Headache attributed to disorders of homeostasis

Handbook of Clinical Neurology, Vol. 97 (3rd series) Headache G. Nappi and M.A. Moskowitz, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 53

Headache attributed to disorders of homeostasis DAVID W. DODICK 1 * AND CARLOS A. BORDINI 2 Department of Neurology, Mayo Clinic Arizona, Phoenix, AZ, USA 2 Department of Neurology, Ribeirão Preto Medical School, São Paulo, Brazil 1

INTRODUCTION Headache associated with disorders of homeostasis has been defined using operational diagnostic criteria established by the revised International Classification of Headache Disorders (ICHD-II: Headache Classification Subcommittee of the International Headache Society, 2004), having previously been referred to as headache associated with metabolic or systemic disease. The use of the term “homeostasis” was felt to capture the range of disorders of homeostatic mechanisms affecting a variety of organ systems, including altered arterial blood gases, systemic arterial pressure, volume disturbances that occur as a result of dialysis, and disorders of endocrine function. Headache attributed to fasting and cardiac ischemia is also included in this category. This chapter will outline each disorder, as outlined by ICHD-II, define the operational diagnostic criteria associated with each, and provide updated information that has appeared subsequent to the evidence that served as the basis for these criteria.

HEADACHE ATTRIBUTED TO HYPOXIA AND/OR HYPERCAPNIA Headache as a result of disturbances in arterial blood gas concentrations is well established, although it is often difficult to distinguish between the effects of hypoxia and hypercapnia.

High-Altitude Headache (HAH) (ICHD-II 10.1.1) SHORT

DESCRIPTION

The headache occurs within 24 h of acute onset of hypoxia with PaO2 <70 mmHg or in chronically hypoxic patients with PaO2 persistently at or below this level.

CLINICAL

FEATURES

Diagnostic criteria A. Headache with at least two of the following characteristics and fulfilling criteria C and D: 1. Bilateral 2. Frontal or frontotemporal 3. Dull or pressing quality 4. Mild or moderate intensity 5. Aggravated by exertion, movement, straining, coughing, or bending B. Ascent to altitude above 2500 m C. Headache develops within 24 h of ascent D. Headache resolves within 8 h of descent. Headache is the most common symptom and complication that occurs during ascent to altitudes greater than 2500 m (Sharma et al., 1975; Hackett and Roach, 2001). In a prospective study involving members of an expeditionary unit to Kanchenjunga base camp in Nepal (5100 m), the incidence, risk factors, and clinical characteristics of HAH were evaluated (Silber et al., 2003). Participants were interviewed before the trip and while trekking: headaches experienced at altitudes above 3000 m were recorded using a structured questionnaire that incorporated the original diagnostic criteria for HAH and acute mountain sickness (AMS) from ICHD-I (Headache Classification Committee of the International Headache Society, 1988). In addition, clinical features of headaches in 19 trekkers from other groups above 3000 m were recorded using the same questionnaire. This study demonstrated that 83% (50/60) reported at least 1 HAH (median 2, range 0–10) at a mean altitude of 4723 m. Those who developed HAH were significantly younger, suggesting that age-related

*Correspondence to: David W. Dodick, MD, Department of Neurology, Mayo Clinic Arizona, 5777 E Mayo Blvd, Phoenix, Arizona 85054, USA, Tel: 480-342-3078, Fax: 480-342-3083, E-mail: [email protected]

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cerebral atrophy might allow a greater capacity to accommodate mild cerebral edema. Women and individuals with a history of recurrent headache were also more likely to report severe headaches at altitude. In this study, 95% of the women reported headaches compared to 82% of the men, and headaches were reported more frequently and were described as more severe in women compared with men. HAHs often awakened participants from sleep or occurred upon awakening, suggesting the possibility that sleep-related breathing disorders and subsequent hypoxia may be a contributing factor, compounding an already hypoxic state related to the high altitude. In addition, headaches were frequently exacerbated by bending, coughing, or sneezing, suggesting the possibility that intracranial pressure is elevated at high altitudes and any Valsalva maneuver that is associated with a brief and transient elevation in intracranial pressure magnifies the headache. In this study, headaches were bilateral, generalized, and described as a dull pressure. The duration was usually less than 1 day. In another prospective cross-sectional study conducted in the Ecuadorian Andes, 98 mountain climbers underwent separate evaluations at 4700–5000 m and 5700–5800 m in an attempt to elicit the clinical features of HAH (Serrano-Duen˜as, 2005). The headaches in this study were mainly holocranial (66%) and of pulsatile burst-type quality (75%), in contrast to the dull pressure quality seen in other studies. The headaches were also exacerbated by exercise in 50% of patients and relieved with rest in 42% of patients. Persons rapidly ascending to high altitudes are also at risk of developing the syndrome of AMS, the principal symptom of which is moderate or severe headache. Individuals with AMS also experience some combination of nausea, anorexia, fatigue, dizziness, and sleep disturbances (Hackett and Roach, 2001). In extreme cases, AMS may progress to high-altitude cerebral edema (HACE), acute encephalopathy, ataxia, and a depressed level of consciousness (Hackett et al., 1998). This suggests that a proportion of headaches at altitude, and certainly AMS, may be part of a similar pathogenic process, with HACE at the extreme of the continuum.

PATHOGENESIS The pathogenesis of HAH is not clear. The exacerbation during sleep and Valsalva maneuvers suggests that hypoxia and/or elevated intracranial or central venous pressure contribute to the symptoms. A recent study combined molecular and neuroimaging techniques to examine if free radical-mediated damage to blood– brain barrier function during hypoxia would result in

extracellular edema and raised intracranial pressure and account for the neurological symptoms of HAH and AMS (Bailey et al., 2006). Twenty-two subjects underwent collection of venous blood at several time points (0, 8, 15, 18 h) and cerebrospinal fluid (CSF: 18 h) while being randomly exposed for 18 h to 12% (hypoxia) and 21% oxygen (O2: normoxia). Electron paramagnetic resonance spectroscopy identified a significant increase in the blood and CSF concentration of O2 and carbon-centered free radicals during hypoxia compared to the hypoxic state. In addition, brain magnetic resonance imaging (MRI) demonstrated a significant increase in brain volume in the hypoxic state that resolved within 6 h of normoxic recovery. However, there was no detectable evidence of disruption of the blood–brain barrier, elevated lumbar epidural opening pressures, T2 prolongation on MRI or evidence of neuronal or astroglial damage. Clinical AMS was diagnosed in 50% of subjects during the hypoxic trial and corresponding headache scores were significantly and markedly elevated in this group. The authors concluded that mild brain swelling occurs during HAH, but that free radical-mediated vasogenic edema is not an important pathophysiological event.

