- Email: [email protected]
First case history presentation and panel discussion
JOEL MORGANROTH, MD, Moderator
V
entricular arrhythmias can be classified into 3 different syndromes: benign, lethal and potentially lethal. Benign ventricular arrhythmias are associated with little or no underlying structural or functional heart disease and have little impact on the risk of sudden cardiac death. At the other end of the spectrum, hemodynamically compromising ventricular arrhythmias often result in syncope or out-of-hospital cardiac arrest. These ventricular arrhythmias, which usually take the form of sustained ventricular arrhythmias, are associated with the highest risk of sudden death and are appropriately termed lethal or malignant. The third group consists of chronic ventricular arrhythmias that may increase the risk of sudden cardiac death, even when asymptomatic, in patients with underlying left ventricular dysfunction or structural heart disease. The more severe the left ventricular dysfunction and the more complex or repetitive the ventricular arrhythmias, the more likely the possibility of sudden cardiac death. Although no one would urge the use of antiarrhythmic agents in patients with benign ventricular arrhythmias, no one would argue against their use in patients with hemodynamically compromising lethal arrhythmias. The major issue in clinical cardiology today is, therefore: How aggressive should we be in the treatment of patients with potentially lethal ventricular arrhythmias? We know there is clearly an increased risk of sudden death in these patients, but does antiarrhythmic therapy result in sudden death prevention? Antiarrhythmic drugs can be classified according to the modified Vaughn Williams system into classes I, II, III and IV. Class IV agents are the calcium-channel blockers, which are particularly valuable for patients with atria1 arrhythmias. Class III drugs, such as bretyhum, sotalol and amiodarone, predominantly affect repolarization. Class II comprises the 8-adrenergic drugs, which are effective both in the treatment of ventricular arrhythmias and in the prevention of sudden cardiac death in post-myocardial infarction pa-
tients. The mechanism for this latter effect may, at least in part, be antiarrhythmic. However, most of the antiarrhythmic drugs used clinically belong to class I. The hallmark of these agents is depression of phase 0 depolarization, which may be moderate, weak or strong. Similarly, the effect on repolarization may vary from shortening, to little effect, to prolongation of the JT interval. Among the class I drugs that strongly depress phase 0 depolarization, subclass IC agents (e-g,, encainide) markedly prolong the QRS interval but have little effect on the ST-T segment or JT interval. On the other hand, subclass IA drugs (e.g., quinidine) have a moderate effect on the QRS interval, but a marked effect on the JT interval Thus, the QT interval may be prolonged by a class IA or IC drug, although the mechanisms differ. This may have a significant impact on the relation between long QT interval and proarrhythmic response. Finally, subclass IB drugs (e.g., tocainide) have little effect on the QRS and JT intervals.
CasePresentation Mrs. A is a mildly obese 51-year-old housewife without a prior history of cardiac disease. She comes to the office after an episode of paroxysmal nocturnal dyspnea. Upon questioning, she describes a Z-month history of progressive dyspnea on exertion without chest pain, palpitations or syncope. She has no known cardiovascular risk factors, and is not on medication of any kind. The blood pressure is 160/99 mm Hg, with a prominent A wave in the jugular venous pulse contour. The ventricular apical impulse is displaced laterally. On auscultation, the pulmonary component of the S2 is increased in intensity. There is a grade l/6 holosystolic murmur at the apex, radiating into the axilla. An S4 is heard, but no S3 is noted. There is no evidence of rales, ascites or edema. The electrocardiogram shows normal sinus rhythm, leftward axis, low frontal plane voltage and marked nonspecific repolarization abnormalities with minimal prolongation of the JT interval. The chest x-ray (Fig. 1) is normal, What is the diagnosis? Dr. Francis (Minneapolis, Minnesota]: Since this patient is a woman with a prominent A wave, one might consider the diagnosis of primary pulmonary
From the Sudden Death Program, Hahnemann University Hospital, Likoff Cardiovascular Institute, Philadelphia. Pennsylvania. 150
16B
A SYMPOSIUM:
MANAGEMENT
OF VENTRICULAR
ARRHYTHMIAS
