C ORR ES POND ENCE

Correspondence been shown to be safe in patients without overt severe symp-

toms. A decline in exercise time may be a more useful pre-
dictor of the onset of symptoms than an increase in peak
aortic-jet velocity alone, and we suggest that this possibil-
ity should be investigated prospectively.

PAUL DAS, M.R.C.P.

Predictors of Outcome in Asymptomatic
Aortic Stenosis
To the Editor: In their prospective study of patients with
asymptomatic aortic stenosis, Rosenhek et al. (Aug. 31 is-
sue)1 note that the rate of progression of aortic-jet velocity
was significantly higher in patients who underwent aortic-
valve replacement or died from cardiac causes. Others have
shown similar results.2
However, the rate of change in the aortic-jet velocity
might in itself influence the decision to perform surgery.
Physicians may refer patients for valve replacement after
observing an increase in aortic-jet velocity because they be-
lieve that the increase indicates a worsening prognosis. This
approach is supported by the guidelines of the American
Heart Association, which include severe asymptomatic aor-
tic stenosis as a class IIb indication for valve replacement.3
The British Cardiac Society recommends surgery both in
the presence of symptoms and if the gradient is particularly
high.4 In the prospective study by Pellikka et al.,5 18 of 143
asymptomatic patients (13 percent) underwent valve replace-
ment because it was thought that the severity of stenosis
itself warranted intervention.
Alternatively, physicians might be more inclined to in-
terpret mild, nonspecific breathlessness as overt exercise lim-
itation if the aortic-jet velocity is high. We recently reviewed
a series of patients with severe aortic stenosis and mild
breathlessness (with a score of 2 on the Specific Activity
Scale). In those referred for aortic-valve replacement, the
average peak velocity was 4.4 m per second. However, de-
spite similar symptoms, other patients were being treated
conservatively, and in these the average peak velocity was
only 3.9 m per second.
It would therefore be an advantage to have an objective
measure of functional capacity. Treadmill exercise testing has
JOHN CHAMBERS, M.D.
Guy’s and St. Thomas’ Hospitals
London SE1 7EH, United Kingdom
1. Rosenhek R, Binder T, Porenta G, et al. Predictors of outcome in se-
vere, asymptomatic aortic stenosis. N Engl J Med 2000;343:611-7.
2. Otto CM, Burwash IG, Legget ME, et al. Prospective study of asymp-
tomatic valvular aortic stenosis: clinical, echocardiographic, and exercise
predictors of outcome. Circulation 1997;95:2262-70.
3. Bonow R, Carabello B, de Leon AC Jr, et al. Guidelines for the man-
agement of patients with valvular disease: executive summary. Circulation
1998;98:1949-84.
4. Prendergast BD, Banning AP, Hall RJC. Valvular heart disease: recom-
mendations for investigation and management. J R Coll Physicians Lond
1996;30:309-15.
5. Pellikka PA, Nishimura RA, Bailey KR, Tajik AJ. The natural history of
adults with asymptomatic, hemodynamically significant aortic stenosis.
J Am Coll Cardiol 1990;15:1012-7.
To the Editor: The results of the enlightening study by
Rosenhek et al. suggest that the degree of aortic-valve cal-
cification and the rate of progression of aortic-jet velocity
are powerful predictors of the risk of death or the need for
aortic-valve replacement in asymptomatic patients with se-
vere aortic stenosis. In her accompanying editorial, Otto1
correctly describes aortic stenosis as a disease process that
leads to the insidious onset of symptoms that often go un-
recognized by both the patient and the physician in spite
of meticulous history taking at routine follow-up. Conse-
quently, some patients are placed at risk for adverse clinical
events such as sudden death. The foremost challenge to phy-
sicians who care for such patients is to determine the opti-
mal timing of aortic-valve replacement.
The current American College of Cardiology–American
Heart Association guidelines for the management of val-
vular heart disease support the use of certain findings on
exercise stress testing and echocardiography to identify pa-
tients with severe aortic stenosis who are at high risk for
clinical events (e.g., hypotension with exercise, the presence
of left ventricular dysfunction, marked left ventricular hy-