MANAGEMENT General and conservative strategies that can prevent or ameliorate the development of HAH include allowing 2 days of acclimatization before engaging in strenuous exercise at high altitudes, avoiding alcohol, and liberal fluid intake. Previous controlled clinical trials have found that common non-steroidal anti-inflammatory drugs, including aspirin, naproxen, and ibuprofen, provide effective analgesia in patients with HAH (Broome et al., 1994; Burtscher et al., 1998). Acetazolamide and dexamethasone have also been found to be effective in prophylaxis or ameliorating AMS symptoms (Larson et al., 1982; Rock et al., 1987; Hackett et al., 1988; Levine et al., 1989). While sumatriptan has been shown in an isolated case report to provide relief of HAH (Bartsch et al., 1994), ibuprofen has been demonstrated to provide far superior relief to sumatriptan (Burtscher et al., 1995). In fact, in this study, not a single patient out of 6 had any relief of headache 2 h after a 100-mg dose whereas all 7 patients who received 600 mg ibuprofen had complete relief of headache within 2 h. In a recent prospective, randomized, double-blind, clinical trial of ibuprofen versus acetaminophen in the Solu Khumbu, Nepal, Mount Everest base camp, Pheriche, Dingboche (4240–5315 m), 74 consecutive patients (aged 13–61 years) were randomized, assessed with the Lake Louise AMS criteria, and received

HEADACHE ATTRIBUTED TO DISORDERS OF HOMEOSTASIS a physical examination (Harris et al., 2003). Patients then received either 400 mg ibuprofen or 1000 mg acetaminophen. Baseline Lake Louise AMS scores were identical in the two groups and no difference in mean Visual Analog Scale (VAS) scores between the ibuprofen and acetaminophen groups were noted at time 0 (presentation), 30, 60, or 120 min. In this study population, acetaminophen was as effective as ibuprofen in relieving the pain of HAH.

Diving headache (ICHD-II 10.1.2) CLINICAL

FEATURES

Diagnostic criteria A. Headache, no typical characteristics known, fulfilling criteria C and D B. Diving to depth below 10 m C. Headache develops during diving and is accompanied by at least one of the following symptoms of carbon dioxide (CO2) intoxication in the absence of decompression illness: 1. Light-headedness 2. Mental confusion 3. Dyspnea 4. Flushed feeling in the face 5. Motor incoordination D. Headache resolves within 1 h after treatment with 100% O2. In a prospective study of Norwegian saturation divers, 4% reported having a headache during the first day of decompression, 23% on the last day of decompression, and 34% on the first day after reaching the surface (Englund and Risberg, 2003). The pain was located over the frontal or vertex regions, recorded as mild in severity with a median of 2.5 on a 10-point VAS (range 0.1–7.8), and lasted a median duration of 6 h (range 1–84 h).

PATHOGENESIS Hypercapnia is felt to be a common cause of headache in divers, as well as a provocative trigger for migraine and cluster headache in susceptible divers (Hannerz and Jogestrand, 1995; Heckmann et al., 1998; Cheshire and Ott, 2001). CO2 may accumulate in a diver who intentionally holds his or her breath intermittently (skip breathing) in a mistaken attempt to conserve air, or takes shallow breaths to minimize buoyancy variations in the narrow passages of a wreck or cave (Cheshire, 2004). Divers may also hypoventilate unintentionally when a tight wetsuit or buoyancy compensator jacket restricts chest wall expansion, or when ventilation is inadequate due to physical exertion. Strenuous exercise

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increases the rate of CO2 production more than 10fold, resulting in a transient elevation of PCO2 to more than 60 mmHg (Cheshire, 2004). Diving headache usually intensifies during the decompression phase of the dive or upon resurfacing. A mechanism analogous to AMS has also been hypothesized to explain headaches affecting professional divers. Hypercapnia (arterial PCO2 >50 mmHg) is known to cause relaxation of cerebrovascular smooth muscle and lead to vasodilation and increased intracranial pressure (Sliwka et al., 1998). Other symptoms of CO2 intoxication include lightheadedness, mental confusion, dyspnea, facial flushing, and motor incoordination. If CO2 tension continues to rise after symptoms develop, central respiratory and cardiac depression may occur followed by loss of consciousness and seizures. Some individuals will have a markedly reduced ventilatory response to elevated PaCO2 and are at greater risk of developing toxicity. Retention of CO2 also potentiates O2 toxicity or inert gas narcosis and may render the diver more susceptible to decompression illness (Cheshire, 2004). Headache is also an early symptom of poisoning from carbon monoxide (CO), an odorless gas that rarely has contaminated a diver’s compressed air supply when, during tank preparation, the air intake system was inadvertently positioned toward street traffic and exposed to the combustion engine exhaust of an idling vehicle (Clark and Thom, 1997). CO binds to hemoglobin with a 250-fold greater affinity than O2, thereby resulting in tissue hypoxia and release of nitric oxide, which may dilate cerebral vessels and sensitize trigeminal sensory afferents. Frontal headache, dizziness, exertional dyspnea, and nausea result once blood carboxyhemoglobin levels exceed 10–15% (Clark and Thom, 1997). Treatment of CO poisoning consists of inhaling 100% O2 or hyperbaric O2 to hasten carboxyhemoglobin dissociation and should be administered without delay (Clark and Thom, 1997).

MANAGEMENT The best treatment of headache in divers is education and taking the necessary precautions to avoid situations that increase the risk of hypercapnia or CO toxicity. The diver should take slow, deep breaths and avoid skip breathing or prolonged physical exertion under water. The regulator should be maintained to a satisfactory performance level in order to minimize breathing resistance. Treatment of hypercapnia consists of ensuring a patent airway, physical rest, and comfortable deep breathing. Non-steroidal anti-inflammatory and ergotamine preparations have been reported to be

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ineffective for the treatment of the headache experienced in divers (Cheshire and Ott, 2001). Sedating medications, such as opioids, butalbital, or phenothiazines, should be avoided when diving because they can depress respiratory drive, increase CO2 retention, and impair alertness and judgment, especially at depths beyond 20–30 m where inert gas narcosis may compound the diver’s cognitive impairment. Betablockers for migraine prophylaxis in the diver should be prescribed cautiously because of their potential to unmask latent asthma and because they can reduce exercise capacity.

SLEEPAPNEA HEADACHE (ICHD-II 10.1.3) Short description Although morning headache (nocturnal headache or headache upon awakening) may be seen in patients with obstructive or central sleep apnea, it is also a feature of a variety of primary headache disorders such as migraine, cluster headache, and other trigeminal autonomic cephalalgias, and hypnic headache. Morning headache may also be seen as part of a secondary headache syndrome such as medication overuse headache, in sleep-related breathing disorders other than sleep apnea (e.g., pickwickian syndrome, chronic obstructive pulmonary disorder), and in other primary sleep disorders such as periodic leg movements of sleep. A definitive diagnosis of sleep apnea headache (10.1.3) requires overnight polysomnography.

