CHEST PAIN 3

GUIDELINES AND CRITICAL PATHWAYS FOR ACUTE CHEST PAIN

Guidelines for the initial evaluation for patients with acute chest pain have been developed by the American College of Emergency Physicians (ACEP) and other organizations. The ACEP statement describes rules and guidelines about the data that should be recorded as part of the evaluation, and the actions that should follow from certain findings. In the ACEP framework, rules are actions that are general principles of good practice, while guidelines are actions that should be considered but are not always followed. Hence, failure to follow a guideline is not necessarily improper care.

Other organizations, including the Agency for Health Care Policy and Research (AHCPR) and the National Heart Attack Alert Program, have also issued guidelines for management of patients with a high probability of acute ischemic heart disease. In these and other guidelines, patients with possible or probable acute myocardial infarction as suggested by the description of their pain or electrocardiographic findings are expected to be admitted to the hospital. The AHCPR guidelines for unstable angina note that not all patients with that syndrome require admission but recommend that patients with unstable angina be monitored electrocardiographically during their evaluation; that those with ongoing rest pain should be placed at bed rest during the initial phase of stabilization. The ACEP policy statement indicates that patients who are discharged should be given a referral for follow-up care and instructions regarding treatment and circumstances that require a return to the emergency department.

Many medical centers have adopted critical pathways and other forms of guidelines to increase efficiency. These guidelines emphasize two strategies:

· Triage to non-coronary care unit monitored facilities such as intermediate care units or chest pain units of patients with a low risk for complications, such as patients without new ischemic changes on their electrocardiograms and without ongoing chest pain. Such patients can usually be safely observed in non-coronary care unit settings, undergo early exercise testing, or be discharged home. Risk stratification can be assisted through use of prospectively validated multivariate algorithms that have been published for acute ischemic heart disease and its complications.

· Shortening lengths of stay in the coronary care unit and hospital. Recommendations regarding the minimum length of stay in a monitored bed for a patient who has no further symptoms have decreased in recent years to 12 h or less if exercise testing or other risk stratification technologies are available.

NONACUTE CHEST DISCOMFORT

The management of patients who do not require admission to the hospital or who no longer require inpatient observation should seek to identify the cause of the symptoms and the likelihood of major complications. Cost-effectiveness analyses support use of noninvasive testing for coronary disease, such as exercise electrocardiography and stress echocardiography. These tests serve both to diagnose coronary disease and to identify patients with high-risk forms of coronary disease who may benefit from revascularization. Gastrointestinal causes of chest pain can be evaluated via endoscopy or radiology studies. Emotional and psychiatric conditions warrant appropriate evaluation and treatment; randomized trial data indicate that cognitive therapy and group interventions lead to decreases in symptoms for such patients.

PALPITATIONS

Palpitations are characterized by an awareness of the beating of the heart. Patients commonly describe "pounding" or "fluttering" heart beats or report a sensation that the heart is stopping or skipping beats. These symptoms may be caused by a change in the heart's rhythm or rate or by an increase in the force of its contractions. In many cases, this awareness reflects lack of competing sensory stimuli, such as when a person is lying in bed, unable to sleep.

Palpitations are often manifestations of psychiatric conditions, the most common of which are depression and panic disorder. For example, in one study of outpatients referred for ambulatory electrocardiographic monitoring to evaluate palpitations, 19% were found to have a psychiatric disorder. Patients with psychiatric disorders were more likely than other patients to report that their palpitations lasted longer than 15 min or were accompanied by ancillary symptoms. In this study, physicians usually recognized the emotional basis of the patients' symptoms but frequently did not refer the patient for specific therapy.

Palpitations can also be caused by virtually any cardiac arrhythmia as well as by other cardiac and noncardiac conditions. A markedly enlarged left ventricle can cause awareness of the heart beat by contact with the chest wall. Any condition associated with increased catecholamine levels can lead to palpitations both by increasing the forcefulness of cardiac contractions and by increasing the rate of premature beats.

Palpitations can be intermittent or sustained and regular or irregular. Patients with this complaint should be asked to describe their palpitations' onset, duration, associated symptoms and the circumstances in which they occur. Abrupt onset and termination after several minutes may reflect a sustained ventricular or supraventricular tachyarrhythmia. Gradual onset and termination of a pounding heart beat is more consistent with sinus tachycardia. Patients should try to replicate the rhythm of their palpitations by tapping on a table. This maneuver can help the physician determine the nature of any cardiac arrhythmia. Patients should also be taught to take their pulse so that they can more accurately report their approximate heart rate and whether the rhythm was regular.

DIFFERENTIAL DIAGNOSIS

Patients who report "skipped" beats or a "flopping" sensation often have atrial or ventricular extrasystoles. These premature beats are followed by a compensatory pause, and the first heart beat after the pause may be unusually strong due to increased left ventricular volume and enhanced contractility (a phenomenon called postextrasystolic potentiation). Sustained bursts of rapid heart beats may be due to ventricular or supraventricular tachyarrhythmias. A sustained irregular rhythm suggests atrial fibrillation.

Conditions that cause marked left ventricular enlargement such as aortic regurgitation can cause an awareness of the heart beat that is sometimes positional. Presumably because of associated arrhythmias, hypertrophic cardiomyopathy, mitral valve prolapse, and other cardiac structural abnormalities are also associated with palpitations.

Palpitations can also be a prominent symptom in noncardiac conditions, including thyrotoxicosis, hypoglycemia, pheochromocytoma, and fever. The physiologic basis of palpitations with these conditions is either arrhythmia or increased catecholamine levels leading to greater myocardial contractility. Drugs that can precipitate arrhythmias and palpitations include tobacco, coffee, tea, alcohol, epinephrine, ephedrine, aminophylline, and atropine.

Approach to the Patient

The first goal in the evaluation of patients with palpitations is to exclude the possibility of life-threatening arrhythmias. The risk for such arrhythmias is highest in patients with coronary artery disease, congestive heart failure, or other structural cardiac abnormalities. The history, physical examination, and electrocardiogram should therefore be focused on stratifying patients according to the risk of such conditions. Palpitations are also more likely to reflect serious arrhythmias if they are associated with symptoms that suggest hemodynamic compromise, such as syncope, light-headedness, dizziness, or shortness of breath.

The most common first test after the initial evaluation of palpitations is continuous electrocardiographic (Holter) monitoring. This test is especially useful if patients have palpitations on a daily basis. For patients with more sporadic palpitations, a variety of new technologies have become available to allow capture of electrocardiographic tracings at the time of their symptoms. These technologies include loop recorders, that can freeze the last several minutes of data when the patient presses a button, and telephonic monitors, which can be used to "call in" tracings when symptoms occur. If episodes are associated with physical stress, exercise electrocardiography can be used in an attempt to elicit an arrhythmia.

Most patients with palpitations do not have evidence of major arrhythmias or abnormal physiologic conditions associated with increased catecholamine levels. Patients with emotional or psychological causes of palpitations should be evaluated for possible cognitive and pharmaceutical therapy. Drugs and medications that may precipitate palpitations should be eliminated or reduced. A trial of beta blockers is often successful in reducing premature beats and symptoms. Regardless of the cause and treatment, the clinician should remain aware that palpitations are extremely bothersome symptoms for patients. Reassurance that a comprehensive evaluation has been performed and that the palpitations do not adversely affect the patient's prognosis is a critical part of the patient's care.

CHEST PAIN 2

Approach to the Patient

The evaluation of the patient with chest discomfort must accommodate two goals¾determining the diagnosis and assessing the safety of the immediate management plan. The latter issue is often dominant when the patient has acute chest discomfort, such as patients seen in the emergency department. In such settings, the clinician must focus on questions such as the safety of discharge to home, admission to a non-coronary care unit facility, or immediate exercise testing. displays a sequence of questions that can be used in the evaluation of the patient with chest discomfort, with the diagnostic entities that are most important for consideration at each stage of the evaluation.

Acute Chest Discomfort In patients with acute chest discomfort, the clinician must first assess the patient's respiratory and hemodynamic status. If either is compromised, initial management should focus on stabilizing the patient before the diagnostic evaluation is pursued. If, however, the patient does not require emergent interventions, then a focused history, physical examination, and laboratory evaluation should be performed to assess the patient's risk of life-threatening conditions, including acute ischemic heart disease, aortic dissection, and pulmonary embolism.

The history should include questions about the quality and location of the chest discomfort. The patient should also be asked about the nature of onset of the pain and its duration. Myocardial ischemia is usually associated with a gradual intensification of symptoms over a period of minutes. Pain that is fleeting or that lasts hours without being associated with electrocardiographic changes is not likely to be ischemic in origin.

The physical examination should include evaluation of blood pressure in both arms and of pulses in both legs. Poor perfusion of a limb may be due to an aortic dissection that has compromised flow to an artery branching from the aorta. Chest auscultation may reveal diminished breath sounds; a pleural rub; or evidence of pneumothorax, pulmonary embolism, pneumonia, or pleurisy. The cardiac examination should seek pericardial rubs, systolic and diastolic murmurs, and third or fourth heart sounds.

