Tissue Plasminogen Activator for Acute Ischemic Stroke

Vol. 334 No. 21 CORRESPONDENCE 1403

CORRESPONDENCE

CLINICAL PROBLEM-SOLVING: IDENTIFYING ADDISON’S DISEASE

To the Editor:

I stopped reading the Clinical Problem-Solv-ing article by Keljo and Squires ( Jan. 4 issue)

1

when I reachedthe second line of the second column, which gives the eryth-rocyte sedimentation rate as 38 mm per hour. I was dissatis-fied with the reasoning of the discussant in the first para-graph. None of the proposed differential diagnoses seemedappropriate. I started again and constructed my own differen-tial diagnosis. My summary of diagnostic signs and symptomsincluded shortness of breath during exercise without wheez-ing or cough, loss of weight, amenorrhea, hypotension with anincreased pulse rate, and a previous vaccination. I came tojust one possibility — Addison’s disease. My request for addi-tional information at this stage would have concerned loss ofappetite, nausea, the effect of exposure to sun, pigmentationof skin folds, orthostatic hypotension, the exact eosinophilcount in circulating blood, and levels of glucose, sodium, andpotassium.

My criticism of the discussant’s differential diagnosis isthat none of the diagnostic items mentioned are suggested bythe complete set of findings known at that stage, except forautoimmune disease, if the discussant had the adrenals inmind. A body-mass index of 16.6 in a patient with anorexianervosa would not give rise to amenorrhea and hypotension;girls with anorexia also tend to be overactive and not tocomplain about exertion. Hyperthyroidism is not character-ized by hypotension and a moderate pulse pressure; neither

are inflammatory diseases of any cause, unless both adrenalsare involved. Malabsorption leading to the symptoms de-scribed would be evident from the medical history, and hy-potension due to a thiamine deficiency in malnutrition shouldbe accompanied by pulmonary edema. Malignant or inflam-matory disease leading to the level of wasting described is al-most certainly accompanied by many other important find-ings. Anemia in itself is not always associated with low bloodpressure.

What went wrong in this clinical case? First, the patient’scirculatory condition was overlooked. This aspect, combinedwith the absence of signs of severe general illness, leads to thediagnosis of hypocortisolism. Second, the discussant and theoriginal clinicians constructed their differential diagnosis byusing different parts of the available information for eachitem, neglecting signals that were contradictory or absent.Third, when there was no solution, they should have startedagain at the very beginning of the diagnostic process and fol-lowed the basic systematics of data collection and evaluation.

W

OLTER

S.

DE

L

OOS

, M.D., P

H

.D.3509 AA Utrecht, Central Military

the Netherlands and University Hospital

1. Keljo DJ, Squires RH Jr. Just in time. N Engl J Med 1996;334:46-8.

To the Editor:

Dr. Keljo and Dr. Squires brilliantly discussthe case of a 15-year-old white girl with a delayed diagnosisof Addison’s disease. Primary physicians, many consultants,and even an endocrinologist did not have a clue to the diag-nosis, nor did they include Addison’s disease in their long listof differential diagnoses. Many tests, even invasive ones, wereperformed in a very sick patient who was almost in adrenalcrisis. The reason for the delay in diagnosis was the absenceof increased pigmentation in the skin and mucous mem-branes. The question, however, is whether gray pigmentationin the mouth and buccal mucosa

1

was missed or whether in-creases in brown pigmentation on the face and especially inpressure points, such as the elbows, knees, palmar creases,

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nipples, and areolae, were misinterpreted as an excessive sun-tan.

2

In 92 percent of cases of Addison’s disease, hyperpig-mentation is found.

2

It can even precede other manifestationsof the disease, such as fatigue, weakness, progressive asthe-nia, and orthostatic hypotension.

The absence of increased pigmentation is very unusual in apatient with primary adrenal insufficiency, except in adrenalinsufficiency due to pituitary failure, which was not the casehere (this patient had a high level of corticotropin). This caseteaches us a lesson: if a crucial sign is missing in a rare dis-ease, the correct diagnosis can be very difficult and frustrat-ing to reach and can be much delayed. But the persistence ofthe physicians who were caring for the patient paid off. Final-ly, just in time, the diagnosis was clinched, and the patient’slife saved. A rare diagnosis that is obvious in retrospect is of-ten not so obvious prospectively, however.

D

USHAN

J. B

ABICH

, M.D.Southampton, NY 11969 P.O. Box 2577

1. Hart FD. French’s index of differential diagnosis. 11th ed. Bristol, England:John Wright, 1979:280.

2. Tyrrell JB, Baxter JD. Disorders of the adrenal cortex. In: Wyngaarden JB,Smith LH, Jr, eds. Cecil textbook of medicine. 17th ed. Vol. 2. Philadelphia:W.B. Saunders, 1985:1311.

To the Editor:

Regarding the clinical case “Just in Time,” Imissed the diagnosis too. However, on rereading, I see that nodifferential count was reported (and perhaps not done?) atthe time of any blood count. Had such a count shown in-creased levels of eosinophils and lymphocytes, said to be com-mon in adrenal insufficiency, would some clinicians have got-ten a clue many weeks and thousands of dollars earlier?

I have seen reports that “routine” differential counts arenot “cost effective.” Well, maybe.

D

AVID

G. B

AXTER

, M.D.Los Angeles, CA 90012 351 E. Temple St.

To the Editor:

In the case of a 15-year-old girl who reportedfatigue and shortness of breath on exertion, after a month ofevaluation and therapeutic trials aimed at various causes offatigue, the invited “expert clinician” arrived at the diagnosis,Addison’s disease. The authors conclude, “Only the toughestcritic could fault any of the clinicians for not making the cor-rect diagnosis earlier.” As with so many arguments, that de-pends on one’s point of view. Or, as my grandfather put it,“Teach a man to use a hammer, and he will treat every prob-lem as if it were a nail.” Both the expert and the authors ap-pear to be gastroenterologists. An alternative analysis mighthave focused the evaluation on the symptom — shortness ofbreath on exertion — that the expert acknowledged is “an un-common symptom in childhood.”

