Headache & Pain
Migraine: pathogenesis and pathophysiology
Nov. 18, 2022
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Homeostasis refers to the concept that organisms must adjust to external stimuli so that internal conditions remain stable. Multiple medical problems that upset this equilibrium may cause headache. This updated article on headaches attributed to disorders of homeostasis reviews both medical conditions, such as arterial hypertension or hypothyroidism, and external factors, such as high altitude or fasting, which commonly produce headache. Among the updates are new revelations for the relationship of hypoxia and migraine and treatment recommendations for the management of high-altitude headache and headache associated with hemodialysis.
Dexamethasone, analgesics, metoclopramide, and preventive acetazolamide are among the effective treatments for high-altitude headache.
Hypertensive encephalopathy may trigger headache in association with arterial hypertension (higher than 180/120 mm Hg), especially in those with pheochromocytoma.
Hemodialysis may trigger headache, especially in those with increased predialysis blood pressure or blood urea nitrogen. Adjusting dialysis frequency and timing may prevent the complication.
Fasting is a trigger for migraine, even in the absence of hypoglycemia. Preemptive frovatriptan may prevent migraine triggered by fasting.
Myocardial ischemia may trigger migraine-like headache, usually aggravated by exercise and relieved by treatment of angina.
Headache attributed to a disorder of homeostasis as defined by classification from the International Headache Society (46) includes headaches that occur during a metabolic disturbance and resolve after normalization. The major disorders of homeostasis known to cause headache include hypoxia and/or hypercapnia, hemodialysis, arterial hypertension, hypothyroidism, fasting, and cardiac cephalalgia.
This review does not consider headaches attributed to inflammatory or autoimmune disorders, infection, vascular disorders, seizures, increased or low cerebrospinal fluid pressure, and headache related to substances that may cause headache due their use or withdrawal.
Headache attributed to hypoxia or hypercapnia. Headache caused by hypoxia or hypercapnia is defined as a headache that occurs when a patient has acute hypoxia with a PaO2 of 70 mm Hg or less or is chronically hypoxic, with PaO2 persistently at or below this level. It can occur at normal ambient oxygen pressures in patients with pulmonary disease, anemia, cardiac failure, carbon monoxide intoxication, or sleep apnea. Hypoxia may precipitate cluster and migraine headache in susceptible individuals.
Headache associated with acute carbon monoxide exposure appears only as levels of carboxyhemoglobin rise above 20%; it is accompanied by nausea, vomiting, confusion, and dizziness. Seizures and coma develop when carboxyhemoglobin is greater than 40%, and death can occur when carboxyhemoglobin is greater than 60%. Acute carbon monoxide exposure is frequently followed by neuropsychiatric symptoms that may be disabling. There is some evidence that the incidence of headache associated with chronic high carbon monoxide exposure is similar to that of control subjects (04).
Some patients with hypercapnia develop severe headache, with papilledema in some. The increased severity of headache is proportional to the degree of hypercapnia (22). The headache is throbbing, bilateral, located mostly over the parietal, temporal, or occipital regions. It is usually associated with nausea and malaise, may last 10 minutes to a few hours, and is alleviated by reversing hypercapnia. Some patients with underlying pulmonary disease or sleep apnea may suffer from hypercapnia, and it is important to recognize its presentation, which includes headache, dry mouth, sore throat, and nocturia, because of the association of atrial fibrillation and sudden death (73; 32). Severe respiratory diseases, such as COVID-19, may worsen existing headache or precipitate de novo headache disease (11).
Acquired methemoglobinemia, usually related to medications in adults, may also precipitate headache due to hypoxia (58).
High-altitude headache. High-altitude headaches are usually bilateral, dull or pressing in nature, and worsened by exertion, movement, and straining. Common descriptions include a pulsatile-burst type quality and "oscillating evolution" (88). In most persons, headache begins at an altitude above 2500 meters within 24 hours of ascent. It increases in incidence at higher elevations and is more or less universal above 4500 m in nonacclimatized persons. A prospective study of high-altitude headaches demonstrated that 83% of subjects developed this common complication (91). Headache onset occurs between 6 hours and 96 hours (sometimes as soon as 1 hour) after arrival at high altitude, and the headache can last 4 days to 8 days. Altitude headache is more common in patients with migraine and is accompanied more often by phonophobia (91). The headache persists for hours or days without intervention or until the individual returns to lower altitudes (64; 47). Risk factors for high-altitude headache include exertion, rapid ascent, poor fluid intake, a personal history of migraine (15), and possibly oral contraceptive use (45). Preacclimatized, experienced mountaineers are less likely to develop high-altitude headache (50).
