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Syndrome de défaillance des barorécepteurs après chirurgie bilatérale pour tumeurs glomiques carotidiennes
Cas cliniques Syndrome de d efaillance des baror ecepteurs apres chirurgie bilat erale pour tumeurs glomiques carotidiennes Ilia Gur, Steven Katz, Pasadena, CA, USA
de 41 ans avait des tumeurs bilate rales du glomus carotidien. Le Un homme en bonne sante environ 8 mois d’e cart. patient avait eu une ablation chirurgicale successive des tumeurs a ratoires avaient e te simples apre s l’ablation de la premie re et plus grosse Les suites postope s l’ablation de la deuxie me tumeur, le patient a de veloppe une tumeur ; cependant, apre te diagnostique un syndrome de de faillance des tachycardie et une hypertension. Il a e cepteurs apre s avoir e limine d’autres causes possibles. Le syndrome de de faillance des barore cepteurs est une complication rare et grave connue pour e ^tre associe a beaucoup de barore tant la de nervation des barore cepteurs pendant la re section circonstances, l’une d’entre elles e rale des tumeurs glomiques. La gestion me dicale de cette condition est ne cessaire pour bilate ^cher des e ve nements ce re brovasculaires ; ainsi, il est important que le chirurgien et empe l’interniste l’identifient pour un traitement agressif.
The patient in this case is a 41-year-old man who presented with left-sided neck swelling that had been present for approximately 3 months. No other symptoms were reported. On physical examination, bilateral nontender neck swelling was found. A computerized tomography angiogram revealed a mass measuring 2.2 2.5 cm2 located at the right carotid bifurcation, and another measuring 4.7 6 cm2 in the same position in the left side of the neck, raising the clinical suspicion of bilateral paragangliomas (Fig. 1). There was no family history of neuroendocrine tumors and the tests for pheochromocytoma were negative. The larger left-sided tumor was excised without complications. Pathology confirmed the diagnosis DOI of original article: 10.1016/j.avsg.2010.05.022. Division of Vascular Surgery, Keck School of Medicine, Huntington Memorial Hospital, Pasadena, CA, USA. Correspondence : Steven Katz, MD, Division of Vascular Surgery, Keck School of Medicine; Huntington Memorial Hospital, Pasadena, CA, USA, E-mail: [email protected] Ann Vasc Surg 2010; 24: 1138.e1-1138.e3 DOI: 10.1016/j.acvfr.2011.05.016 Ó Annals of Vascular Surgery Inc. e par ELSEVIER MASSON SAS Edit
of paraganglioma. The patient recovered uneventfully, was discharged from the hospital on the first postoperative day, and was followed up as an outpatient. After 8 months, the patient was readmitted for surgical excision of the contralateral carotid body tumor. Initially, the patient did well after the surgery; however, the following morning, he developed unexplained hypertension and tachycardia. His blood pressure increased to 160/120 mm Hg and the heart rate to140 beats per minute. The patient denied pain, chest pain, dizziness, and shortness of breath. Subjectively, he felt well and was eager to go home, but his uncontrolled hypertension and tachycardia precluded his safe discharge. His hemoglobin level was stable and there was no evidence of hypovolemia. In view of the absence of a previous history of hypertension and the lack of any other plausible explanation for the elevated blood pressure and tachycardia, and given the clinical setting of bilateral carotid body tumor excision, a tentative diagnosis of baroreceptor failure syndrome (BFS) was considered. The patient was treated with beta blockers and clonidine and was discharged from the hospital 1229.e9
1229.e10 Cas cliniques
Fig. 1. Computerized Tomography angiogram showing bilateral carotid body tumors.
on the following day. Currently he is 4 months after operation and requires two drug therapies to maintain a normotensive state.