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 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
pertrophy, and an aortic-valve area of less than 0.6 cm2 or an
aortic-valve index no higher than 0.6 cm2 per square meter
of body-surface area).2 However, none of these echocardio-
graphic findings have demonstrated the predictive power
that Rosenhek et al. report for the degree of valvular cal-
cification and the increase in aortic-jet velocity. Their results
add to the existing evidence that an absence of symptoms
is an insufficient reason to delay aortic-valve replacement
in certain cases. The findings also shed light on the matter
of which patients should be considered for early surgery.
KEVIN E. O’BRIEN, M.D.
CAREY L. O’BRYAN, M.D.
ROBERT SAAD, M.D.
Wilford Hall U.S. Air Force Medical Center
San Antonio, TX 78236
1. Otto CM. Aortic stenosis — listen to the patient, look at the valve.
N Engl J Med 2000;343:652-4.
2. Task Force on Practice Guidelines (Committee on Management of Pa-
tients with Valvular Heart Disease). ACC/AHA guidelines for the manage-
ment of patients with valvular heart disease: a report of the American Col-
lege of Cardiology/American Heart Association. J Am Coll Cardiol 1998;
32:1486-588.
The authors reply:
To the Editor: We appreciate the interest of Drs. Das and
Chambers in our study of patients with asymptomatic but
hemodynamically severe aortic stenosis. Our data suggest
that the echocardiographically determined extent of calci-
fication of the valve and the observed rate of hemodynamic
progression permit the early identification of patients at risk
who should undergo surgery despite the absence of symp-
toms. As pointed out in our article, the patients who were
followed and treated conservatively underwent surgery only
when symptoms developed, not because of hemodynamic
progression or a certain degree of hemodynamic severity.
The current American College of Cardiology–American
Heart Association guidelines1 do not support the approach
of operating on asymptomatic patients just because their
stenosis is severe. According to these guidelines, valve re-
placement is definitely recommended in symptomatic pa-
tients only (those with a class I indication) and is probably
indicated in asymptomatic patients with impaired left ven-
tricular function or abnormal exercise response (class IIa).
Although there is some controversy surrounding the matter,
these guidelines state that evidence is lacking to support
surgery in asymptomatic patients solely because hypertro-
phy is severe or because the aortic-valve area is smaller than
0.6 cm 2 (a class IIb indication). The rate of progression is
not mentioned at all. Thus, in a patient with an increase
in aortic-jet velocity whose aortic-valve area is still at least
0.6 cm 2, the guidelines would not recommend surgery.
As discussed in detail in our article, we agree with Das
and Chambers that it may be difficult to distinguish between
asymptomatic and mildly symptomatic patients. Finally, we
also agree that exercise testing plays an important part in the
treatment of asymptomatic patients. Nevertheless, there are
few data addressing this issue.
HELMUT BAUMGARTNER, M.D.
RAPHAEL ROSENHEK, M.D.
University of Vienna
1090 Vienna, Austria
228 · N Engl J Med, Vol. 344, No. 3 · January 18, 2001 · www.nejm.org
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1. Task Force on Practice Guidelines (Committee on Management of Pa-
tients with Valvular Heart Disease). ACC/AHA guidelines for the manage-
ment of patients with valvular heart disease: a report of the American Col-
lege of Cardiology/American Heart Association. J Am Coll Cardiol 1998;
32:1486-588.
The editorialist replies:
To the Editor: The primary factors determining the op-
timal timing of valve replacement for severe aortic stenosis
are the relative clinical outcomes with and without surgical
intervention. The observations by Rosenhek et al. that mod-
erate-to-severe valve calcification and a rapid increase in aor-
tic-jet velocity are associated with a higher rate of onset of
symptoms are helpful in ensuring that patients with these
conditions receive close clinical and echocardiographic fol-
low-up and are educated about the expected course of dis-
ease and the probable need for valve surgery. However, one
cannot extrapolate from these data the suggestion that valve
replacement should be performed before the onset of symp-
toms in these patients.
In the absence of symptoms, the risk of sudden death is
very low (less than 1 percent per year), even with severe ste-
nosis, as confirmed by the occurrence of only 1 sudden death
among 128 patients during more than two years in our
prospective study. In contrast, aortic-valve replacement is
associated with an operative mortality of 2 to 10 percent.1
In addition, there is no ideal substitute for the valve: the
hemodynamics after valve replacement are suboptimal as
compared with those associated with a normal native valve;
complications occur at a rate of 2 to 3 percent per year af-
ter surgery; and it is estimated that the risk of death due
to a prosthetic valve is about 1 percent per year.2-4
The American College of Cardiology–American Heart
Association guidelines for the treatment of patients with val-
vular heart disease should continue to serve as the bench-
mark for the optimal care of adults with severe aortic ste-
nosis.4 The only class I indications for valve replacement
— those for which there is evidence or general agreement
(or both) that the procedure is useful and effective — are
severe symptomatic stenosis and severe stenosis in patients
who are undergoing coronary-artery bypass grafting, aor-
tic-root surgery, or other valve surgery. The evidence also
favors valve replacement in patients with moderate aortic
stenosis who are undergoing other cardiac surgery and for
asymptomatic patients with severe stenosis and left ven-
tricular systolic dysfunction or exertional hypotension. In
other asymptomatic adults with severe stenosis, we should
defer valve surgery until symptoms occur, because we can
then be certain that our recommendation is associated with
improved clinical outcomes. After all, it is difficult to make
an asymptomatic patient feel better.
CATHERINE M. OTTO, M.D.
University of Washington School of Medicine
Seattle, WA 98195
1. Otto CM. Aortic stenosis. In: Otto CM, ed. Valvular heart disease. Phil-
adelphia: W.B. Saunders, 1999:179-217.
2. Vongpatanasin W, Hillis LD, Lange RA. Prosthetic heart valves. N Engl
J Med 1996;335:407-16.
3. Hammermeister KE, Sethi GK, Henderson WG, Oprian C, Kim T, Ra-
himtoola S. A comparison of outcomes in men 11 years after heart-valve
replacement with a mechanical valve or bioprosthesis. N Engl J Med 1993;
328:1289-96.
4. Task Force on Practice Guidelines (Committee on Management of Pa-