Shortness of breath indicates that unexpected work is re-quired to move the flow of air or blood in order to meet theincreasing demands for oxygen consumption and carbon diox-ide removal with exercise. Thus, one would like to have meas-ured ventilation and gas exchange during graded exercise inorder to determine which physiologic variable was perturbedin this girl. Had this been done, the clinician would probablyhave discovered a cardiovascular limitation to gas exchange,with little change in the stroke volume and at best a doublingof the heart rate; the initial heart rate was 94 beats perminute. A two-dimensional echocardiogram would probablyhave revealed small ventricles and no evidence of cardiovas-cular disease. These findings would have raised questionsabout circulatory volume, and the appropriate diagnosis would

probably have been “nailed” more expeditiously. Thus, theauthors’ conclusion that only the toughest critic could faultthe clinicians depends on one’s point of view and on whetherone was taught to use a hammer or a saw.

D

ANIEL

C. S

HANNON

, M.D.Boston, MA 02114 Massachusetts General Hospital

To the Editor:

The article by Keljo and Squires presented anintriguing opportunity to test DXplain, a decision-supportsystem designed to provide appropriate clinical informationto physicians faced with puzzling cases.

I entered the data in the order they were presented. Afterthe data obtained during the initial history taking and physi-cal examination were entered, the list of diagnoses proposedby the system focused, as did the physicians, on (relatively)common disorders, such as anorexia nervosa and Graves’ dis-ease. When the epigastric pain and nausea and all the normalinitial basic laboratory-test results were entered, chronic pan-creatitis and several lymphomas moved to the top of the list,with chronic adrenal insufficiency now appearing as number17. When I added the vomiting, the dehydration, and the sec-ond round of laboratory tests, Addison’s disease moved up tonumber 2 — well before this disease was considered by thephysicians caring for the patient or by the discussant.

This test shows the strength of a decision-support system:it suggests possible diseases to the physician, who is in a muchbetter position to make a diagnosis once the disease has beenconsidered.

E

DWARD

P. H

OFFER


To the Editor:

In the Clinical Problem-Solving case by Keljoand Squires, little was said about the possible causes of Ad-dison’s disease, and nothing about the causative roles of his-toplasmosis and tuberculosis. In these days of our awarenessof problems with tuberculosis control, this subject seemsworth a word or two. Thus, information about the area wherethis 15-year-old lives or lived, her living conditions, and thepossibility of contact with tuberculosis becomes important.

G

ERALD

L. B

AUM

, M.D.Tel-Aviv 63346, Israel Israel Lung Association

The authors reply:

To the Editor:

The patient’s physicians believed that the di-agnoses considered did not explain all the features of her ill-ness, and they continued to explore new avenues. Had the di-agnosis of Addison’s disease been entertained before herelectrolyte levels became abnormal, it might well have beenmade earlier. The question at issue is, What pointers mayhave been missed?

We agree with Dr. de Loos and Dr. Shannon that the pa-tient had evidence of hypovolemia throughout her illness,suggesting the diagnosis of Addison’s disease. Earlier recog-nition of the chronic nature of the hypovolemia might wellhave speeded the diagnosis. Her cardiovascular status at thetime of presentation did not, however, exclude malnutritiondue to inflammatory bowel disease.

Amenorrhea is uncommon in Addison’s disease, and ifpresent it generally indicates cachexia.

1

The presence ofamenorrhea cannot therefore be used to distinguish Addison’sdisease from any other source of malnutrition. (Ovarian fail-ure is also seen in patients with Addison’s disease, but that




clearly did not apply to this patient, whose menses returnedafter treatment.)

The immunization and the Addison’s disease were notlinked, because the amenorrhea began six months before theimmunization was given. The family simply did not notice herillness until after the immunization.

Dr. Baum reminds us that tuberculosis was the most com-mon cause of Addison’s disease not so very long ago and thattuberculosis is becoming more common again. This patienthad a normal chest film and a negative response to a purified-protein-derivative tuberculin skin test.

Multiple caretakers commented on the patient’s large num-ber of deeply pigmented nevi, and there is a report of suchchanges in Addison’s disease.

2

This child did not have the moreclassic dermatologic changes of Addison’s disease brought upby Dr. Babich.

Dr. Baxter’s question is appropriate. However, the patient’sdifferential count was normal: 50 percent segmented neutro-phils, 1 percent band forms, 2 percent monocytes, and 47 per-cent lymphocytes.

Dr. Hoffer’s report on the performance of DXplain is im-pressive. As Dr. Shannon implies, clinicians work from shortlists, and these short lists vary widely from specialty to spe-cialty. When none of the diagnoses entertained explain thefindings, the list must be expanded. DXplain provides oneway to do this.

D

AVID

J. K

ELJO

, M.D., P

H

.D.R

OBERT

H. S

QUIRES

, J

R

., M.D.University of Texas Southwestern

Dallas, TX 75235 Medical Center at Dallas

1. Bethune JE. The diagnosis and treatment of adrenal insufficiency. In: De-Groot LJ, Besser GM, Cahill GF Jr, et al., eds. Endocrinology. 2nd ed. Vol.2. Philadelphia: W.B. Saunders, 1989:1647-59.