DISCUSSION AND LITERATURE REVIEW Advances in surgical technology and operative techniques have reduced the perioperative mortality risk of carotid body tumor resection to 0.5-1%, the risk of stroke to 2-3%, and postoperative cranial nerve deficit to 0-70%.1 With an increasing number of patients undergoing surgical resection, many authors have begun to report a poorly understood and an unusual complication after bilateral neck dissections for carotid body tumor. The syndrome, designated as ‘‘BFS,’’ is characterized by varying degrees of hypertension, tachycardia, headache, and anxiety. In some instances, it has led to hypertensive encephalopathy and stroke. Baroreceptors are the stretch receptors which participate in the control of arterial blood pressure. They are located in the wall of main arteries in the neck and thorax, and are particularly abundant in the carotid sinuses and aortic arch. In the event of elevated blood pressure, the signals from the baroreceptors inhibit the vasoconstrictor center and excite the vagal center, causing vasodilation and slowing the heart rate. With hypotension, the rate of impulses slows down causing the opposite effect. Canine studies have shown that interruption of the baroreceptor impulses causes unopposed sympathetic signals from the brainstem, which may cause extremely labile blood pressure after minor events such as excitation, changing body position, eating, defecating, or with external stimuli, such as noise.
Annales de chirurgie vasculaire
One of the first cases was reported by Sugarbaker et al., describing a patient with familial bilateral carotid body tumors.2 The patient underwent a staged surgical excision of tumors, and after resection of the second tumor developed unexplained tachycardia and hypertension. Other causes of hypertension including pheochromocytoma were excluded. The authors suggested that bilateral denervation of the baroreceptors may have been responsible for these symptoms. Since this description, other authors too have described similar symptoms appearing after bilateral carotid body tumor resection.3-5 Because these symptoms are not seen after resection of unilateral tumors, it would seem that the contralateral baroreceptor is sufficient to maintain blood pressure control. The common findings for patients diagnosed with BFS were the onset of sudden severe hypertension 24-72 hours postoperatively along with sinus tachycardia and headache. Many patients were also found to have high levels emotional lability which further contributed to unstable blood pressure. Some studies have suggested that clonidine is probably the medication of choice for treating this condition and partial improvement of symptoms is seen frequently. However, there are no publications documenting a complete remission of BFS after bilateral carotid body tumor surgery. One of the largest series of patients with carotid body tumors was reported by Netterville et al.6 Besides an extensive discussion about clinical features of the carotid body tumors and many aspects of the surgical technique, the authors concentrated on the results of the treatment. Of the 30 patients, 16 presented with bilateral carotid body tumors. Eleven patients with bilateral tumors demonstrated a familial pattern. Patients with a familial pattern were also prone to paragangliomas in other locations. Resection of cranial nerves along with the tumor was necessary in four patients, and metastatic spread of tumor was found in two patients. Because of the unusually high percentage of bilateral carotid body tumors, these authors had a unique opportunity to get a better insight into BFS. The authors encountered symptoms of BFS in 2 of 10 patients operated upon for bilateral tumors. They also noticed a correlation between anxiety and other stressors and episodes of hypertension in these patients and suggested that benzodiazepines may be used along with clonidine. Several other conditions have also been found to be associated with BFS including neck trauma,7 brainstem stroke,8 neck irradiation,9,10 and in very rare cases, bilateral carotid endarterectomy.11,12
Vol. 24, No. 8, 2010
It has been suggested that the true incidence of BFS may be higher than reported as it may have variable presentations and severity of symptoms. The following four possible clinical manifestations may exist together or in isolated form: hypertensive crisis, volatile hypertension, orthostatic tachycardia, and malignant vagotonia.13 The hypertensive crisis is most frequently associated with sudden denervation of baroreceptors, caused by surgical intervention. Systolic blood pressure may exceed 250 mm Hg accompanied with tachycardia and headache. Urgent measures are required to prevent cerebrovascular complications. Volatile hypertension is less striking but a far more frequent manifestation of BFS. It usually presents a few days to weeks after