 C ORR ES POND ENCE
tients with Valvular Heart Disease). ACC/AHA guidelines for the manage-
ment of patients with valvular heart disease: a report of the American Col-
lege of Cardiology/American Heart Association. J Am Coll Cardiol 1998;
32:1486-588.
Interferon Beta-1a during a First Demyelinating
Event
To the Editor: Jacobs et al. (Sept. 28 issue)1 suggest that
interferon beta-1a therapy for some patients with a first clin-
ically isolated syndrome of multiple sclerosis may delay the
onset of clinically definite multiple sclerosis. The diagnosis
of multiple sclerosis has long been based on dissemination
in both space and time. If this approach still holds, can a
valid assessment of a potential disorder be made before the
appearance of the symptoms that define it? I find this study
troubling for several reasons.
Optic neuritis is easy to identify, but no criteria are given
for “incomplete transverse myelitis.” Is it paraparesis, numb-
ness of one arm, or gait ataxia? The term “brain-stem syn-
drome” is also vague: is this diplopia, facial weakness, or
dysphagia? The criteria for findings on magnetic resonance
imaging (MRI) are not helpful, since many conditions mimic
multiple sclerosis on MRI.2,3 Unfortunately, a radiologist’s
interpretation of the MRI scan is often the exclusive basis
for the diagnosis of multiple sclerosis. In a previous study,
this resulted in a 35 percent incidence of erroneous diag-
noses, leading to interferon therapy for patients with dis-
seminated encephalomyelitis and chronic fatigue syndrome.4
The study by Jacobs et al. did not address the clinical
import of a second bout of multiple sclerosis. In my more
than 40 years of experience, the majority of patients with
multiple sclerosis had benign disease, even after many years.
In only a handful of patients was the second episode dev-
astating or did it fail to respond to corticosteroid therapy.
O’Riordan et al.5 noted that after 10 years, three fourths
of patients with fewer than 10 lesions on magnetic reso-
nance imaging at study entry had benign disease (score on
the Expanded Disability Status Scale, «3). They waited six
months after the clinically isolated syndrome in order to rule
out disseminated encephalomyelitis, whereas Jacobs et al.
chose to wait only one month. The lack of data on func-
tional status and the length of time to clinically definite mul-
tiple sclerosis in the study by Jacobs et al. make its clinical
applicability doubtful.
The lack of correlation between the number, size, and lo-
cation of areas of increased signal intensity on T2-weighted
MRI and the patients’ clinical status militates against the
validity of the popular concept of burden of disease. Its clin-
ical significance may be similar to that of the optic atrophy
and delayed visual evoked responses of some patients with
multiple sclerosis who have perfectly normal vision.
Follow-up studies of clinically isolated syndromes of mul-
tiple sclerosis suggest that about half the patients have pro-
gression to clinically definite multiple sclerosis.4 It would
seem more prudent to delay treatment with disease-mod-
ifying drugs until the familiar criteria of dissemination in
time and space are fulfilled.
CHARLES M. POSER, M.D.
Harvard Medical School
Boston, MA 02115
N Engl J Med, Vol. 344, No. 3 · January 18, 2001 · www.nejm.org · 229
The New England Journal of Medicine
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Copyright © 2001 Massachusetts Medical Society. All rights reserved.
1. Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a
therapy initiated during a first demyelinating event in multiple sclerosis.
N Engl J Med 2000;343:898-904.
2. Triulzi F, Scotti G. Differential diagnosis of multiple sclerosis: contribu-
tion of magnetic resonance techniques. J Neurol Neurosurg Psychiatry
1998;64:Suppl 1:S6-S14.
3. Poser CM. An atlas of multiple sclerosis. Carnsworth, United Kingdom:
Parthenon Publishing, 1998:104-22.
4. . Misdiagnosis of multiple sclerosis and beta-interferon. Lancet 1997;
349:1916.
5. O’Riordan JI, Thompson AJ, Kingsley DP, et al. The prognostic value
of brain MRI in clinically isolated syndromes of the CNS: a 10-year follow-
up. Brain 1998;121:495-503.
To the Editor: The article by Jacobs et al. suggests that
the early treatment of a first demyelinating episode with
intramuscular interferon beta-1a, when the episode is ac-
companied by at least two clinically silent lesions on MRI
scanning, may be beneficial. This may have important im-
plications, given the expense of the treatment and the cur-
rent lack of data on the optimal duration of treatment. Be-
fore such a policy is applied as part of routine neurologic
practice, all available evidence relating to the natural history
of isolated demyelinating episodes needs careful review.
The placebo group in the study by Jacobs et al. may not
be entirely representative of the natural history of multiple
sclerosis. Jacobs et al. quote the findings of the Optic Neu-
ritis Treatment Trial,1 but in that study the risk of devel-
opment of clinically definite multiple sclerosis after three
years among patients with isolated optic neuritis and three
or more clinically silent lesions on MRI was only 38 per-
cent. This figure is very close to the 35 percent probability
of progression to clinically definite multiple sclerosis in the
group treated with interferon beta-1a in the present study
but below that in the placebo group, suggesting that the
placebo group had more aggressive disease than is usually
seen in clinical practice. Furthermore, the dropout rate in
both groups was about 15 percent, and this may have in-
fluenced the interpretation of the results. I believe that this
study was prematurely terminated. There is no evidence that
the treatment effect was becoming more pronounced with
the passage of time.
THOMAS F.G. ESMONDE, M.D.
Royal Victoria Hospital
Belfast BT12 6BA, Northern Ireland
1. The Optic Neuritis Study Group. The 5-year risk of MS after optic neu-
ritis: experience of the Optic Neuritis Treatment Trial. Neurology 1997;49:
1404-13.
The authors reply:
To the Editor: To be included in our study, patients had
to have symptoms, objective clinical signs, and clinically silent
lesions characteristic of multiple sclerosis of the brain on
MRI. This combination of clinical and MRI findings is high-
ly specific for multiple sclerosis. During follow-up, a causal
diagnosis other than multiple sclerosis was made in only 1 of
our 383 patients (a cerebellar infarct diagnosed after one
month). We believe that these patients already have patho-
logical multiple sclerosis and are at high risk for a second
clinical event, which will fulfill the criteria for clinically def-
inite multiple sclerosis. Clinically definite multiple sclerosis is