An electrocardiogram is an essential test for adults with chest discomfort that is not due to an obvious traumatic cause. The presence of electrocardiographic changes consistent with ischemia or infarction is associated with high risks of acute myocardial infarction or unstable angina such patients should be admitted to a unit with electrocardiographic monitoring and the capacity to respond to a cardiac arrest. The absence of such changes does not exclude acute ischemic heart disease, but the risk of life-threatening complications is low for patients with normal electrocardiograms or only nonspecific ST-T-wave changes. If these patients are not considered appropriate for immediate discharge, they are often candidates for early or immediate exercise testing.

Markers of myocardial injury are often obtained in the emergency department evaluation of acute chest discomfort. The most commonly used markers are creatine kinase (CK), CK-MB, and the cardiac troponins (I and T). Single values of these markers do not have high sensitivity for acute myocardial infarction or for prediction of complications. Hence, decisions to discharge patients home should not be made on the basis of single negative values of these tests.

Provocative tests for coronary artery disease are not appropriate for patients with ongoing chest pain. In such patients, rest myocardial perfusion scans can be considered; a normal scan reduces the likelihood of coronary artery disease. Clinicians frequently employ therapeutic trials with sublingual nitroglycerin or antacids, and a common error is to assume that a response to either of these interventions clarifies the diagnosis. While such information is often helpful, the patient's response may be due to the placebo effect. Hence, myocardial ischemia should never be considered excluded solely because of a response to antacid therapy. Similarly, failure of nitroglycerin to relieve pain does not exclude the diagnosis of coronary disease.

If the patient's history or examination is consistent with aortic dissection, imaging studies to evaluate the aorta must be pursued promptly because of the high risk of catastrophic complications with this condition. A chest x-ray is not sufficient to exclude this diagnosis. Appropriate tests include a chest computed tomography scan with contrast or a magnetic resonance imaging scan in patients who are hemodynamically stable, or a transesophageal echocardiogram in patients who are less stable. Aortic angiography is no longer a first test at most institutions.

Acute pulmonary embolism should be considered in patients with respiratory symptoms, pleuritic chest pain, hemoptysis, or a history of venous thromboembolism or coagulation abnormalities. Initial tests usually include a lung scan and/or pulmonary arteriography.

If patients with acute chest discomfort show no evidence of life-threatening conditions, the clinician should then focus on serious chronic conditions with the potential to cause major complications, the most common of which is stable angina. Early use of treadmill exercise testing for such patients, whether in the office or the emergency department, is now an accepted management strategy for low-risk patients. Exercise testing is not appropriate, however, for patients who (1) report pain that is believed to be ischemic occurring at rest or (2) have electrocardiographic changes consistent with ischemia not known to be old.

Patients with sustained chest discomfort who do not have evidence for life-threatening conditions should be evaluated for evidence of conditions likely to benefit from acute treatment. Pericarditis may be suggested by the history, physical examination, and electrocardiogram . Clinicians should carefully assess blood pressure patterns and consider echocardiography in such patients to detect evidence of impending pericardial tamponade. Chest x-rays can be used to evaluate the possibility of pulmonary disease.

CHEST PAIN 1

CHEST DISCOMFORT AND PALPITATIONS

CHEST DISCOMFORT

Chest discomfort is one of the most common challenges for clinicians in the office or emergency department. The differential diagnosis includes conditions affecting organs throughout the thorax and abdomen, with prognostic implications that vary from benign to life-threatening . Failure to recognize potentially serious conditions such as acute ischemic heart disease, aortic dissection, or pulmonary embolism can lead to serious complications, including death. Conversely, overly conservative management of low-risk patients leads to unnecessary hospital admissions, tests, and procedures.

CAUSES OF CHEST DISCOMFORT

Myocardial Ischemia and Injury Myocardial ischemia occurs when the oxygen supply to the heart is not sufficient to meet metabolic needs. This mismatch can result from a decrease in oxygen supply, a rise in demand, or both. The most common underlying cause of myocardial ischemia is obstruction of coronary arteries by atherosclerosis; in the presence of such obstruction, transient ischemic episodes are usually precipitated by an increase in oxygen demand as a result of physical exertion. However, ischemia can also result from psychological stress, fever, or large meals or from compromised oxygen delivery due to anemia, hypoxia, or hypotension. Ventricular hypertrophy due to valvular heart disease, hypertrophic cardiomyopathy, or hypertension can predispose the myocardium to ischemia because of impaired penetration of blood flow from epicardial coronary arteries to the endocardium.

Angina Pectoris The chest discomfort of myocardial ischemia is a visceral discomfort that is usually described as a heaviness, pressure, or squeezing. Other common adjectives for anginal pain are burning and aching. Some patients deny any "pain" but may admit to dyspnea or a vague sense of anxiety. The word "sharp" is sometimes used by patients to describe intensity rather than quality.

The location of angina pectoris is usually retrosternal; most patients do not localize the pain to any small area. The discomfort may radiate to the neck, jaw, teeth, arms, or shoulders, reflecting the common origin in the posterior horn of the spinal cord of sensory neurons supplying the heart and these areas. Some patients present with aching in sites of radiated pain as their only symptoms of ischemia. Occasional patients report epigastric distress with ischemic episodes. Less common is radiation to below the umbilicus or to the back.

Stable angina pectoris usually develops gradually with exertion, emotional excitement, or after heavy meals. Rest or treatment with sublingual nitroglycerin typically leads to relief within several minutes. In contrast, pain that is fleeting (lasting only a few seconds) is rarely ischemic in origin. Similarly, pain that lasts for several hours is unlikely to represent angina, particularly if the patient's electrocardiogram does not show evidence of ischemia.

Anginal episodes can be precipitated by any physiologic or psychological stress that induces tachycardia. Most myocardial perfusion occurs during diastole, when there is minimal pressure opposing coronary artery flow from within the left ventricle. Since tachycardia decreases the percentage of the time in which the heart is in diastole, it decreases myocardial perfusion.

Unstable angina and myocardial infarction Patients with these acute ischemic syndromes usually complain of symptoms similar in quality to angina pectoris, but more prolonged and severe. The onset of these syndromes may occur with the patient at rest, and sublingual nitroglycerin may lead to transient or no relief. Accompanying symptoms may include diaphoresis, dyspnea, nausea, and light-headedness.

The physical examination may be completely normal in patients with chest discomfort due to ischemic heart disease. Careful auscultation during ischemic episodes may reveal a third or fourth heart sound, reflecting myocardial systolic or diastolic dysfunction. A transient murmur of mitral regurgitation suggests ischemic papillary muscle dysfunction. Severe episodes of ischemia can lead to pulmonary congestion and even pulmonary edema.

Other Cardiac Causes Myocardial ischemia caused by hypertrophic cardiomyopathy, aortic stenosis, or other conditions leads to angina pectoris similar to that caused by coronary atherosclerosis. In such cases, a systolic murmur or other findings usually suggest abnormalities other than coronary atherosclerosis that may be contributing to the patient's symptoms.

Pericarditis The pain in pericarditis is believed to be due to inflammation of the adjacent parietal pleura, since most of the pericardium is believed to be insensitive to pain. Thus, infectious pericarditis, which usually involves adjoining pleura surfaces, tends to be associated with pain, while conditions that cause only local inflammation (e.g., myocardial infarction or uremia) and cardiac tamponade tend to result in mild or no chest pain.

The adjacent parietal pleura receives its sensory supply from several sources, so the pain of pericarditis can be experienced in areas ranging from the shoulder and neck to the abdomen and back. Most typically, the pain is retrosternal and is aggravated by coughing, deep breaths, or changes in position¾all of which lead to movements of pleural surfaces. The pain is often worse in the supine position and relieved by sitting upright and leaning forward. Less common is a steady aching discomfort that mimics acute myocardial infarction.

Diseases of the Aorta Aortic dissection is a potentially catastrophic condition that is due to spread within the wall of the aorta of a subintimal hematoma. The hematoma may begin with a tear in the intima of the aorta or with rupture of the vasa vasorum within the aortic media. This syndrome can occur with trauma to the aorta, including motor vehicle accidents or medical procedures in which catheters or intraaortic balloon pumps damage the intima of the aorta. Nontraumatic aortic dissections are rare in the absence of hypertension and/or conditions associated with deterioration of the elastic or muscular components of the media within the aorta's wall. Cystic medial degeneration is a feature of several inherited connective tissue diseases, including Marfan and Ehlers-Danlos syndromes. About half of all aortic dissections in women under 40 years of age occur during pregnancy.