the injury, or may develop invidiously with a gradual decline of baroreceptor function. This phase is more permanent and characterized by surges of elevated blood pressure frequently in response to external stimuli, intermingled with periods of relative normotension. Orthostatic tachycardia is one of the more common reasons patients eventually diagnosed with BFS are referred to a tertiary center. Malignant vagotonia may present as severe bradycardia or asystole, and is postulated to be caused by a complete or near complete obliteration of baroreceptor input to the medulla resulting in unopposed parasympathetic outflow to the heart. Because BFS may mimic other conditions, it should be considered in the differential diagnosis of new onset hypertension along with pheochromocytoma and autonomic neuropathy. Both the hypertensive surges of BFS and pheochromocytoma may produce elevated levels of catecholamines and metanephrines. Differentiation from the autonomic failure may also be challenging. In contrast to BFS that is caused by the damage to afferent innervation of baroreceptors, autonomic neuropathy is characterized by abnormal efferent innervation to the heart and arteries. Patients with autonomic failure are more prone to have orthostatic hypotension and postprandial hypotension, whereas those with BFS more often have labile hypertension and episodic tachycardia. Early treatment of BFS was largely empiric. Authors have described relative success with the central alpha agonist clonidine. A biological rationale for the use of this drug is that it stimulates alpha 2 receptors in the brainstem, thus inhibiting central sympathetic outflow and preventing the peripheral release of norepinephrine. It also stimulates the parasympathetic outflow which contributes to the slowing of the heart rate. Because it treats both the hypertension and tachycardia, clonidine has become the drug of choice for the treatment of BFS. Other medications with short half-lives, such
Cas cliniques 1229.e11
as nitroprusside, phentolamine, and labetalol, are effective in case of hypertensive emergency. Apart from antihypertensive agents, benzodiazepines may be used to help with anxiety-associated symptoms. Because the chronic phase of BFS may last for years, patients may require chronic antihypertensive medication and long-term follow-up. If there is partial recovery and stabilization of the blood pressure, an attempt may be made to taper off antihypertensive medications. It has also been suggested that patients with BFS should be referred to and treated at specialized centers that have the ability to perform a careful assessment of the autonomic function.14 In summary, BFS is an unusual but important clinical entity that is frequently overlooked. BFS results from baroreceptor denervation and presents as tachycardia, sustained or labile hypertension, headache, and anxiety. It is particularly likely to develop after carotid body tumor surgery but may rarely be seen after carotid artery surgery, neck irradiation, and trauma. Bilateral injury to the baroreceptors is required to produce the symptoms. BFS should be promptly recognized in these cases and appropriate therapy instituted to prevent serious cerebrovascular and cardiovascular complications. REFERENCES 1. Rutherford R. Vascular Surgery. 6th ed. New York, NY: Saunders, 2005. pp 2066-2071. 2. Sugarbaker EV, Chretien PB, Jacobs JB. Bilateral familial carotid body tumors: report of a patient with an occult contralateral tumor and postoperative hypertension. Ann Surg 1971;174:242-247. 3. Boyle JR, London NJ, Tan SG, et al. Labile blood pressure after bilateral carotid body tumor surgery. Eur J Vasc Endovasc Surg 1995;9:346-348. 4. Robertson D, Hollister AS, Biaggioni I, et al. The diagnosis of baroreceptor failure. N Eng J Med 1993;329:1449-1455. 5. De Toma G, Nicolanti V, Plocco M, et al. Baroreflex failure syndrome after bilateral excision of carotid body tumors: an underestimated problem. J Vasc Surg 2000;31:806-810. 6. Netterville JL, Reilly KM, Robertson, et al. Carotid body tumors: a review of 30 patients with 46 tumors. Laryngoscope 1995;105:115-126. 7. Robertson D, Hollister AS, Biaggioni I, et al. The diagnosis and treatment of baroreceptor failure. N Eng J Med 1993;329:1449-1455. 8. Biaggioni I, Whetsell WO, Jobe J, Nadeau JH. Baroreflex failure in a patient with central nervous system lesion involving the nucleus tractus solitarii. Hypertension 1994;23:491-495. 9. Sharabi Y, Dendi R, Holmes C, Goldstein DS. Baroreflex failure as a late sequela of neck irradiation. Hypertension 2003;42:110-116. 10. Timmers HJ, Karemaker JM, Lenders JW, Weiling W. Baroreflex failure following radiation therapy for nasopharingeal carcinoma. Clin Auton Res 1999;9:317-324. 11. Ille O, Woimant F, Pruna A, et al. Hypertensive encephalopathy after bilateral carotid body tumor surgery. Stroke 1995;26:488-491.