2. Ibsen HH, Clemmensen O. Eruptive nevi in Addison’s disease. Arch Derma-tol 1990;126:1239-40.

TISSUE PLASMINOGEN ACTIVATOR FOR ACUTE ISCHEMIC STROKE

To the Editor:

In “Tissue Plasminogen Activator [t-PA] forAcute Ischemic Stroke” (Dec. 14 issue),

1

it is reported thattreatment with t-PA increases a patient’s chance of recoveringfrom an ischemic stroke without any, or only minimal, disabil-ity or neurologic deficit. Despite this optimistic conclusion,several methodologic issues and the demonstrated risks oftreatment with t-PA suggest a more cautious interpretation.Although the study was randomized, there were importantbase-line differences that favored the t-PA–treated patients.Overall, more patients in the t-PA–treated group than in theplacebo group had been receiving aspirin before the event(odds ratio, 1.697; 95 percent confidence interval, 1.199 to2.404; P

�

0.002). This difference may have been more impor-tant than suggested by post hoc analysis, since some of thepatients may have actually had a transient ischemic attack —for which aspirin is known to be beneficial — rather than acompleted stroke. The importance of this possible pretreat-ment advantage may have been enhanced by the protocol,which precluded the use of aspirin or other antithrombotictherapy during the early phase of treatment. By contrast, theaspirin-like actions of t-PA would have been helpful to suchpatients.

2

Another pretreatment advantage in the t-PA group was the

presence of significantly more patients with small-vessel oc-clusions. As shown in the study, such patients are destined tohave a better outcome irrespective of treatment, and, accord-

ing to the study, the outcome is further improved by t-PAtherapy.

Perhaps most discouraging was the finding, also evident inan earlier investigation of t-PA in stroke,

3

that patients withearly indications suggesting a devastating stroke are the onesat the greatest risk of having an untoward reaction to thedrug. Indeed, it is somewhat puzzling that despite the in-creased number of deaths due to parenchymal hemorrhageamong the t-PA–treated patients, this difference was not evi-dent in the overall outcome, but emerged in another study.

3

This study and the previous investigation

3

suggest that t-PAtherapy would benefit only a small subgroup of patients withstroke yet would expose a larger population to a potentiallydire complication. Even when t-PA was administered withinthe context of a carefully controlled study, departure from thestrict protocol resulted in a 50 percent increase in the mortal-ity rate.

3

It is not likely that the strict guidelines necessary toproduce a small benefit in a limited number of patients whohave had a stroke could realistically be adhered to in generalpractice.

H

OWARD

S. F

RIEDMAN

, M.D.Brooklyn, NY 11201 Long Island College Hospital

1. The National Institute of Neurological Disorders and Stroke rt-PA StrokeStudy Group. Tissue plasminogen activator for acute ischemic stroke. N EnglJ Med 1995;333:1581-7.

2. Kamat SG, Michelson AD, Benoit SE, et al. Fibrinolysis inhibits shear stress-induced platelet aggregation. Circulation 1995;92:1399-407.

3. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombi-nant tissue plasminogen activator for acute hemispheric stroke. JAMA 1995;274:1017-25.

To the Editor:

The National Institute of Neurological Disor-ders and Stroke (NINDS) rt-PA Stroke Study Group’s positivefindings in a trial of the thrombolytic agent t-PA for acute is-chemic symptoms is a landmark study. Improved outcome inthe treated group is clear. However, the paper does not pro-vide the data necessary to guide the treatment of individualpatients. Dissolution of clot in intracranial vessels is an obvi-ous therapeutic goal in stroke. Intraarterial thrombolysis hasbeen performed with dramatic angiographic and clinical suc-cess in certain instances.

1

However, multiple (11) trials of in-travenous thrombolysis have been plagued by the risk of fatalhemorrhage,

2

which is most likely compounded by the rela-tively weak ability of intravenous agents to dissolve emboliand the difficulty of selecting appropriate patients on the ba-sis of clinical criteria and computed tomography alone.

In the NINDS study, half the patients were treated within90 minutes of the onset of symptoms, but the rate of fatalhemorrhage was increased ninefold by t-PA; rapid neurologicimprovement, expected after recanalization, was rare; andthere were no data regarding the incidence of recanalization.There are also major qualifications associated with the re-ported benefit. Some of the improved outcome with t-PA is re-lated to the unequal randomization of patients with varioustypes of stroke: as compared with patients assigned to place-bo, 21 more patients with less severe, small-vessel disease and18 fewer patients with more severe, large-vessel disease wereassigned to t-PA. This by itself would improve outcome andreduce death in the treated group. Some of the overall benefitwas due to better outcome in treating small-vessel occlusivedisease, the natural history of which is the recovery of rela-tively good function. In their haste to treat all patients withischemic deficits, physicians should be wary of causing fatalhemorrhage in patients who otherwise will have rapidly re-solving deficits or tiny lacunes in the white matter. Patients




with large-vessel occlusion are at highest risk for horribly dis-abling stroke if left untreated. In this group the risk of throm-bolysis-induced fatal hemorrhage can be more easily acceptedif there is a significant probability of improvement with t-PA.Did t-PA treatment in the NINDS study cause a statisticallysignificant improvement in outcome in patients at risk forlarge-vessel strokes? Was treatment accompanied by an in-crease in death due to cerebral hemorrhage or cerebral ede-ma? Treatment with t-PA is probably not indicated for everypatient with an hour-long ischemic deficit. Before this therapyis introduced into general use, better criteria are needed tohelp select patients in whom the benefits outweigh the risks.

W

ALTER

J. K

OROSHETZ


FOR

THE

M

ASSACHUSETTS

G

ENERAL

H

OSPITAL

S

TROKE

S

ERVICE

1. Hacke W, Zeumer H, Ferbert A, Bruckmann H, del Zoppo GJ. Intra-arterialthrombolytic therapy improves outcome in patients with acute vertebrobasi-lar occlusive disease. Stroke 1988;19:1216-22.

2. Wardlaw J, Yamaguchi T, del Zoppo G, Hacke W. Thrombolysis in acute is-chaemic stroke. In: Warlow C, Van Gijn J, Sandercock P, eds. Stroke module,Cochrane database of systematic reviews. London: British Medical JournalPublishing, 1995.