Epidemiology and clinical features DIAGNOSTIC

CRITERIA

A. Recurrent headache with at least one of the following characteristics and fulfilling criteria C and D: 1. Occurs on >15 days per month 2. Bilateral, pressing quality and not accompanied by nausea, photophobia, or phonophobia 3. Each headache resolves within 30 min B. Sleep apnea (respiratory disturbance index
5) demonstrated by overnight polysomnography C. Headache is present upon awakening D. Headache ceases within 72 h, and does not recur, after effective treatment of sleep apnea. Sleep apnea and headache are both very prevalent conditions in the population. In the general adult population, the prevalence of obstructive sleep apnea (OSA) syndrome is estimated to be 2% in women and 4% in men, applying the minimum diagnostic criteria of nocturnal apnea/hypopnea index >5/h and daytime sleepiness (Young et al., 1993). Sleep-associated disturbances of breathing without daytime sleepiness are

even more frequent, demonstrating the importance of applying standardized diagnostic criteria (Young et al., 1993). Previous studies have suggested that headache in general, and morning headache in particular, is more common in patients with sleep apnea than in control subjects (Ulfberg et al., 1996; Paiva et al., 1997). On the other hand, others have reported that, although morning headache is common in OSA, it occurred just as frequently in other sleep-related disorders, and the headache characteristics are quite non-specific (Aldrich and Chauncey, 1990; Poceta and Dalessio, 1995; Neau et al., 2002). Furthermore, in a study involving tertiary care headache patients who reported heavy snoring and episodes of interrupted nocturnal breathing, only 1.5% who were examined with polysomnography had an apnea/hypopnea index of 5 or higher (Jensen et al., 2004). However, Paiva et al. (1997) found not only that about half of the patients with nocturnal or earlymorning headache suffered from a sleep disorder, including OSA, but also that headache relief was correlated with successful treatment of OSA. Headaches claimed to be associated with OSA are brief and headache severity has been correlated with the severity of OSA in one study (Loh et al., 1999). A series of 56 consecutive patients with OSA and 50 patients with insomnia underwent a detailed headache evaluation (Alberti et al., 2005). Headache was reported by 49% of OSA patients and 48% of insomnia patients. However, headache upon awakening occurred significantly more often in OSA patients (75%) compared to insomnia patients (40%) and the occurrence of morning headache was significantly correlated with nocturnal O2 desaturation and OSA severity. These findings confirmed those from a previous study which also demonstrated an association between morning headache and the severity of OSA and nocturnal O2 desaturation (Loh et al., 1999). Taken together, these results appear to demonstrate that headache is a common finding in both OSA and insomnia patients, but that morning headache appears to be more specific for OSA and the occurrence and severity of headache are associated with the severity of OSA.

Pathogenesis The pathogenesis of headache in patients with OSA is not clear, but elevated intracranial pressure during apneic episodes and altered cerebrovascular reactivity have been implicated in patients with OSA. In one study, CSF pressure was measured continuously at the lumbar level during nocturnal sleep in 3 patients with OSA (Sugita et al., 1985). When the patients were awake and relaxed in the supine position, their CSF

HEADACHE ATTRIBUTED TO DISORDERS OF HOMEOSTASIS 631 pressure was stable and within the normal range. EpiIn many patients, lifestyle modifications including sodic marked elevations of CSF pressure occurred freweight loss, avoiding alcohol and other sedatives, quently during sleep, and each elevation was preceded smoking cessation, avoidance of sleep deprivation, and accompanied by an episode of sleep apnea or and, if appropriate, sleep position restriction will hypopnea. Significant correlations were found decrease both the symptoms of OSA and the comorbid between both the duration of apneic episodes and conditions. decrease in O2 saturation, and the corresponding Continuous positive airway pressure (CPAP) is the increase in CSF pressure. The duration of sleep apnea standard treatment for OSA. CPAP involves the use was longer, the increase in CSF pressure greater, and of a device that pneumatically splints the upper airway O2 desaturation more marked during rapid eye moveduring inspiration and expiration. A placeboment (REM) sleep than during non-REM sleep. controlled, randomized trial showed that CPAP The authors suggested that frequent marked episodic decreases sleepiness and increases quality of life (Engelevations of CSF pressure were caused by an increase leman, 2002). During polysomnography, CPAP is in the intracranial vascular volume occurring mainly titrated to a level that eliminates snoring and apneas– in response to transient hypercapnia and hypoxia, hypopneas and is then most often prescribed at a which were induced by pulmonary hypoventilation “fixed” pressure level that will maintain airway during the episodes of sleep apnea. patency during conditions of greatest vulnerability In another study, elevations of arterial pressure (REM sleep while supine). For most patients, the preand intracranial pressure were related to the apneic scribed pressure is in the 7–11-cmH2O range. Compliance with CPAP continues to be a major episodes and there were highly significant correlations issue limiting its use. Usage patterns and problems with between duration of apnea and variation in arterial CPAP vary among patients and patient characteristics and intracranial pressure (Jennum and Borgesen, that consistently predict CPAP compliance have not 1989). The highest values of intracranial pressure been identified. Only a few comprehensive, long-term occurred during REM sleep. Vascular response was compliance studies have been published, and they indinot changed during REM sleep, and the higher intracate that continuing CPAP use generally correlates with cranial pressure during REM could only be explained apnea–hypopnea index (AHI) severity, average nightly by the longer apneas seen during REM sleep. use of less than 2 h at 3 months predicts failure, and In addition to elevations in intracranial pressure ongoing use at 5 years is 65–90% (Krieger, 1992; during apnea episodes, significantly lower cerebroMcArdle et al., 1999). vascular reactivity has been demonstrated in the Alternative treatment options, including oral applimorning and afternoon in patients with OSA comances, have been developed for mechanically enlarging pared to control subjects (Diomedi et al., 1998). In or stabilizing the upper airway by advancing the mandaddition, cerebrovascular reactivity was significantly ible or tongue. Subjective improvements in snoring are higher in the afternoon than it was in the morning in reported in most case series with oral appliances. both patients and controls. These data indicate that Approximately 50% of patients achieve an AHI lower cerebrovascular reactivity is lowest in the morning in than 10 with the use of oral appliances, and long-term general, but significantly lower in patients with OSA compliance rates are 50–100% (Schmidt-Nowara et al., compared to controls. 1995). Randomized crossover comparisons reveal that CPAP devices are more effective at lowering the AHI Management than oral appliances, which are most appropriate for OSA–hypopnea syndrome (OSA/HS) is a chronic patients with mild to moderate OSA (White et al., 2002). disease that requires consultation and ongoing folUvulopalatopharyngoplasty, an operation that modilow-up with a sleep medicine specialist, patient educafies the retropalatal airway by excision of the uvula, a tion, and alleviation of upper-airway obstruction. portion of the soft palate, and tonsils (if present), proBecause many patients with OSA/HS are overweight duces mixed results. Although snoring is usually subor have comorbid cardiovascular risk factors or jectively improved, objective improvements have not diseases, they must be informed of the interaction been well documented. Furthermore, less than 50% of of OSA and overall health. Prospective data on the patients achieve an apnea index lower than 10 and at cardiovascular and perioperative benefits of OSA/ least a 50% reduction in apneas (Sher et al., 1996). HS treatment are emerging, but the current, most Laser-assisted uvulopalatoplasty is not currently widely accepted, patient and physician treatment recommended for the treatment of OSA/HS (Littner target is hypersomnolence (Engleman, 2002; Olson et al., 2001). Radiofrequency ablation techniques can et al., 2003). be applied focally to reduce the size of the palate and

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base of tongue, but efficacy data are limited. Other surgical options include tracheostomy (used rarely) and oral maxillofacial procedures.