1229.e12 Cas cliniques
12. Ejas AA, Meschia JF. Thalamic hemorrhage following carotid endarterectomy. Case report and therapeutic considerations. Arch Intern Med 1984;144:1489-1491. 13. Ketch T, Biaggioni I, Robertson R, Robertson D. Four faces of baroreceptor failure: hypertensive crisis, volatile
Annales de chirurgie vasculaire
hypertension, orthostatic tachycardia and malignant vagotonia. Circulation 2002;105:2518-2523. 14. Timmers HJ, Wieling W, Karemaker, Lenders JW. Baroreflex failure: a neglected type of secondary hypertension. N Eng J Med 2004;62:151-155.
de 41 ans avait des tumeurs bilate rales du glomus carotidien. Le Un homme en bonne sante environ 8 mois d’e cart. patient avait eu une ablation chirurgicale successive des tumeurs a ratoires avaient e te simples apre s l’ablation de la premie re et plus grosse Les suites postope s l’ablation de la deuxie me tumeur, le patient a de veloppe une tumeur ; cependant, apre te diagnostique un syndrome de de faillance des tachycardie et une hypertension. Il a e cepteurs apre s avoir e limine d’autres causes possibles. Le syndrome de de faillance des barore cepteurs est une complication rare et grave connue pour e ^tre associe a beaucoup de barore tant la de nervation des barore cepteurs pendant la re section circonstances, l’une d’entre elles e rale des tumeurs glomiques. La gestion me dicale de cette condition est ne cessaire pour bilate ^cher des e ve nements ce re brovasculaires ; ainsi, il est important que le chirurgien et empe l’interniste l’identifient pour un traitement agressif.
The patient in this case is a 41-year-old man who presented with left-sided neck swelling that had been present for approximately 3 months. No other symptoms were reported. On physical examination, bilateral nontender neck swelling was found. A computerized tomography angiogram revealed a mass measuring 2.2 2.5 cm2 located at the right carotid bifurcation, and another measuring 4.7 6 cm2 in the same position in the left side of the neck, raising the clinical suspicion of bilateral paragangliomas (Fig. 1). There was no family history of neuroendocrine tumors and the tests for pheochromocytoma were negative. The larger left-sided tumor was excised without complications. Pathology confirmed the diagnosis DOI of original article: 10.1016/j.avsg.2010.05.022. Division of Vascular Surgery, Keck School of Medicine, Huntington Memorial Hospital, Pasadena, CA, USA. Correspondence : Steven Katz, MD, Division of Vascular Surgery, Keck School of Medicine; Huntington Memorial Hospital, Pasadena, CA, USA, E-mail: [email protected] Ann Vasc Surg 2010; 24: 1138.e1-1138.e3 DOI: 10.1016/j.acvfr.2011.05.016 Ó Annals of Vascular Surgery Inc. e par ELSEVIER MASSON SAS Edit
of paraganglioma. The patient recovered uneventfully, was discharged from the hospital on the first postoperative day, and was followed up as an outpatient. After 8 months, the patient was readmitted for surgical excision of the contralateral carotid body tumor. Initially, the patient did well after the surgery; however, the following morning, he developed unexplained hypertension and tachycardia. His blood pressure increased to 160/120 mm Hg and the heart rate to140 beats per minute. The patient denied pain, chest pain, dizziness, and shortness of breath. Subjectively, he felt well and was eager to go home, but his uncontrolled hypertension and tachycardia precluded his safe discharge. His hemoglobin level was stable and there was no evidence of hypovolemia. In view of the absence of a previous history of hypertension and the lack of any other plausible explanation for the elevated blood pressure and tachycardia, and given the clinical setting of bilateral carotid body tumor excision, a tentative diagnosis of baroreceptor failure syndrome (BFS) was considered. The patient was treated with beta blockers and clonidine and was discharged from the hospital 1229.e9
1229.e10 Cas cliniques
Fig. 1. Computerized Tomography angiogram showing bilateral carotid body tumors.
on the following day. Currently he is 4 months after operation and requires two drug therapies to maintain a normotensive state.
DISCUSSION AND LITERATURE REVIEW Advances in surgical technology and operative techniques have reduced the perioperative mortality risk of carotid body tumor resection to 0.5-1%, the risk of stroke to 2-3%, and postoperative cranial nerve deficit to 0-70%.1 With an increasing number of patients undergoing surgical resection, many authors have begun to report a poorly understood and an unusual complication after bilateral neck dissections for carotid body tumor. The syndrome, designated as ‘‘BFS,’’ is characterized by varying degrees of hypertension, tachycardia, headache, and anxiety. In some instances, it has led to hypertensive encephalopathy and stroke. Baroreceptors are the stretch receptors which participate in the control of arterial blood pressure. They are located in the wall of main arteries in the neck and thorax, and are particularly abundant in the carotid sinuses and aortic arch. In the event of elevated blood pressure, the signals from the baroreceptors inhibit the vasoconstrictor center and excite the vagal center, causing vasodilation and slowing the heart rate. With hypotension, the rate of impulses slows down causing the opposite effect. Canine studies have shown that interruption of the baroreceptor impulses causes unopposed sympathetic signals from the brainstem, which may cause extremely labile blood pressure after minor events such as excitation, changing body position, eating, defecating, or with external stimuli, such as noise.
