, LP, and opening pressure are normal and headaches persist, temporal arteritis (with special attention to sedimentation rate in the elderly), acute hypertensive crisis, trigeminal neuralgia, and sinusitis should be considered.

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CLASSIFICATION AND TREATMENT

For similar headaches that recur regularly and cause significant morbidity, a comprehensive classification system has been developed to define the syndrome and aid treatment.¹⁹ The International Headache Society has (IHS) published the diagnostic criteria for tension headache (most prevalent), migraine without aura, migraine with aura, and cluster headache (Table 1).

When these syndromes are relatively typical and have continued without variation for long periods, diagnostic studies are not routinely necessary.²⁰ Once the primary headache syndrome has been established, a variety of empirically tested abortive and prophylactic treatments are available. Lifestyle adjustments are often important adjuncts.

Treatment trials for tension headache should begin with assessment for hypertension, eyestrain, caffeine use, sleep deprivation, missed meals, unusual work postures, or excessive stress that can serve as triggers. If the headaches persist at a rate of once a week or are disabling despite modification of these triggers, chronic prophylactic therapy is indicated. Longer-acting nonsteroidal anti-inflammatory drugs (NSAIDs) including naproxen and sometimes sustained-release indomethacin can be used prophylactically for these headaches. Tricyclic antidepressants (eg, amitriptyline, nortriptyline) in doses of 25 mg/d increasing to 75 mg/d may be more effective for preventing severe tension headaches. Other agents with documented efficacy in chronic daily headache are extended-release valproate, 500 to 1,000 mg/d, and gabapentin, 300 to 600 mg tid.

For migraine, which is commonly more disabling, a number of clinical treatment options are available. Nonpharmacologic measures include all of those cited for tension headache, and are just as significant. Changes in sleep, stress, and eating patterns can be especially powerful. Caffeine has been documented to present serious concerns to the migraineur in terms of rebound headaches,²¹ and the use of abortive caffeine-containing preparations must be carefully limited. Additional triggers for migraine may include exertion, alcohol, allergies, motion sickness, nitrates, artificial sweeteners, and monosodium glutamate. Many of these agents and exposures directly affect serotonergic, adenosine-producing, or dopaminergic transmitters in the central nervous system.

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The majority of migraine patients try numerous over-the-counter (OTC) analgesics prior to presentation.²² The NSAIDs are a reasonable option for first-line therapy, and often involve longer-acting agents (eg, naproxen). If these treatments fail, a variety of combination analgesics are available. The most widely used OTC preparations are mixtures of NSAIDs and caffeine in various dosages. Again, caution must be exercised with caffeine-containing drugs due to the risk of rebound headaches. Prescription combinations of NSAIDs with butalbital, caffeine, isometheptene, and dichloralphenazone may all be useful in limited amounts for some patients.

The most effective abortives currently available are the triptans, serotonin 1B/1D agonists that are 60% to 80% effective in relieving migraine at 2 hours in various trials. Almotriptan, rizatriptan, sumatriptan, and zolmitriptan have similar efficacy, with some dose-dependence. Naratriptan has a slower onset of action and perhaps less initial efficacy but a much longer half-life, and may be useful in those who have frequent recurrences. The injectable triptans should probably be reserved for second-line therapy because of their capacity to increase cardiac workload and worsen or precipitate angina. Other agents effective in acute management of an attack include ketorolac (particularly in injectable form), antidopaminergic agents that can relieve nausea and pain, and ergots (which are increasingly difficult to obtain).