DIALYSIS HEADACHE (ICHD-II 10.2) Short description Headache commonly occurs in association with hypotension and dialysis disequilibrium syndrome. The disequilibrium syndrome may begin as headache and then progress to obtundation and finally coma, with or without seizures. This syndrome is relatively rare and may be prevented by changing dialysis parameters. As caffeine is rapidly removed by dialysis, caffeine withdrawal headache should be considered in patients who consume large quantities of caffeine.

Clinical features DIAGNOSTIC

CRITERIA

A. At least three attacks of acute headache fulfilling criteria C and D B. Patient is on hemodialysis C. Headache develops during at least half of hemodialysis sessions D. Headache resolves within 72 h of each hemodialysis session and/or ceases altogether after successful transplantation. Approximately 70% of patients receiving dialysis complain of headaches (Bana et al., 1972; Antoniazzi et al., 2003). Until recently, headaches in this population of patients have not been systematically evaluated. A prospective study of 123 patients with chronic renal failure from three Brazilian hemodialysis services reported headache in 87/123 (70.7%) (Antoniazzi et al., 2003). Before beginning dialysis, 48% had migraine, 19% had episodic tension-type headache, and 8% had both. Headache related to arterial hypertension was the second most frequent headache diagnosis in these patients (25.4%). Fifty patients (57.5%) experienced headache during the session of hemodialysis. Thirty-four were classified as dialysis headache, 7 were classified as migraine, 7 as episodic tension-type headache, and 2 were unclassified. Twenty-four patients (27.6%) reported dramatic improvement of their headaches after the beginning of the dialysis program. Similar to other studies, there was a male preponderance in this study, and when headache occurred during hemodialysis, a higher incidence was observed between the third and fourth hour. Similarly, another recent study showed that the prevalence of headaches during hemodialysis was directly proportional to the

number of hours in session (Brunet et al., 1996). The headaches that occurred during hemodialysis sessions resembled migraine without aura in 19 patients, tension-type headache in 13, probable migraine in 1, and tension-type headache disorder not fulfilling all criteria in 1 patient. They also observed a relative increase in the prevalence of tension-type headaches after the beginning of the dialysis program.

Pathogenesis While it is clear that hemodialysis can be a trigger for antecendent headache disorders (migraine, tension-type headache), it is equally clear that headaches can occur de novo during hemodialysis. However, the clinical features and their pathogenesis have yet to be elucidated. A number of mechanisms may be involved, including hypoxemia that occurs at the beginning of the sessions, hyponatremia, changes in serotonin levels, alterations in levels of urea, aldosterone, and dialysis disequilibrium syndrome. Because these metabolic derangements do not resolve immediately, the resolution of dialysis headaches has been lengthened in ICHD-II from 24 h to 72 h after a hemodialysis session. A recent study has suggested that elevated levels of calcitonin gene-related peptide (CGRP) in patients with dialysis headache may play a role in the generation of headaches associated with dialysis (Alessandri et al., 2006). Alessandri and colleagues obtained blood samples for radioimmunoassay of CGRP and substance P (SP) from the arteriovenous fistula before and after dialysis treatment in 12 patients with and 12 patients without dialysis headache. Basal plasma concentrations of CGRP, but not SP, were found to be higher in headache patients. However, dialysis significantly decreased CGRP concentrations in both groups, although plasma SP concentrations were reduced in headache-free patients but increased in headache patients. The significance of dialysis-induced elevations in SP is unclear, but raises the possibility that this too may play a role in dialysis headache, although this neuropeptide is not believed to play a role in the pathogenesis of primary headache disorders in humans.

HEADACHE ATTRIBUTED TO ARTERIAL HYPERTENSION (ICHD-II 10.3) Short description Mild (140–159/90–99 mmHg) or moderate (160–179/ 100–109 mmHg) chronic arterial hypertension does not appear to cause headache. Ambulatory blood pressure monitoring in patients with mild and moderate hypertension has shown no convincing relationship between blood pressure fluctuations over a 24-h period

HEADACHE ATTRIBUTED TO DISORDERS OF HOMEOSTASIS and the presence or absence of headache. However, headache related to various disorders that lead to abrupt and severe elevations in arterial blood pressure are associated with headache.

HEADACHE ATTRIBUTED TO PHEOCHROMOCYTOMA (ICHD-II 10.3.1) Clinical features DIAGNOSTIC

CRITERIA

A. Intermittent discrete attacks of headache accompanied by at least one of the following and fulfilling criteria C and D: 1. Sweating 2. Palpitations 3. Anxiety 4. Pallor B. Pheochromocytoma demonstrated by biochemical investigations, imaging, and/or surgery C. Headache develops concomitantly with an abrupt rise in blood pressure D. Headache resolves or markedly improves within 1 h of normalization of blood pressure. Pheochromocytomas are catecholamine-producing tumors that arise from chromaffin cells. Although rare, pheochromocytomas must be considered in patients with hypertension, autonomic disturbances, panic attacks, adrenal incidentalomas, or familial diseases (multiple endocrine neoplasia type II, von Hippel–Lindau disease, neurofibromatosis type 1, familial carotid body tumors) featuring a predisposition to develop pheochromocytoma. These tumors are mostly situated within the adrenal medulla, although in about 9–23% of cases tumors develop from extra-adrenal chromaffin tissue (adjacent to sympathetic ganglia of the neck, mediastinum, abdomen, and pelvis) and are often referred to as paragangliomas (Kudva et al., 2003). Sudden-onset headache is the most common symptom of pheochromocytoma, occurring in up to 80% of patients (Thompson, 2002). The headache is often severe, frontal, or occipital and generally described as either pulsating or steady in quality. An important feature of the headache is its short duration: <15 min in 50% and <1 h in 70% of patients. Hypertension is present in 80% and is paroxysmal in 50% of patients (Lance and Hinterberger, 1976). However, 13% have normal blood pressure, and 8% are completely asymptomatic. For these reasons, the definitive diagnosis of pheochromocytoma rests primarily on the demonstration of excessive and inappropriate catecholamine production. When paroxysms do occur, they may last 15–60 min and can occur several times per day or once or twice per year. They can occur spontaneously

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or may be provoked by physical exertion, emotional stress, pressor medications, changes in posture, or increases in intra-abdominal pressure. Symptoms and signs of adrenergic stimulation, such as sweating, palpitations, facial pallor or flushing, and tachycardia are each present in about 70% of patients, while other features, such as anxiety, sense of impending doom, tremor, visual disturbances, abdominal or chest pain, nausea, vomiting, and occasionally paresthesia may occur as well.

