332 THE NEW ENGLAND JOURNAL OF MEDICINE Feb.

2, 1995

CORRESPONDENCE porphobilinogen, and her brother had a value that was at the
upper limit of the normal range. Coproporphyrin III excre-
tion in feces and coproporphyrinogen oxidase in leukocytes
and cultured skin fibroblasts were not assayed. The erythro-
cyte porphobilinogen deaminase activity was normal, as one
would have predicted, since it is characteristically normal in
patients with hereditary coproporphyria.2
MARWAN S. AKASHEH, M.D.
Amman, Jordan P.O. Box 9668
1. Ben-Chetrit E, Putterman C. Still hazy after all these years. N Engl J Med
E-MAIL ADDRESS FOR LETTERS 1994;331:934-8.
2. Meyer UA. Porphyrias. In: Braunwald E, Isselbacher KJ, Petersdorf RG, Wil-
The Journal now accepts Letters to the Editor by son JD, Martin JB, Fauci AS, eds. Harrison’s principles of internal medicine.
electronic mail. The Internet address is: 11th ed. Vol. 2. New York: McGraw-Hill, 1987:1638-43.

letters@edit.nejm.org
CLINICAL PROBLEM-SOLVING: STILL HAZY
AFTER ALL THESE YEARS
To the Editor: In the medical conundrum presented by Ben-
Chetrit and Putterman (Oct. 6 issue),1 despite a 21-year
search for a diagnosis, the patient’s illness remains hazy. The
diagnosis is most obviously hereditary coproporphyria. The
patient and her brother were both affected.
The patient had a 21-year history of recurrent abdominal
pain, with neither clinical nor surgical peritonitis and in the
absence of remarkable sequelae. There was evidence of auto-
nomic disturbances: a rapid pulse, an episode of urinary re-
tention, and decreased peristalsis with dilated loops on a
plain film of the abdomen. There was also evidence of neu-
ropsychiatric phenomena: anxiety, myalgia, and an episode
of transient hemianopia, a form of focal seizure, and a post-
ictal headache, which was misinterpreted as a conversion re-
action. There was a history of intolerance of amitriptyline,
isoniazid, and rifampin, which are considered unsafe in pa-
tients with porphyria. The coincidental findings of dry cough
and splenomegaly probably amount to a red herring and did
not contribute to the patient’s illness.
Several quantitative tests of spot urine samples from the
patient revealed a threefold to fivefold elevation in the level of
To the Editor: The case discussion by Ben-Chetrit and
Putterman highlights the difficulties often encountered in the
diagnosis of porphyria. The authors favored a diagnosis of
acute intermittent porphyria even though the activity of the
affected enzyme (porphobilinogen deaminase) in the patient’s
red cells was normal. They suggest that the patient had one
of the rare variants of this disease in which the defect is not
expressed in erythrocytes.
A more likely explanation, which must be considered in the
differential diagnosis, is that the patient had either variegate
porphyria or hereditary coproporphyria, which could easily
have been identified by a fecal analysis. Both forms of por-
phyria often present with life-threatening acute attacks that
are clinically indistinguishable from acute intermittent por-
phyria and are also characterized by increased porphobilino-
gen excretion. Photosensitivity may occur, although in ap-
proximately a third of the cases there are no dermatologic
manifestations.1 Therefore, the absence of skin lesions would
not rule out these two diseases.
In symptomatic patients, a fecal analysis can be used to
differentiate among the three types of acute porphyria. Var-
iegate porphyria is characterized by an elevated value for
fecal protoporphyrin IX (with a smaller increase in the value
for coproporphyrin III), and hereditary coproporphyria is
characterized by a gross elevation in the value for fecal
coproporphyrin III. Normal fecal porphyrin values during

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Vol. 332 No. 5 CORRESPONDENCE
an acute attack (when the porphobilinogen value is clearly
elevated) are virtually diagnostic of acute intermittent por-
phyria.
Since all three diseases are inherited in an autosomal dom-
inant manner, family studies are essential to identify latent
cases of porphyria so that known precipitants can be avoided,
and potentially fatal acute attacks prevented. Accurate deter-
mination of the type of porphyria will dictate the most appro-
priate diagnostic test (or tests) for the identification of people
at high risk. The hallmark of an acute porphyric attack is an
elevation in the urinary excretion of porphobilinogen; during
remission the excretion of porphobilinogen is often minimally
elevated or even normal. The initial Watson–Schwartz test
for excess porphobilinogen, performed on a urine sample ob-
tained from this patient during one of her episodes of abdom-
inal pain, was negative. There is now an increasing body of
opinion2-4 that qualitative screening tests for porphobilinogen
are insensitive and should be replaced by quantitative meth-
ods. I suggest that quantitation of porphobilinogen in this
urine specimen would have resulted in an earlier diagnosis.
Harrow, Middlesex HA1 3UJ, A.C. D EACON, PH.D.
United Kingdom Northwick Park Hospital
1. Eales L, Linder GC. Porphyria—the acute attack: an analysis of 80 cases.
S Afr Med J 1962;36:284-92.
2. Deacon AC. Performance of screening tests for porphyria. Ann Clin Biochem
1988;25:392-7.
3. Schreiber WE, Jamani A, Pudek MR. Screening tests for porphobilinogen are
insensitive: the problem and its solution. Am J Clin Pathol 1989;92:644-9.