Prophylactic therapy of migraines has been well summarized in several recent monographs (Table 2).^23-25 First-line agents approved by the US Food and Drug Administration (FDA) include amitriptyline, gabapentin, propanolol, timolol, and valproate. Methysergide is also FDA-approved for this indication, but can only be used for 6 months at a time to avoid the serious risk of retroperitoneal fibrosis. The choice of drug usually depends on comorbidities; for instance, a tricyclic antidepressant should be used first in a case of migraine with depression and sleep disturbances, whereas a b-blocker is more appropriate for migraine with hypertension. Other antidepressants (eg, nortriptyline), calcium-channel blockers (eg, slow-release verapamil, 120 to 240 mg/d), antispasticity agents (eg, baclofen, 10 mg qd to tid), and lithium compounds can also be used for prophylaxis as individual cases and predispositions indicate. Verapamil is particularly useful in those with protracted or troublesome aura symptoms involving numbness or vision. Topiramate is a relatively new anticonvulsant with some preventive efficacy in migraine at 50 to 200 mg/d; side effects may include cognitive impairment and mild weight loss. Cyproheptadine seems particularly useful in adolescent patients with migraine, but may lead to weight gain. Acute, continuous, or very frequent migraines (also called status migrainosus) can be treated effectively with a burst and taper of prednisone. Other modalities offering possible amelioration of frequent headaches include biofeedback, botulinum toxin injections, and local trigger-point injections for focal cephalgia syndromes.
Cluster headaches also respond to triptans and bursts of steroids at the onset of a cluster. Oxygen by nasal cannula can often abort individual headaches. Prophylactic therapy for cluster headaches includes valproate, lithium, calcium-channel blockade, and evaluation for sleep disorders.

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THE FEMALE FACTOR

Hormones and Headaches

Hormonal influences on migraine-and possibly idiopathic intracranial hypertension as well-have long been recognized, but adjusting for normal physiologic changes that can trigger migraine has proved more difficult than anticipated. Estradiol has been proven to work at sites closely linked to catecholamine neurons in the locus ceruleus.²⁶ There is some evidence for increased neuropathic pain following injury to female animals.²⁴ Estrogen and progesterone have been shown to modify central g-aminobutyric acid-A (GABA-A) and enkephalin receptors,²⁷ and have a powerful impact on nitric oxide synthetase and calcium-dependant potassium channels.²⁸ In general, declines in estrogen concentration have been shown to precipitate migraine, and sustained exposure to high levels of estrogen during pregnancy improves migraine frequency in most women.

Catemenial Migraine

The IHS defines menstrual migraine (without aura) as generally occurring between 2 days prior to menses and at the end of menstrual bleeding. More than 60% of female patients describe an association between the onset of menses and migraine, and migraines begin in 18% of affected women within one year of menarche.^29,30 The mechanism for this is poorly documented, but is presumed to be the rapid decline in estradiol that correlates with the rise in prostaglandins and increased sensitivity to serotonin and dopamine.

Treatment of acute menstrual migraine is similar to migraine therapy in other circumstances. Nearly all of the triptans have been shown to be specifically effective in this setting. For patients with predictable cycles, using NSAIDs a few days prior to menses is another strategy. Hormonal modification with transdermal estradiol patches, 3.9 mg, can moderate hormone fluctuations and prevent migraine while allowing normal menses.³¹ Some experts recommend taking oral contraceptives (OCs) with a low estrogen dosage during the menstrual cycle. Ergotamines and perimenstrual methysergide are also useful in some refractory cases when the timing of the migraines is well established.³² Recent treatment trials with bromocriptine, 2.5 mg tid during the luteal phase, have been promising.³¹ Magnesium supplementation during menses has also been effective in some patients. The usual prophylactic therapies can also be employed; patients taking chronic prophylactic medications may increase the dosage perimenstrually.

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Exogenous Hormone Therapy

The relationship between estrogen-containing OCs and migraines and the role of exogenous hormones in other disorders has proved to be complex. New-onset migraine was observed in 10% to 30% of patients using the first-generation agents with higher estrogen doses.^33,34 The severity of preexisting headaches increased in up to 50% of patients on these older OCs, but a small percentage of headache patients reported improvement.³⁴ With newer agents, which have less than 33% of the estrogen used in previous preparations, there is a much smaller impact on migraines, perhaps only a 5% increase in frequency.³⁵ Some patients have noted an increase in auras associated with their migraines.³⁶
There is a 2- to 4-fold higher risk of stroke in OC users with migraine compared with migraine-free women, and this risk persists even with the newer, low-dose estrogen pills.³⁷ Therefore, complicated migraine is a relative contraindication to OC use, and there is some potential risk increase with estrogen use for both stroke and headache frequency in patients with migraines of any type. Certainly, women with additional risk factors such as smoking and small-vessel disease (eg, hypertension, diabetes) should probably be discouraged from using OCs, especially if they also have migraine. The increase in stroke risk or migraine frequency generally tapers off within 6 to 12 months after discontinuation of therapy.³⁴