hypertension.However, the ECG is inconsistentwith this diagnosisbecausethere is no right axis deviation. In fact, her axis is leftward. Dr. Morganroth (Philadelphia, Pennsylvania): If the chestx-ray showed a nondilated cardiac shadow, hypertrophic cardiomyopathycould be responsiblefor the symptoms of dyspnea and paroxysmal nocturnal dyspnea.The possibility of restrictive myopathywith a normal-sizedheart must alsobe considered.However, this patient’schestx-ray (Fig.1)suggestsa dilated (congestive)cardiomyopathy or possibly pericardial effusion. Since the physical examination revealed a clearly displaced left ventricular apical impulse, dilated cardiomyopathy would be most likely. At thir;point, the best,most cost-effectivediagnostic testis an M-mode echocardiogram.This testallows for precise measurement of ventricular size and wall thickness,as well asthe detection of fluid in the pericardial space.A 2-dimensional echocardiogram(2-D echo] [Fig. 21provides spatial relations and a more accurateestimation of ventricular function. Dr. Francis: The 2-D echoappearsto show a dilated left ventricular chamber, which is consistentwith the x-ray findings (Fig. I]. I don’t seeevidence of pericardial effusion. Dr. Morganroth: The apical systolic murmur is probably due to mitral regurgitation from the very large ventricle, with resultant interference of the normal mitral valve closure apparatus. The 2-D echo shows no evidence of left ventricular clot. Patients with idiopathic dilated cardiomyopathy frequently have diffuse cardiomyopathy although in many pa-
I
FIGURE 1. The chest ble with the cllnlcal cardiomyopathy.
x-ray reveals marked cardiomegaly, compatldiagnosis of ldiopathlc dllated (congestive)
IN PATIENTS
WITH
CONGESTIVE
HEART
FAILURE
tients, left ventricular symptoms may predominate. Other patients may have biventricular symptomsand signsof heart failure, while a minority predominantly present with symptoms of right-sided heart failure. The left ventricular ejection fraction in this patient according to radionuclide angiography was 20%, which confirms the findings suggestedby 2-D echo. Should digitalis be prescribedfor this patientwhen seen in the office? Dr. Pitt (Ann Arbor, Michigan]: If you look at the published data, digitalis has a variable effect. In patients with severeheart failure the only indication of benefit hasbeenthe presenceof S3,which this patient doesnot have.Without that,the imperative to usedigitalis is somewhat low. I would prefer to start with a vasodilator and diuretics rather than digitalis. Dr. Bigger (New York, New York): I would treat this woman with digitalis, althoughher symptomsaremild. I would consider that she probably has an S3, even thoughit was reportedly absent.There are times when S3is variably heard,and in this case,the pathophysiology suggestsit should be present.Digitalis might completely control her symptoms;it is a once-a-daydrug, and it’s relatively safe when given alone and with caution. Most studies to date involving patients with severe heart failure have used digitalis and diuretic therapy, and it is still generally regardedas standard management. Although that might be challenged, it probably should bestudied. On the other hand,digitalis is relatively weak and usually doesn’thave asstrong an effect on ventricular performance as some of the other available drugs.Nevertheless,I would prescribe it on the basis of convenience. Dr. Woosley [Nashville, Tennessee):Since I’m not completely sure of what’s going on with this patient, I would feel uncomfortablegiving digitalis. Becauseshe is only mildly symptomatic, perhaps dietary salt restriction and weight reduction might be attemptedbefore going to drug therapy. Dr. Francis: I agreewith Dr. Pitt. The patient is not tachycardic and doesnot have S3.The available data thus suggestthat digitalis may not be beneficial. Dr. Morganroth: If you decideon medical management, should a Holter recording be ordered first? Dr. Bigger: You could argueeither side of this question, and I’ll arguethe negative.If you were not going to treat asymptomatic ventricular arrhythmia, then perhapsyou would be better off not to identify it and highlight it. If you do order Holter recordingsand find arrhythmias, I think you are obligated to discussthe implications of this problem with the patient.If you tell the patient that arrhythmias increaseher risk of death but you are not going to treat them becauseyou don’t know if treatment is effective, you are probably promoting considerableanxiety and distress.You might, therefore, be better off not raising the issue at all. Dr. Woosley: I would probably order a Holter recording since the patient had paroxysmalsymptomsat night, which might be related to an arrhythmia.