Headache is one of many neurologic symptoms seen in those with acute mountain sickness. Acute mountain sickness (Lake Louise Consensus Group) occurs in nonacclimatized persons who arrive at a greater than 2500 meter altitude and is associated with one or more of the following symptoms (98):
gastrointestinal symptoms: anorexia, nausea, or vomiting
Sleep disturbances, including Cheyne-Stokes respiration and sleep apnea, often become prominent (82). Papilledema and retinal hemorrhages have been observed in some patients. Transient ischemic attacks or stroke (09), transient global amnesia (67), cerebral venous thrombosis (30), seizures (21), and cranial nerve palsies (104) are among the many potential significant neurologic presentations at high altitudes. High-altitude cerebral edema is heralded by global encephalopathy in a patient with acute mountain sickness and is considered to be the end stage of mountain sickness (107).
Chronic mountain sickness, also called Monge disease, develops in predisposed individuals living at high altitudes for a period of time. Chronic headache is a common symptom in addition to polycythemia, dizziness, tinnitus, sleep disturbance, fatigue, and mental confusion (86).
Diving headache. Diving, such as recreational scuba diving, can cause headache due to hypercapnia below 10 m, with increased intensity on resurfacing. Headache may occur independently of decompression sickness or "the bends," which typically presents with peripheral symptoms such as joint pain or arm or leg symptoms, occasionally due to spinal cord involvement. Severe headache associated with diving may signify arterial gas embolism, the second cause of mortality in divers, especially during rapid ascents (18). Any headache temporally related to scuba diving may signal an underlying neurologic disorder and should be taken seriously. Other common manifestations of cerebral arterial gas embolism are cognitive deficits, focal neurologic signs, and loss of consciousness (19).
Headache associated with fasting. Fasting commonly triggers headache, which may increase in intensity with the duration of the fast (75; 05). Fasting for religious reasons such as Yom Kippur (61) or Ramadan (05) may trigger diffuse headache or resemble migraine in those with a history of migraine. Fasting headache usually occurs without hypoglycemia.
Headache associated with dialysis. Headaches are a frequent complication of hemodialysis, with approximately 50% to 70% affected (02; 36). This phenomenon has also been observed in pediatric patients (42). Soon after the initiation of dialysis, some patients develop a dialysis disequilibrium syndrome consisting of headache, nausea, emesis, blurred vision, muscular twitching, and cramps. Disorientation, restlessness, and seizures may also occur (69). Onset of headache may be delayed with a mean onset of almost 3 hours and mean duration over 6 hours (37). In a long-term, prospective study of hemodialysis patients, dialysis headaches were typically frontotemporal in location, moderate in severity, and of short duration (lasting less than 4 hours) (36). The syndrome is self-limited, with recovery occurring within a few days. The headache symptoms in dialysis patients with a migraine history often resemble those of their previous migraine attacks. Risk factors for dialysis headache include weight change during dialysis sessions, arterial hypertension, or hypotension (36). Aggressive correction of the anemia associated with chronic renal disease and hemodialysis may cause headache, compared with partial correction of hemoglobin (80). The majority of persons with dialysis-related headache also have headaches with no temporal relationship to treatment (105).
Headache attributed to arterial hypertension. Headaches due to arterial hypertension include hypertensive crisis with or without encephalopathy, preeclampsia or preeclampsia, autonomic dysreflexia, and pheochromocytoma. Although these disorders have similar manifestations, such as a diffuse and pulsatile headache aggravated by physical exertion, their clinical presentations may vary considerably.