diagnosed in more than 50 percent of such patients within
 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
3 to 5 years and in more than 80 percent within 10 years.1
In many patients the course is not benign. In one study,
after 10 years, 44 percent of patients had moderate disability
(score on the Expanded Disability Status Scale, »3), and
approximately 25 percent already had secondary chronic pro-
gressive multiple sclerosis.1 The number and volume of le-
sions on T2-weighted MRI of the brain at the time of and
after the initial demyelinating event have been shown to
be predictive of long-term disability.1,2
In patients who meet the eligibility criteria used in our
study, we believe it is appropriate to make a definitive di-
agnosis of multiple sclerosis and to consider early treatment
with interferon beta-1a, an agent with proven efficacy for
preventing or delaying subclinical, “smoldering” multiple
sclerosis, which can cause inflammation, scarring, axonopa-
thy, atrophy, wallerian degeneration, and cognitive decline,
even early in the course of the disease.3,4
The three-year rate of clinically definite multiple sclero-
sis in our study cannot be directly compared with that of
the Optic Neuritis Treatment Trial,5 because the criteria for
and the ascertainment of clinically definite multiple sclerosis
differed in the two studies. In designing our trial, we ex-
trapolated from the results of the Optic Neuritis Treatment
Trial and other published data to project a three-year rate
of clinically definite multiple sclerosis in the placebo group
of 50 percent, which is what we found. The number of pa-
tients who withdrew early from the study was approximate-
ly what we had projected, and there was no indication that
the withdrawals affected the observed treatment effect.
The trial was stopped early on the recommendation of
an independent data and safety monitoring committee. Valu-
able information could have been gained from continued
accrual of data, but the interim analysis so clearly supported
the benefit of treatment with respect to both clinical and
MRI measures of outcome that continued use of a placebo
group was no longer ethically justified.
We agree that for patients in whom the diagnosis of mul-
tiple sclerosis is equivocal, interferon beta-1a therapy should
not be started. However, when the diagnosis appears un-
equivocal, as in our patients, initiation of interferon beta-
1a treatment at the time of the first clinical demyelinating
event is justified and appears to be cost effective.6
LAWRENCE D. JACOBS, M.D.
Buffalo General Hospital
Buffalo, NY 14203
ROY W. BECK, M.D., PH.D.
Jaeb Center for Health Research
Tampa, FL 33613
R. PHILLIP KINKEL, M.D.
Mellen Center for Multiple Sclerosis Treatment and Research
Cleveland, OH 44195
1. O’Riordan JI, Thompson AJ, Kingsley DPE, et al. The prognostic value
of brain MRI in clinically isolated syndromes of the CNS: a 10-year follow-
up. Brain 1998;121:495-503.
2. Sailer M, O’Riordan JI, Thompson AJ, et al. Quantitative MRI in pa-
tients with clinically isolated syndromes suggestive of demyelination. Neu-
rology 1999;52:599-606.
3. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, Bö L. Axonal
transection in the lesions of multiple sclerosis. N Engl J Med 1998;338:
278-85.
4. Simon JH, Kinkel RP, Jacobs L, Bub L, Simonian N. A Wallerian de-
generation pattern in patients at risk for MS. Neurology 2000;54:1155-60.
230 · N Engl J Med, Vol. 344, No. 3 · January 18, 2001 · www.nejm.org
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5. The Optic Neuritis Study Group. The 5-year risk of MS after optic neu-
ritis: experience of the Optic Neuritis Treatment Trial. Neurology 1997;49:
1404-13.
6. Kendrick M, Johnson KI. Long-term treatment of multiple sclerosis
with interferon-beta may be cost effective. Pharmacoeconomics 2000;18:
45-53.
Thromboangiitis Obliterans (Buerger’s Disease)
To the Editor: As Olin points out in his review (Sept. 21
issue),1 exposure to tobacco plays a central part in the initi-
ation and progression of thromboangiitis obliterans (Buer-
ger’s disease). However, the cause of Buerger’s disease re-
mains unknown. Not all patients with the disease smoke
or use smokeless tobacco, and in some patients who stop
smoking the disease is still progressive. Dr. Olin does not
mention hyperhomocysteinemia, which may have an im-
portant and nicotine-independent role in the pathogenesis
of Buerger’s disease. Hyperhomocysteinemia is known to be
an important risk factor in the early onset of atherosclerotic
occlusive disease and deep-vein thrombosis.2,3 In our study,
homocysteine levels increased (to at least 31 nmol per mil-
liliter) four hours after methionine loading (0.1 g per kil-
ogram of body weight) in 60 percent of the patients with
active Buerger’s disease (9 of 15) but in none of the 15
matched healthy smokers and 15 nonsmokers (P=0.01).4
We confirmed these results in a new investigation in which
55 percent of the patients with Buerger’s disease (11 of 20)
had increased homocysteine levels after methionine load-
ing, as compared with 24 percent of the smokers (5 of 21)
and 19 percent of the nonsmokers (4 of 21) without vas-
cular disease (P=0.01 and P=0.04, respectively).
There are several pathophysiological mechanisms that may
link hyperhomocysteinemia to Buerger’s disease. In vitro
studies suggest that homocysteine limits the bioavailability
of nitric oxide, impairs endothelium-dependent vasorelax-
ation, increases oxidative stress, stimulates smooth-muscle-
cell proliferation, alters the elastic properties of vessel walls,
and generates a prothrombotic state through the activation
of factor V.5
We favor screening for hyperhomocysteinemia in patients
with thromboangiitis obliterans, especially those with a pro-
gressive course. Since hyperhomocysteinemia is easily re-
versed by pyridoxine and folic acid supplementation, screen-
ing for and treatment of hyperhomocysteinemia may be an
important therapeutic strategy for patients with Buerger’s
disease.
CURT DIEHM, M.D.
FRANK STAMMLER, M.D.
University of Heidelberg
D-76307 Karlsbad, Germany
1. Olin JW. Thromboangiitis obliterans (Buerger’s disease). N Engl J Med
2000;343:864-9.
2. Brattström L, Israelsson B, Norrving B, et al. Impaired homocysteine
metabolism in early-onset cerebral and peripheral occlusive arterial disease:
effects of pyridoxine and folic acid treatment. Atherosclerosis 1990;81:51-60.
3. den Heijer M, Koster T, Blom HJ, et al. Hyperhomocysteinemia as a
risk factor for deep-vein thrombosis. N Engl J Med 1996;334:759-62.
4. Stammler F, Diehm C, Hsu E, Stockinger K, Amendt K. Prevalence of
hyperhomocysteinemia in thromboangiitis obliterans (Buerger’s disease):
does homocysteine play a pathogenetic role? Dtsch Med Wochenschr