4. Buttery JE, Carrera AM, Pannall PR. Analytical sensitivity and specificity of
two screening methods for urinary porphobilinogen. Ann Clin Biochem 1990;
27:165-6.
To the Editor: Although acute porphyria was considered in
the differential diagnosis early in the workup, it appears that
it was discarded as a diagnostic possibility on the basis of a
single negative Watson–Schwartz test. Unfortunately, acute
porphyrias cannot be ruled out by a single negative Watson–
Schwartz test, because the sensitivity of this test in acute por-
phyria is only about 40 to 60 percent (28 to 53 percent when
the color of the urine is normal).1 On the other hand, a quan-
titatively determined increase in porphobilinogen has a spec-
ificity approaching 100 percent for the acute porphyrias
(acute intermittent porphyria, variegate porphyria, and he-
reditary coproporphyria) during the acute phase of illness.1
There is disagreement in the literature about whether the sen-
sitivity of the test for porphobilinogen is also close to 100 per-
cent. This appears to be the sensitivity when the test is per-
formed in patients with acute symptoms, but the test probably
has some false negative results in patients who are in full clin-
ical remission.
Similarly, the sensitivity and specificity of the test for por-
phobilinogen deaminase activity are 90 and 98 percent, re-
spectively, for acute intermittent porphyria.1 The normal re-
sult of this test in the patient (and in her brother, who had
similar symptoms, pointing to an autosomal dominant type of
hereditary disorder) may have been a false negative result, or
the patient may have had other types of acute porphyria,
which were not discussed by the authors.
BENJAMIN DJULBEGOVIC, M.D.
Louisville, KY 40292 University of Louisville
1. Beganovic S, Djulbegovic B. Porphyrias: diagnosis. In: Djulbegovic B, ed.
Reasoning and decision making in hematology. New York: Churchill Living-
stone, 1992:67-9.
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333
To the Editor: The most likely diagnosis in the case de-
scribed in the Clinical Problem-Solving article jumps off the
page: migraine. It is unfortunate that the patient’s transient
hemianopia followed by severe headache was thought to be a
conversion reaction, since in retrospect it was undoubtedly
migraine. That this episode accompanied her abdominal pain
on at least one reported occasion supports the diagnosis of
migraine, as does the improvement with dietary manipulation
and the history of similar problems in her brother.
Although head pain is the most common manifestation of
migraine, it may be overshadowed by other symptoms or ab-
sent altogether, which was probably the case with this patient.
People with features of migraine other than pain, such as vi-
sual, somatosensory, or vegetative symptoms (including ab-
dominal pain), may minimize or ignore headache, and physi-
cians are apt to do the same.
Migraine is an important yet frequently overlooked consid-
eration in the differential diagnosis of visual, sensory, motor,
or vegetative symptoms in a young patient, especially a wom-
an, that are unexplained, paroxysmal, and self-limited. The
appropriate diagnosis can be made only by recognizing the
varied manifestations of migraine, taking a careful history,
and disavowing the incorrect assumption that in most cases
head pain is psychogenic. In retrospect, maybe this case was
not as “hazy” as it seemed.
STEPHEN G. REICH, M.D.
Baltimore, MD 21287-0857 Johns Hopkins Hospital
The authors reply:
To the Editor: We agree with Drs. Akasheh, Deacon, and
Djulbegovic that variegate porphyria and hereditary copro-
porphyria are important diagnostic considerations in the
case of our patient. An accurate analysis of fecal porphyrins
is the key to establishing the correct diagnosis, but the in-
terpretation of such an analysis can be difficult.1 Dietary
constituents and bacterial metabolism may affect fecal por-
phyrin excretion and blur the border between a normal and
an abnormal result. Furthermore, there is a substantial en-
terohepatic circulation of porphyrins secreted into the bile,
which can also affect fecal measurements. These problems
can be overcome by analyzing biliary rather than fecal por-
phyrins.2
In the patient we described, the urinary level of porphobi-
linogen was not elevated in many of her acute attacks. In sev-
eral stool samples, the porphyrin levels were variable and in-
conclusive. Clinically, the patient could have had any of the
acute porphyrias, but none of the tests were diagnostic.
The fact that Dr. Reich bases the diagnosis of migraine on
the same clinical data that are consistent with the acute por-
phyrias only emphasizes our point that the diagnosis of this
patient’s disorder is not obvious and indeed is still hazy after
all these years.
ELDAD BEN-CHETRIT, M.D.
Jerusalem 91120, Israel Hadassah University Hospital
CHAIM PUTTERMAN, M.D.
Bronx, NY 10461 Albert Einstein College of Medicine
1. Kushner JP. Laboratory diagnosis of the porphyrias. N Engl J Med 1991;324:
1432-4.
2. Logan GM, Weimer MK, Ellefson M, Pierach CA, Bloomer JR. Bile porphy-
rin analysis in the evaluation of variegate porphyria. N Engl J Med 1991;324:
1408-11.