Diagnosis The diagnosis is established by the demonstration of increased 24-h urinary excretion of metanephrine and normetanephrine (98%), vanillylmandelic acid (60%), and total catecholamines (60–80%) (Ilias and Pacak, 2004). Computed tomography (CT) and MRI of the neck, chest, abdomen, and pelvis have a sensitivity of 86–95% and 93–100% respectively, for detecting adrenal pheochromocytoma. CT is the imaging modality of first choice at most institutions, but if the CT is negative, in a patient with biochemically proven pheochromocytoma, MRI should be performed. MRI should be substituted for CT in children, pregnant women, and situations where radiation exposure must be minimized (Ilias and Pacak, 2004). Adrenal masses are present in about 5–9% of the general population. Although most adrenal masses are benign, non-functional incidentalomas, about 6.5% of incidentally discovered adrenal masses are indeed pheochromocytoma (Ilias and Pacak, 2004). Thus, most adrenal abnormalities are not pheochromocytoma, highlighting the need for specific diagnostic imaging after anatomical studies are performed in patients with suspicion of pheochromocytoma. Additionally, there is no consensus on the existence of absolute clinical, imaging, or laboratory criteria to predict malignancy and multiplicity of pheochromocytoma (Pommier et al., 1993; van der Harst et al., 2000). Thus, in patients diagnosed with pheochromocytoma, the need to exclude metastatic disease or multiple tumors is important. This need might be fulfilled with functional imaging modalities using various radiopharmaceuticals that provide physicians with whole-body, pheochromocytoma-specific, scans. Pheochromocytoma cells usually abundantly express specific catecholamine plasma membrane and vesicular transporter systems, enabling imaging with [131I] and [123I]MIBG, as well as with several positron emission tomography (PET) ligands. [123I]MIBG scintigraphy has a sensitivity ranging from 83% to 100% and a high specificity (95–100%) for pheochromocytoma (Nielsen et al., 1996; van der Harst E et al., 2001). [18F]DOPA PET imaging may have a higher sensitivity and specificity than [123I]MIBG scintigraphy, but further studies are needed to compare the two modalities (Ilias and Pacak, 2004).

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D.W. DODICK AND C.A. BORDINI Paroxysmal hypertension may occur in association with Treatment failure of baroreceptor reflexes. The arterial barorecepThe management of pheochromocytoma has been domitors play a critical role in the control of arterial pressure nated by efforts to prevent hypertensive episodes and assoin humans by buffering moment-to-moment changes ciated complications and to diminish the magnitude of so that acute and excessive fluctuations do not occur. postoperative hypotension. For control of blood pressure, Baroreceptors in each carotid sinus relay information selective postsynaptic alpha-1 adrenergic receptor antagoregarding vessel distension via the glossopharyngeal nists (prazosin, terazosin, doxazosin) have been used to cirnerves to the nucleus of the tractus solitarius which in cumvent some of the disadvantages of phenoxybenzamine turn activates cardiac parasympathetic outflow and inhi(a non-specific alpha-blocking agent). Phenoxybenzamine bits sympathetic vasomotor outflow. Other mechanoproduces significant orthostatic hypotension and reflex receptors in the aortic arch and great vessels of the tachycardia and may prolong and contribute to the hypothorax transmit similar information via the vagus nerves tension that follows removal of the tumor. to the nucleus tractus solitarius and generate similar Labetalol, an alpha-adrenergic and beta-adrenergic depressor responses. Because of this functional redunblocker, was reported to be effective in the control of dancy, bilateral lesions involving the carotid sinus are blood pressure and clinical manifestations associated frequently required to produce baroreflex failure, with pheochromocytoma. Its safety has been quesalthough a central lesion in the region of the nucleus tioned, however, because it has precipitated hypertenof the solitary tract can produce the same effect. sive crises in some patients (Ilias and Pacak, 2004). Baroreceptor reflex failure has been described in Calcium channel blockers have also been successful in patients with bilateral lesions of the nucleus of the solicontrolling blood pressure in pheochromocytoma. These tary tract or familial paraganglioma syndrome and agents do not produce hypotension or orthostatic hypotenafter surgical resection of the glossopharyngeal nerves sion and therefore may be used safely in patients who are (Dodick, 2000). Idiopathic cases, referred to as Page normotensive but have occasional episodes of paroxysmal syndrome, have been described (Robertson et al., hypertension. Calcium channel blockers are useful agents 1993). The syndrome has also been well described as in managing cardiovascular complications because they a delayed consequence in patients who have undergone may also prevent catecholamine-induced coronary vasoradiation therapy to the neck for head and neck spasm and myocarditis. It is likely that they reduce malignancies, as well as after carotid endarterectomy arterial pressure by inhibiting the norepinephrine-mediated (Aksamit et al., 1987; Benzel and Hoppens, 1991). This increase in intracellular calcium in vascular smooth musmay reflect the relative importance of carotid barocle, not by decreasing catecholamine synthesis in tumors. receptor input over the cardiopulmonary afferents. In patients with chronic baroreflex failure, the pressor episodes are associated with transient increases HEADACHE ATTRIBUTED TO in plasma norepinephrine concentration (Benarroch, HYPERTENSIVE CRISIS WITHOUT 1997). This correlation suggests that these episodes are HYPERTENSIVE ENCEPHALOPATHY caused by unrestrained activation of the sympathetic (ICHD-II 10.3.2) nervous system. A spectrum of symptoms may accomClinical features pany these pressor episodes, including headache, palpitation, a hot sensation, diaphoresis, cutaneous flushing, DIAGNOSTIC CRITERIA and emotional lability (Robertson et al., 1993). The A. Headache with at least one of the following characclinical presentation of baroreflex failure bears a teristics and fulfilling criteria C and D: striking resemblance to pheochromocytoma. However, 1. Bilateral although patients with baroreceptor failure may have 2. Pulsating quality elevated circulating levels of norepinephrine, urinary 3. Precipitated by physical activity catecholamine and metanephrine levels and negative B. Hypertensive crisis defined as a paroxysmal rise imaging studies for pheochromocytoma are usually in systolic (to >160 mmHg) and/or diastolic sufficient to distinguish between the two entities. (to >120 mmHg) blood pressure but no clinical feaFurthermore, patients with baroreceptor failure have tures of hypertensive encephalopathy been reported to have a dramatic response to clonidine, C. Headache develops during hypertensive crisis a centrally acting sympathetic inhibitor (Dodick, 2000). D. Headache resolves within 1 h of normalization of Clonidine acts at the level of the rostral ventrolateral blood pressure medulla to produce sympathoinhibition and, perhaps, E. Appropriate investigations have ruled out vasopresat the level of the nucleus of the solitary tract, to sensisor toxins or medications as causative factors. tize baroreflex responses (Benarroch, 1997). Clonidine

HEADACHE ATTRIBUTED TO DISORDERS OF HOMEOSTASIS produces a significant decrease of arterial pressure in patients with baroreflex failure and autonomic dysreflexia, another centrally mediated hypertensive syndrome, but not in patients with pheochromocytoma.