Ja~ay
3’,
Dr. Francis: I agree.If there’s a chanceher symptoms were due to a ventricular tachycardia, I would order the Holter recording,If present,I, like most physicians, would treat it. Dr. Pitt: I also would obtain a Halter recording to determine if this patient had nonsustainedventricular tachycardia, which could be potentially lethal, Dr. Morganrotlx: In summary,we’re not 100% certain whether ventricular arrhythmias should be treated if found in this patient. Thus, we could ignore the issueand not obtain the Holter recording,particularly since we would have to explain the results to the patient. On the other hand, if a diagnosisis uncovered that, if treated,could improve the patient’scondition, obtaining a relatively inexpensive,noninvasiveoutpatient test suchasa Holter recordingwould certainly be indicated. Patients with marked ventricular dysfunction and asymptomatic nonsustained ventricular tachycardia (VT) havea high risk of suddendeath.These high-risk patients can be identified with a Holter recording. In fact, a Holter recording,which was performed in this patient, showed a mean ventricular premature complex frequency of lOO/hourwith frequent episodesof nonsustainedVT. Now that we have the data, should we treat the arrhythmia in this particular patient who has a low ejection fraction of 20%? The treatment of the high-risk patient for sudden deathprevention is one of the key controversialissues in cardiology today. Although it is clear that this pa-
FlGURE 2. Four different views of the heart obtained by 2-dimenslonal echocardlography. Upper panels show a markedly dilated left ventricle (LV), along with dllatatlon of thr rlght ventricle (RV), right atrium (RA) and left atrlum (LA). The aorta (Ao) ls normal sized. In the lower Iefl panel, a cross-sectlonal vlew of the left ventricle at the level of the mitral valve reveals uniform normal thickness In the left ventrkular walls. In the lower right panel, a cross-sectlonal vlew of the heart at the level of the great vessels shows a normal rlght ventrlcular outflow tract (RVOT) and normal pulmonary artery (PA).
‘??C
I“5
AEQ!CAN
JOLJPNAL
OF CARDIOLOGY
Volume
57
178
tient’s arrll.~~thmiais p(~tentiallylethal, there is little data on whether treatment of nonsustainedVT will prlevent death. We do know that there is a risk of proar~lyt~~:miaassociatedwith the use of antiarrhythmic drugs. In light of the long QT interval in this patient, the ejection fraction of 20% and the presenceof nonsustained VT, the selection of a specific antiarrhythmic drug requires careful assessment.The class IV calcium-channel blockers do not suppressventricular arrhythmias and may in fact be proarrhythmic. Recent data that we have obtained on diltiazem compared with bepridil suggestthat calcium blockerscan induce a state of ventricular proarrhythmia. The prevaIence may be as high as that of class I drugs. The calcium blockerscan alsoprovokenew atria1fibrillation, probably as a result of their effects on the sinoatrial node. The classIII agentamiodaroneis, in my opinion, relatively contraindicatedin this asymptomaticpatient becauseof its high degreeof long-term toxicity. I tend to think this drug should be used only in patients with lethal ventricular arrhythmias. Treatment with class II P-adrenergicblockers in this patient (with a left ventricular ejection fraction of 20%)requiresmore thought.The patient’s heartrate at rest is not ta~hycardicand enhancedsympathetictone is not required to maintain her compensatedstate at rest. Cautioususe might be considered. The classIA antiarrhythmic agentsmay alsonot be an appropriatefirst-line treatment in this patient, be-
188
A SYMPOSIUM:
MANAGEMENT
OF VENTRICULAR
ARRHYTHMIAS
cause they tend to prolong the JT interval more than the QRS interval. Because this patient had a long JT interval at baseline, which was responsible for the QT prolongation, class IA agents may synergize and further worsen an underlying myocardial repolarization abnormality. On the other hand, the class IB drug, tocainide, is a good first choice because it does not significantly depress left ventricular function and has little effect on the JT interval-in fact, it may shorten it a bit. Approximately 40% of patients respond, with a 75% reduction
IN PATIENTS
WITH
CONGESTIVE
HEART
FAILURE
in ventricular arrhythmias. Between 25% and 30% of patients experience adverse effects, predominantly dizziness and nausea. The class IC drugs, such as encainide and flecainide, represent another option. We know that encainide has very little negative inotropic effect, whereas flecainide tends to be more negatively inotropic. Both these agents have little or no effect on the JT interval, so either would be a reasonable choice in this regard. Their efficacy rate is extremely high: 80% to 90% of patients respond to treatment.