334 THE NEW ENGLAND JOURNAL OF MEDICINE
POST-REMISSION CHEMOTHERAPY FOR ACUTE
MYELOID LEUKEMIA
To the Editor: Mayer et al. (Oct. 6 issue)1 conclude that
adults with acute myeloid leukemia (AML) in remission who
are 60 years of age or younger benefit from high-dose cyt-
arabine therapy. It should be noted that the population these
authors treated was selected to exclude patients with prior
hematologic disorders and those who had received cytotoxic
chemotherapy or radiation therapy. At the M.D. Anderson
Cancer Center, patients with these characteristics made up
23 percent (107 of 472) of the adults 60 years of age or
younger who entered complete remission after receiving che-
motherapy for previously untreated AML between 1980 and
1993. The probability of remaining alive and in remission
from the onset of complete remission was less for the pa-
tients with prior hematologic disorders or who had received
cytotoxic chemotherapy or radiation therapy than for the pa-
tients without these characteristics (P0.001, by two-tailed
log-rank test). The same was true regardless of whether the
patients received high-dose cytarabine and regardless of
whether the 29 (of 472) patients who received allogeneic or
autologous bone marrow transplants were included. The
poorer results in the patients who had prior hematologic dis-
orders or had received cytotoxic chemotherapy or radiation
therapy may reflect the association between these character-
istics and the leukemia-cell karyotype. Thus, among the 107
adults 60 years of age or younger who had prior hematologic
disorders or had received cytotoxic chemotherapy or radia-
tion therapy, 38 of the 98 (39 percent) in whom karyotyping
was successful had abnormalities of chromosome 5, 7, or
both (5/7); trisomy 8 (8); deletion of part of the long
arm of chromosome 11 (11q); or other abnormalities, ex-
cluding inv(16), t(8;21), and t(15;17). In contrast, these
karyotypes were found in 94 of 340 adults 60 years of age
or younger who underwent successful karyotyping and did
not have a history of hematologic disorders, cytotoxic ther-
apy, or radiation therapy (P  0.035, by the chi-square test).
Ghaddar et al.2 have reported the poor results of high-dose
cytarabine therapy in patients with 5/7, 8, 11q,
or other abnormalities, excluding inv(16), t(8;21), and
t(15;17). Four years after entering complete remission, adults
60 years of age or younger had a mean (SE) probability
of remaining alive and in complete remission of 107
percent.
In conclusion, we believe physicians need to take into ac-
count a patient’s history of hematologic disorders, cytotoxic
therapy, or radiation therapy, as well as cytogenetic findings,
when considering the use of high-dose cytarabine as post-
remission therapy in adults 60 years of age or younger with
previously untreated AML. Bone marrow transplantation, in-
vestigational chemotherapy, or immunotherapy may be more
fruitful in patients with such histories or with the cytogenetic
findings described above.
ELIHU H. ESTEY, M.D.
MICHAEL J. KEATING, M.D.
University of Texas
Houston, TX 77030 M.D. Anderson Cancer Center
1. Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemo-
therapy in adults with acute myeloid leukemia. N Engl J Med 1994;331:
896-903.
2. Ghaddar HM, Plunkett W, Kantarjian HM, et al. Long-term results following
treatment of newly diagnosed acute myelogenous leukemia with continuous-
infusion high-dose cytosine arabinoside. Leukemia 1994;8:1269-74.
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Feb. 2, 1995
To the Editor: In their report on post-remission chemother-
apy for acute myeloid leukemia, Mayer et al. note that of 1104
patients registered, “Sixteen patients were considered ineligi-
ble or unable to be evaluated.” They also note that “Of the
693 patients in complete remission, 97 (14 percent) did not
continue in this trial for a variety of reasons.” The reasons for
ineligibility, inability to be evaluated, and failure to continue
the trial should be enumerated so that readers can evaluate
their validity. There should also be an explicit statement to in-
dicate whether patients were excluded before or after ran-
domization.
In addition, the authors fail to provide details of the distri-
bution of base-line characteristics among the three treatment
groups. They also fail to indicate the treatment assignments
of the 14 patients who underwent bone marrow transplanta-
tion and the 6 patients who were lost to follow-up.
Finally, the study methods were changed in April 1989,
when patients over 60 years of age were excluded from the
high-dose treatment group, creating an imbalance with re-
gard to age among the treatment groups. The authors at-
tempt to adjust for this imbalance by using the proportional-
hazards model to obtain age-adjusted hazard ratios. This is
not optimal, because that model assumes independence of
variables.1 It would seem better either to restrict the survival
analysis to patients 60 or younger or to analyze only patients
randomized before April 1989.
The size of the trial was such that these issues are not like-
ly to alter the authors’ finding of the value of high-dose cytar-
abine in patients 60 years of age or younger. However, this
likelihood does not obviate the need for clear reporting of
methods and results.2
CARL D. ATKINS, M.D.
Rockville Centre, NY 11570 242 Merrick Rd.
1. Lagakos SW. Statistical analysis of survival data. In: Bailar JC III, Mosteller
F, eds. Medical uses of statistics. 2nd ed. Boston: NEJM Books, 1992:290.
2. Guidelines for statistical reporting in articles for medical journals: amplifica-
tions and explanations. In: Bailar JC III, Mosteller F, eds. Medical uses of sta-
tistics. 2nd ed. Boston: NEJM Books, 1992:313-31.
The authors reply:
To the Editor: Dr. Atkins requests more details about the pa-
tients in our study. Of the 1104 registered patients, 16 (1.4
percent) could not be evaluated or were ineligible (6 because
of a history of myelodysplasia, 4 because further review of the
bone marrow smears led to a diagnosis of acute lymphoblastic
leukemia, 2 because of major irregularities in the induction
regimen, and 1 each because of treatment before registration,
a myocardial infarction before the start of therapy, the pa-
tient’s refusal to participate, and a decision not to participate
by the attending physician). Of the 693 patients who entered
complete remission, 97 (14 percent) did not continue in the
trial and were not randomly assigned to receive post-remis-
sion intensive chemotherapy (44 because of severe toxic ef-
fects of induction therapy, 27 because of the patient’s refusal
to participate, 10 because the patient underwent allogeneic
bone marrow transplantation, 4 because of persistent hepati-
tis, 4 because of a decision not to participate by the attending
physician, 2 because of insufficient finances, and 6 for miscel-
laneous reasons).