Headache attributed to hypertensive crisis with or without hypertensive encephalopathy. Acute changes in either systolic (higher than 180 mm Hg) or diastolic blood pressure (higher than 120 mm Hg) can trigger headache. Hypertensive emergency requires the presence of end-organ injury such as pulmonary edema and renal or heart failure, and may present with neurologic complications such as seizure, stroke, or delirium. Abnormalities on funduscopic examination, such as hemorrhages, papilledema, or exudates (cotton-wool spots), can be associated with encephalopathy (56). If the diagnosis is correct, signs of hypertensive encephalopathy, including headache, nausea, or confusion, should improve with lowering of blood pressure. Routine changes in blood pressure do not correlate with headache or migraine (60; 39), although there are studies suggesting a modestly increased risk of headache in those with chronic hypertension (35).
Headache attributed to preeclampsia or eclampsia. New-onset headache in pregnancy, especially in the setting of new-onset hypertension and proteinuria should raise concerns for preeclampsia (85). Headache is a common symptom in pregnancy and the postpartum period and is a common premonitory symptom of eclampsia. Unfortunately, the presence of headache is not a reliable predictor of poor outcomes or potential seizures (96). Over half of women who develop eclampsia have a history of migraine, which insinuates migraine is an important risk factor for the disorder (29). In severe cases, eclampsia can lead to significant neurologic complications such as posterior reversible encephalopathy syndrome (25).
Headache attributed to autonomic dysreflexia. Autonomic dysreflexia is a condition in patients with cervical or upper thoracic spinal cord injuries in which noxious stimuli such as infection, pressure sores, burns, and bladder or bowel distention, infection, or blockage triggers increases in blood pressure, heart rate, sweating, and sudden severe throbbing headache (66). In patients with significant acute upper spinal cord injuries, the loss of descending sympathetic control significantly reduces blood pressure. Without this regulation, the sympathetic preganglionic neurons may reorganize to hyperexcitable after the initial "shock," highly sensitive to peripheral input (59). Most patients with autonomic dysreflexia experience severe headache with other severe complications, including seizures, stroke, and death (31). Severe, sudden-onset headache in a patient with significant upper spinal cord injury should be assumed to be autonomic dysreflexia unless proven otherwise.
Headache attributed to pheochromocytoma. Headaches associated with pheochromocytoma tend to be severe but are usually paroxysmal and short-lasting rather than progressive or constant. Episodes usually last 10 minutes to 1 hour (70% of patients) and are often accompanied by other symptoms such as sweating, pallor, palpitations, or anxiety, including a sense of impending death (100). An abrupt rise in blood pressure triggering headache is an important clue to trigger further investigation.
Headache attributed to hypothyroidism. Headache is a common symptom in patients with hypothyroidism, affecting about 30% of those with the disorder (74). The mean time between the occurrence of hypothyroidism and the appearance of headache in one study was 56 days (74). Headache resolves with appropriate replacement. Women with migraine and subclinical hypothyroidism also respond well to treatment (10). Despite these observations, one large trial indicated that high thyroid-stimulating hormone values are associated with a low prevalence of headache, most evident in women without a history of thyroid disease (43). Hypothyroidism and its treatment can be associated with pseudotumor cerebri and headache.
It should be mentioned that almost any significant endocrinopathy or metabolic disorder may cause headache, although for most disorders, there is not sufficient evidence for a clear association. Hyperparathyroidism and Bartter syndrome, for example, present with hypokalemia, metabolic acidosis, high renin/aldosterone levels, and, often, headache (77; 79).
Headache attributed to airplane travel. Airplane headache is a distinct syndrome of short-lasting headache (usually less than 30 minutes) during airplane travel, typically during descent. The pain is nonspecific but is often unilateral with few associated symptoms (70). The character of short-lasting but often severe headache attacks in airplane headache may be similar to headaches related to rapid descent from high mountains and ascent during diving, suggesting a common mechanism (71). Space headache is another described headache disorder: in one study, 12 of 17 subjects reported new-onset headache during space flights (103).
Cardiac cephalalgia. Cardiac cephalalgia is a rare headache disorder that occurs during episodes of myocardial ischemia, usually but not always aggravated by exercise. Treatment with nitroglycerin or myocardial revascularization resolves headache (17). Although ischemia is the most common cause, a case report described the improvement of late-life migraine in a 63-year-old with supraventricular tachycardia and bradycardia after pacemaker implantation (72). Cardiac cephalgia may mimic migraine, and recognition is important for avoiding vasoconstrictive drugs such as triptans or ergotamine.