HEADACHE ATTRIBUTED TO HYPERTENSIVE ENCEPHALOPATHY (ICHD-II 10.3.3) Diagnostic criteria A. Headache with at least one of the following characteristics and fulfilling criteria C and D: 1. Diffuse pain 2. Pulsating quality 3. Aggravated by physical activity B. Persistent blood pressure elevation to >160/ 100 mmHg with at least two of the following: 1. Confusion 2. Reduced level of consciousness 3. Visual disturbances (other than those of typical migraine aura), including blindness 4. Seizures C. Headache develops in close temporal relation to blood pressure elevation D. Headache resolves within 3 months of effective treatment and control of hypertension E. Other causes of the neurological symptoms have been excluded. Hypertensive encephalopathy is an acute cerebral syndrome caused by sudden severe hypertension. The rate and extent of the rise in blood pressure are the most important factors in the development of this syndrome. Encephalopathy may develop in previously normotensive persons at a level of 160/100 mmHg with no evidence of retinopathy at the time of clinical presentation. However, in patients with chronic hypertension, hypertensive encephalopathy is usually not observed until significant elevations in systolic (>250 mmHg) and diastolic (>120 mmHg) blood pressures occur. These patients often have grade 3 or 4 hypertensive retinopathy (Keith– Wagner classification) at the time of presentation. Hypertensive encephalopathy has become part of an emerging clinical–neuroradiological entity referred to as posterior reversible leukoencephalopathy syndrome (PRES). PRES is a rapidly evolving neurological condition characterized by headache, nausea and vomiting, visual disturbances, altered mental status, decreased alertness, seizures, focal neurological signs, and a diagnostic MRI picture (Healton et al., 1982; Hinchey et al., 1996). PLES is associated with an abrupt and severe increase in blood pressure in most cases, including patients with pre-eclampsia, eclampsia, or renal disease with hypertension. Although hypertensive

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encephalopathy is the most common cause of PLES, there have been a number of cases described which occurred in the absence of severe hypertension. The syndrome is also seen in patients treated with immunosuppressive drugs such as intravenous immunoglobulin, cyclosporin A, tacrolimus, and interferon-alpha (Healton et al., 1982). The main finding in neuroimaging and autopsy studies is posterior white-matter edema, particularly involving the parietal and occipital lobes, which may spread to the basal ganglia, brainstem, and cerebellum (Chester et al., 1978; Hinchey et al., 1996; Schwartz et al., 1998). Complete clinical and radiological recovery often occurs with prompt antihypertensive treatment or withdrawal of the immunosuppressive drug. Occasionally, the clinical features and CT or standard MRI findings may be indistinguishable from a bilateral posterior cerebral artery stroke syndrome. Thus, early recognition of PLES is essential. The pathogenesis is unclear, but a failure of cerebral autoregulation that may be facilitated in posterior brain regions due to a sparse sympathetic innervation of the vertebrobasilar vascular system has been proposed (Hinchey et al., 1996). In these cases, compensatory cerebrovascular vasoconstriction can no longer prevent cerebral hyperperfusion as blood pressure rises. As normal cerebral autoregulation of blood flow is overwhelmed, endothelial permeability increases and cerebral edema occurs.

HEADACHE ATTRIBUTED TO PRE-ECLAMPSIA (ICHD-II 10.3.4) Clinical features and epidemiology DIAGNOSTIC

CRITERIA

A. Headache with at least one of the following characteristics and fulfilling criteria C and D: 1. Bilateral 2. Pulsating quality 3. Aggravated by physical activity B. Pregnancy or puerperium (up to 4 weeks postpartum), and pre-eclampsia defined by both of the following: 1. Hypertension (>140/90 mmHg) documented on two blood pressure readings at least 4 h apart 2. Urinary protein excretion >0.3 g/24 h C. Headache develops during periods of high blood pressure D. Headache resolves within 7 days of effective treatment of hypertension E. Appropriate investigations have ruled out vasopressor toxins, medications, or pheochromocytoma as causative factors.

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HEADACHE ATTRIBUTED TO ECLAMPSIA (ICHD-II 10.3.5) Diagnostic criteria A. Headache with at least one of the following characteristics and fulfilling criteria C and D: 1. Bilateral 2. Pulsating quality 3. Aggravated by physical activity B. Pregnancy or puerperium (up to 4 weeks postpartum), and eclampsia defined by all of the following: 1. Hypertension (>140/90 mmHg) documented on two blood pressure readings at least 4 h apart 2. Urinary protein excretion >0.3 g/24 h 3. A seizure has occurred C. Headache develops during periods of high blood pressure D. Headache resolves within 7 days of effective treatment of hypertension E. Appropriate investigations have ruled out vasopressor toxins, medications, or pheochromocytoma as causative factors F. Stroke has been excluded. Pre-eclampsia is a multisystem disorder that usually occurs after 20 weeks’ gestation. It was classically defined as a triad of hypertension, edema, and proteinuria, but a more modern definition of pre-eclampsia concentrates on a gestational elevation of blood pressure in combination with >0.3 g proteinuria per 24 h. Edema is no longer included because of the lack of specificity (Brown et al., 2000; Rachael and Nelson-Piercy, 2004). Eclampsia is defined as the occurrence of a generalized seizure in association with pre-eclampsia, although it may be the first presentation of the condition. Approximately 6.5% of patients have other neurological problems, including aphasia, paralysis, blindness, strokes, psychosis, or coma (Rachael and Nelson-Piercy, 2004). The headache associated with pre-eclampsia and eclampsia is often bilateral, pulsating, and aggravated by activity. Thunderclap headache has been described and reversible cerebral vasospasm in association with posterior leukoencephalopathy syndrome may also be seen (Van den Veyver et al., 1994; Apollon et al., 2000). Pre-eclampsia and eclampsia complicate 5–6% and 1–2% of pregnancies, respectively. The incidence is significantly influenced by the presence of existing hypertension, although other risk factors are recognized, including nulliparity, multiple pregnancies, previous history or family history of pre-eclampsia, and chronic hypertension (Broughton Pipkin, 2001). An estimated 50 000 women die annually from

pre-eclampsia worldwide and morbidity includes placental abruption, intra-abdominal hemorrhage, cardiac failure, intracerebral hemorrhage, and multiorgan failure (Broughton Pipkin, 2001; Royal College of Obstetricians and Gynaecologists, 2001). The risks to the fetus from pre-eclampsia include growth restriction secondary to placental insufficiency, and premature delivery.