Dr. Atkins desires further information about the base-line
characteristics of the three treatment groups. As noted in the
manuscript, the groups were well balanced with regard to leu-
Vol. 332 No. 5 CORRESPONDENCE
kocyte count at the time of diagnosis and histologic subtype
and were stratified at the time of randomization according to
the number of courses of induction therapy (one or two) and
the patient’s age (less than 40, 40 to 60, and more than 60
years). Of the 14 patients withdrawn from postremission
treatment to undergo bone marrow transplantation, 7 were in
the group assigned to receive 100 mg of cytarabine per square
meter of body-surface area, 5 were in the group assigned to
receive 400 mg per square meter, and 2 were in the high-dose
cytarabine group. Of the six patients who were lost to follow-
up, one was assigned to the 100-mg group, three to the
400-mg group, and two to the high-dose group. Finally, the
primary comparison of treatment groups in our analysis was
based not on a proportional-hazards model, as suggested by
Dr. Atkins, but rather on a stratified log-rank test. The exclu-
sion of patients over the age of 60 would have yielded even
stronger support for the dose–response effect of cytarabine
that we observed, but it would have been statistically inappro-
priate given the initial design of the study.
Drs. Estey and Keating focus on the poorer prognosis as-
sociated with patients with AML (including those 60 years of
age or younger) who have prior hematologic disorders or pre-
vious exposures to cytotoxic chemotherapy or radiation ther-
apy. The purpose of our clinical trial was to assess objectively
the concept of a dose–response effect of cytarabine on a
population of patients with AML that was as homogeneous
as possible. Consequently, we restricted our study to patients
with primary AML. The influence of cytogenetics on progno-
sis, to which Drs. Estey and Keating refer, was addressed in a
preliminary analysis. High-dose cytarabine has a positive
effect on the post-remission outcome of patients with fa-
vorable leukemic karyotypes, such as t(8;21)(q22;q22) and
inv(16)(p13q22), or intermediate karyotypes, such as t(15;
17)(q22;q12), or normal karyotypes, but it does not influence
the outcome in people with unfavorable cytogenetic patterns
involving abnormal karyotypes, such as those that are fre-
quent in secondary AML.1
ROBERT J. MAYER, M.D.
Dana–Farber Cancer Institute
ROGER B. DAVIS, SC.D.
Beth Israel Hospital
DEBORAH T. BERG, R.N., B.S.N.
Boston, MA 02115 Dana–Farber Cancer Institute
1. Bloomfield CD, Lawrence C, Arthur DC, Berg DT, Schiffer CA, Mayer RJ.
Curative impact of intensification with high-dose cytarabine (HiDAC) in
acute myeloid leukemia (AML) varies by cytogenetic group. Blood 1994;84:
Suppl 1:111a. abstract.
ROTH’S SPOTS IN LEUKEMIC RETINOPATHY
To the Editor: Although the term “leukemic infiltrates” accu-
rately describes the pertinent funduscopic findings in retinop-
athy in leukemia, which are strikingly pictured in the image
by Perazella and Magaldi (Oct. 6 issue),1 the legend fails to
indicate that the distinctive hemorrhages with white centers
are Roth’s spots. Classically, Roth’s spots have been linked
with subacute bacterial endocarditis, but the association is
not exclusive, since they occur in diverse conditions including
leukemia and anemia.2 Similarly, the pathologic basis of the
pale white centers can be focal ischemia, inflammatory infil-
trate, a colony of infectious organisms, fibrin and platelets, or
an accumulation of neoplastic cells.3
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335
Ironically, the white-centered hemorrhages recognized as
Roth’s spots by present-day clinicians may differ from the
white retinal spots Moritz Roth described in 1872 and at-
tributed to degeneration of the nerve-fiber layer.4 Neverthe-
less, this dramatic photograph of leukemic retinopathy
should underline the fact that the clinical usefulness of
Roth’s spots is not limited to the diagnosis of subacute bac-
terial endocarditis.
FREDERICK E. LEPORE, M.D.
Robert Wood Johnson
New Brunswick, NJ 08903 Medical School
1. Perazella MA, Magaldi J. Retinopathy in leukemia. N Engl J Med 1994;331:
922.
2. Significance of fundus signs. In: Cogan DG. Ophthalmic manifestations of
systemic vascular disease. Vol. 3 of Major problems in internal medicine.
Philadelphia: W.B. Saunders, 1974:52.
3. Kaur B, Taylor D. Fundus hemorrhages in infancy. Surv Ophthalmol 1992;
37:1-17.
4. Roth M. Ueber Netzhautaffectionen bei Wundfiebern. Dtsch Z Chim 1872;1:
471-84.
MANAGEMENT OF CANCER OF THE PROSTATE
To the Editor: Dr. Catalona’s article on the management of
cancer of the prostate (Oct. 13 issue)1 was informative and
thorough, except for two omissions concerning the treatment
of patients with end-stage disease.