Almost all patients with acute dissections present with severe chest pain, although some patients with chronic dissections are identified without associated symptoms. Unlike the pain of ischemic heart disease, symptoms of aortic dissection tend to reach peak severity immediately, often causing the patient to collapse from its intensity. The adjectives used to describe the pain reflect the process occurring within the wall of the aorta¾"ripping" and "tearing"¾and the location usually correlates with the site and extent of the dissection. Thus, dissections that begin in the ascending aorta and extend to the descending aorta tend to cause pain in the front of the chest that extends into the back, between the shoulder blades.

Physical findings may also reflect extension of the aortic dissection that compromises flow into arteries branching off the aorta. Thus, loss of a pulse in one or both arms, cerebrovascular accident, or paraplegia can all be catastrophic consequences of aortic dissection. Hematomas that extend proximally and undermine the coronary arteries or aortic valve apparatus may lead to acute myocardial infarction or acute aortic insufficiency. Rupture of the hematoma into the pericardial space leads to pericardial tamponade.

Another abnormality of the aorta that can cause chest pain is a thoracic aortic aneurysm. Aortic aneurysms are frequently asymptomatic but can cause chest pain and other symptoms by compressing adjacent structures. This pain tends to be steady, deep, and sometimes severe.

Pulmonary Embolism Chest pain due to pulmonary embolism is believed to be due to distention of the pulmonary artery or infarction of a segment of the lung adjacent to the pleura. Massive pulmonary emboli may lead to substernal pain that is suggestive of acute myocardial infarction. More commonly, smaller emboli lead to focal pulmonary infarctions that cause pain that is lateral and pleuritic. Associated symptoms include dyspnea and, occasionally, hemoptysis. Tachycardia is usually present.

Pneumonia or Pleuritis Lung diseases that damage and cause inflammation of the pleura of the lung usually cause a sharp, knifelike pain that is aggravated by inspiration or coughing.

Gastrointestinal Conditions Esophageal pain from acid reflux from the stomach, spasm, obstruction, or injury can be difficult to discern from myocardial syndromes. Acid reflux typically causes a deep burning discomfort that may be exacerbated by alcohol, aspirin, or some foods; this discomfort is often relieved by antacid or other acid-reducing therapies. Acid reflux tends to be exacerbated by lying down and may be worse in early morning when the stomach is empty of food that might otherwise absorb gastric acid.

Esophageal spasm may occur in the presence or absence of acid reflux, and leads to a squeezing pain indistinguishable from angina. Prompt relief of esophageal spasm is often provided by antianginal therapies such as sublingual nifedipine, further promoting confusion between these syndromes. Chest pain can also result from injury to the esophagus, such as a Mallory-Weiss tear caused by severe vomiting.

Chest pain can result from diseases of the gastrointestinal tract below the diaphragm, including peptic ulcer disease, biliary disease, and pancreatitis. These conditions usually cause abdominal pain as well as chest discomfort; symptoms are not likely to be associated with exertion. The pain of ulcer disease typically occurs 60 to 90 min after meals, when postprandial acid production is no longer neutralized by food in the stomach. Cholecystitis usually causes a pain that is described as aching, occurring an hour or more after meals.

Neuromusculoskeletal Conditions Cervical disk disease can cause chest pain by compression of nerve roots. Pain in a dermatomal distribution can also be caused by intercostal muscle cramps or by herpes zoster. Chest pain symptoms due to herpes zoster may occur before skin lesions are apparent.

Costochondral and chondrosternal syndromes are the most common causes of anterior chest musculoskeletal pain. Only occasionally are physical signs of costochondritis such as swelling, redness, and warmth (Tietze's syndrome) present. The pain of such syndromes is usually fleeting and sharp, but some patients experience a dull ache that lasts for hours. Direct pressure on the chondrosternal and costochondral junctions may reproduce the pain from these and other musculoskeletal syndromes. Arthritis of the shoulder and spine and bursitis may also cause chest pain. Some patients who have these conditions and myocardial ischemia blur and confuse symptoms of these syndromes.

Emotional and Psychiatric Conditions As many as 10% of patients who present to emergency departments with acute chest pain have panic disorder or other emotional conditions. The symptoms in these populations are highly variable, but frequently the discomfort is described as visceral tightness or aching that lasts more than 30 min. Some patients offer other atypical descriptions, such as pain that is fleeting, sharp, and/or localized to a small region. The electrocardiogram in patients with emotional conditions may be difficult to interpret if hyperventilation causes ST-T-wave abnormalities. A careful history may elicit clues of depression, prior panic attacks, somatization, agoraphobia, or other phobias.

ABDOMINAL PAIN 2

Approach to the Patient

Few abdominal conditions require such urgent operative intervention that an orderly approach need be abandoned, no matter how ill the patient. Only those patients with exsanguinating hemorrhage must be rushed to the operating room immediately, but in such instances, only a few minutes are required to assess the critical nature of the problem. Under these circumstances, all obstacles must be swept aside, adequate venous access for fluid replacement obtained, and the operation begun. Many patients of this type have died in the radiology department or the emergency room while awaiting such unnecessary examinations as electrocardiograms or abdominal films. There are no contraindications to operation when massive hemorrhage is present. This situation fortunately is relatively rare.

Nothing will supplant an orderly, painstakingly detailed history, which is far more valuable than any laboratory or radiographic examination. This kind of history is laborious and time-consuming, making it not especially popular, even though a reasonably accurate diagnosis can be made on the basis of the history alone in the majority of cases. Computer-aided diagnosis of abdominal pain provides no advantage over clinical assessment alone. In cases of acute abdominal pain, a diagnosis is readily established in most instances, whereas success is not so frequent in patients with chronic pain. Irritable bowel syndrome is one of the most common causes of abdominal pain and must always be kept in mind. The chronological sequence of events in the patient's history is often more important than emphasis on the location of pain. If the examiner is sufficiently open-minded and unhurried, asks the proper questions, and listens, the patient will usually provide the diagnosis. Careful attention should be paid to the extraabdominal regions that may be responsible for abdominal pain. An accurate menstrual history in a female patient is essential. Narcotics or analgesics should not be withheld until a definitive diagnosis or a definitive plan has been formulated; obfuscation of the diagnosis by adequate analgesia is unlikely.

In the examination, simple critical inspection of the patient, e.g., of facies, position in bed, and respiratory activity, may provide valuable clues. The amount of information to be gleaned is directly proportional to the gentleness and thoroughness of the examiner. Once a patient with peritoneal inflammation has been examined brusquely, accurate assessment by the next examiner becomes almost impossible. Eliciting rebound tenderness by sudden release of a deeply palpating hand in a patient with suspected peritonitis is cruel and unnecessary. The same information can be obtained by gentle percussion of the abdomen (rebound tenderness on a miniature scale), a maneuver that can be far more precise and localizing. Asking the patient to cough will elicit true rebound tenderness without the need for placing a hand on the abdomen. Furthermore, the forceful demonstration of rebound tenderness will startle and induce protective spasm in a nervous or worried patient in whom true rebound tenderness is not present. A palpable gallbladder will be missed if palpation is so brusque that voluntary muscle spasm becomes superimposed on involuntary muscular rigidity.

As in history taking, there is no substitute for sufficient time spent in the examination. Abdominal signs may be minimal but nevertheless, if accompanied by consistent symptoms, may be exceptionally meaningful. Abdominal signs may be virtually or totally absent in cases of pelvic peritonitis, so careful pelvic and rectal examinations are mandatory in every patient with abdominal pain. Tenderness on pelvic or rectal examination in the absence of other abdominal signs can be caused by operative indications such as perforated appendicitis, diverticulitis, twisted ovarian cyst, and many others.

Much attention has been paid to the presence or absence of peristaltic sounds, their quality, and their frequency. Auscultation of the abdomen is one of the least revealing aspects of the physical examination of a patient with abdominal pain. Catastrophes such as strangulating small intestinal obstruction or perforated appendicitis may occur in the presence of normal peristalsis. Conversely, when the proximal part of the intestine above an obstruction becomes markedly distended and edematous, peristaltic sounds may lose the characteristics of borborygmi and become weak or absent, even when peritonitis is not present. It is usually the severe chemical peritonitis of sudden onset that is associated with the truly silent abdomen. Assessment of the patient's state of hydration is important.

Laboratory examinations may be of great value in assessment of the patient with abdominal pain, yet with few exceptions they rarely establish a diagnosis. Leukocytosis should never be the single deciding factor as to whether or not operation is indicated. A white blood cell count greater than 20,000/uL may be observed with perforation of a viscus, but pancreatitis, acute cholecystitis, pelvic inflammatory disease, and intestinal infarction may be associated with marked leukocytosis. A normal white blood cell count is not rare in cases of perforation of abdominal viscera. The diagnosis of anemia may be more helpful than the white blood cell count, especially when combined with the history.

The urinalysis may reveal the state of hydration or rule out severe renal disease, diabetes, or urinary infection. Blood urea nitrogen, glucose, and serum bilirubin levels may be helpful. Serum amylase levels may be increased by many diseases other than pancreatitis, e.g., perforated ulcer, strangulating intestinal obstruction, and acute cholecystitis; thus, elevations of serum amylase do not rule out the need for an operation. The determination of the serum lipase may have greater accuracy than that of the serum amylase.