Annales de chirurgie vasculaire
One of the first cases was reported by Sugarbaker et al., describing a patient with familial bilateral carotid body tumors.2 The patient underwent a staged surgical excision of tumors, and after resection of the second tumor developed unexplained tachycardia and hypertension. Other causes of hypertension including pheochromocytoma were excluded. The authors suggested that bilateral denervation of the baroreceptors may have been responsible for these symptoms. Since this description, other authors too have described similar symptoms appearing after bilateral carotid body tumor resection.3-5 Because these symptoms are not seen after resection of unilateral tumors, it would seem that the contralateral baroreceptor is sufficient to maintain blood pressure control. The common findings for patients diagnosed with BFS were the onset of sudden severe hypertension 24-72 hours postoperatively along with sinus tachycardia and headache. Many patients were also found to have high levels emotional lability which further contributed to unstable blood pressure. Some studies have suggested that clonidine is probably the medication of choice for treating this condition and partial improvement of symptoms is seen frequently. However, there are no publications documenting a complete remission of BFS after bilateral carotid body tumor surgery. One of the largest series of patients with carotid body tumors was reported by Netterville et al.6 Besides an extensive discussion about clinical features of the carotid body tumors and many aspects of the surgical technique, the authors concentrated on the results of the treatment. Of the 30 patients, 16 presented with bilateral carotid body tumors. Eleven patients with bilateral tumors demonstrated a familial pattern. Patients with a familial pattern were also prone to paragangliomas in other locations. Resection of cranial nerves along with the tumor was necessary in four patients, and metastatic spread of tumor was found in two patients. Because of the unusually high percentage of bilateral carotid body tumors, these authors had a unique opportunity to get a better insight into BFS. The authors encountered symptoms of BFS in 2 of 10 patients operated upon for bilateral tumors. They also noticed a correlation between anxiety and other stressors and episodes of hypertension in these patients and suggested that benzodiazepines may be used along with clonidine. Several other conditions have also been found to be associated with BFS including neck trauma,7 brainstem stroke,8 neck irradiation,9,10 and in very rare cases, bilateral carotid endarterectomy.11,12
Vol. 24, No. 8, 2010
It has been suggested that the true incidence of BFS may be higher than reported as it may have variable presentations and severity of symptoms. The following four possible clinical manifestations may exist together or in isolated form: hypertensive crisis, volatile hypertension, orthostatic tachycardia, and malignant vagotonia.13 The hypertensive crisis is most frequently associated with sudden denervation of baroreceptors, caused by surgical intervention. Systolic blood pressure may exceed 250 mm Hg accompanied with tachycardia and headache. Urgent measures are required to prevent cerebrovascular complications. Volatile hypertension is less striking but a far more frequent manifestation of BFS. It usually presents a few days to weeks after the injury, or may develop invidiously with a gradual decline of baroreceptor function. This phase is more permanent and characterized by surges of elevated blood pressure frequently in response to external stimuli, intermingled with periods of relative normotension. Orthostatic tachycardia is one of the more common reasons patients eventually diagnosed with BFS are referred to a tertiary center. Malignant vagotonia may present as severe bradycardia or asystole, and is postulated to be caused by a complete or near complete obliteration of baroreceptor input to the medulla resulting in unopposed parasympathetic outflow to the heart. Because BFS may mimic other conditions, it should be considered in the differential diagnosis of new onset hypertension along with pheochromocytoma and autonomic neuropathy. Both the hypertensive surges of BFS and pheochromocytoma may produce elevated levels of catecholamines and metanephrines. Differentiation from the autonomic failure may also be challenging. In contrast to BFS