1996;121:1417-23.
5. van Guldener C, Stehouwer CD. Hyperhomocysteinemia, vascular pa-
thology, and endothelial dysfunction. Semin Thromb Hemost 2000;26:
281-9.
 C ORR ES POND ENCE
Dr. Olin replies:
To the Editor: Drs. Diehm and Stammler state that not
all patients with thromboangiitis obliterans (Buerger’s dis-
ease) smoke or use tobacco. I have yet to see a well-doc-
umented case of thromboangiitis obliterans in a person who
did not use tobacco in some form. It is very easy to doc-
ument tobacco use by measuring nicotine or cotinine levels
in the urine. Lie described one case of pathologically con-
firmed Buerger’s disease affecting the upper limbs of a 62-
year-old man who had allegedly discontinued smoking 15
years earlier.1 However, this report did not contain measure-
ments of urinary nicotine and cotinine levels or of carboxy-
hemoglobin levels; therefore, it is possible that the man
was still smoking.
My colleagues and I have reported on the measurement
of plasma homocysteine in patients with Buerger’s disease,
and we agree with Diehm and Stammler that it may have
some role in the pathophysiology of thromboangiitis ob-
literans.2 Plasma homocysteine levels were measured in nine
patients (22.5 percent of the population with thromboangi-
itis obliterans at our institution from 1988 through 1996).
The values were elevated (to more than 12.9 µmol per liter)
in five patients and were normal in four patients. Four of the
five patients with elevated homocysteine levels underwent
amputation; all were active smokers. None of the four pa-
tients with normal homocysteine levels underwent ampu-
tation. Of the five patients with elevated homocysteine levels,
two had superficial venous thrombosis and one had deep
venous thrombosis. Elevated plasma homocysteine levels
may be important in determining which patients will even-
tually require amputation, but a prospective study is needed
to confirm this hypothesis.
JEFFREY W. OLIN, D.O.
Heart and Vascular Institute
Morristown, NJ 07960
1. Lie JT. Thromboangiitis obliterans (Buerger’s disease) in an elderly man
after cessation of cigarette smoking: a case report. Angiology 1987;38:864-
7.
2. Olin JW, Childs MB, Bartholomew JR, Calabrese LH, Young JR. An-
ticardiolipin antibodies and homocysteine levels in patients with throm-
boangiitis obliterans. Arthritis Rheum 1996;39:S-47.
The Diversity of T Cells
To the Editor: The excellent review by von Andrian and
Mackay (Oct. 5 issue)1 outlines the challenges faced by the
lymphoid system when it responds to a diverse array of
pathogens. In their introduction the authors restate a com-
mon misconception about the magnitude of the T-cell re-
sponse to individual pathogens, noting that “the number
of cells whose T-cell receptors recognize any individual an-
tigen is very limited (several thousand at most).” Histori-
cal estimates of the frequencies of precursor T cells specific
for recall antigens (e.g., in influenza), derived primarily from
limiting-dilution assays and analogous techniques, have been
consistent with such an estimate.
These estimates are in sharp contrast to the estimated
frequency of antigen-specific T cells in the setting of cer-
tain human and murine viral infections. With the use of cy-
tokine flow-cytometric studies to evaluate functional CD4+
T-cell responses, the frequencies of cytomegalovirus-specific
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cells in healthy subjects and in patients infected with the
human immunodeficiency virus type 1 (HIV-1) have been
found to range from 1 in 100 to 1 in 10 CD4+ T cells, even
in the absence of detectable viremia.2 Likewise, analysis of
the T-cell response to Epstein–Barr virus in humans3 and
of the T-cell response to lymphocytic choriomeningitis vi-
rus in mice,4 in studies using major-histocompatibility-com-
plex (MHC) class I tetramers to enumerate antigen-specific
CD8+ T cells, showed that the frequencies of antigen-spe-
cific T cells were as high as 40 percent of peripheral-blood
CD8+ cells in the setting of acute infection. High frequen-
cies of antigen-specific CD8+ memory T cells (>1 in 100)
have also been reported during chronic infection with these
viruses.5 On the basis of these estimates, the total number
of T cells that respond to human herpesvirus may well be
more than several million, rather than several thousand, as
von Andrian and Mackay suggest.
The authors ask, how is it that a relatively small number
of antigen-specific T cells can locate and eliminate remote-
ly scattered targets over a broad territory? Their question
is no less important in the light of these revised estimates.
Another challenge facing those studying T-cell immunity
is to understand why memory T cells specific for other vi-
ruses (e.g., HIV-1) and cancers appear to be much more rare
than those that respond to cytomegalovirus and Epstein–
Barr virus. An answer to this question may provide insights
into both the pathogenesis of these diseases and the use
of vaccines to prevent them.
KRISHNA V. KOMANDURI, M.D.
University of Texas M.D. Anderson Cancer Center
Houston, TX 77030
JOSEPH M. MCCUNE, M.D., PH.D.
University of California, San Francisco
San Francisco, CA 94103
1. von Andrian UH, Mackay CR. T-cell function and migration: two sides
of the same coin. N Engl J Med 2000;343:1020-34.
2. Komanduri KV, Viswanathan MN, Wieder ED, et al. Restoration of cy-
tomegalovirus-specific CD4+ T-lymphocyte responses after ganciclovir
and highly active antiretroviral therapy in individuals infected with HIV-1.
Nat Med 1998;4:953-6.
3. Murali-Krishna K, Altman JD, Suresh M, et al. Counting antigen-spe-
cific CD8 T cells: a reevaluation of bystander activation during viral infec-
tion. Immunity 1998;8:177-87.
4. Callan MFC, Tan L, Annels N, et al. Direct visualization of antigen-
specific CD8+ T cells during the primary immune response to Epstein-
Barr virus in vivo. J Exp Med 1998;187:1395-402.
The authors reply:
To the Editor: Komanduri and McCune comment on a
statement we made in discussing the diversity of “T cells
that have never encountered antigen, referred to as naive
T cells.” We arrived at the number of such cells that bear
any particular T-cell receptor on the basis of the estimate
that about half the 5¬1011 lymphocytes in adults are T cells.1
About 70 percent are naive, but this fraction is much
smaller in older persons. The most common T-cell receptor,
consisting of a/b chains, is found on approximately 90 per-
cent of all T cells. Thus, we estimate that the naive a/b
T-cell pool in adults contains approximately 1.5¬1011 cells.
There are at least 25¬106 different a/b T-cell receptors
on naive T cells in human peripheral blood.2 On average,
this amounts to 6000 naive T cells at most for each a/b
 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