Plain and upright or lateral decubitus radiographs of the abdomen may be of value in cases of intestinal obstruction, perforated ulcer, and a variety of other conditions. They are usually unnecessary in patients with acute appendicitis or strangulated external hernias. In rare instances, barium or water-soluble contrast study of the upper part of the gastrointestinal tract may demonstrate partial intestinal obstruction that may elude diagnosis by other means. If there is any question of obstruction of the colon, oral administration of barium sulfate should be avoided. On the other hand, in cases of suspected colonic obstruction (with perforation), contrast enema may be diagnostic.

In the absence of trauma, peritoneal lavage has been replaced as a diagnostic tool by ultrasound, computed tomography (CT), and laparoscopy. Ultrasonography has proved to be useful in detecting an enlarged gallbladder or pancreas, the presence of gallstones, an enlarged ovary, or a tubal pregnancy. Laparoscopy is especially helpful in diagnosing pelvic conditions, such as ovarian cysts, tubal pregnancies, salpingitis, and acute appendicitis. Radioisotopic scans (HIDA) may help differentiate acute cholecystitis from acute pancreatitis. A CT scan may demonstrate an enlarged pancreas, ruptured spleen, or thickened colonic or appendiceal wall and streaking of the mesocolon or mesoappendix characteristic of diverticulitis or appendicitis.

Sometimes, even under the best circumstances with all available aids and with the greatest of clinical skill, a definitive diagnosis cannot be established at the time of the initial examination. Nevertheless, despite lack of a clear anatomic diagnosis, it may be abundantly clear to an experienced and thoughtful physician and surgeon that on clinical grounds alone operation is indicated. Should that decision be questionable, watchful waiting with repeated questioning and examination will often elucidate the true nature of the illness and indicate the proper course of action.

ABDOMINAL PAIN 1

ABDOMINAL PAIN

The correct interpretation of acute abdominal pain is challenging. Since proper therapy may require urgent action, the unhurried approach suitable for the study of other conditions is sometimes denied. Few other clinical situations demand greater judgment, because the most catastrophic of events may be forecast by the subtlest of symptoms and signs. A meticulously executed, detailed history and physical examination is of great importance. The etiologic classification in , although not complete, forms a useful basis for the evaluation of patients with abdominal pain.

The diagnosis of "acute or surgical abdomen" is not an acceptable one because of its often misleading and erroneous connotation. The most obvious of "acute abdomens" may not require operative intervention, and the mildest of abdominal pains may herald an urgently correctable lesion. Any patient with abdominal pain of recent onset requires early and thorough evaluation and accurate diagnosis.

SOME MECHANISMS OF PAIN ORIGINATING IN THE ABDOMEN

Inflammation of the Parietal Peritoneum The pain of parietal peritoneal inflammation is steady and aching in character and is located directly over the inflamed area, its exact reference being possible because it is transmitted by somatic nerves supplying the parietal peritoneum. The intensity of the pain is dependent on the type and amount of material to which the peritoneal surfaces are exposed in a given time period. For example, the sudden release into the peritoneal cavity of a small quantity of sterile acid gastric juice causes much more pain than the same amount of grossly contaminated neutral feces. Enzymatically active pancreatic juice incites more pain and inflammation than does the same amount of sterile bile containing no potent enzymes. Blood and urine are often so bland as to go undetected if exposure of the peritoneum has not been sudden and massive. In the case of bacterial contamination, such as in pelvic inflammatory disease, the pain is frequently of low intensity early in the illness until bacterial multiplication has caused the elaboration of irritating substances.

The rate at which the irritating material is applied to the peritoneum is important. Perforated peptic ulcer may be associated with entirely different clinical pictures dependent only on the rapidity with which the gastric juice enters the peritoneal cavity.

The pain of peritoneal inflammation is invariably accentuated by pressure or changes in tension of the peritoneum, whether produced by palpation or by movement, as in coughing or sneezing. The patient with peritonitis lies quietly in bed, preferring to avoid motion, in contrast to the patient with colic, who may writhe incessantly.

Another characteristic feature of peritoneal irritation is tonic reflex spasm of the abdominal musculature, localized to the involved body segment. The intensity of the tonic muscle spasm accompanying peritoneal inflammation is dependent on the location of the inflammatory process, the rate at which it develops, and the integrity of the nervous system. Spasm over a perforated retrocecal appendix or perforated ulcer into the lesser peritoneal sac may be minimal or absent because of the protective effect of overlying viscera. A slowly developing process often greatly attenuates the degree of muscle spasm. Catastrophic abdominal emergencies such as a perforated ulcer may be associated with minimal or no detectable pain or muscle spasm in obtunded, seriously ill, debilitated elderly patients or in psychotic patients.

Obstruction of Hollow Viscera The pain of obstruction of hollow abdominal viscera is classically described as intermittent, or colicky. Yet the lack of a truly cramping character should not be misleading, because distention of a hollow viscus may produce steady pain with only very occasional exacerbations. It is not nearly as well localized as the pain of parietal peritoneal inflammation.

The colicky pain of obstruction of the small intestine is usually periumbilical or supraumbilical and is poorly localized. As the intestine becomes progressively dilated with loss of muscular tone, the colicky nature of the pain may diminish. With superimposed strangulating obstruction, pain may spread to the lower lumbar region if there is traction on the root of the mesentery. The colicky pain of colonic obstruction is of lesser intensity than that of the small intestine and is often located in the infraumbilical area. Lumbar radiation of pain is common in colonic obstruction.

Sudden distention of the biliary tree produces a steady rather than colicky type of pain; hence the term biliary colic is misleading. Acute distention of the gallbladder usually causes pain in the right upper quadrant with radiation to the right posterior region of the thorax or to the tip of the right scapula, and distention of the common bile duct is often associated with pain in the epigastrium radiating to the upper part of the lumbar region. Considerable variation is common, however, so that differentiation between these may be impossible. The typical subscapular pain or lumbar radiation is frequently absent. Gradual dilatation of the biliary tree, as in carcinoma of the head of the pancreas, may cause no pain or only a mild aching sensation in the epigastrium or right upper quadrant. The pain of distention of the pancreatic ducts is similar to that described for distention of the common bile duct but, in addition, is very frequently accentuated by recumbency and relieved by the upright position.

Obstruction of the urinary bladder results in dull suprapubic pain, usually low in intensity. Restlessness without specific complaint of pain may be the only sign of a distended bladder in an obtunded patient. In contrast, acute obstruction of the intravesicular portion of the ureter is characterized by severe suprapubic and flank pain that radiates to the penis, scrotum, or inner aspect of the upper thigh. Obstruction of the ureteropelvic junction is felt as pain in the costovertebral angle, whereas obstruction of the remainder of the ureter is associated with flank pain that often extends into the same side of the abdomen.

Vascular Disturbances A frequent misconception, despite abundant experience to the contrary, is that pain associated with intraabdominal vascular disturbances is sudden and catastrophic in nature. The pain of embolism or thrombosis of the superior mesenteric artery or that of impending rupture of an abdominal aortic aneurysm certainly may be severe and diffuse. Yet, just as frequently, the patient with occlusion of the superior mesenteric artery has only mild continuous diffuse pain for 2 or 3 days before vascular collapse or findings of peritoneal inflammation appear. The early, seemingly insignificant discomfort is caused by hyperperistalsis rather than peritoneal inflammation. Indeed, absence of tenderness and rigidity in the presence of continuous, diffuse pain in a patient likely to have vascular disease is quite characteristic of occlusion of the superior mesenteric artery. Abdominal pain with radiation to the sacral region, flank, or genitalia should always signal the possible presence of a rupturing abdominal aortic aneurysm. This pain may persist over a period of several days before rupture and collapse occur.

Abdominal Wall Pain arising from the abdominal wall is usually constant and aching. Movement, prolonged standing, and pressure accentuate the discomfort and muscle spasm. In the case of hematoma of the rectus sheath, now most frequently encountered in association with anticoagulant therapy, a mass may be present in the lower quadrants of the abdomen. Simultaneous involvement of muscles in other parts of the body usually serves to differentiate myositis of the abdominal wall from an intraabdominal process that might cause pain in the same region.

REFERRED PAIN IN ABDOMINAL DISEASES

Pain referred to the abdomen from the thorax, spine, or genitalia may prove a vexing diagnostic problem, because diseases of the upper part of the abdominal cavity such as acute cholecystitis or perforated ulcer are frequently associated with intrathoracic complications. A most important, yet often forgotten, dictum is that the possibility of intrathoracic disease must be considered in every patient with abdominal pain, especially if the pain is in the upper part of the abdomen. Systematic questioning and examination directed toward detecting myocardial or pulmonary infarction, pneumonia, pericarditis, or esophageal disease (the intrathoracic diseases that most often masquerade as abdominal emergencies) will often provide sufficient clues to establish the proper diagnosis. Diaphragmatic pleuritis resulting from pneumonia or pulmonary infarction may cause pain in the right upper quadrant and pain in the supraclavicular area, the latter radiation to be distinguished from the referred subscapular pain caused by acute distention of the extrahepatic biliary tree. The ultimate decision as to the origin of abdominal pain may require deliberate and planned observation over a period of several hours, during which repeated questioning and examination will provide the diagnosis.