V
entricular arrhythmias can be classified into 3 different syndromes: benign, lethal and potentially lethal. Benign ventricular arrhythmias are associated with little or no underlying structural or functional heart disease and have little impact on the risk of sudden cardiac death. At the other end of the spectrum, hemodynamically compromising ventricular arrhythmias often result in syncope or out-of-hospital cardiac arrest. These ventricular arrhythmias, which usually take the form of sustained ventricular arrhythmias, are associated with the highest risk of sudden death and are appropriately termed lethal or malignant. The third group consists of chronic ventricular arrhythmias that may increase the risk of sudden cardiac death, even when asymptomatic, in patients with underlying left ventricular dysfunction or structural heart disease. The more severe the left ventricular dysfunction and the more complex or repetitive the ventricular arrhythmias, the more likely the possibility of sudden cardiac death. Although no one would urge the use of antiarrhythmic agents in patients with benign ventricular arrhythmias, no one would argue against their use in patients with hemodynamically compromising lethal arrhythmias. The major issue in clinical cardiology today is, therefore: How aggressive should we be in the treatment of patients with potentially lethal ventricular arrhythmias? We know there is clearly an increased risk of sudden death in these patients, but does antiarrhythmic therapy result in sudden death prevention? Antiarrhythmic drugs can be classified according to the modified Vaughn Williams system into classes I, II, III and IV. Class IV agents are the calcium-channel blockers, which are particularly valuable for patients with atria1 arrhythmias. Class III drugs, such as bretyhum, sotalol and amiodarone, predominantly affect repolarization. Class II comprises the 8-adrenergic drugs, which are effective both in the treatment of ventricular arrhythmias and in the prevention of sudden cardiac death in post-myocardial infarction pa-
tients. The mechanism for this latter effect may, at least in part, be antiarrhythmic. However, most of the antiarrhythmic drugs used clinically belong to class I. The hallmark of these agents is depression of phase 0 depolarization, which may be moderate, weak or strong. Similarly, the effect on repolarization may vary from shortening, to little effect, to prolongation of the JT interval. Among the class I drugs that strongly depress phase 0 depolarization, subclass IC agents (e-g,, encainide) markedly prolong the QRS interval but have little effect on the ST-T segment or JT interval. On the other hand, subclass IA drugs (e.g., quinidine) have a moderate effect on the QRS interval, but a marked effect on the JT interval Thus, the QT interval may be prolonged by a class IA or IC drug, although the mechanisms differ. This may have a significant impact on the relation between long QT interval and proarrhythmic response. Finally, subclass IB drugs (e.g., tocainide) have little effect on the QRS and JT intervals.
CasePresentation Mrs. A is a mildly obese 51-year-old housewife without a prior history of cardiac disease. She comes to the office after an episode of paroxysmal nocturnal dyspnea. Upon questioning, she describes a Z-month history of progressive dyspnea on exertion without chest pain, palpitations or syncope. She has no known cardiovascular risk factors, and is not on medication of any kind. The blood pressure is 160/99 mm Hg, with a prominent A wave in the jugular venous pulse contour. The ventricular apical impulse is displaced laterally. On auscultation, the pulmonary component of the S2 is increased in intensity. There is a grade l/6 holosystolic murmur at the apex, radiating into the axilla. An S4 is heard, but no S3 is noted. There is no evidence of rales, ascites or edema. The electrocardiogram shows normal sinus rhythm, leftward axis, low frontal plane voltage and marked nonspecific repolarization abnormalities with minimal prolongation of the JT interval. The chest x-ray (Fig. 1) is normal, What is the diagnosis? Dr. Francis (Minneapolis, Minnesota]: Since this patient is a woman with a prominent A wave, one might consider the diagnosis of primary pulmonary
From the Sudden Death Program, Hahnemann University Hospital, Likoff Cardiovascular Institute, Philadelphia. Pennsylvania. 150
16B
A SYMPOSIUM:
MANAGEMENT
OF VENTRICULAR
ARRHYTHMIAS