To the Editor:

I would like to point out a discrepancy be-tween the NINDS study of t-PA and Dr. del Zoppo’s editorial(Dec. 14 issue)

1

on this study. Dr. del Zoppo states, “patientswith symptoms of cerebral ischemia . . . were randomlyassigned to receive intravenous tissue plasminogen activator(t-PA) or placebo if they arrived at the hospital within threehours of the onset of symptoms.” In the study itself, the three-hour time limit actually pertains to the duration between theonset of symptoms of stroke and the time when treatmentwith t-PA or placebo was begun.

The discrepancy is important because, as del Zoppo pointsout, after arrival at the hospital the patients need to undergoa neurologic evaluation and computed tomography of thehead and to provide informed consent before they undergorandomization and receive treatment.

N

AUMAN

Q

URESHI

, M.D.Athens, AL 35611 1005 W. Market St.

1. del Zoppo GJ. Acute stroke — on the threshold of a therapy? N Engl J Med1995;333:1632-3.

The authors reply:

To the Editor:

Dr. Friedman asks whether the beneficial ef-fect we reported for t-PA in the treatment of acute stroke wasdue to the unequal distribution between the t-PA and placebogroups of patients who had been taking aspirin before theirstroke. As we stated, the positive effect of t-PA on all outcomemeasures at three months was seen consistently in all sub-groups categorized according to age, stroke subtype, severityof the stroke, and use of aspirin before the stroke. The imbal-ance in the randomization of patients taking aspirin beforetheir stroke had little effect on the outcome of our trial be-cause t-PA also increased favorable outcomes in those not tak-ing aspirin.

Dr. Friedman and Dr. Koroshetz have questions regardingthe risk and benefit of t-PA in various subgroups of patientswith acute stroke. Both observed that there were more small-vessel occlusive strokes in the t-PA–treated group. It is truethat patients assigned to the small-vessel occlusive category atbase line were more likely to have a favorable outcome when

treated with t-PA. But examination of Table 5 in our reportshows that for each stroke subtype t-PA–treated patients hada favorable outcome more frequently than did patients whoreceived placebo. Although stroke subtype helps predict out-come at three months, it does not help predict whether t-PAwill be beneficial, since patients with all types of strokes havebetter outcomes when treated with t-PA.

The benefits of t-PA come at the expense of additionaldeaths due to intracerebral hemorrhage, but there are corre-spondingly fewer deaths due to other causes. Fewer t-PA–treat-ed patients than placebo-treated patients had died at threemonths (17 percent vs. 21 percent).

Dr. Koroshetz is concerned that haste in treatment will ex-pose patients to an unnecessary risk of intracerebral hemor-rhage. On the contrary, we think that early treatment withinthree hours of the onset of stroke is required to obtain the fullbenefit of t-PA. Delaying treatment will not help select pa-tients who will benefit from t-PA and may expose patients toa greater risk of hemorrhage, with less benefit in return.

This trial provides a basis for developing an acute care re-sponse to stroke. Further research may lower risks and increasebenefits. In the meantime, we urge the development of theteams needed to treat stroke as the true emergency that it is.

J

OHN

R. M

ARLER

, M.D.Bethesda, MD 20892 National Institutes of Health

FOR

THE

NINDS rt-PA S

TROKE

S

TUDY

G

ROUP

To the Editor:

Dr. Qureshi raises an important point aboutthe interval from the onset of stroke to the initiation of treat-ment with t-PA as opposed to the interval from stroke onsetto arrival at the hospital in patients with acute ischemicstroke. Time to treatment was a relevant issue in the designof the NINDS rt-PA Stroke Study, as indicated by the timelimitations of 90 and 180 minutes. But the difference in pa-tient outcomes associated with those times was apparently notcritical. Although unproved, the longer time before treatmentin the European Cooperative Acute Stroke Study may havebeen partly responsible for the difference in the outcomes re-ported for that study.

1

The point to be taken from both studiesis that treatment requires the ready availability of high-qual-ity brain-imaging techniques and a well-prepared medicalteam, which at this time are primarily available only at largermedical centers. The interval from stroke onset to arrival inthe hospital is thus very important.

Furthermore, treatment without adherence to the strictclinical requirements outlined by these and other studies pos-es an unacceptable risk. In other words, initiating treatmentwithout first performing the proper imaging studies is danger-ous. Also, since the clinical impression of the time at whichsymptoms began may be quite subjective,

2

proper techniquesare needed to assess the severity and duration of the ischemicinjury, both of which vary among patients.

3

At this stage inthe development of plasminogen activators for use in acute is-chemic stroke, it is the delay in bringing the patient to medi-cal attention (e.g., hospital) that must be addressed.

G

REGORY

J.

DEL

Z

OPPO

, M.D.La Jolla, CA 92037 Scripps Research Institute

1. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombi-nant tissue plasminogen activator for acute hemispheric stroke. JAMA 1995;274:1017-25.

2. del Zoppo GJ, Ferbert A, Otis S, et al. Local intra-arterial fibrinolytic therapyin acute carotid territory stroke: a pilot study. Stroke 1988;19:307-13.

3. Baron JC, von Kummer R, del Zoppo GJ. Treatment of acute ischemicstroke: challenging the concept of a rigid and universal time window. Stroke1995;26:2219-21.




LOW-MOLECULAR-WEIGHT HEPARIN FOR THE TREATMENT OF ACUTE ISCHEMIC STROKE

To the Editor:

The conclusion by Kay et al. (Dec. 14 issue)

1

that low-molecular-weight heparin improves the outcomes ofpatients with acute ischemic stroke can be questioned for tworeasons. First, aspirin should have been administered to thepatients in the control group, because aspirin is regarded asstandard therapy in this clinical situation.