First, patients with extensive, painful bony metastases may
benefit from treatment with strontium chloride labeled with
strontium-89.2 This radionuclide is easily administered, is
usually effective within a few weeks, and has beneficial effects
that usually last for several months or more. The main disad-
vantages are cost and occasional thrombocytopenia. Al-
though external-beam radiation therapy will remain the
mainstay of treatment for the majority of patients with bony
metastases, strontium-89 is worth considering as an addition-
al agent.
Second, glucocorticoid therapy receives only cursory men-
tion in Catalona’s review. Glucocorticoids alone decrease se-
rum androgen concentrations in men who have undergone or-
chiectomy.3,4 Thus, they have palliative as well as supportive
value in this group of patients. In our experience, glucocorti-
coid therapy may be quite beneficial in patients with ad-
vanced disease and should be routinely considered for their
treatment.
PATRICK STONE, M.A., M.R.C.P.
CLARE PHILLIPS, B.SC., M.R.C.G.P.
London E1 1BB, Royal Hospitals
United Kingdom National Health Service Trust
1. Catalona WJ. Management of cancer of the prostate. N Engl J Med 1994;331:
996-1004.
2. Laing AH, Ackery DM, Bayly RJ, et al. Strontium-89 chloride for pain palli-
ation in prostatic skeletal malignancy. Br J Radiol 1991;64:816-22.
3. Plowman PN, Perry LA, Chard T. Androgen suppression by hydrocortisone
without aminoglutethimide in orchiectomised men with prostatic cancer. Br J
Urol 1987;59:255-7.
4. Dowsett M, Shearer RJ, Ponder BA, Malone P, Jeffcoate SL. The effects of
aminoglutethimide and hydrocortisone, alone and combined, on androgen lev-
els in post-orchiectomy prostatic cancer patients. Br J Cancer 1988;57:190-2.
Dr. Catalona replies:
To the Editor: My own clinical experience and that of my
colleagues has not confirmed the very favorable response rate
reported in patients with painful bony metastases treated with
336 THE NEW ENGLAND JOURNAL OF MEDICINE
strontium-89. About 20 percent of our patients have had a
flare response in which the pain became more severe. Only
about one third have pain relief lasting for three to six
months. Although strontium-89 may augment the beneficial
effects of external-beam irradiation, we are withholding judg-
ment until more data become available. The high cost of
treatment with strontium-89 is an important issue.
I agree that glucocorticoid therapy is beneficial to some pa-
tients, but the responses are usually short-lived.
There were two errors in my article. On page 1001, right-
hand column, last paragraph, the second sentence should
have read, “In a trial comparing orchiectomy with goserelin
plus flutamide, there was a significant (48 week) delay in the
objective progression of disease and a significant (7 month)
survival advantage among the patients who received com-
bined therapy.88” In Table 3, the units for plasma suramin
concentrations should have been given as micrograms per
milliliter instead of micrograms per liter.
WILLIAM J. CATALONA, M.D.
Washington University
St. Louis, MO 63110 School of Medicine
MORE ON PRIMARY BILIARY CIRRHOSIS IN
MONOZYGOTIC TWINS
To the Editor: The letter “Discordant Occurrence of Primary
Biliary Cirrhosis in Monozygotic Twins” (October 6 issue)1
reflects a common misconception regarding the determina-
tion of zygosity. Although the sisters described in the report
are twins, inadequate evidence of monozygosity was given.
Identifying HLA haplotypes does not establish zygosity. The
sisters have the same HLA haplotypes, as do 25 percent of
siblings. They are also the same sex, as are 50 percent of di-
zygotic twins.
Monozygotic twins are formed from a single conceptus and
therefore have the same member of each pair of chromo-
somes from each parent. Testing for concordance for markers
from several different chromosomes can demonstrate that the
probability of monozygosity is greater than 99 percent,2 pro-
vided one parent is heterozygous at each locus and no techni-
cal errors are made in typing the markers.
Proof of the sisters’ monozygosity would provide evidence
that an environmental trigger precipitated the clinical mani-
festations. If they are dizygotic twins, however, the discordant
occurrence of primary biliary cirrhosis could represent the in-
heritance of other genes that modify the response to a com-
mon environmental stimulus in two siblings with the same
HLA haplotypes. Establishment of zygosity is crucial to dis-
tinguish between these possibilities.3
CHRIS FRIEDRICH, M.D., PH.D.
Johns Hopkins University
Baltimore, MD 21287 School of Medicine
1. Kaplan MM, Rabson AR, Lee Y-M, Williams DL, Montaperto PA. Discordant
occurrence of primary biliary cirrhosis in monozygotic twins. N Engl J Med
1994;331:952.
2. Das Chaudhuri AB. Efficient sequential search of genetic systems for diagno-
sis of twin zygosity. Acta Genet Med Gemellol (Roma) 1991;40:159-64.
3. Machin GA. Twins and their zygosity. Lancet 1994;343:1577.
The authors reply:
To the Editor: We appreciate the comments of Dr. Friedrich.
The two sisters have been referred to as identical twins since
birth. This plus the fact that they have identical HLA haplo-
types makes it probable that they are monozygotic twins. We
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Feb. 2, 1995
agree that more extensive genetic testing would be required
to approach the 100 percent probability that Dr. Friedrich de-
sires.
MARSHALL KAPLAN, M.D.
ARTHUR R. RABSON, M.D.