Pathogenesis Pre-eclampsia involves uteroplacental maladaption with failure of the normal cardiovascular changes of pregnancy, resulting in hypertension, reduction in plasma volume, and impaired perfusion to virtually every organ of the body. There is vasospasm and activation of platelets and the coagulation system, resulting in microthrombi formation. The link between the placenta and the systemic disorder appears to involve endothelial dysfunction and oxidative stress. The management of pre-eclampsia involves recognition of the syndrome and delivery of the placenta, which is curative. Since pre-eclampsia may arise with few symptoms, all women are screened during pregnancy through regular antenatal care. Those women who are recognized to be at increased risk have additional screening and more intensive monitoring. Because of the circulating plasma volume contraction, women may be very sensitive to relatively small doses of antihypertensive agents (and diuretics), risking abrupt reductions in blood pressure. Good control of hypertension in severe pre-eclampsia can reduce the incidence of complications such as cerebral hemorrhage until delivery of the placenta. Management of severe hypertension involves adequate blood pressure control using parenteral hydralazine or labetalol. Hydralazine should be given after a colloid challenge to reduce the reflex tachycardia and abrupt hypotension, precipitated by vasodilation of a volumecontracted circulation. Both angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are fetotoxic and the greatest risk to the fetus appears to be associated with exposure in the third trimester (Rachael and Nelson-Piercy, 2004). These drugs should therefore be avoided in the third trimester. These women are at high risk and should be managed in a high-dependency unit setting, because of the risk of non-cardiac pulmonary edema, through capillary leak, respiratory failure, or the development of a severe systemic inflammatory response syndrome. Seizure prophylaxis, with intravenous magnesium sulfate, may be required in these cases (Rachael and Nelson-Piercy, 2004).

HEADACHE ATTRIBUTED TO DISORDERS OF HOMEOSTASIS

HEADACHE ATTRIBUTED TO ACUTE PRESSOR RESPONSE TO EXOGENOUS AGENT (ICHD-II 10.3.6; CODED ELSEWHERE 8.1.6 COCAINE-INDUCED HEADACHE) Diagnostic criteria A. Headache, no typical characteristics known, fulfilling criteria C and D B. An appropriate agent or toxin has been administered or ingested and an acute rise in blood pressure has occurred C. Headache develops in close temporal relation to the acute rise in blood pressure D. Headache resolves within 24 h of normalization of blood pressure E. No other mechanism for the headache is apparent. Apart from cocaine, agents that can produce acute elevations of blood pressure include sympathomimetics and amfetamines, and monoamine oxidase inhibitors when interactions with tyramine-containing foods or other drugs such as opioids occur. There is insufficient evidence to set criteria for how large an elevation in blood pressure is required to produce headache, and this may vary from person to person. Criterion D is arbitrary, but included to increase the specificity of the diagnostic criteria.

HEADACHE ATTRIBUTED TO HYPOTHYROIDISM (ICHD-II 10.4) Clinical features DIAGNOSTIC

CRITERIA

A. Headache with at least one of the following characteristics and fulfilling criteria C and D: 1. Bilateral 2. Non-pulsatile 3. Continuous B. Hypothyroidism is demonstrated by appropriate investigations C. Headache develops within 2 months after other symptoms of hypothyroidism become evident D. Headache resolves within 2 months after effective treatment of hypothyroidism. Although headache has been associated with hypothyroidism since the 1940s (Fenichel, 1948), the only prospective trial evaluating patients with de novo hypothyroidism employing ICHD-I criteria was conducted in 1988 (Moreau, 1988). In this study, 31/102 (30.4%) newly identified patients with hypothyroidism were noted to have a recent history of headache. The major characteristics of the headache were: female predominance, bilateral

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localization (80%), non-pulsating quality (90%), continuous pain with no paroxysmal attacks (95%), mild intensity (95%), nausea, vomiting, or phonophobia, good response to salicylate therapy, and a duration greater than 72 h (82%). The headache decreased in intensity and duration near the 15th day after hormonal therapy in 18 patients, while in the remaining 13 patients the headache disappeared during a 12-month follow-up. A personal and family history of migraine was present in 39.8% and 12.6% of patients. The rate of migraine in hypothyroid patients who did not present with headache was 15.4%, whereas both headache and non-headache patients had equal rates of migraine in the family. The female predominance and the high rate of migraine in the hypothyroid patients with headache suggest that migraneurs are more susceptible to developing headache in the setting of hypothyroidism. In a randomized, case–control study designed to identify somatic and lifestyle factors associated with the development of chronic migraine (CM) and new daily-persistent headache (NDPH), a strong correlation was found between hypothyroidism and NDPH (odds ratio 16.0 when compared with migraine controls, and 10.3 when compared with chronic posttraumatic headache) and CM (odds ratios of 8.4 and 5.4, respectively) (Bigal et al., 2002). The mechanism of headaches in hypothyroidism is not known.

HEADACHE ATTRIBUTED TO FASTING (ICHD-II 10.5; CODED ELSEWHERE HYPOGLYCEMIA-INDUCED MIGRAINE ACCORDING TO SUBTYPE UNDER 1. MIGRAINE,WITH HYPOGLYCEMIA CONSIDERED AS A PRECIPITATING FACTOR) Clinical features DIAGNOSTIC

CRITERIA

A. Headache with at least one of the following characteristics and fulfilling criteria C and D: 1. Frontal location 2. Diffuse pain 3. Non-pulsating quality 4. Mild or moderate intensity B. The patient has fasted for >16 h C. Headache develops during fasting D. Headache resolves within 72 h after resumption of food intake. Fasting is frequently reported by patients and noted in textbooks as a trigger for headache. A systematic study of the relationship between fasting and headache was conducted by Mosek and Korczyn (1995).

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Headache history was documented in 370 hospital employees (60% female) before and immediately after a 25-h fast for the 1993 day of atonement (Yom Kippur). A history of recurrent headache was reported by 101 (29%) of those screened; 52 (15%) were migraineurs, 45 (13%) suffered from tension-type headache, and 4 (1%) had other types of headache. Of the 211 participants, 39% of those who fasted developed headache, compared with only 7% of non-fasters, a result that was highly significant. Headache was usually of a non-pulsating quality, mild to moderate in intensity, and bilateral and frontal in location. Subjects with a history of headache were more likely to develop fasting-induced headache than were those without such history (66% versus 29%; P < 0.000002). Moreover, photophobia, phonophobia, nausea, and vomiting accompanied the headache significantly more often among previous headache sufferers than among those not reporting a history of previous headache (39% versus 18%; P < 0.05). The number of headache sufferers increased in direct relation to the duration of the fast. Headaches first appeared after about 16 h of fasting (in the morning hours of the holiday), and additional headaches developed in other fasters at later time points after the fast began. However, 15 subjects developed their headache 30–60 min after the meal that concluded the fast. Caffeine and nicotine withdrawal, or oversleeping, did not appear to have an influence on the development of headache. The authors concluded that fasting is a strong trigger for headache, especially but not exclusively in those with a prior headache history. In another study designed to estimate the frequency and characteristics of headaches occurring on the first day of Ramadan (Muslims’ fasting month), headaches were reported by 37 (41%) of the 91 persons who had fasted compared to only 2 (8%) of those 25 who did not fast (Awada and Al Jumah, 1999). This difference was highly significant. The headache had a tension-type phenotype in 78% of cases. Headache frequency increased with the duration of fasting and affected mainly those prone to have tension-type headaches; the most important associated factor was caffeine withdrawal. Other factors such as lack of sleep, hypoglycemia, and dehydration may have been involved in a small number of cases. The headache associated with fasting does not appear to be associated with hypoglycemia, although this relationship has not been systematically examined (Dalton, 1975; Dexter et al., 1978; Malouf and Brust, 1985). Fasting headache can occur in the absence of hypoglycemia, insulin-induced hypoglycemia does not precipitate headache in migraine sufferers, and headache is not a complaint of patients presenting to the emergency department with symptomatic hypoglycemia

(Pearce, 1971; Dalton, 1975; Dexter et al., 1978; Malouf and Brust, 1985). The role of caffeine withdrawal as the main factor involved in the pathogenesis of headaches associated with fasting still needs to be systematically studied.