2

Without the ad-ministration of aspirin in the control group, it cannot be con-cluded that nadroparin had a significant effect beyond thecurrent standard of care.

Second, there was a high rate of complications in the pla-cebo group after the treatment period, including an in-creased number of patients with hemorrhagic transformation(almost twice the number among those who received anti-coagulation therapy), and an increased number of recurrentischemic strokes (more than double the number in the high-dose group). The authors “speculate that antithrombotictreatment [with nadroparin] may have reduced the volumeof the infarct by limiting the extension of thrombus to the is-chemic penumbra . . . and by maintaining blood flow inthat region. Treated patients would thus have more potentialfor survival and recovery.” Aspirin likewise might have ade-quately limited the extension of infarction in the placebogroup.

We may lack strong data supporting the efficacy of aspirinor heparin for the treatment of acute ischemic stroke, butwhen there are no contraindications, aspirin is well estab-lished as the standard treatment in acute nonhemorrhagic is-chemic stroke.

J

EFFREY

M. B

LOOM

, M.D.San Luis Obispo, CA 93401 San Luis Medical Clinic

1. Kay R, Wong KS, Yu YL, et al. Low-molecular-weight heparin for the treat-ment of acute ischemic stroke. N Engl J Med 1995;333:1588-93.

2. Barnett HJM, Eliasziw M, Meldrum HE. Drugs and surgery in the preventionof ischemic stroke. N Engl J Med 1995;332:238-48.

The authors reply:

To the Editor:

The value of aspirin, if any, in the treatmentof acute ischemic stroke has not been established.

1,2

Therecommendations by Barnett et al. refer to the prevention ofischemic stroke.

3

For the use of aspirin in patients with acuteischemic stroke, the only support from randomized studiescomes from a recently suspended clinical trial comparingstreptokinase, aspirin, and the two drugs combined.

4

In thattrial, aspirin reduced the risk of death or severe disability atsix months by 10 percent, but this reduction was not statisti-cally significant. At least two major clinical trials (the Inter-national Stroke Trial and the Chinese Acute Stroke Trial) are

currently investigating the effect of aspirin given within 48hours after an ischemic stroke. If these trials show that aspi-rin improves the outcome, then it will be reasonable to dis-cuss whether future trials of therapy for acute stroke shouldinclude the administration of aspirin in the control group.

The higher rates of complications in the placebo groupin our study were not statistically significant. In the case ofhemorrhagic transformation of the infarct, there were more he-matomas in the low-dose group than in either the high-dosegroup or the placebo group (Table 1). The numbers were small,and such differences could well have been due to chance.

R

ICHARD

K

AY

, M.D.K

A

S

ING

W

ONG

, M.B.J

EAN

W

OO

, M.D.Shatin, Hong Kong Chinese University of Hong Kong

1. Sandercock PA, van den Belt AG, Lindley RI, Slattery J. Antithrombotictherapy in acute ischaemic stroke: an overview of the completed randomisedtrials. J Neurol Neurosurg Psychiatry 1993;56:17-25.

2. Adams HP Jr, Brott TG, Crowell RM, et al. Guidelines for the managementof patients with acute ischemic stroke: a statement for healthcare profession-als from a special writing group of the Stroke Council, American Heart As-sociation. Stroke 1994;25:1901-14.

3. Barnett HJM, Eliasziw M, Meldrum HE. Drugs and surgery in the preventionof ischemic stroke. N Engl J Med 1995;332:238-48.

4. Multicentre Acute Stroke Trial–Italy (MAST-I) Group. Randomised con-trolled trial of streptokinase, aspirin, and combination of both in treatment ofacute ischaemic stroke. Lancet 1995;346:1509-14.

CARDIAC MYXOMAS

To the Editor:

Reynen (Dec. 14 issue)

1

provides an extensiveand informative review of cardiac myxomas. He points outthat myxomas are histologically benign but may be lethal be-cause of their strategic position. He further states that the ma-lignant potential of cardiac myxomas remains doubtful. A fewmalignant atrial myxomas have been reported, however.

2,3

Wedescribe a cardiac left atrial tumor that resembled malignantmyxoma clinically and grossly.

An 18-year-old woman presented with fever, joint pain, anda diastolic murmur. She was treated for rheumatoid arthri-tis, but signs of increased intracranial pressure developed 16months later. Radiologic studies revealed tumors in the mitralvalve and the left temporal lobe. The brain tumor was re-moved, and the atrial tumor was resected. The brain lesionand the primary heart tumor were histologically similar, rep-resenting high-grade sarcoma with spindle-cell and pleomor-phic features. Immunohistochemically, the tumor cells showedfocal reactivity of muscle actin but were negative for desmin,as is compatible with a diagnosis of pleomorphic sarcoma(malignant fibrous histiocytoma).

Despite brain and cardiac irradiation and cytotoxic treat-ment (with ifosfamide, epirubicin, dacarbazine, and etopo-side), another lesion developed in the brain, first visualized byantibody scanning and then verified by computed tomogra-phy. An indium-111–labeled monoclonal antimyosin antibody(R11D10) specific for cardiac myosin, with some cross-reac-tivity with skeletal myosin, was used to detect distant metas-tases.

4

Figure 1A shows a single-photon-emission computedtomographic (SPECT) study of the brain recorded 72 hoursafter injection, demonstrating pronounced intracranial uptakeof antibody.

The patient died two years after the first symptoms. Theautopsy showed extensive tumor growth in both the left atri-um and the left ventricle, as well as regrowth of the metasta-sis in the left temporal lobe (Fig. 1B).

Two patients with malignant atrial myxoma have been de-

*P

�

0.19 by the chi-square test for trend.

Table 1. Findings on Second Computed Tomographic Scans in245 Patients, According to Treatment Group.