hypertension.However, the ECG is inconsistentwith this diagnosisbecausethere is no right axis deviation. In fact, her axis is leftward. Dr. Morganroth (Philadelphia, Pennsylvania): If the chestx-ray showed a nondilated cardiac shadow, hypertrophic cardiomyopathycould be responsiblefor the symptoms of dyspnea and paroxysmal nocturnal dyspnea.The possibility of restrictive myopathywith a normal-sizedheart must alsobe considered.However, this patient’schestx-ray (Fig.1)suggestsa dilated (congestive)cardiomyopathy or possibly pericardial effusion. Since the physical examination revealed a clearly displaced left ventricular apical impulse, dilated cardiomyopathy would be most likely. At thir;point, the best,most cost-effectivediagnostic testis an M-mode echocardiogram.This testallows for precise measurement of ventricular size and wall thickness,as well asthe detection of fluid in the pericardial space.A 2-dimensional echocardiogram(2-D echo] [Fig. 21provides spatial relations and a more accurateestimation of ventricular function. Dr. Francis: The 2-D echoappearsto show a dilated left ventricular chamber, which is consistentwith the x-ray findings (Fig. I]. I don’t seeevidence of pericardial effusion. Dr. Morganroth: The apical systolic murmur is probably due to mitral regurgitation from the very large ventricle, with resultant interference of the normal mitral valve closure apparatus. The 2-D echo shows no evidence of left ventricular clot. Patients with idiopathic dilated cardiomyopathy frequently have diffuse cardiomyopathy although in many pa-
I
FIGURE 1. The chest ble with the cllnlcal cardiomyopathy.
x-ray reveals marked cardiomegaly, compatldiagnosis of ldiopathlc dllated (congestive)
IN PATIENTS
WITH
CONGESTIVE
HEART
FAILURE
tients, left ventricular symptoms may predominate. Other patients may have biventricular symptomsand signsof heart failure, while a minority predominantly present with symptoms of right-sided heart failure. The left ventricular ejection fraction in this patient according to radionuclide angiography was 20%, which confirms the findings suggestedby 2-D echo. Should digitalis be prescribedfor this patientwhen seen in the office? Dr. Pitt (Ann Arbor, Michigan]: If you look at the published data, digitalis has a variable effect. In patients with severeheart failure the only indication of benefit hasbeenthe presenceof S3,which this patient doesnot have.Without that,the imperative to usedigitalis is somewhat low. I would prefer to start with a vasodilator and diuretics rather than digitalis. Dr. Bigger (New York, New York): I would treat this woman with digitalis, althoughher symptomsaremild. I would consider that she probably has an S3, even thoughit was reportedly absent.There are times when S3is variably heard,and in this case,the pathophysiology suggestsit should be present.Digitalis might completely control her symptoms;it is a once-a-daydrug, and it’s relatively safe when given alone and with caution. Most studies to date involving patients with severe heart failure have used digitalis and diuretic therapy, and it is still generally regardedas standard management. Although that might be challenged, it probably should bestudied. On the other hand,digitalis is relatively weak and usually doesn’thave asstrong an effect on ventricular performance as some of the other available drugs.Nevertheless,I would prescribe it on the basis of convenience. Dr. Woosley [Nashville, Tennessee):Since I’m not completely sure of what’s going on with this patient, I would feel uncomfortablegiving digitalis. Becauseshe is only mildly symptomatic, perhaps dietary salt restriction and weight reduction might be attemptedbefore going to drug therapy. Dr. Francis: I agreewith Dr. Pitt. The patient is not tachycardic and doesnot have S3.The available data thus suggestthat digitalis may not be beneficial. Dr. Morganroth: If you decideon medical management, should a Holter recording be ordered first? Dr. Bigger: You could argueeither side of this question, and I’ll arguethe negative.If you were not going to treat asymptomatic ventricular arrhythmia, then perhapsyou would be better off not to identify it and highlight it. If you do order Holter recordingsand find arrhythmias, I think you are obligated to discussthe implications of this problem with the patient.If you tell the patient that arrhythmias increaseher risk of death but you are not going to treat them becauseyou don’t know if treatment is effective, you are probably promoting considerableanxiety and distress.You might, therefore, be better off not raising the issue at all. Dr. Woosley: I would probably order a Holter recording since the patient had paroxysmalsymptomsat night, which might be related to an arrhythmia.