Other disorders of homeostasis. Although not specifically listed in the classification, many patients report headache in association with worsening of other medical disorders, such as anemia, hypoglycemia, or hyponatremia. If the headache resolves in temporal relationship to the medical condition, you may make the diagnosis of headache related to another disorder of homeostasis (46). Medical conditions may trigger other headache disorders, as seen with a case report of hypoglycemia causing hypnic headache (92). The presence of other medical conditions (eg, low blood sugar) may predict the emergence of headache disorders, such as postdural puncture headache (49).
The prognosis and complications of headache depend on recognition and correction of the underlying homeostatic disorders. In some cases, such as high-altitude headache, the diagnosis is obvious and symptoms resolve with treatment. In other disorders, such as dialysis headache, treatment of the underlying problem may be more difficult.
An otherwise healthy 47-year-old who sees you for migraine management wants to discuss her upcoming vacation: a 2-week hiking adventure with her family to the summit of Mount Kilimanjaro. Although physically fit, she is concerned about the chances of travel or altitude triggering migraine. Currently, the only daily medication she uses is amitriptyline 25 mg at night; she does not use oral contraceptives and rarely drinks alcohol. She takes sumatriptan 100 mg as needed with or without ibuprofen 600 mg depending on migraine severity. She is curious about why altitude triggers headache and wants to know what she can do to prevent or treat headache on her trip.
To decrease her risk of headache, you recommend a slow ascent with good hydration. You review symptoms of altitude sickness such as dizziness, lightheadedness, and nausea/vomiting that may require halting ascent. You also prescribe acetazolamide 250 mg to take twice daily starting 2 days before the ascent for up to 7 days as a preventive measure, and dexamethasone 4 mg to use for acute headache not responsive to sumatriptan or ibuprofen.
Hypoxic headaches. Mechanisms of high altitude or hypoxic headache include the following:
(1) Experimentally induced cerebral hypoxemia, especially when coupled with an increase in carbon dioxide tension in the blood, results in extreme dilation of cerebral vessels, notably arteries and arterioles (108). Cerebral hypoxia leads to cerebral vasodilation, increased cerebral blood flow, altered endothelial and blood-brain barrier permeability, cerebral edema (40), and increased intracranial pressure. Cerebral hypoxia also causes a failure in ATP-dependent sodium pumps, which allows sodium and water to accumulate within brain cells (24). Furthermore, hypoxemia upregulates nitric oxide synthase, stimulates prostaglandin synthesis, and elevates anti-diuretic hormone levels, thus, worsening brain swelling and increased intracranial pressure. Older age reduces the risk of headache at high altitudes, presumably due to brain atrophy (91). Common gene polymorphisms related to poor adaption to hypoxia may also confer increased risk (90), suggesting the importance of genetic factors.
(2) Nocturnal periodic breathing with apnea or sleep apnea commonly occurs at high altitudes and results in hypercapnia, which may further increase cerebral blood flow and cerebral edema (99).
(3) Exercising in cold temperatures produces systemic hypertension that increases cerebral blood flow as autoregulation becomes impaired and worsens cerebral edema (24). Also, exercising in hypoxic conditions worsens cerebral oxygen desaturation.
At high altitudes, altered brain compliance results in a significant rise in CSF pressure in response to similar cerebral blood flow changes. Narrowing of the transverse sinuses may predict hypoxemia and the development of headache at high altitudes (107).
High-altitude headache responds to 5-HT1 receptor agonists, which suggests that dilation of intracranial arteries or neuropeptide-related inflammatory response may play a causative role in this pathophysiology (06). It may be caused by the mechanical (vasodilation, increased intracranial pressure) or chemical (prostaglandins, nitrous oxide) activation of the trigeminovascular system.
Headache associated with hypercapnia. Multiple pulmonary disorders that cause chronic hypoxia and hypercapnia are associated with headache, including asthma, chronic obstructive pulmonary disease, sleep apnea, and heart failure (78). Carbon dioxide relaxes vascular smooth muscle, potentially causing cerebral vasodilation, increased intracranial pressure, and headache. Hypercapnia is associated with increased generation of hydrogen ions (H+) that may cause nitric oxide-mediated vasodilation.