Idiopathic intracranial hypertension can also intensify in some patients using hormonal therapy. In particular, the levonorgestrel implant seems to be a risk factor associated with the development of idiopathic intracranial hypertension.³⁸ Hormonal therapy might also increase the risk of venous thrombosis, a diagnosis that must be considered in patients on OCs or hormonal treatment presenting acutely with new headaches.

Pregnancy

In general, pregnancy stabilizes hormonal fluctuations and ameliorates migraines, particularly during the second and third trimesters. Several studies have indicated improvement in 50% to 75% of pregnant migraine patients, particularly in those with migraine without aura.³⁹ This effect seems especially powerful in those with catemenial migraines. Many patients who need to discontinue prophylactic medications for the safety of the fetus can be reassured that their headaches are likely to be less severe. During the first trimester, however, 10% to 25% of women with no history of migraine develop new-onset migraines.⁴⁰ Again, it should be stressed that the most common serious concern for pregnant women with new headaches is the possibility of venous thrombosis. Patients with new, substantial, ongoing headaches should usually undergo magnetic resonance angiography/venography (MRA/MRV) unless they have had similar headaches prepregnancy.⁴¹ Imaging is always indicated if there are new neurologic signs. Eclampsia is generally more evident clinically, but also merits careful consideration. The incidence of new migraine headaches is even higher postpartum, up to 40% in the first week following delivery.⁴² Other factors such as sleep deprivation and the metabolic stress of delivery may also contribute to the increase in headaches postpartum.

There are limited treatment options for pregnant migraine patients (Table 3). Medications that can safely be administered during pregnancy include only acetaminophen, cyproheptadine, occasional opiates or butalbital, some antiemetics (metoclopramide is best), corticosteroids, and fluoxetine or propranolol only if necessary. Ergotamines are absolutely contraindicated, and there are no data clearly supporting the use of triptans in pregnancy.

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Lactation does not seem to alter the frequency of migraines, despite the complex hormonal changes that occur during this period. The nursing mother can treat her migraines safely with caffeine and/or NSAIDs (except aspirin due to the putative risk of Reye’s syndrome) without risk to the fetus. Barbiturates and opiates may cause sedation in the infant, and ergotamines and triptans are contraindicated. A greater variety of prophylactic drugs is permissible; b-blockers (except atenolol, which passes into breast milk in larger quantities), verapamil, low-dose tricyclics, and valproate are all possible alternatives for the lactating patient with substantial migraines.

Perimenopausal and Postmenopausal Headache

During the 4 or 5 years prior to menopause, some patients experience a transient exacerbation of migraines, often accompanied by an increase in auras or aura without migraine. These symptoms are substantially troublesome in a minority of patients, and generally wane as estradiol decreases and estrone increases. At natural menopause, up to 67% of women experience a decline in migraines.⁴³

Given the current concerns regarding hormone replacement therapy (HRT), it is useful to know that hormonal replacement does not seem to alleviate headaches in most patients with worsening perimenopausal migraine. Indeed, studies indicate that HRT exacerbates migraine as often as it ameliorates it.^44,45 Many of these patients do respond well to the usual prophylactic medications, however.

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CONCLUSION

Headache disorders are prevalent, disabling medical illnesses that are two to three times more common in women than in men. The mechanisms by which hormones influence the complex neurovascular cascade that initiates migraine are still incompletely understood. Hormonal therapy does not seem to provide the ideal balance that might improve migraines in women. However, recent advances in treatment including the serotonin 1B/1D agonists and anticonvulsants are improving headache control for both women and men with migraine.

Linda M. Selwa, MD, is clinical associate professor in the University of Michigan Department of Neurology in Ann Arbor.

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