F

INDING

H

IGH

-D

OSE

G

ROUP

L

OW

-D

OSE

G

ROUP

P

LACEBO

G

ROUP

no. of patients

No hemorrhagic transformation 76 74 73

Hemorrhagic transformation*Petechiae onlyHematoma

54

72

108

�

2 cm in diameter

�

2 cm to 5 cm in diameter

�

5 cm in diameter

010

041

101




scribed in the literature,

2,3

both presenting with an intracra-nial mass like that in our patient. Although the histologic fea-tures in our patient were different, her clinical course wassimilar to that in these two described cases of malignant atrialmyxoma.

K

ALEVI

J.A. K

AIREMO

, M.D., P

H

.D.C

ARL

P. B

LOMQVIST

, M.D., P

H

.D.Helsinki University

FIN-00290 Helsinki, Finland Central Hospital

M

ARKKU

M

IETTINEN

, M.D., P

H

.D.Jefferson Medical College

Philadelphia, PA 19107 of Thomas Jefferson University

1. Reynen K. Cardiac myxomas. N Engl J Med 1995;333:1610-7.2. Rankin LI, DeSousa AL. Metastatic atrial myxoma presenting as intracranial

mass. Chest 1978;74:451-2.3. Pastakia B. Malignant atrial myxoma presenting as intracranial mass. Chest

1979;75:531-2.4. Kairemo KJ, Wiklund TA, Liewendahl K, et al. Imaging of soft-tissue sarco-

mas with indium-111-labeled monoclonal antimyosin Fab fragments. J NuclMed 1990;31:23-31.

To the Editor:

Dr. Reynen reports that “myxomas consist ofa myxoid matrix composed of an acid-mucopolysaccharide–rich stroma.” The term “acid mucopolysaccharide” reflectsthe histologic appearance when conventional staining proce-dures are used. However, the term should be replaced, nowthat the biochemical bases of the staining reactions have beenelucidated. The proteoglycans, consisting of straight-chain sug-ars or glycosaminoglycans covalently attached to a protein core,are the chief component of acid mucopolysaccharides. Theonly glycosaminoglycan not attached to a protein core, hyalu-ronan (also known as hyaluronic acid), present in tissue un-dergoing rapid turnover and in association with cancers isfound in particularly rich concentration in embryonic tissues.My colleagues and I have established that the stroma of myx-omas contains predominantly hyaluronan.

1,2

This finding sup-ports the suggestion that such tumors arise from embryonicrests remaining from the period when septation of the heartwas occurring, which also explains the prevalence of myxo-mas in the atrial septum.

R

OBERT

S

TERN

, M.D.University of California,

San Francisco,San Francisco, CA 94143-0506 School of Medicine

1. Hendin BN, Longaker MT, Finkbeiner WE, Roberts LJ, Stern R. Hyaluronicacid deposition in cardiac myxomas: localization using a hyaluronate-specificbinding protein. Am J Cardiovasc Pathol 1991;3:209-15.

2. Longaker MT, Chiu ES, Hendin B, Finkbeiner WE, Stern R. Hyaluronic acidin a cardiac myxoma: a biochemical and histological analysis. Virchows ArchA Pathol Anat Histopathol 1991;418:435-7.

The author and a colleague reply:

To the Editor:

Kairemo et al. report the very rare case of amalignant fibrous histiocytoma in the left atrium. Histolog-ically, such histiocytomas represent pleomorphic sarcomaswith partial fibroblastic and histiocytic differentiation. Be-cause of preferential left atrial growth, malignant fibroushistiocytoma may clinically mimic left atrial myxoma. Fur-thermore, in patients with myxoid variants of this tumor,thorough microscopical examination of multiple sections maybe needed to achieve reliable histologic differentiation frommyxoma.

1

In this case, as well as in the case described byPastakia,

2

a malignant tumor of the heart, not a myxoma,metastasized to the brain. In contrast, cardiac myxomas arehistologically benign, without nuclear atypia or mitoses. Nev-

Figure 1. Brain Metastasis of a Cardiac Tumor.Panel A shows a single-photon-emission computed tomograph-ic scan demonstrating intense uptake by an indium-111–labeledmonoclonal antibody against cardiac myosin in the left temporallobe of the brain, 72 hours after the injection of antibody. Theratio of uptake in the tumor to that in the background in the con-tralateral site was as high as 26:1. Panel B shows a pleomorphicleft atrial sarcoma (malignant fibrous histiocytoma) metastatic to

the brain (hematoxylin and eosin,

�350).

A

B




ertheless, such myxomas are consideredsometimes to possess malignant poten-tial: In histologically benign myxo-mas, extensive local invasion of cardiactissue3 and remote growth of embolizedtumor material have been observed,with and without malignant transforma-tion.4,5

Histologically, the bulk of myxomasconsists of a myxoid matrix in whichacid mucopolysaccharides are the pre-dominant substances. Polygonal cells withscant eosinophilic cytoplasm are embed-ded in the matrix. In addition, reticular,collagen, and elastic fibers, as well assmooth-muscle cells, are found in dif-fering amounts. The systematic name ofmucopolysaccharides is glycosamino-glycans. With the exception of hyaluron-ic acid, acid glycosaminoglycans suchas chondroitin sulfate A and C, derma-tan sulfate, heparin, heparan sulfate, andkeratan sulfate are covalently bound tospecific proteins and are accordinglycalled proteoglycans. Keratan sulfate, hy-aluronic acid, and chondroitin sulfateA and C have been identified in myx-omas6; in the myxoid matrix of an ex-cised myxoma, hyaluronic acid was foundat a level 30 times higher than that innormal atrial septum.7 We agree withDr. Stern that since the glycosaminoglycan pattern is charac-teristic of embryonic tissue, it is reasonable to assume thatmyxomas arise from embryonic rests remaining from the pe-riod of septation of the heart.