Referred pain of thoracic origin is often accompanied by splinting of the involved hemithorax with respiratory lag and decrease in excursion more marked than that seen in the presence of intraabdominal disease. In addition, apparent abdominal muscle spasm caused by referred pain will diminish during the inspiratory phase of respiration, whereas it is persistent throughout both respiratory phases if it is of abdominal origin. Palpation over the area of referred pain in the abdomen also does not usually accentuate the pain and in many instances actually seems to relieve it. Thoracic and abdominal disease frequently coexist and may be difficult or impossible to differentiate. For example, the patient with known biliary tract disease often has epigastric pain during myocardial infarction, or biliary colic may be referred to the precordium or left shoulder in a patient who has suffered previously from angina pectoris.

Referred pain from the spine, which usually involves compression or irritation of nerve roots, is characteristically intensified by certain motions such as cough, sneeze, or strain and is associated with hyperesthesia over the involved dermatomes. Pain referred to the abdomen from the testicles or seminal vesicles is generally accentuated by the slightest pressure on either of these organs. The abdominal discomfort is of dull aching character and is poorly localized.

METABOLIC ABDOMINAL CRISES

Pain of metabolic origin may simulate almost any other type of intraabdominal disease. Several mechanisms may be at work. In certain instances, such as hyperlipidemia, the metabolic disease itself may be accompanied by an intraabdominal process such as pancreatitis, which can lead to unnecessary laparotomy unless recognized. C¢l esterase deficiency associated with angioneurotic edema is often associated with episodes of severe abdominal pain. Whenever the cause of abdominal pain is obscure, a metabolic origin always must be considered. Abdominal pain is also the hallmark of familial Mediterranean fever.

The problem of differential diagnosis is often not readily resolved. The pain of porphyria and of lead colic is usually difficult to distinguish from that of intestinal obstruction, because severe hyperperistalsis is a prominent feature of both. The pain of uremia or diabetes is nonspecific, and the pain and tenderness frequently shift in location and intensity. Diabetic acidosis may be precipitated by acute appendicitis or intestinal obstruction, so if prompt resolution of the abdominal pain does not result from correction of the metabolic abnormalities, an underlying organic problem should be suspected. Black widow spider bites produce intense pain and rigidity of the abdominal muscles and back, an area infrequently involved in intraabdominal disease.

NEUROGENIC CAUSES

Causalgic pain may occur in diseases that injure sensory nerves. It has a burning character and is usually limited to the distribution of a given peripheral nerve. Normal stimuli such as touch or change in temperature may be transformed into this type of pain, which is frequently present in a patient at rest. The demonstration of irregularly spaced cutaneous pain spots may be the only indication of an old nerve lesion underlying causalgic pain. Even though the pain may be precipitated by gentle palpation, rigidity of the abdominal muscles is absent, and the respirations are not disturbed. Distention of the abdomen is uncommon, and the pain has no relationship to the intake of food.

Pain arising from spinal nerves or roots comes and goes suddenly and is of a lancinating type. It may be caused by herpes zoster, impingement by arthritis, tumors, herniated nucleus pulposus, diabetes, or syphilis. It is not associated with food intake, abdominal distention, or changes in respiration. Severe muscle spasm, as in the gastric crises of tabes dorsalis, is common but is either relieved or is not accentuated by abdominal palpation. The pain is made worse by movement of the spine and is usually confined to a few dermatomes. Hyperesthesia is very common.

Psychogenic pain conforms to none of the aforementioned patterns. Mechanism is hard to define. The most common problem is the hysterical adolescent or young person who develops abdominal pain and who frequently loses an appendix or other organs because of it. Ovulation or some other natural event that causes brief mild abdominal discomfort may be experienced as an abdominal catastrophe.

Psychogenic pain varies enormously in type and location but usually has no relation to meals. It is often markedly accentuated during the night. Nausea and vomiting are rarely observed. Spasm is seldom induced in the abdominal musculature and, if present, does not persist, especially if the attention of the patient can be distracted. Persistent localized tenderness is rare, and if found, the muscle spasm in the area is inconsistent or absent. Shallow respiration is the most common breathing abnormality; anxiety may produce a smothering or choking sensation. It occurs in the absence of thoracic splinting or change in the respiratory rate.

HEADACHE, INCLUDING MIGRAINE 3

TREATMENT

Nonpharmacologic Approaches for All Migraineurs Migraine can often be managed to some degree by a variety of nonpharmacologic approaches. The measures that apply to a given individual should be used routinely since they provide a simple, cost-effective approach to migraine management. Patients with migraine do not encounter more stress than headache-free individuals; overresponsiveness to stress appears to be the issue. Since the stresses of everyday living cannot be eliminated, lessening one's response to stress by various techniques is helpful for many patients. These include yoga, transcendental meditation, hypnosis, and conditioning techniques such as biofeedback. For most patients, this approach is, at best, an adjunct to pharmacotherapy. Avoidance of migraine trigger factors may also provide significant prophylactic benefits . Unfortunately, these measures are unlikely to prevent all migraine attacks. When these measures fail to prevent an attack, then pharmacologic approaches are needed to abort an attack.

Pharmacologic Treatment of Acute Migraine The mainstay of pharmacologic therapy is the judicious use of one or more of the many drugs that are effective in migraine. The selection of the optimal regimen for a given patient depends on a number of factors, the most important of which is the severity of the attack. Mild migraine attacks can usually be managed by oral agents; the average efficacy rate is 50-70%. Severe migraine attacks may require parenteral therapy. Most drugs effective in the treatment of migraine are members of one of three major pharmacologic classes: anti-inflammatory agents, 5-HT1 agonists, and dopamine antagonists.

lists specific drugs effective in migraine. In general, an adequate dose of whichever agent is chosen should be used as soon as possible after the onset of an attack. If additional medication is required within 60 min because symptoms return or have not abated, the initial dose should be increased for subsequent attacks. Migraine therapy must be individualized for each patient; a standard approach for all patients is not possible. A therapeutic regimen may need to be constantly refined and personalized until one is identified that provides the patient with rapid, complete, and consistent relief with minimal side effects.

Nonsteroidal anti-inflammatory agents Both the severity and duration of a migraine attack can be reduced significantly by anti- inflammatory agents. Indeed, many undiagnosed migraineurs are self- treated with nonprescription anti-inflammatory agents. A general consensus is that NSAIDs are most effective when taken early in the migraine attack. However, the effectiveness of anti-inflammatory agents in migraine is usually less than optimal in moderate or severe migraine attacks. The combination of acetaminophen, aspirin, and caffeine (Excedrin Migraine) has been approved for use by the U.S. Food and Drug Administration (FDA) for the treatment of mild to moderate migraine. The combination of aspirin and metoclopramide has been show to be equivalent to a single dose of sumatriptan. Major side effects of NSAIDs include dyspepsia and gastrointestinal irritation.

5-HT1 agonists

ORAL Stimulation of 5-HT1 receptors can stop an acute migraine attack. Ergotamine and dihydroergotamine are nonselective receptor agonists, while the series of drugs known as triptans are selective 5-HT1 receptor agonists. A variety of triptans (e.g., naratriptan, rizatriptan, sumatriptan, zolmitriptan) are now available for the treatment of migraine .

Each of the triptan class of drugs has similar pharmacologic properties, but varies slightly in terms of clinical efficacy. Rizatriptan appears to be the fastest acting and most efficacious of the triptans currently available in the United States. Sumatriptan and zolmitriptan have similar rates of efficacy as well as time to onset, whereas naratriptan is the slowest acting and the least efficacious. Clinical efficacy appears to be related more to the tmax (time to peak plasma level) than to the potency, half-life, or bioavailability . This observation is in keeping with a significant body of data indicating that faster-acting analgesics are more efficacious than slower-acting agents.

Unfortunately, monotherapy with a selective oral 5-HT1 agonist does not result in rapid, consistent, and complete relief of migraine in all patients. Triptans are not effective in migraine with aura unless given after the aura is completed and the headache initiated. Side effects, although often mild and transient, occur in up to 89% of patients. Moreover, 5-HT1 agonists are contraindicated in individuals with a history of cardiovascular disease. Recurrence of headache is a major limitation of triptan use, and occurs at least occasionally in 40 to 78% of patients.