In carbon monoxide poisoning, the brain is edematous, and diffuse petechiae and hemorrhages are noted. The degree of edema and hemorrhage seems to correlate better with the degree of hypotension rather than hypoxia. Many of these changes in the brain are similar to postischemic reperfusion injury (102).
Diving headache. Divers may develop hypercapnia due to strenuous exercise, breath-holding, or shallow breathing, and affected divers may develop symptoms of CO2 intoxication. Although diving headache is common, more serious complications include arterial gas embolism, decompression sickness, or barotrauma. Intravascular bubbling can cause activation of plasma kinins and subsequent inflammatory changes consisting of vasodilation edema formation and leukocyte chemotaxis as well as increased blood viscosity (18). Intracerebral bubbles form an arterial gas embolism when gas enters the blood, forced into solution by increased pressure at depths, separated from solution during ascent and decompression. Unless exhaled, this gas forms bubbles in the venous system. Bubbles impair microcirculation, damage endothelium, activate complement, and increase blood viscosity. Fat emboli can form secondary to protein denaturation and release the fatty acids from cell membranes.
The greatest change in gas volume secondary to pressure changes seems to occur within the first 5 meters from the surface, although arterial gas embolism could occur even at a depth of only 1 meter (18).
Hypoglycemic and fasting-related headache. Hypoglycemia alone is an unlikely cause of fasting headache because hepatic glycogen is usually sufficient for 24 hours, and most of the fasting-related headaches start within the first 18 hours (75; 05). Caffeine withdrawal contributed to fasting headache in some populations with high, chronic use of such product (05), but not in others (75).
Headache associated with dialysis. Headache is extremely common in hemodialysis settings, occurring in 30% to 70% of patients (36). Although chronic headache is common in patients with renal failure, there is a strong correlation between hypotension and dialysis disequilibrium syndrome. Following hemodialysis, CSF pressure generally rises, regardless of whether symptoms of dialysis disequilibrium syndrome are present or not. Elevated CSF pressures may be due to increases in intracranial volumes of CSF or blood, cerebral edema, or any combination thereof. The rate of removal of urea from brain closely parallels its rate of removal from plasma, but the clearance of urea from CSF is delayed, which probably accounts for the formation of an osmotic gradient between CSF and plasma following hemodialysis. This osmotic gradient leads to a net movement of water into the CSF, thus, raising its pressure. Elevated CSF pressure, although not necessarily associated with brain edema, may contribute to some symptoms of dialysis disequilibrium syndrome, including headache, emesis, and nausea (57). Other pathophysiological considerations of the dialysis headache are elevated serum urea and higher systolic and diastolic blood pressures at the onset of hemodialysis (36). Hemodialysis may also precipitate caffeine withdrawal and should be considered a potential cause of headache in heavy caffeine users (76).
Headache attributed to arterial hypertension. Disorders of headache associated with acute hypertension have considerable overlap. These include headache attributed to preeclampsia or eclampsia, hypertensive crisis with or without encephalopathy, autonomic dysreflexia, pheochromocytoma, and posterior reversible encephalopathy syndrome. There may also be a link between these disorders and reversible cerebral vasoconstriction syndrome (28). It is important to recognize that acute changes in blood pressure are more likely to cause headache than chronic hypertension.
Airplane headache. Case reports to date note a high prevalence of unilateral tearing and other localized parasympathetic symptoms, with relatively low rates of nausea, photophobia, or phonophobia. The prevailing hypothesis is that airplane headache is due to an imbalance between intrasinus and external air pressures and sinus pathology (70).
Cardiac cephalalgia. The cause may be related to neural convergence with somatic and sympathetic impulses converging in the spinal cord or transient increases of intracardiac pressure increasing intracranial pressure (106).
Hypoxic headache. Headache is the most common complication of high altitude. Approximately 80% of patients will develop headache at altitudes higher than 2000 meters (91). The incidence of acute mountain sickness at altitudes between 11,000 ft and 18,000 ft under identical circumstances varies from 1.01 to 83.3 per 1000 (93). The incidence of acute mountain sickness at altitudes between 1850 and 2750 m (7000 to 9000 ft) was found to be 22% and 42% at 3000 m (10,000 ft) in Summit County, Colorado (40). No significant gender difference in the susceptibility to acute mountain sickness has been documented, and physical fitness does not seem to be protective. A personal history of migraine increases the risk of high-altitude headache (15).