KLAUS REYNEN, M.D.WERNER G. DANIEL, M.D.

D-01307 Dresden, Germany University Clinic Dresden

1. Laya MB, Mailliard JA, Bewtra C, Levin HS. Malignant fibrous histiocytomaof the heart: a case report and review of the literature. Cancer 1987;59:1026-31.

2. Pastakia B. Malignant atrial myxoma presenting as intracranial mass. Chest1979;75:531-2.

3. Hannah H III, Eisemann G, Hiszcznskyj R, Winsky M, Cohen L. Invasiveatrial myxoma: documentation of malignant potential of cardiac myxomas.Am Heart J 1982;104:881-3.

4. Kotani K, Matsuzawa Y, Funahashi T, et al. Left atrial myxoma metastasizingto the aorta, with intraluminal growth causing renovascular hypertension.Cardiology 1991;78:72-7.

5. Wada A, Kanda T, Hayashi R, Imai S, Suzuki T, Murata K. Cardiac myxomametastasized to the brain: potential role of endogenous interleukin-6. Cardi-ology 1993;83:208-11.

6. Mikuz G, Hofstädter F, Hausen A, Hager J. Das sog: Endokardmyxom: his-tologische, elektronenmikroskopische, immunfluoreszenz- und biochemischeUntersuchungen an drei Fällen. Virchows Arch A Pathol Anat Histopathol1978;380:221-36.

7. Longaker MT, Chiu ES, Hendin B, Finkbeiner WE, Stern R. Hyaluronic acidin a cardiac myxoma: a biochemical and histological analysis. Virchows ArchA Pathol Anat Histopathol 1991;418:435-7.

PRENATAL SCREENING FOR DOWN’S SYNDROME IN MAINE, 1980 TO 1993

To the Editor: Prenatal screening and diagnostic services forfetal Down’s syndrome have been offered to women since theearly 1970s, when reliable techniques of chromosome analysisbecame available. Screening was initially based only on thepregnant woman’s age but has been broadened in recent years,

first with the discovery of maternal serum alpha-fetoprotein1,2

and then with the discovery of additional maternal serummarkers.3,4 Although it has been possible to document the num-ber of pregnant women who choose certain prenatal screeningservices,5 little information is available about the use of diag-nostic services, including decisions about terminating or con-tinuing affected pregnancies.

Table 1 shows the use of prenatal screening and diagnosticservices for Down’s syndrome in Maine between 1980 and1993. Before 1986, screening was based on maternal age, andamniocentesis was offered to women 35 years old or older. Be-tween 1986 and 1990, serum screening based on alpha-feto-protein measurements was also offered, but only to womenyounger than 35. Between 1991 and 1993, screening for mul-tiple serum markers replaced screening for alpha-fetoprotein,4and some women who were 35 or older opted for this screen-ing test rather than amniocentesis.

Table 1 also shows the expected numbers of live-born in-fants with Down’s syndrome in each of these intervals andcompares them with the numbers of cases ascertainedthrough vital statistics, cytogenetic laboratory records, andphysicians’ reports (after adjustment of the ascertained valuesto account for spontaneous fetal losses occurring between 18weeks of gestation and full term). The estimated and ascer-tained numbers are similar. (Also shown are the percentagesof infants with Down’s syndrome born to women youngerthan 35.) In the first six years, 9 cases of Down’s syndromewere identified prenatally, as compared with 35 in the nextfive years and 40 in the final three years. Termination of preg-nancy was chosen in 89, 83, and 92 percent of these pregnan-cies during the three periods, respectively, and the overallprevalence of Down’s syndrome among live births was re-duced by 7, 23, and 46 percent, respectively.

Approximately two thirds of all pregnant women in Mainechoose serum screening; that figure has remained stable forseveral years and is consistent with data from other estab-

*The expected number of cases is based on the maternal age distribution and the maternal-age–specific prevalence ofDown’s syndrome among live births.

†The ascertained number of live-born infants with Down’s syndrome, in the absence of prenatal diagnosis and selectivetermination of pregnancy, was calculated as the number of live-born infants with Down’s syndrome that was not detectedprenatally � the number of live-born infants with Down’s syndrome that was detected prenatally � (the number of termi-nated pregnancies � 0.77), which takes into account spontaneous loss.

‡The prevalence of Down’s syndrome among live births was calculated as 1 � (the number of live-born infants withDown’s syndrome not detected prenatally � the number of live-born infants with Down’s syndrome detected prenatally)� the total number of ascertained cases of Down’s syndrome.

Table 1. Results of Prenatal Screening for Down’s Syndrome in Maine between 1980and 1993.

VARIABLE 1980 – 1985 1986 – 1990 1991 – 1993 TOTAL

Live birthsTotal no.Maternal age 20 yr — %Maternal age 35 yr — %

96,28713.44.1

82,33511.26.8

46,93410.58.7

225,55612.06.1

Cases of Down’s syndromeExpected*

No. of cases% with maternal age 35 yr

Ascertained†No. of cases% with maternal age 35 yr

97.480

85.279

95.172

99.361

60.365

61.575

252.973

245.371

Cases of Down’s syndrome identifiedBy amniocentesis alone

No. of casesNo. of pregnancies terminated

By serum screeningNo. of casesNo. of pregnancies terminated

After birth — no. of cases

98

00

78

2019

151071

1010

302730

3937

4537

179Reduction in prevalence of Down’s syn-

drome among live births — %‡7.2 22.5 46.3 23.2




lished programs. Given the voluntary nature of prenatalscreening and diagnostic services, which provide the opportu-nity for individual decision making at each step, it is likelythat the findings in the period from 1991 to 1993 reflect themaximal participation that might be expected when serviceshave become well established in a given region.

GLENN E. PALOMAKI, B.S.JAMES E. HADDOW, M.D.