T-cell receptor. Although the size of individual clones may

vary, the number of cells that actively recirculate at any point
in time may be smaller, since 98 percent of all lymphocytes
are sequestered in tissues.1 Studies using MHC tetramers and
T-cell–receptor sequencing in nonimmune mice have shown
that the upper limit for the number of T-cell precursors in
the spleen is 200,3 a finding that is consistent with our es-
timate in humans.
Komanduri and McCune correctly point out that the
frequency of antigen-reactive T cells increases dramatically
during and after viral infections. Indeed, clonal expansion
of antigen-primed T cells is a fundamental tenet of immu-
nity and immunologic memory. This concept is entirely con-
sistent with one of the central points in our review — that
T-cell migration changes after antigen priming. T-cell ex-
pansion is accompanied by differentiation into effector and
memory cells and the adoption of new pathways for migra-
tion and positioning, allowing for immunologic protection
at sites such as epithelial surfaces, where pathogens are first
encountered. Epithelial tissues cover an enormous surface
area, which cannot be efficiently surveyed by small num-
bers of antigen-specific lymphocytes in the pool of naive
T cells; this feat can be accomplished only with a greatly in-
creased frequency of antigen-specific T cells, such as the fre-
Figure 1. Capsule Endoscope (11 mm¬26 mm).
quencies noted by Komanduri and McCune. As they point
out, the degree of clonal expansion can vary, depending on The camera lens and four white-light–emitting diodes can be
seen beneath the transparent optical dome.
the nature of the pathogen. This variability is indeed in-
triguing but does not bear directly on our model of T-cell
migration and functional responses.