that is caused by the damage to afferent innervation of baroreceptors, autonomic neuropathy is characterized by abnormal efferent innervation to the heart and arteries. Patients with autonomic failure are more prone to have orthostatic hypotension and postprandial hypotension, whereas those with BFS more often have labile hypertension and episodic tachycardia. Early treatment of BFS was largely empiric. Authors have described relative success with the central alpha agonist clonidine. A biological rationale for the use of this drug is that it stimulates alpha 2 receptors in the brainstem, thus inhibiting central sympathetic outflow and preventing the peripheral release of norepinephrine. It also stimulates the parasympathetic outflow which contributes to the slowing of the heart rate. Because it treats both the hypertension and tachycardia, clonidine has become the drug of choice for the treatment of BFS. Other medications with short half-lives, such
Cas cliniques 1229.e11
as nitroprusside, phentolamine, and labetalol, are effective in case of hypertensive emergency. Apart from antihypertensive agents, benzodiazepines may be used to help with anxiety-associated symptoms. Because the chronic phase of BFS may last for years, patients may require chronic antihypertensive medication and long-term follow-up. If there is partial recovery and stabilization of the blood pressure, an attempt may be made to taper off antihypertensive medications. It has also been suggested that patients with BFS should be referred to and treated at specialized centers that have the ability to perform a careful assessment of the autonomic function.14 In summary, BFS is an unusual but important clinical entity that is frequently overlooked. BFS results from baroreceptor denervation and presents as tachycardia, sustained or labile hypertension, headache, and anxiety. It is particularly likely to develop after carotid body tumor surgery but may rarely be seen after carotid artery surgery, neck irradiation, and trauma. Bilateral injury to the baroreceptors is required to produce the symptoms. BFS should be promptly recognized in these cases and appropriate therapy instituted to prevent serious cerebrovascular and cardiovascular complications. REFERENCES 1. Rutherford R. Vascular Surgery. 6th ed. New York, NY: Saunders, 2005. pp 2066-2071. 2. Sugarbaker EV, Chretien PB, Jacobs JB. Bilateral familial carotid body tumors: report of a patient with an occult contralateral tumor and postoperative hypertension. Ann Surg 1971;174:242-247. 3. Boyle JR, London NJ, Tan SG, et al. Labile blood pressure after bilateral carotid body tumor surgery. Eur J Vasc Endovasc Surg 1995;9:346-348. 4. Robertson D, Hollister AS, Biaggioni I, et al. The diagnosis of baroreceptor failure. N Eng J Med 1993;329:1449-1455. 5. De Toma G, Nicolanti V, Plocco M, et al. Baroreflex failure syndrome after bilateral excision of carotid body tumors: an underestimated problem. J Vasc Surg 2000;31:806-810. 6. Netterville JL, Reilly KM, Robertson, et al. Carotid body tumors: a review of 30 patients with 46 tumors. Laryngoscope 1995;105:115-126. 7. Robertson D, Hollister AS, Biaggioni I, et al. The diagnosis and treatment of baroreceptor failure. N Eng J Med 1993;329:1449-1455. 8. Biaggioni I, Whetsell WO, Jobe J, Nadeau JH. Baroreflex failure in a patient with central nervous system lesion involving the nucleus tractus solitarii. Hypertension 1994;23:491-495. 9. Sharabi Y, Dendi R, Holmes C, Goldstein DS. Baroreflex failure as a late sequela of neck irradiation. Hypertension 2003;42:110-116. 10. Timmers HJ, Karemaker JM, Lenders JW, Weiling W. Baroreflex failure following radiation therapy for nasopharingeal carcinoma. Clin Auton Res 1999;9:317-324. 11. Ille O, Woimant F, Pruna A, et al. Hypertensive encephalopathy after bilateral carotid body tumor surgery. Stroke 1995;26:488-491.
1229.e12 Cas cliniques
12. Ejas AA, Meschia JF. Thalamic hemorrhage following carotid endarterectomy. Case report and therapeutic considerations. Arch Intern Med 1984;144:1489-1491. 13. Ketch T, Biaggioni I, Robertson R, Robertson D. Four faces of baroreceptor failure: hypertensive crisis, volatile
Annales de chirurgie vasculaire
hypertension, orthostatic tachycardia and malignant vagotonia. Circulation 2002;105:2518-2523. 14. Timmers HJ, Wieling W, Karemaker, Lenders JW. Baroreflex failure: a neglected type of secondary hypertension. N Eng J Med 2004;62:151-155.