Boston, MA 02111 New England Medical Center
DRUG MALABSORPTION AND RESISTANT
TUBERCULOSIS IN HIV-INFECTED PATIENTS
To the Editor: Directly observed therapy for tuberculosis has
been advocated as a way to improve compliance and control
the emergence of drug resistance.1,2 We recently cared for two
patients with human immunodeficiency virus (HIV) infection
who were receiving therapy under direct observation when
they relapsed with drug-resistant isolates of Mycobacterium
tuberculosis, presumably due to subtherapeutic drug levels
caused by malabsorption.
Patient 1, a 30-year-old man, began receiving directly ob-
served therapy in December 1993; his therapy consisted of
isoniazid (300 mg), rifampin (600 mg), and pyrazinamide
(800 mg) daily for ileocecal and pulmonary tuberculosis. At
that time tuberculosis isolates from sputum and stool were
susceptible to all drugs tested. In April 1994, after four
months of observed therapy, he was found to have a new cav-
itary pulmonary lesion. Sputum cultures grew M. tuberculosis
resistant to rifampin but still sensitive to isoniazid, pyrazina-
mide, ethambutol, and streptomycin.
Patient 2, a 51-year-old man, was given a diagnosis of pul-
monary tuberculosis in 1993. He received isoniazid (300 mg),
rifampin (600 mg), pyrazinamide (1.5 g), and ethambutol
(1.5 g) daily under direct supervision in a homeless shelter. Af-
ter 10 months of continuous therapy, a new right-upper-lobe
infiltrate appeared. His initial isolate of M. tuberculosis had
been sensitive to all first-line drugs, but in April 1994 an iso-
late from sputum was resistant to both isoniazid and rifam-
pin, while remaining sensitive to pyrazinamide, ethambutol,
and streptomycin.
Serum levels of antimycobacterial drugs from both patients
measured two hours after oral administration were assayed at
the National Jewish Center for Immunology and Respiratory
Medicine.2 The results are shown in Table 1.
Serum samples were also obtained from Patient 2 at the
time of an oral dose of 600 mg of rifampin and 400 mg of iso-
niazid at steady state and 0.5, 1, 1.5, 2, 4, 6, 8, and 12 hours
thereafter. Isoniazid was undetectable in all samples except
the one obtained at 2 hours, when the concentration was
0.43 mg per milliliter. Rifampin was undetectable at 0, 0.5, 1,
and 1.5 hours; the concentration was 0.42 mg per milliliter at
2 hours, 3.01 mg per milliliter at 4 hours, 1.37 mg per milliliter
at 6 hours, 1.07 mg per milliliter at 8 hours, and 0.58 mg per
milliliter at 12 hours. The peak rifampin level was seen at
Table 1. Concentrations of Antituberculous Drugs
in Two Patients.
DRUG OPTIMAL LEVEL PATIENT 1 PATIENT 2
mg/ml
Isoniazid 3–5 0.80 0.92
Rifampin 8–24 0 0
Pyrazinamide 20–60 24.29 34.81
Ethambutol 2–6 0.40 0.86
Ciprofloxacin 4–6 0.47 1.30
Vol. 332 No. 5 CORRESPONDENCE
4 hours rather than 2 hours, but it remained subtherapeutic.
Patient 1 had no clinical evidence of malabsorption, but Pa-
tient 2 had chronic diarrhea and a subnormal result on a
D-xylose–absorption test, believed to be due to HIV enter-
opathy.
Although malabsorption of antituberculous medication has
been described in HIV-infected patients,3,4 therapeutic drug
monitoring is not widely practiced. These patients could have
acquired another strain of M. tuberculosis,5 but the temporal se-
quence argues against this, and they had no known contact
with patients infected with drug-resistant tuberculosis.
These cases demonstrate that drug malabsorption may con-
tribute to the emergence of acquired drug resistance, as some
have theorized.3 In addition to the use of directly observed
therapy to ensure compliance, we advocate routine screening
of antimycobacterial-drug levels in HIV-infected patients with
tuberculosis, particularly those with advanced HIV disease.
Still at issue, however, is the timing of such screening relative
to dosing, since our data with regard to rifampin suggest that
delayed absorption, in addition to malabsorption, may occur
in HIV-infected patients.
KALPANA B. PATEL, PHARM.D.
ROMELLE BELMONTE, M.D.
HELEN M. CROWE, M.D.
Hartford, CT 06102-5037 Hartford Hospital
1. Initial therapy for tuberculosis in the era of multidrug resistance: recommen-
dations of the Advisory Council for the Elimination of Tuberculosis. MMWR
Morb Mortal Wkly Rep 1993;42(RR-7):1-8.
2. Weis SE, Slocum PC, Blais FX, et al. The effect of directly observed therapy
on the rates of drug resistance and relapse in tuberculosis. N Engl J Med
1994;330:1179-84.
3. Peloquin CA, MacPhee AA, Berning SE. Malabsorption of antimycobacterial
medications. N Engl J Med 1993;329:1122-3.
4. Berning SE, Huitt GA, Iseman MD, Peloquin CA. Malabsorption of antitu-
berculosis medications by a patient with AIDS. N Engl J Med 1992;327:
1817-8.
5. Horn DL, Hewlett D Jr, Haas WH, et al. Superinfection with rifampin-isoni-
azid-streptomycin-ethambutol (RISE)-resistant tuberculosis in three patients
with AIDS: confirmation by polymerase chain reaction fingerprinting. Ann
Intern Med 1994;121:115-6.