ULRICH H. VON ANDRIAN, M.D., PH.D.
Harvard Medical School
Boston, MA 02115
CHARLES R. MACKAY, PH.D.
Garvan Institute of Medical Research
Darlinghurst, NSW 2010, Australia
1. Westermann J, Pabst R. Distribution of lymphocyte subsets and natural
killer cells in the human body. Clin Invest 1992;70:539-44.
2. Arstila TP, Casrouge A, Baron V, Even J, Kanellopoulos J, Kourilsky P.
A direct estimate of the human alphabeta T cell receptor diversity. Science
1999;286:958-61.
3. Bousso P, Casrouge A, Altman JD, et al. Individual variations in the
murine T cell response to a specific peptide reflect variability in naive rep-
ertoires. Immunity 1998;9:169-78.
Wireless-Capsule Diagnostic Endoscopy
for Recurrent Small-Bowel Bleeding
To the Editor: We used wireless-capsule endoscopy1 to
assess patients with obscure or uncontrolled gastrointestinal
bleeding. The capsule endoscope contains a miniature video
camera, a light source, batteries, and a radio transmitter (Fig.
1). Video images are transmitted by means of radio telem-
etry to aerials taped to the body that allow images to be
captured. The strength of the signal is used to calculate
the position of the capsule in the body. Moving images
from a period as long as six hours are stored on a portable
recorder. With the approval of the ethics committee, four
patients swallowed the device. We present here the first im-
ages of pathologic conditions in the human small bowel we
obtained using this new endoscopic system (Given Imag-
ing, Yoqneam, Israel).
Patient 1 was a 60-year-old woman with hereditary hem-
orrhagic telangiectasia who required the transfusion of 12
to 15 units of blood per year. Treatment with estrogens and
push enteroscopy with bipolar electrocoagulation of bleed-
ing lesions reduced the requirement to approximately 4 units
per year. Capsule endoscopy revealed angiodysplasias in
the stomach, duodenum, and proximal jejunum. Two large,
actively bleeding lesions were seen in the jejunum and ile-
um. Surgery was considered, but the bleeding stopped spon-
taneously.
Patient 2 was a 39-year-old man with hereditary hem-
orrhagic telangiectasia who required transfusion with 10
units of blood every two months and was unresponsive to
hormonal therapy and to endoscopic treatment. Capsule
endoscopy revealed eight angiodysplasias in the duodenum
and proximal jejunum. No lesions were seen in the distal
small bowel. Good views of the large bowel to the sigmoid
colon revealed three angiodysplasias that had not been seen
during recent colonoscopy. Intraoperative enteroscopy was
deferred, and further treatment of the colonic and upper
gastrointestinal angiodysplasias was recommended.
Patient 3 was a 16-year-old boy with melena and a pre-
vious intestinal hemorrhage at the age of 2. His hemoglo-
bin level was 9 g per deciliter with normal results on push
enteroscopy, colonoscopy, and Meckel scanning. Capsule
endoscopy revealed no abnormality. The proposed intraop-
erative enteroscopy was averted.
Patient 4 was a 78-year-old man with multiple gastroin-
testinal angiodysplasias who required transfusion with 72
units of blood per year. Treatment with bipolar electroco-
agulation of angiodysplasias reduced his transfusion require-
ment to 36 units per year. The patient had undergone gas-
troenterostomy and vagotomy for duodenal ulcer in 1955.
Capsule endoscopy revealed multiple angiodysplasias affect-