Hypoglycemic and fasting-related headache. Headache associated with fasting does not show a significant gender difference. A personal history of headache or migraine predisposes to fasting headaches (23).
Headache associated with dialysis. Two large prospective studies of newly hemodialyzed patients found incidence rates of 48% and 70% (02; 36). The disorder occurs at all ages but appears to be more common among younger patients, particularly children (38). Male sex and high predialysis blood pressure may also increase the risk (37).
Headache attributed to airplane travel. Previously considered a rare disorder, airplane headache may be more common than previously realized. A prospective study of medical students found a prevalence of 7.5% (80/1070) for each trip and 14.2% (22/155) of the passengers, especially during takeoff or landing (17/22; 77.3%), with most occurrences reported as stabbing headaches lasting less than 30 minutes (65). Many subjects experienced headache only in a minority of flights, rather than with each flight.
Treating the underlying metabolic disorder resolves the associated headaches in most cases. More specific measures are needed in certain situations.
High-altitude headache. Prevention of acute high-altitude headache includes gradual ascent, sleeping at altitudes as low as possible, remaining at the same altitude if symptoms appear, and further ascent only after symptoms resolve (24). Measures should be taken to avoid direct ascent to an altitude of more than 2750 m. Alcohol and drugs that depress ventilation, such as benzodiazepines, should be avoided. For patients who take longer to acclimatize, there are a few medications that may prevent complications such as mountain sickness or high-altitude headache:
Acetazolamide. Acetazolamide is a carbonic anhydrase inhibitor that causes bicarbonate diureses and metabolic acidosis and reduces cerebrospinal fluid production. Acetazolamide 250 mg every 8 hours for 2 days before and during the ascent (47) or 125 mg to 250 mg twice daily 1 day before ascent and 2 days at high altitude (40) reduces the risk of acute mountain sickness. The lowest effective daily dose is 250 mg per day (68). In a clinical trial, acetazolamide 125 mg twice daily was relatively more effective than ibuprofen 600 mg 3 times daily for the prevention of altitude sickness with significantly higher peripheral capillary oxygen saturations (13).
Aspirin. In one study three doses of 320 mg aspirin every 4 hours taken respectively 2 hours before reaching high altitude proved beneficial in headache prevention in subjects resting or exercising, without improving oxygenation (14).
Dexamethasone. Dexamethasone is a corticosteroid that reduces capillary permeability and cytokine release of cytokines, important for the treatment of high-altitude cerebral edema. Dexamethasone has been used prophylactically in doses of 4 mg every 6 hours for 48 hours prior to ascending to 4300 m elevation (55). In a separate study, dexamethasone prevented mountain sickness in soldiers undergoing rapid ascent from sea level to 4400 m (41), but recurrent symptoms after stopping were common.
Ginkgo biloba. Hackett and Roach reported that Ginkgo biloba 160 mg twice daily reduced the intensity and incidence of symptoms by 50% during an abrupt ascent to 4100 m (40). However, the benefit of gingko biloba for preventing acute mountain sickness and high-altitude headache remains controversial, with one study finding limited therapeutic value (33).
Clonidine. A single study of clonidine 0.2 mg/day showed promising results in preventing acute mountain sickness (40).
Nifedipine. In one trial, a 20 mg extended-release preparation of nifedipine was more effective than placebo in preventing high altitude pulmonary edema subjects with a proven history of the disorder. Nifedipine was superior in terms of symptom score, pulmonary-artery pressure, and alveolar-arterial pressure gradient (07).
Gabapentin. A study of 600 mg gabapentin at 3500 m in 204 subjects reduced headache severity, but not incidence compared to placebo (51).
Sumatriptan. In a study of 102 adults, sumatriptan 50 mg given 1 hour prior to ascent reduced the incidence of headache and acute mountain sickness compared with placebo (52).
Phosphodiesterase type 5 inhibitors. Phosphodiesterase type 5 inhibitors, including sildenafil and tadalafil, are oral medications used to treat erectile dysfunction and may be effective as a treatment for pulmonary hypertension (03). Although headache is normally a potential side effect of treatment with these medications, they may have a role in reducing hypoxia and increasing exercise capacity at high altitudes (34).