Scarborough, ME 04074 Foundation for Blood Research

LAURENT J. BEAUREGARD, PH.D.Bangor, ME 04401 Eastern Maine Medical Center

1. Cuckle HS, Wald NJ, Lindenbaum RH. Maternal serum alpha-fetoproteinmeasurement: a screening test for Down syndrome. Lancet 1984;1:926-9.

2. New England Regional Genetics Group Prenatal Collaborative Study ofDown Syndrome Screening. Combining maternal serum a-fetoprotein meas-urements and age to screen for Down syndrome in pregnant women underage 35. Am J Obstet Gynecol 1989;160:575-81.

3. Wald NJ, Cuckle HS, Densem JW, et al. Maternal serum screening forDown’s syndrome in early pregnancy. BMJ 1988;297:883-7. [Erratum, BMJ1988;297:1029.]

4. Haddow JE, Palomaki GE, Knight GJ, et al. Prenatal screening for Down’s syn-drome with use of maternal serum markers. N Engl J Med 1992;327:588-93.

5. Palomaki GE, Knight GJ, McCarthy J, Haddow JE, Eckfeldt JH. Maternal se-rum screening for fetal Down syndrome in the United States: a 1992 survey.Am J Obstet Gynecol 1993;169:1558-62.

1996, Massachusetts Medical Society.

BOOK REVIEWSTHE DEPRESSED CHILD AND ADOLESCENT:

DEVELOPMENTAL AND CLINICAL PERSPECTIVES

(Cambridge Monographs in Child and Adolescent Psychia-try.) Edited by Ian M. Goodyer. 354 pp. New York, Cam-bridge University Press, 1995. $79.95. ISBN 0-521-43326-6.

In their contribution to this excellent monograph, Kovacsand Bastiaens may have sensed the growing impatience as thereader struggles with the mountain of studies presented. Theywrite: “Although, over the past 15 years, considerable advanc-es have been made in clinical and psychometric assessment,specification of diagnostic criteria, and phenomenologic de-scription of depressed youths, no novel or comprehensive the-ories of early-onset depressions have been proposed.” Itseems that the false surety of the previously dominant view,psychoanalysis, has evaporated and that, perhaps in reactionto its excesses, the scientific hard core of psychiatry has triedto exist in a sea of empirical findings without theory — tostrap itself, so to speak, to the mast of a rigorous empiricismand resist the siren song of comprehensive theorizing. Thisbook is a good example.

Ian Goodyer has assembled an internationally recognizedgroup of researchers as authors. The stage is set by a historicalaccount of the evolution of concepts of mood disorders in chil-dren that demonstrates the episodic and sometimes retrogradeprogress in this area. Each of the current scientific perspec-tives on depression in children is then examined, and to eachthe dissecting scalpel of the controlled study is applied. Theentire span of development, from prepuberty to adolescence, isaddressed. In the resulting tour de force, we are taken from anexposition of the development of emotional behavior and un-derstanding, through the contributions of temperament, at-tachment, and personality development, to depressive vulner-ability. What is known of the effect of physiologic variables onthe development of depression is detailed, as well as physio-logic correlates of depression. Phenomenologic, epidemiolog-ic, and family-genetics aspects of the disorder are reviewed, asis the contribution of life events. The clinical perspectives arecompleted by chapters on suicidality, pharmacologic treatmentand psychotherapy, and the findings of longitudinal studies ofdepressed children and adolescents.

Each chapter contains a depth of information not found inusual textbooks and a subtlety of understanding that only ex-perts of international standing who are reviewing the areas oftheir own research can provide. A consistent theme is thatwhile standard diagnostic criteria derived from the study of

adults has brought us thus far, future advances will depend onour developing ways of detecting and tracking depression asthe development of children unfolds and exerts marked influ-ences on their emotional and behavioral repertoire. One ex-ample of the complexities involved is Terwogt and Stegge’sdescription of the development of children’s ability to displayemotions. By the age of 3, they may be able to conceal disap-pointment spontaneously but will believe the examiner knowshow they truly feel. By the age of 6, children will know thatfacial expressions can be misleading, and by the age of 7 to11 they will be able to feign emotions for self-protection or outof consideration for others. It is not a surprise, then, whenKolvin states in chapter 5 that parents are often unaware oftheir children’s depression and that for a generation psycho-analysis denied that there was such a thing as childhood de-pressive disorder.

This book is remarkable for the consensus of its authors onstandards for the admissibility of evidence across the manyperspectives they review. By and large, they rely only on theresults of controlled studies on populations of subjects. Unlikemost psychiatric textbooks, this one offers no case studies.Connecting the abstract descriptions of research findings andthe clinical picture of a depressed child is an act of synthesisand reconstruction that the clinicians reading this book willneed to undertake on their own. When they do so, however,their formulation of the child’s problems and treatment willbe richer, and they will proceed on a sounder scientific footingfor having made the effort. They will bring to their work thenewest scientific and developmental information. To the re-searcher in childhood depression, this book documents, withreferences, the great strides child and adolescent psychiatryand psychology have made in the past 30 years.

Like any true milestone, this book indicates not only howfar we have traveled but how much farther there is to go. Italso makes clearer the limitations of the method of inquiry. Itis striking how tremendously difficult it is to establish by con-trolled clinical trials relations that seem obvious to the prac-titioner. Thus, it is as hard to imagine reaching a true under-standing of childhood depression by applying the rating scalesand other measures cited to populations as it is to imagine un-derstanding the activity of the brain by applying thermody-namics alone. The problem is that when a population is stud-ied the individual becomes the gaussian noise and is lost. Bycontrast, with the paradigm used 30 years ago, when the casehistory was the focus, generalizability and falsifiability weresacrificed. The way out of this predicament has not yet beenfound. In his preface, Goodyer states the hope that this bookwill stimulate further scientific research. I believe he and his



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