Ergotamine preparations offer a nonselective means of stimulating 5-HT receptors. A nonnauseating dose of ergotamine should be sought since a dose that provokes nausea is too high and may intensify head pain. Except for a sublingual formulation of ergotamine (Ergomar), oral formulations of ergotamine also contain 100 mg caffeine (theoretically to enhance ergotamine absorption and possibly to add additional vasoconstrictor activity). The average oral ergotamine dose for a migraine attack is 2 mg. Since the clinical studies demonstrating the efficacy of ergotamine in migraine predated the clinical trial methodologies used with the triptans, it is difficult to assess the clinical efficacy of ergotamine versus the triptans. In general, ergotamine appears to have a much higher incidence of nausea than triptans, but less headache recurrence.

NASAL The fastest acting nonparenteral antimigraine therapies that can be self-administered include nasal formulations of dihydroergotamine (Migranal) or sumatriptan (Imitrex Nasal). The nasal sprays result in substantial blood levels within 30 to 60 min. However, the nasal formulations suffer from inconsistent dosing, poor taste, and variable efficacy. Although in theory the nasal sprays might provide faster and more effective relief of a migraine attack than oral formulations, their reported efficacy is only approximately 50 to 60%.

PARENTERAL Parenteral administration of drugs such as dihydroergotamine (DHE-45 Injectable) and sumatriptan (Imitrex SC) is approved by the FDA for the rapid relief of a migraine attack. Peak plasma levels of dihydroergotamine are achieved 3 min after intravenous dosing, 30 min after intramuscular dosing, and 45 min after subcutaneous dosing. If an attack has not already peaked, subcutaneous or intramuscular administration of 1 mg dihydroergotamine suffices for about 80 to 90% of patients. Sumatriptan, 6 mg subcutaneously is effective in approximately 70 to 80% of patients.

Dopamine Antagonists

ORAL Oral dopamine antagonists should be considered as adjunctive therapy in migraine. Drug absorption is impaired during migrainous attacks because of reduced gastrointestinal motility. Delayed absorption occurs in the absence of nausea and is related to the severity of the attack and not its duration. Therefore, when oral NSAIDs and/or triptan agents fail, the addition of a dopamine antagonist such as metoclopramide, 10 mg, should be considered to enhance gastric absorption. In addition, dopamine antagonists decrease nausea/vomiting and restore normal gastric motility.

PARENTERAL Parenteral dopamine antagonists (e.g., chlorpromazine, prochlorperazine, metoclopramide) can also provide significant acute relief of migraine; they can be used in combination with parenteral 5-HT1 agonists. A common intravenous protocol used for the treatment of severe migraine is the administration over 2 min of a mixture of 5 mg of prochlorperazine and 0.5 mg of dihydroergotamine.

Other Medications for Acute Migraine

ORAL The combination of acetaminophen, dichloralphenazone, and isometheptene (i.e., Midrin, Duradrin, generic), one to two capsules, has been classified by the FDA as "possibly" effective in the treatment of migraine. Since the clinical studies demonstrating the efficacy of this combination analgesic in migraine predated the clinical trial methodologies used with the triptans, it is difficult to assess the clinical efficacy of this sympathomimetic compound in comparison to other agents.

NASAL A nasal preparation of butorphanol is available for the treatment of acute pain. As with all narcotics, the use of nasal butorphanol should be limited to a select group of migraineurs, as described below.

PARENTERAL Narcotics are effective in the acute treatment of migraine. For example, intravenous meperidene (Demerol), 50 to 100 mg, is given frequently in the emergency room. This regimen "works" in the sense that the pain of migraine is eliminated. However, this regimen is clearly suboptimal in patients with recurrent headache for two major reasons. First, narcotics do not treat the underlying headache mechanism; rather, they act at the thalamic level to alter pain sensation. Second, the recurrent use of narcotics can lead to significant problems. In patients taking oral narcotics such as oxycodone (Percodan) or hydrocodone (Vicoden), narcotic addiction can greatly confuse the treatment of migraine. The headache that results from narcotic craving and/ or withdrawal can be difficult to distinguish from chronic migraine. Therefore, it is recommended that narcotic use in migraine be limited to patients with severe, but infrequent, headaches that are unresponsive to other pharmacologic approaches.

Prophylactic Treatment of Migraine A substantial number of drugs are now available that have the capacity to stabilize migraine. The decision of whether to use this approach depends on the frequency of attacks and on how well acute treatment is working. The occurrence of at least three attacks per month could be an indication for this approach. Drugs must be taken daily and there is usually a lag of at least 2 to 6 weeks before an effect is seen. The drugs that have been approved by the FDA for the prophylactic treatment of migraine include propranolol, timolol, sodium valproate, and methysergide. In addition, a number of other drugs appear to display prophylactic efficacy. This group of drugs includes amitriptyline, nortriptyline, verapamil, phenelzine, isocarbazid, and cyproheptadine. Phenelzine and methysergide are usually reserved for recalcitrant cases because of their serious potential side effects. Phenelzine is an MAOI; therefore, tyramine-containing foods, decongestants, and meperidine are contraindicated. Methysergide may cause retroperitoneal or cardiac valvular fibrosis when it is used for more than 8 months, thus monitoring is required for patients using this drug; the risk of the fibrotic complication is about 1:1500 and is likely to reverse after the drug is stopped.

The probability of success with any one of the antimigraine drugs is 50 to 75%; thus, if one drug is assessed each month, there is a good chance that effective stabilization will be achieved within a few months. Many patients are managed adequately with low-dose amitriptyline, propranolol, or valproate. If these agents fail or lead to unacceptable side effects, then methysergide or phenelzine can be used. Once effective stabilization is achieved, the drug is continued for 5 to 6 months and then slowly tapered to assess the continued need. Many patients are able to discontinue medication and experience fewer and milder attacks for long periods, suggesting that these drugs may alter the natural history of migraine.

CLUSTER HEADACHE

A variety of names have been used for this condition, including Raeder's syndrome, histamine cephalalgia, and sphenopalatine neuralgia. Cluster headache is a distinctive and treatable vascular headache syndrome. The episodic type is most common and is characterized by one to three short-lived attacks of periorbital pain per day over a 4- to 8-week period, followed by a pain- free interval that averages 1 year. The chronic form, which may begin de novo or several years after an episodic pattern has become established, is characterized by the absence of sustained periods of remission. Each type may transform into the other. Men are affected seven to eight times more often than women; hereditary factors are usually absent. Although the onset is generally between ages 20 and 50, it may occur as early as the first decade of life. Propranolol and amitriptyline are largely ineffective. Lithium is beneficial for cluster headache and ineffective in migraine. The cluster syndrome is thus clinically, genetically, and therapeutically different from migraine. Nevertheless, mixed features of the two disorders are occasionally present, suggesting some common elements to their pathogenesis.

Clinical Features Periorbital or, less commonly, temporal pain begins without warning and reaches a crescendo within 5 min. It is often excruciating in intensity and is deep, nonfluctuating, and explosive in quality; only rarely is it pulsatile. Pain is strictly unilateral and usually affects the same side in subsequent months. Attacks last from 30 min to 2 h; there are often associated symptoms of homolateral lacrimation, reddening of the eye, nasal stuffiness, lid ptosis, and nausea. Alcohol provokes attacks in about 70% of patients but ceases to be provocative when the bout remits; this on-off vulnerability to alcohol is pathognomonic of cluster headache. Only rarely do foods or emotional factors precipitate pain, in contrast to migraine.

There is a striking periodicity of attacks in at least 85% of patients. At least one of the daily attacks of pain recurs at about the same hour each day for the duration of a cluster bout. Onset is nocturnal in about 50% of the cases, and then the pain usually awakens the patient within 2 h of falling asleep.

Pathogenesis No consistent cerebral blood flow changes accompany attacks of pain. Perhaps the strongest evidence for a central mechanism is the periodicity of attacks; the existence of a central mechanism is also suggested by the observation that autonomic symptoms that accompany the pain are bilateral and are more severe on the painful side. The hypothalamus may be the site of activation in this disorder. The posterior hypothalamus contains cells that regulate autonomic functions, and the anterior hypothalamus contains cells (in the suprachiasmatic nuclei) that constitute the principal circadian pacemaker in mammals. Activation of both is necessary to explain the symptoms of cluster headache. The pacemaker is modulated via serotonergic dorsal raphe projections. It can be concluded tentatively that both migraine and cluster headache result from abnormal serotonergic neurotransmission, albeit at different loci.

TREATMENT

The most satisfactory treatment is the administration of drugs to prevent cluster attacks until the bout is over. Effective prophylactic drugs are prednisone, lithium, methysergide, ergotamine, sodium valproate, and verapamil. Lithium (600 to 900 mg daily) appears to be particularly useful for the chronic form of the disorder. A 10-day course of prednisone, beginning at 60 mg daily for 7 days followed by a rapid taper, may interrupt the pain bout for many patients. When ergotamine is used, it is most effective when given 1 to 2 h before an expected attack. Patients must be educated regarding the early symptoms of ergotism when ergotamine is used daily; a weekly limit of 14 mg should be adhered to.