Headache associated with obstructive sleep apnea. A few studies report better outcomes after successful treatment of sleep apnea in headache and pain, especially in terms of pain severity (16).
Headache associated with dialysis. Our understanding of hemodialysis pathophysiology and clinical experience provides us with treatment recommendations. Bicarbonate-containing dialyzing solutions (neutralized dialysate) are better tolerated than acetate-containing solutions. The former prevent hypoxemia and adjust pH better. Shorter duration hemodialysis may be beneficial because significant headache-causing accumulations of acetaldehyde may occur during acetate dialysis, especially in those patients whose metabolizing capacity for acetate is impaired. Finally, there may be some benefit in lowering the dialysate temperature (95). Studies suggest effective kidney transplantation may either improve or cure headache in patients with renal failure, not only in those with headache associated with dialysis (105).
Headache attributed to autonomic dysreflexia. Antihypertensives such as terazosin and prazosin may reduce the incidence of episodes (31).
Fasting headache. Fasting is fairly reliable trigger of migraine in many individuals. In certain circumstances, such as fasting for religious reasons, the use of preemptive acute treatment prior to migraine onset may prevent migraine. In a study of 71 subjects, those taking frovatriptan 5 mg prior to a 20-hour fast had fewer headaches than placebo, although results did not reach statistical significance (62). Another study of 189 patients compared the Cox-2 inhibitor etoricoxib 90mg to placebo taking prior to a 15-hour Ramadan fast for the first 2 weeks (27). Patients taking etoricoxib had fewer headaches during the 2-week study period than placebo (0.86 mean vs. 1.60 placebo, p = 0.003). A similar study of fasting headache associated with a 25-hour Yom Kippur fast found that subjects using etoricoxib 120 mg were less likely to develop any headache and had less severe headache (26).
The main challenges in diagnosing headache due to homeostasis are: (1) distinguishing between primary or secondary headache in patients with a history of headache such as migraine; and (2) ruling out serious, life-threatening causes of headache such as high-altitude cerebral edema, cerebral venous thrombosis, or hypertensive encephalopathy. The recognition of neurologic signs or symptoms such as focal neurologic deficits, seizure, confusion, or ataxia should suggest a need for more urgent workup and treatment.
The diagnosis of headache attributed to homeostasis may be obvious in many clinical situations such as high-altitude, fasting, or dialysis-related headache. However, diagnostic testing is often necessary to rule out serious disorders or confirm the diagnosis.
Supportive diagnostic testing
Carbon monoxide poisoning
Increased carboxyhemoglobin level, metabolic acidosis.
Sleep study demonstrating apnea events.
Hypertensive crisis, eclampsia, or preeclampsia
Consider angiography for suspected cerebral reversible vasoconstrictive syndrome or MRI for possible infarction.
Increased blood pressure should correlate with episodes. Look for inciting event such as urinary tract infection.
Plasma metanephrines or 24-hour urine metabolites. CT or MRI to localize tumor.
Increased TSH and low serum free T4.
EKG, stress test, coronary angiography. Nitroglycerin helps headache.
High-altitude headache. Mild cases respond to analgesics, hydration, supplemental oxygen, and halting the ascent. When the symptoms persist, or if moderate-severe acute mountain sickness develops, descent to lower altitudes becomes essential. Avoiding medications that decrease respiratory drive, such as opioids or benzodiazepines, is recommended (40). In addition to preventive treatments mentioned above, multiple treatment options have been evaluated for the acute treatment of high-altitude headache:
Dexamethasone. Dexamethasone 4 mg every 6 hours is superior to placebo for treating high-altitude headache and can be used orally, intramuscularly, or intravenously for relatively short periods of time (41) and may also reduce the risk of pulmonary edema and improve exercise tolerance.
Acetazolamide. Although effective in preventing acute mountain sickness, acetazolamide may or may not be effective after onset of symptoms.
Furosemide. Furosemide is a potent loop diuretic that may treat acute mountain sickness by reducing cerebral or pulmonary edema. A few small studies suggest doses of 40 to 80 mg are effective, but given that it may cause dehydration, it is typically used acutely, not preventively (48). Spironolactone 100 mg/day is not effective in acute mountain sickness (08).
Nonsteroidal anti-inflammatories. Nonsteroidal anti-inflammatories, including ibuprofen 400 mg (12) and acetaminophen 1000 mg (44), effectively treat high-altitude headache.