MORE ON HANTAVIRUS IN NEW ENGLAND AND
NEW YORK
To the Editor: The report of a fatal case of hantavirus pul-
monary syndrome in a Rhode Island resident (Aug. 25 issue)1
prompted us to examine whether hantaviruses are enzootic in
New England. Because deer mice (Peromyscus maniculatus)
serve as the main reservoir of the agent of hantavirus pulmo-
nary syndrome in the western states,2 we reasoned that the
closely related white-footed mouse (P. leucopus) might fill this
role in New England.
We studied two sites2 with a high prevalence of the Lyme
disease spirochete and Babesia microti, which are tick-borne
pathogens carried by the white-footed mouse. Both sites are
densely inhabited by this mouse (median annual maximal
density, 25 per hectare over a 10-year period), which in-
vades virtually all homes there during the winter and spring,
thus exposing residents. We analyzed serum samples from
142 P. leucopus and 41 Microtus pennsylvanicus (meadow voles)
trapped at these sites during 1992 and 1993 as part of a
long-term ecologic study. To determine whether humans
were at risk of acquiring hantaviral infection, we examined
serum samples from 248 persons with homes near our trap
sites, as well as from 10 laboratory personnel engaged in re-
search on tick-borne zoonoses, 5 of whom had examined
about 15,000 live rodents without using gloves or masks.
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Copyright © 1995 Massachusetts Medical Society. All rights reserved.
337
All serum samples were tested by the indirect immunoflu-
orescent-antibody technique for IgG antibodies against Pros-
pect Hill virus, a hantavirus that served as the surrogate an-
tigen in studies of hantavirus pulmonary syndrome in the
Four Corners region of New Mexico, Arizona, Colorado, and
Utah.3 All serum samples from the mice and the humans
were nonreactive, whereas 27 percent of the serum samples
from the meadow voles had antibodies against Prospect Hill
virus (geometric mean antibody titer, 136; range, 64 to 1024).
We conclude that hantaviruses are not maintained in
white-footed mice in two coastal New England sites where
Prospect Hill virus frequently infects meadow voles. Although
these two types of rodents were trapped in the same area, this
virus appears to infect just the voles. Accordingly, the absence
of serologic evidence of hantaviral infection in humans may
reflect either the behavior of voles, which rarely invade
homes, or the low transmissibility of Prospect Hill virus, even
among persons with frequent exposure to rodents.4 Because
hantaviruses may exist in microfoci, however, rodents from
other areas should be studied to determine their importance
to public health in the region.
SAM R. TELFORD III, D.SC.
Boston, MA 02115 Harvard School of Public Health
JIN-WON SONG, M.D., PH.D.
RICHARD YANAGIHARA, M.D.
Bethesda, MD 20892 National Institutes of Health
1. Brackett LE, Rotenberg J, Sherman CB. Hantavirus pulmonary syndrome in
New England and Europe. N Engl J Med 1994;331:545.
2. Wilson ML, Telford SR III, Piesman J, Spielman A. Reduced abundance of
immature Ixodes dammini (Acari: Ixodidae) following elimination of deer.
J Med Entomol 1988;25:224-8.
3. Childs JE, Ksiazek TG, Spiropoulou CF, et al. Serologic and genetic identifi-
cation of Peromyscus maniculatus as the primary rodent reservoir for a new
hantavirus in the Southwestern United States. J Infect Dis 1994;169:1271-80.
4. Yanagihara R, Gajdusek DC, Gibbs CJ Jr, Traub R. Prospect Hill virus: sero-
logic evidence for infection in mammalogists. N Engl J Med 1984;310:1325-6.
To the Editor: New hantaviruses are the cause of an often
fatal respiratory disease called hantavirus pulmonary syn-
drome.1-3 One death due to hantavirus has been reported in
the northeastern United States, in Rhode Island.4 In that case
the infection was probably contracted in Shelter Island, New
York, which is just off Long Island.5 We analyzed the sero-
prevalence of hantaviruses in the Long Island and Shelter Is-
land areas and found that the G2 neutralization antigen of
the Shelter Island hantavirus is virtually identical to that of
pathogenic hantaviruses responsible for hantavirus pulmo-
nary syndrome.
In 782 residents of Long Island who were screened for
Lyme disease, we detected a 2.6 percent rate of seropreva-
lence for hantavirus, which indicates substantial exposure of
humans to hantaviruses on Long Island. The white-footed
mouse, P. leucopus, is the predominant woodland mouse spe-
cies in northeastern coastal areas and has been associated
with nonpathogenic hantavirus infections.6 The seropreva-
lence of hantavirus in P. leucopus was determined to be 15 to
41 percent (n=293) in three locations on Long Island be-
tween 1984 and 1994, with an overall seroprevalence rate of
26 percent. As early as 1984 28 percent of serum samples
from peromyscus on Shelter Island (47 of 169 mice) were se-
ropositive for hantavirus. In the fall of 1994 we found a simi-
lar seroprevalence rate of 25 percent (4 of 16 mice) in P. leu-
copus on Shelter Island.
A 220-base-pair fragment of the hantavirus M segment car-
ried by seropositive mice on Shelter Island was cloned and se-
quenced. These hantavirus clones (termed “NY-3”) are dis-
338 THE NEW ENGLAND JOURNAL OF MEDICINE
tantly related to the nonpathogenic Prospect Hill virus, with
84 percent of amino acids identical in the two viruses and an-
other 5 percent similar. In contrast, amino acid sequences ob-
tained from NY-3 clones are virtually identical to the strains
causing hantavirus pulmonary syndrome in humans (with 95
percent of amino acids identical and another 5 percent simi-
lar).1,3 The unique genetic structure of these hantaviruses was
verified by the finding that the nucleic acid sequence differed
by 21 percent from that of other strains causing hantavirus
pulmonary syndrome and by the failure of standard oligonu-
cleotides from strains causing hantavirus pulmonary syn-
drome to amplify M-segment sequences by means of the pol-
ymerase chain reaction.