For the attacks themselves, oxygen inhalation (9 L/min via a loose mask) is the most effective modality; 15 min of inhalation of 100% oxygen is often necessary. Sumatriptan, 6 mg subcutaneously, will usually shorten an attack to 10 to 15 min.

HEADACHE, INCLUDING MIGRAINE 2

PRINCIPAL CLINICAL VARIETIES OF RECURRENT HEADACHE

There is usually little difficulty in diagnosing the serious types of headaches listed above because of the clues provided by the associated symptoms and signs. It is when headache is chronic, recurrent, and unattended by other important signs of disease that the physician faces a challenging and unique medical problem. The following sections describe a variety of headache types, ranging from the most common (e.g., tension-type headache) to rare causes of recurrent headache.

TENSION-TYPE HEADACHE

The term tension-type headache is still commonly used to describe a chronic head pain syndrome characterized by bilateral tight, bandlike discomfort. Patients may report that the head feels as if it is in a vise or that the posterior neck muscles are tight. The pain typically builds slowly, fluctuates in severity, and may persist more or less continuously for many days. Exertion does not usually worsen the headache. The headache may be episodic or chronic (i.e., present more than 15 days per month). Tension-type headache is common in all age groups, and females tend to predominate. In some patients, anxiety or depression coexist with tension headache.

The pathophysiologic basis of tension-type headache remains unknown. Some investigators believe that periodic tension headache is biologically indistinguishable from migraine, whereas others believe that tension-type headache and migraine are two distinct clinical entities. Abnormalities of cervical and temporal muscle contraction are likely to exist, but the exact nature of the dysfunction has not yet been elucidated.

Relaxation almost always relieves tension-type headaches. Patients should be encouraged to find a means of relaxation, which, for a given individual, could include bed rest, massage, and/or formal biofeedback training. Pharmacologic treatment consists of either simple analgesics and/or muscle relaxants. Ibuprofen and naproxen sodium are useful treatments for most individuals. When simple over-the-counter analgesics such as acetaminophen, aspirin, ibuprofen, and/or other nonsteroidal anti-inflammatory drugs (NSAIDs) alone fail, the addition of butalbital and caffeine (in a combination compound such as Fiorinal, Fioricet) to these analgesics may be effective. A list of commonly used analgesics for tension-type headaches is presented in . For chronic tension-type headache, prophylactic therapy is recommended. Low doses of amitriptyline (10 to 50 mg at bedtime) can provide effective prophylaxis.

MIGRAINE

Migraine, the most common cause of vascular headache, afflicts approximately 15% of women and 6% of men. A useful definition of migraine is a benign and recurring syndrome of headache, nausea, vomiting, and/or other symptoms of neurologic dysfunction in varying admixtures. Migraine can often be recognized by its activators (red wine, menses, hunger, lack of sleep, glare, estrogen, worry, perfumes, let-down periods) and its deactivators (sleep, pregnancy, exhiliration, sumatriptan). A classification of the many subtypes of migraine, as defined by the International Headache Society, is shown in .

Severe headache attacks, regardless of cause, are more likely to be described as throbbing and associated with vomiting and scalp tenderness. Milder headaches tend to be nondescript¾tight, bandlike discomfort often involving the entire head¾the profile of tension-type headache.

Pathogenesis

Genetic Basis of Migraine Migraine has a definite genetic predisposition. Specific mutations leading to rare causes of vascular headache have been identified. For example, the MELAS syndrome consists of a mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes and is caused by an A ® G point mutation in the mitochondrial gene encoding for tRNALeu(UUR) at nucleotide position 3243. Episodic migraine-like headaches are another common clinical feature of this syndrome, especially early in the course of the disease. The genetic pattern of mitochondrial disorders is unique, since only mothers transmit mitochondrial DNA. Thus, all children of mothers with MELAS syndrome are affected with the disorder.

Familial hemiplegic migraine (FHM) is characterized by episodes of recurrent hemiparesis or hemiplegia during the aura phase of a migraine headache. Other associated symptoms may include hemianesthesia or paresthesia; hemianopic visual field disturbances; dysphasia; and variable degrees of drowsiness, confusion, and/or coma. In severe attacks, these symptoms can be quite prolonged and persist for days or weeks, but characteristically they last for only 30 to 60 min and are followed by a unilateral throbbing headache.

Approximately 50% of cases of FHM appear to be caused by mutations within the CACNL1A4 gene on chromosome 19, which encodes a P/Q type calcium channel subunit expressed only in the central nervous system. The gene is very large (>300 kb in length) and consists of 47 exons. Four distinct point mutations have been identified within the gene (in five different families) that cosegregate with the clinical diagnosis of FHM. Analysis of haplotypes in the two families with the same mutation suggest that each mutation arose independently rather than representing a founder effect. Thus, certain subtypes of FHM are caused by mutations in the CACNL1A4 gene. The function of the CACNL1A4 gene remains unknown, but it is likely to play a role in calcium-induced neurotransmitter release and/or contraction of smooth muscle. Different mutations within this gene are the cause of another neurogenetic disorder, episodic ataxia type 2.

In a genetic association study, a NcoI polymorphism in the gene encoding the D2 dopamine receptor (DRD2) was overrepresented in a population of patients with migraine with aura compared to a control group of nonmigraineurs, suggesting that susceptibility to migraine with aura is modified by certain DRD2 alleles. In a Sardinian population, an association between different DRD2 alleles and migraine has also been demonstrated. Therefore, these initial studies suggest that variations in dopamine receptor regulation and/or function may alter susceptibility to migraine since molecular variations within the DRD2 gene have been associated with variations in dopaminergic function. However, since not all individuals with certain DRD2 genotypes suffer from migraine with aura, additional genes or factors must also be involved. Migraine is likely to be a complex disorder with polygenic inheritance and a strong environmental component.

The Vascular Theory of Migraine It was widely held for many years that the headache phase of migrainous attacks was caused by extracranial vasodilatation and that the neurologic symptoms were produced by intracranial vasoconstriction (i.e., the "vascular" hypothesis of migraine). Regional cerebral blood flow studies have shown that in patients with classic migraine there is, during attacks, a modest cortical hypoperfusion that begins in the visual cortex and spreads forward at a rate of 2 to 3 mm/min. The decrease in blood flow averages 25 to 30% (insufficient to explain symptoms on the basis of ischemia) and progresses anteriorly in a wavelike fashion independent of the topography of cerebral arteries. The wave of hypoperfusion persists for 4 to 6 h, appears to follow the convolutions of the cortex, and does not cross the central or lateral sulcus, progressing to the frontal lobe via the insula. Perfusion of subcortical structures is normal. Contralateral neurologic symptoms appear during temporoparietal hypoperfusion; at times, hypoperfusion persists in these regions after symptoms cease. More often, frontal spread continues as the headache phase begins. A few patients with classic migraine show no flow abnormalities; an occasional patient has developed focal ischemia sufficient to cause symptoms. However, focal ischemia does not appear to be necessary for focal symptoms to occur.

The ability of these changes to induce the symptoms of migraine has been questioned. Specifically, the decrease in blood flow that is observed does not appear to be significant enough to cause focal neurologic symptoms. Second, the increase in blood flow per se is not painful, and vasodilatation alone cannot account for the local edema and focal tenderness often observed in migraineurs. Moreover, in migraine without aura, no flow abnormalities are usually seen. Thus, it is unlikely that simple vasoconstriction and vasodilatation are the fundamental pathophysiologic abnormalities in migraine. However, it is clear that cerebral blood flow is altered during certain migraine attacks, and these changes may explain some, but clearly not all, of the clinical syndrome of migraine.

The Neuronal Theory of Migraine In 1941, the psychologist KS Lashley charted his own fortification spectrum, which is a migraine aura characterized by a slowly enlarging visual scotoma with luminous edges (see below). He was able to estimate that the evolution of his own scotoma proceeded across the occipital cortex at a rate of 3 mm/min. He speculated that a wavefront of intense excitation followed by a wave of complete inhibition of activity were propagated across the visual cortex. In 1944, the phenomenon that has come to be known as spreading depression was described by the Brazilian physiologist Leao in the cerebral cortex of laboratory animals. It is a slowly moving (2 to 3 mm/min), potassium-liberating depression of cortical activity, preceded by a wavefront of increased metabolic activity that can be produced by a variety of experimental stimuli, including hypoxia, mechanical trauma, and the topical application of potassium. These observations suggest that neuronal abnormalities, most likely initiated in the brainstem, could be the cause of a migraine attack. More recently, both cortical and brainstem changes have been observed in positron emission tomography (PET) scan studies of migraine. Thus, the existence of a specific "brainstem generator" for migraine remains an intriguing possibility that might represent the pathophysiologic basis of migraine.