Sumatriptan . Sumatriptan may be effective for the treatment of acute high-altitude headache. A randomized clinical trial of sumatriptan 100 mg among mountaineers demonstrated a transient reduction in the severity of high-altitude headache in the first 3 hours after treatment but similar headaches scores after 3 hours (101).
Metoclopramide. Metoclopramide 10 mg may be effective for treating both headache and nausea in those ascending to high altitudes.
Sleep apnea headache. Treatment consists of continuous positive air pressure or surgical treatment of the obstruction.
Diving headache. In most cases, diving headache is relatively benign (18). In more serious cases, such as decompression illness, treatment includes early use of 100% oxygen and recompression in a hyperbaric chamber.
Headache associated with dialysis. In several studies, dialysis headache has been treated by adding either hyperosmotic or hyperoncotic solute (glucose, glycerol, albumin, urea, fructose, sodium chloride, mannitol) to the dialysis solution or by substituting sodium bicarbonate for sodium lactate (or acetate) in the dialysis (83). Studies of uremic patients undergoing hemodialysis, with glycerol or mannitol added to the dialysate, suggest that these agents lessen the symptoms of increased intracranial pressure that may be associated with dialysis disequilibrium syndrome. Sodium ramping can decrease the overall number of side effects occurring during hemodialysis but increases interdialysis symptoms, including weight gain and hypertension (87). Sodium balancing and ultrafiltration techniques effectively decrease the adverse reactions, including headache, in patients undergoing dialysis (01). Dialysis headaches have also been reported to improve with the use of ACE-inhibitors but not with angiotensin II receptor blockers (63).
Headache associated with hypertensive disorders. Although few significant trials compare interventions in hypertensive emergencies, it is generally recommended to reduce blood pressure by no more than 25% within the first hour and then to 160/100 to 110 mm Hg within 2 to 6 hours (20). An assessment for secondary causes of hypertension such as kidney or heart failure, eclampsia, stroke, or arterial dissection, or pheochromocytoma is recommended. In many scenarios, the treatment is based on the suspected cause of the problem:
In most acute ischemic stroke or arterial dissection settings, rapid lowering of blood pressure is not recommended. Nitroprusside, in particular, should not be used due to its potential to worsen intracranial edema (97). An important consideration is the potential treatment of tissue plasminogen activator, which recommends a target 185/110 mm Hg or less before administration of the drug (54).
In pre-eclampsia and eclampsia, the definitive treatment is delivery of the fetus. However, intravenous medications such as labetalol, hydralazine, or magnesium can be used (97).
Avoid using beta-blockers alone to treat pheochromocytoma and other states of catecholamine excess because they could cause unopposed alpha-adrenergic stimulation and additional peripheral vasoconstriction, worsening the hypertension. Intravenous phentolamine is a first-line option (97).
The acute treatment of autonomic dysreflexia includes moving to a sitting position if the person is supine, removing or loosening constrictive clothing or devices, and evaluating for bladder distension and bowel impaction. Although treating the underlying trigger is important, rapid-acting antihypertensives may be necessary to treat acute episodes. Nifedipine, phenoxybenzamine, β-adrenergic blockers, and clonidine may be effective.
Secondary headache is not uncommon during pregnancy (85), and a new onset of significant headache in pregnancy should be evaluated carefully. New-onset, non-iatrogenic headache during pregnancy is most commonly associated with eclampsia or pregnancy-induced hypertension. The differential diagnosis should include nonaneurysmal primary subarachnoid hemorrhage (89), cerebral metastases of a choriocarcinoma (81), pituitary apoplexy (53), and postpartum angiopathy with reversible posterior leukoencephalopathy (94).
Michael J Marmura MD
Dr. Marmura of Thomas Jefferson University Hospital received research support from AbbVie and Teva; he received honorariums from Amgen/Novartis and Lilly for serving on a speaker bureau, from Lundbeck and Upsher-Smithnica as a consultant, and from Theranica for service on an advisory board.See Profile
Shuu-Jiun Wang MD
Dr. Wang of the Brain Research Center, National Yang-Ming University, and the Neurological Institute, Taipei Veterans General Hospital, has no relevant financial relationships to disclose.See Profile
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