Treatment The only treatment for fasting headache that has been subjected to a controlled trial is a recent study with rofecoxib. Drescher and Elstein (2006) performed a doubleblind randomized prospective trial of rofecoxib 50 mg versus placebo, taken just prior to the onset of fasting, Yom Kippur 2004. Of those subjects receiving rofecoxib (n ¼ 53), 10 or 18.9% versus 34 or 65.4% of the placebo group (n ¼ 52) had headache at some point during the fast (P < 0.0001). Severity of headache was significantly less for the treatment group (3.45 versus 6.29 on a VAS of 10; P ¼ 0.009). This study demonstrated that rofecoxib 50 mg taken before a 25-h ritual fast prevents and attenuates fasting headache. Although this medication is no longer available, other cyclooxygenase-2 inhibitors are available and are likely safe taken as a single dose prior to an annual 25-h fast.

CARDIAC CEPHALALGIA (ICHD-II 10.6) Clinical features DIAGNOSTIC

CRITERIA

A. Headache, which may be severe, aggravated by exertion and accompanied by nausea and fulfilling criteria C and D B. Acute myocardial ischemia has occurred C. Headache develops concomitantly with acute myocardial ischemia D. Headache resolves and does not recur after effective medical therapy for myocardial ischemia or coronary revascularization.

Short description Diagnosis must include careful documentation of headache and simultaneous cardiac ischemia during treadmill or nuclear cardiac stress testing. Failure to recognize and correctly diagnose cardiac cephalalgia (10.6) can have grave consequences. Therefore, distinguishing this disorder from migraine without aura (1.1) is of crucial importance, particularly since vasoconstrictor medications (e.g., triptans, ergots) are indicated in the treatment of migraine but contraindicated in patients with ischemic heart disease. Both disorders can produce severe head pain accompanied by nausea, and both disorders can be triggered by exertion. Migraine-like headache may be triggered by angina treatment such as nitroglycerine.

HEADACHE ATTRIBUTED TO DISORDERS OF HOMEOSTASIS Headache occurring during acute myocardial ischemia (cardiac cephalalgia) has now been carefully documented in several cases (Lefkowitz and Biller, 1982; Fleetcroft and Maddocks, 1985; Blacky et al., 1987; Vernay et al., 1989; Bowen and Oppenheimer, 1993; Grace et al., 1997; Lipton et al., 1997). Cardiac cephalalgia can often be distinguished from other forms of exertional headache by the temporal profile of the pain. The headache typically begins in close proximity to the onset of vigorous exercise, and subsides with rest or with antianginal treatment. However, just as symptomatic myocardial ischemia can occur at rest, cardiac cephalalgia occurring at rest has been described (Guitierrez-Morlote and Pascual, 2002). The headache is often unilateral but may be located at the vertex, and is usually moderate or severe. Nausea is a frequent accompanying symptom, but other migrainous symptoms, such as vomiting, photophobia, and phonophobia, are absent. Valsalva maneuvers, such as coughing, sneezing, and bending, do not precipitate cardiac cephalalgia. The diagnosis should be suspected in patients with headache onset after age 50 and in patients with risk factors for cardiac disease. In such patients, a prompt cardiac evaluation is essential before a diagnosis of primary exertional headache, primary sexual headache, or migraine is diagnosed. This is especially important since treatment with specific antimigraine drugs has the potential to cause coronary vasoconstriction and could potentially lead to serious adverse outcomes in patients with unstable occlusive coronary disease. Headache onset must be demonstrated to occur with evidence of acute myocardial ischemia, and the headache should resolve after effective medical or endovascular therapy or surgical revascularization.

Pathogenesis The mechanism of cardiac cephalalgia is speculative, but likely involves convergence of sympathetic or vagal input at the level of the trigeminal nucleus caudalis (Grace et al., 1997). However, there are other possibilities, such as raised intracranial pressure as a result of impaired cardiac venous return due to raised right heart pressures, or the result of an as yet unidentified mediator released secondary to cardiac ischemia that might act on intracranial pain-sensitive structures. Serotonin, bradykinin, histamine, and SP have been proposed as mediators of ischemic pain and may also have distant intracranial effects (Lipton et al., 1997).

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HEADACHE ATTRIBUTED TO OTHER DISORDERS OF HOMEOSTASIS (ICHD-II 10.7) Diagnostic criteria A. Headache fulfilling criteria C and D B. Evidence of a disorder of homeostasis other than those described above C. Headache develops within 2 months after onset of the disorder, and other evidence exists that the disorder can cause headache D. Headache resolves within 3 months after relief from the disorder of homeostasis. Although the relationship between headache and a variety of other systemic and metabolic diseases has been proposed, systematic evaluation of these relationships has not been performed and there is insufficient evidence to allow for operational diagnostic criteria. This is clearly an area with tremendous potential for future clinical and nosological research. The disorders for which there is insufficient evidence have been outlined in the appendix of the ICHD-II (A10.7.1). Headaches attributed to the following disorders are not sufficiently validated: anemia, hypercapnia, adrenocortical insufficiency, mineralocorticoid deficiency, hyperaldosteronism, polycythemia, hyperviscosity syndrome, thrombotic thrombocytopenic purpura, plasmapheresis-induced headache, anticardiolipin antibody syndrome, Cushing’s disease, hyponatremia, hyperthyroidism, hyperglycemia, hypercalcemia, systemic lupus erythematosus, chronic fatigue syndrome, and fibromyalgia. Well-controlled prospective studies are needed to define more clearly the incidence and characteristics of headaches that occur in association with these disorders. In each case, only those patients who meet well-established diagnostic criteria for the disorders should be evaluated. In addition, there is insufficient evidence to validate the persistence of headache as a result of a disorder of homeostasis. Consequently, ICHD-II also includes a category in the appendix (A10.8 chronic posthomeostasis disorder headache). Operational criteria have been proposed to facilitate future nosological research in this area.

CHRONIC POSTHOMEOSTASIS DISORDER HEADACHE (ICHD-II 10.8) Diagnostic criteria

Treatment The management of cardiac cephalalgia involves coronary revascularization or treatment of the underlying cardiac condition. The alleviation of myocardial ischemia will alleviate the headache.

A. Headache, no typical characteristics known, fulfilling criteria C and D B. A disorder of homeostasis has been present but has been effectively treated or has remitted spontaneously

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C. Headache has been attributed to the disorder of homeostasis D. Headache persists for >3 months after treatment or remission of the disorder of homeostasis.

Short description Some patients may suffer from persistent headache after resolution of a disorder of homeostasis. Such headache has never been the subject of systematic study.

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