232 · N Engl J Med, Vol. 344, No. 3 · January 18, 2001 · www.nejm.org

The New England Journal of Medicine

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Copyright © 2001 Massachusetts Medical Society. All rights reserved.
 C ORR ES POND ENCE
A the capsule. Dr. Appleyard is a research fellow in receipt of a
B hours, fever developed, with swelling and erythema around
Figure 2. Capsule-Endoscopic Images of Angiodysplasia in the
Distal Jejunum (Panel A) and Bleeding Angiodysplasia in the
Ileum (Panel B).
The location of the capsule is calculated on the basis of the
time it has traveled within the small bowel relative to the total
small-bowel transit time and a trigonometric analysis of the
strength of the capsule’s transmission signal.
N Engl J Med, Vol. 344, No. 3 · January 18, 2001 · www.nejm.org · 233
The New England Journal of Medicine
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Copyright © 2001 Massachusetts Medical Society. All rights reserved.
ing only the proximal small bowel. The results of previous
surgery did not hinder the movement of the capsule. Con-
tinued treatment of the proximal angiodysplasias was rec-
ommended.
In general, capsule endoscopy provided good views from
mouth to colon and successfully imaged small-bowel patho-
logic features (Fig. 2). All four patients described the cap-
sule as easy to swallow, painless, and preferable to conven-
tional endoscopy. The information gained was helpful in
directing further treatment in these patients. Although this
technology cannot be used for biopsy or therapy, it may
prove valuable in the assessment of bleeding in patients with
negative results on gastroscopy and colonoscopy.
MARK APPLEYARD, F.R.A.C.P.
ARKADY GLUKHOVSKY, D.SC.
PAUL SWAIN, M.D.
Royal London Hospital
London E1 1BB, United Kingdom
Editor’s note: Dr. Swain has a consulting agreement with
Given Imaging, which is making the capsule. Dr. Glukhovsky
is an engineer responsible for research and development of
grant from the Special Trustees of the Royal London Hos-
pital.
1. Iddan G, Meron G, Glukhovsky A, Swain P. Wireless capsule endoscopy.
Nature 2000;405:417.
Abiotrophia Species Bacteremia and a Mycotic
Aneurysm in an Intravenous Drug Abuser
To the Editor: Recently there have been reports of unex-
plained sepsis and deaths among intravenous drug abusers
in Scotland, Ireland, and England.1 Approximately one quar-
ter of these cases have been associated with clostridium
species, of which half were identified as Clostridium novyi.
We report a case of bacteremia in an intravenous drug abus-
er who developed a mycotic aneurysm due to another un-
usual, fastidious organism.
A 42-year-old man presented with a three-day history of
fever and soft-tissue swelling in his right upper arm. The
patient was an intravenous drug abuser. Four days earlier he
had crushed a lorazepam tablet, mixed it with tap water, and
injected it into his right antecubital vein. Over the next 72
the site of injection, which he incised and drained himself.
He continued to have fever and swelling of his arm and
came to the hospital.
His temperature was 38.6°C. A 3-by-4-cm area of erythe-
ma and swelling with drainage was present in the right an-
tecubital fossa. The physical examination was otherwise
unremarkable. The white-cell count was 18,000 per cubic
millimeter (11 percent band forms, 70 percent neutrophils,
15 percent monocytes, and 4 percent lymphocytes). A com-
puted tomographic scan of the patient’s arm revealed soft-
tissue swelling, with no evidence of an underlying aneurysm
or abscess. He was admitted, and treatment with ampicil-
lin–sulbactam was initiated.
Blood cultures at the time of admission grew abiotrophia
species (formerly known as nutritionally variant streptococ-
 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

travenous drug abusers, Binswanger et al. reported a high

rate of abscesses in this population (68 percent), and 27
percent of those with abscesses reported that they had in-
cised and drained their own abscesses.2 Most soft-tissue ab-
scesses and associated bacteremia in intravenous drug abus-
ers are caused by staphylococci (Staphylococcus aureus) or
streptococci (Streptococcus viridans or group A streptococ-
ci).3-6 In a large review of cases of bacteremia in intrave-
nous drug abusers, mycotic aneurysms, pseudoaneurysms
that develop when an extravascular hematoma communi-
cates with the intravascular space, occurred in 9 percent of
the cases.5 Bacteremia involving abiotrophia species in in-
travenous drug abusers appears to be unusual, but given the
fastidious nature of this organism, the incidence may be
underreported.

MICHAEL K. LEONARD, M.D.

Figure 1. Doppler Ultrasound Image Showing a Pseudoaneu-
rysm (Arrows), with Turbulent Flow (Orange), Arising from the
Right Brachial Artery.
The overall diameter of the aneurysm was 2.2 cm.
cus) from the anaerobic bottles of two separate cultures at
72 hours. Transesophageal echocardiography revealed no
vegetations on the heart valves. The antibiotic regimen was
changed to ampicillin and gentamicin.
On the 15th hospital day, a pulsatile mass was noted in
the right antecubital fossa. A Doppler ultrasound study con-
firmed the presence of a pseudoaneurysm in the right bra-
chial artery (Fig. 1), which was ligated. Intraoperative cul-
tures and repeated blood cultures were negative.
In a recent review of abscesses and cellulitis among in-
CHRISTIAN P. POX, M.D.
DAVID S. STEPHENS, M.D.
Emory University School of Medicine
Atlanta, GA 30303
1. Update: Clostridium novyi and unexplained illness among injecting-
drug users — Scotland, Ireland, and England, April–June 2000. MMWR
Morb Mortal Wkly Rep 2000;49:543-5.
2. Binswanger IA, Kral AH, Bluthenthal RN, Rybold DJ, Edlin BR. High
prevalence of abscesses and cellulitis among community-recruited injection
drug users in San Francisco. Clin Infect Dis 2000;30:579-81.
3. Orangio GR, Pitlick SD, Della Latta P, et al. Soft tissue infections in
parenteral drug abusers. Ann Surg 1984;199:97-100.
4. Simmen HP, Giovanoli P, Battaglia H, Wust J, Meyer VE. Soft tissue
infections of the upper extremities with special consideration of abscesses
in parenteral drug abusers: a prospective study. J Hand Surg 1995;20:797-
800.
5. Crane LR, Levine DP, Zervos MJ, Cummings G. Bacteremia in narcotic
addicts at the Detroit Medical Center. I. Microbiology, epidemiology, risk
factors, and empiric therapy. Rev Infect Dis 1986;8:364-73.
6. Benitez PR, Newell MA. Vascular trauma in drug abuse: patterns of in-
jury. Ann Vasc Surg 1986;1:175-81.
Correspondence Copyright © 2001 Massachusetts Medical Society.

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