The Trigeminovascular System in Migraine Activation of cells in the trigeminal nucleus caudalis in the medulla (a pain-processing center for the head and face region) results in the release of vasoactive neuropeptides, including substance P and calcitonin gene-related peptide (CGRP), at vascular terminations of the trigeminal nerve. These peptide neurotransmitters have been proposed to induce a sterile inflammation that activates trigeminal nociceptive afferents originating on the vessel wall, further contributing to the production of pain. This mechanism also provides a potential mechanism for the soft tissue swelling and tenderness of blood vessels that attend migraine attacks. However, numerous pharmacologic agents that are effective in preventing or reducing inflammation in this animal model (e.g., selective 5-HT1D agonists, NK-1 antagonists, endothelin antagonists) have failed to demonstrate any clinical efficacy in recent migraine trials.

5-Hydroxytryptamine in Migraine Pharmacologic and other data point to the involvement of the neurotransmitter 5-hydroxytryptamine (5-HT; also know as serotonin) in migraine. Approximately 40 years ago, methysergide was found to antagonize certain peripheral actions of 5-HT and was introduced as the first drug capable of preventing migraine attacks. Subsequently, it was found that platelet levels of 5-HT fall consistently at the onset of headache and that drugs that cause 5-HT to be released may trigger migrainous episodes. Such changes in circulating 5-HT levels proved to be pharmacologically trivial, however, and interest in the humoral role of 5-HT in migraine declined.

More recently, interest in the role of 5-HT in migraine has been renewed due to the introduction of the triptan class of antimigraine drugs. The triptans are designed to stimulate selectively a particular subpopulation of 5-HT receptors. Molecular cloning studies have demonstrated that at least 14 specific 5-HT receptors exist in humans. The triptans (e.g., naratriptan, rizatriptan, sumatriptan, and zolmitriptan) are potent agonists of 5-HT1B, 5-HT1D, and 5-HT1F receptors and are less potent at 5-HT1A and 5-HT1E receptors. A growing body of data indicates that the antimigraine efficacy of the triptans relates to their ability to stimulate 5-HT1B receptors, which are located both on blood vessels and nerve terminals. Selective 5-HT1D receptor agonists have, thus far, failed to demonstrate clinical efficacy in migraine. Triptans that are weak 5-HT1F agonists are also effective in migraine; however, only 5-HT1B efficacy is currently thought to be essential for antimigraine efficacy.

Physiologically, electrical stimulation near dorsal raphe neurons can result in migraine-like headaches. Blood flow in the pons and midbrain increases focally during migraine headache episodes; this alteration probably results from increased activity of cells in the dorsal raphe and locus caeruleus. There are projections from the dorsal raphe that terminate on cerebral arteries and alter cerebral blood flow. There are also major projections from the dorsal raphe to important visual centers, including the lateral geniculate body, superior colliculus, retina, and visual cortex. These various serotonergic projections may represent the neural substrate for the circulatory and visual characteristics of migraine. The dorsal raphe cells stop firing during deep sleep, and sleep is known to ameliorate migraine; the antimigraine prophylactic drugs also inhibit activity of the dorsal raphe cells through a direct or indirect agonist effect.

Recent PET scan studies have demonstrated that midbrain structures near the dorsal raphe are differentially activated during a migraine attack. In one study of acute migraine, an injection of sumatriptan relieved the headache, but did not alter the brainstem changes noted on the PET scan. These data suggest that a "brainstem generator" may be the cause of migraine and that certain antimigraine medications may not interfere with the underlying pathologic process in migraine.

Dopamine in Migraine A growing body of biologic, pharmacologic, and genetic data support a role for dopamine in the pathophysiology of certain subtypes of migraine. Most migraine symptoms can be induced by dopaminergic stimulation. Moreover, there is dopamine receptor hypersensitivity in migraineurs, as demonstrated by the induction of yawning, nausea, vomiting, hypotension, and other symptoms of a migraine attack by dopaminergic agonists at doses that do not affect nonmigraineurs. Conversely, dopamine receptor antagonists are effective therapeutic agents in migraine, especially when given parenterally or concurrently with other antimigraine agents. As noted above, recent genetic data also suggest that molecular variations within dopamine receptor genes play a modifying role in the pathophysiology of migraine with aura. Therefore, modulation of dopaminergic neurotransmission should be considered in the therapeutic management of migraine.

The Sympathetic Nervous System in Migraine Biochemical changes occur within the sympathetic nervous system (SNS) of migraineurs before, during, and between migraine attacks. Factors that activate the SNS are all trigger factors for migraine. Specific examples include environmental changes (e.g., stress, sleep patterns, hormonal shifts, hypoglycemia) and agents that cause release and a secondary depletion of peripheral catecholamines [e.g., tyramine, phenylethylamine, fenfluramine, m-chlorophenylpiperazine (mCPP) and reserpine]. By contrast, effective therapeutic approaches to migraine share an ability to mimic and/or enhance the effects of norepinephrine in the peripheral SNS. For example, norepinephrine itself, sympathomimetics (e.g., isometheptene), monoamine oxidase inhibitors (MAOIs) and reuptake blockers alleviate migraine. Dopamine antagonists, prostaglandin synthesis inhibitors, and adenosine antagonists are pharmacologic agents effective in the acute treatment of migraine. These drugs block the negative feedback inhibition or norepinephrine release induced by endogenous dopamine, prostaglandins, and adenosine. Therefore, migraine susceptibility may relate to genetically based variations in the ability to maintain adequate concentrations of certain neurotransmitters within postganglionic sympathetic nerve terminals. This hypothesis has been called the empty neuron theory of migraine.

Clinical Features

Migraine without Aura (Common Migraine) In this syndrome no focal neurologic disturbance precedes the recurrent headaches. Migraine without aura is by far the more frequent type of vascular headache. The International Headache Society criteria for migraine include moderate to severe head pain, pulsating quality, unilateral location, aggravation by walking stairs or similar routine activity, attendant nausea and/or vomiting, photophobia and phonophobia, and multiple attacks, each lasting 4 to 72 h.

Migraine with Aura (Classic Migraine) In this syndrome headache is associated with characteristic premonitory sensory, motor, or visual symptoms. Focal neurologic disturbances are more common during headache attacks than as prodromal symptoms. Focal neurologic disturbances without headache or vomiting have come to be known as migraine equivalents or migraine accompaniments and appear to occur more commonly in patients between the ages of 40 and 70 years. The term complicated migraine has generally been used to describe migraine with dramatic transient focal neurologic features or a migraine attack that leaves a persisting residual neurologic deficit.

The most common premonitory symptoms reported by migraineurs are visual, arising from dysfunction of occipital lobe neurons. Scotomas and/or hallucinations occur in about one-third of migraineurs and usually appear in the central portions of the visual fields. A highly characteristic syndrome occurs in about 10% of patients; it usually begins as a small paracentral scotoma, which slowly expands into a "C" shape. Luminous angles appear at the enlarging outer edge, becoming colored as the scintillating scotoma expands and moves toward the periphery of the involved half of the visual field, eventually disappearing over the horizon of peripheral vision. The entire process lasts 20 to 25 min. This phenomenon is pathognomonic for migraine, and has never been described in association with a cerebral structural anomaly. It is commonly referred to as a fortification spectrum because the serrated edges of the hallucinated "C" seemed to resemble a "fortified town with bastions all round it"; "spectrum" is used in the sense of an apparition or specter.

Basilar Migraine Symptoms referable to a disturbance in brainstem function, such as vertigo, dysarthria, or diplopia, occur as the only neurologic symptoms of the attack in about 25% of patients. A dramatic form of basilar migraine (Bickerstaff's migraine) occurs primarily in adolescent females. Episodes begin with total blindness accompanied or followed by admixtures of vertigo, ataxia, dysarthria, tinnitus, and distal and perioral paresthesia. In about one-quarter of patients, a confusional state supervenes. The neurologic symptoms usually persist for 20 to 30 min and are generally followed by a throbbing occipital headache. This basilar migraine syndrome is now known also to occur in children and in adults over age 50. An altered sensorium may persist for as long as 5 days and may take the form of confusional states superficially resembling psychotic reactions. Full recovery after the episode is the rule.

Carotidynia The carotidynia syndrome, sometimes called lower- half headache or facial migraine, is most common among older patients, with the incidence peaking in the fourth through sixth decades. Pain is usually located at the jaw or neck, although sometimes periorbital or maxillary pain occurs; it may be continuous, deep, dull, and aching, and it becomes pounding or throbbing episodically. There are often superimposed sharp, ice pick-like jabs. Attacks occur one to several times per week, each lasting several minutes to hours. Tenderness and prominent pulsations of the cervical carotid artery and soft tissue swelling overlying the carotid are usually present ipsilateral to the pain; many patients also report throbbing ipsilateral headache concurrent with carotidynia attacks as well as between attacks. Dental trauma is a common precipitant of this syndrome. Carotid artery involvement also appears to be common in the more traditional forms of migraine; over 50% of patients with frequent migraine attacks are found to have carotid tenderness at several points on the side most often involved during hemicranial migraine attacks.