Ja~ay
3’,
Dr. Francis: I agree.If there’s a chanceher symptoms were due to a ventricular tachycardia, I would order the Holter recording,If present,I, like most physicians, would treat it. Dr. Pitt: I also would obtain a Halter recording to determine if this patient had nonsustainedventricular tachycardia, which could be potentially lethal, Dr. Morganrotlx: In summary,we’re not 100% certain whether ventricular arrhythmias should be treated if found in this patient. Thus, we could ignore the issueand not obtain the Holter recording,particularly since we would have to explain the results to the patient. On the other hand, if a diagnosisis uncovered that, if treated,could improve the patient’scondition, obtaining a relatively inexpensive,noninvasiveoutpatient test suchasa Holter recordingwould certainly be indicated. Patients with marked ventricular dysfunction and asymptomatic nonsustained ventricular tachycardia (VT) havea high risk of suddendeath.These high-risk patients can be identified with a Holter recording. In fact, a Holter recording,which was performed in this patient, showed a mean ventricular premature complex frequency of lOO/hourwith frequent episodesof nonsustainedVT. Now that we have the data, should we treat the arrhythmia in this particular patient who has a low ejection fraction of 20%? The treatment of the high-risk patient for sudden deathprevention is one of the key controversialissues in cardiology today. Although it is clear that this pa-
FlGURE 2. Four different views of the heart obtained by 2-dimenslonal echocardlography. Upper panels show a markedly dilated left ventricle (LV), along with dllatatlon of thr rlght ventricle (RV), right atrium (RA) and left atrlum (LA). The aorta (Ao) ls normal sized. In the lower Iefl panel, a cross-sectlonal vlew of the left ventricle at the level of the mitral valve reveals uniform normal thickness In the left ventrkular walls. In the lower right panel, a cross-sectlonal vlew of the heart at the level of the great vessels shows a normal rlght ventrlcular outflow tract (RVOT) and normal pulmonary artery (PA).
‘??C
I“5
AEQ!CAN
JOLJPNAL
OF CARDIOLOGY
Volume
57
178
tient’s arrll.~~thmiais p(~tentiallylethal, there is little data on whether treatment of nonsustainedVT will prlevent death. We do know that there is a risk of proar~lyt~~:miaassociatedwith the use of antiarrhythmic drugs. In light of the long QT interval in this patient, the ejection fraction of 20% and the presenceof nonsustained VT, the selection of a specific antiarrhythmic drug requires careful assessment.The class IV calcium-channel blockers do not suppressventricular arrhythmias and may in fact be proarrhythmic. Recent data that we have obtained on diltiazem compared with bepridil suggestthat calcium blockerscan induce a state of ventricular proarrhythmia. The prevaIence may be as high as that of class I drugs. The calcium blockerscan alsoprovokenew atria1fibrillation, probably as a result of their effects on the sinoatrial node. The classIII agentamiodaroneis, in my opinion, relatively contraindicatedin this asymptomaticpatient becauseof its high degreeof long-term toxicity. I tend to think this drug should be used only in patients with lethal ventricular arrhythmias. Treatment with class II P-adrenergicblockers in this patient (with a left ventricular ejection fraction of 20%)requiresmore thought.The patient’s heartrate at rest is not ta~hycardicand enhancedsympathetictone is not required to maintain her compensatedstate at rest. Cautioususe might be considered. The classIA antiarrhythmic agentsmay alsonot be an appropriatefirst-line treatment in this patient, be-
188
A SYMPOSIUM:
MANAGEMENT
OF VENTRICULAR
ARRHYTHMIAS
cause they tend to prolong the JT interval more than the QRS interval. Because this patient had a long JT interval at baseline, which was responsible for the QT prolongation, class IA agents may synergize and further worsen an underlying myocardial repolarization abnormality. On the other hand, the class IB drug, tocainide, is a good first choice because it does not significantly depress left ventricular function and has little effect on the JT interval-in fact, it may shorten it a bit. Approximately 40% of patients respond, with a 75% reduction
IN PATIENTS
WITH
CONGESTIVE
HEART
FAILURE
in ventricular arrhythmias. Between 25% and 30% of patients experience adverse effects, predominantly dizziness and nausea. The class IC drugs, such as encainide and flecainide, represent another option. We know that encainide has very little negative inotropic effect, whereas flecainide tends to be more negatively inotropic. Both these agents have little or no effect on the JT interval, so either would be a reasonable choice in this regard. Their efficacy rate is extremely high: 80% to 90% of patients respond to treatment.