These results indicate that genetically unique hantaviruses
resembling those causing hantavirus pulmonary syndrome
are carried by P. leucopus on Shelter Island and further impli-
cate these mice as the source of infection in the patient who
died of hantavirus pulmonary syndrome in Rhode Island. The
seroprevalence of hantaviruses in the New York area and the
presence on Shelter Island of hantaviruses resembling those
causing hantavirus pulmonary syndrome warrant further sur-
veillance and suggest that greater clinical awareness of han-
taviruses is appropriate in northeastern states.
ERICH R. MACKOW, PH.D.
BENJAMIN J. LUFT, M.D.
Stony Brook, NY 11794 University Hospital, SUNY
ED BOSLER, PH.D.
New York State
Northport, NY 11733 Department of Health
DMITRY GOLDGABER, PH.D.
IRINA N. GAVRILOVSKAYA , M.D.
Stony Brook, NY 11794 University Hospital, SUNY
1. Nichol ST, Spiropoulou CF, Morzunov S, et al. Genetic identification of a
hantavirus associated with an outbreak of acute respiratory illness. Science
1993;262:914-7.
2. Duchin JS, Koster FT, Peters CJ, et al. Hantavirus pulmonary syndrome: a
clinical description of 17 patients with a newly recognized disease. N Engl J
Med 1994;330:949-55.
3. Spiropoulou CF, Morzunov S, Feldmann H, Sanchez A, Peters CJ, Nichol ST.
Genome structure and variability of a virus causing hantavirus pulmonary
syndrome. Virology 1994;200:715-23.
4. Brackett LE, Rotenberg J, Sherman CB. Hantavirus pulmonary syndrome in
New England and Europe. N Engl J Med 1994;331:545.
5. Song JW, Baek LJ, Gajdusek DC, et al. Isolation of pathogenic hantavirus
from white-footed mouse (Peromyscus leucopus). Lancet 1994;344:1637.
6. Lee P-W, Amyx HL, Yanagihara R, Gajdusek DC, Goldgaber D, Gibbs CJ Jr.
Partial characterization of Prospect Hill virus isolated from meadow voles in
the United States. J Infect Dis 1985;152:826-9.
THE TERRIER AND THE TENDINITIS
To the Editor: Numerous infectious diseases can be transmit-
ted from pets to their owners.1 The zoonotic spread of myco-
bacterial infections, however, is extremely uncommon.2 We
report a case of Mycobacterium chelonae infection of soft tissue,
which was acquired from contact with a pet dog.
A 37-year-old woman was in excellent health until chronic
pain developed in her right heel, which did not respond to
treatment with a nonsteroidal antiinflammatory drug. A podi-
atrist discovered numerous dog hairs embedded in the skin
overlying the right Achilles tendon. On questioning, the pa-
tient reported that she spent many hours rubbing her pet
Scottish terrier with the back of her right ankle. Two months
later, more dog fur was removed from the same location, al-
though she had not rubbed the dog in the interim.
Because of persistent, unexplained pain she underwent sur-
gical exploration of the right ankle, which revealed purulent
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Copyright © 1995 Massachusetts Medical Society. All rights reserved.
Feb. 2, 1995
material in the soft tissue surrounding the insertion site of the
Achilles tendon. A culture grew a strain of M. chelonae suscep-
tible to clarithromycin. Despite treatment with clarithromy-
cin (500 mg twice a day), there was progressive destruction
of the Achilles tendon. The tendon was débrided, and a gra-
cilis muscle free flap placed. There has been no evidence of
recurrent disease during a postoperative follow-up period of
four months. Cultures of the pet terrier’s hair and of tap wa-
ter from the patient’s home were negative for mycobacteria.
M. chelonae is a rapidly growing, atypical mycobacterium.
In immunocompetent patients, it can cause cellulitis, soft-tis-
sue abscess, or osteomyelitis after a penetrating trauma, injec-
tion, or surgical procedure.3 Although M. chelonae is thought
to be widely distributed in the environment, no specific envi-
ronmental reservoirs have been identified.3
In this case, prolonged and vigorous rubbing of the pet ter-
rier resulted in the penetration of dog hair into the patient’s
skin over the right Achilles tendon. We speculate that this
process led to subcutaneous inoculation of M. chelonae organ-
isms, which then caused a chronic soft-tissue infection. We
were unable to determine whether the terrier’s coat was colo-
nized with M. chelonae or merely served as a fomite for the
transmission of the organism from another source.
DAVID S. MCKINSEY, M.D.
MARK DYKSTRA, PH.D.
DAVID L. SMITH, M.D.
Kansas City, MO 64132 2316 E. Meyer Blvd.
1. Elliot DL, Tolle SW, Goldberg L, Miller JB. Pet-associated illness. N Engl J
Med 1985;313:985-95.
2. Thoen CO, Williams DE. Tuberculosis, tuberculoidoses, and other mycobac-
terial infections. In: Baron GW, ed. Handbook of zoonoses. Boca Raton, Fla.:
CRC Press, 1994:41-60.
3. Wallace RJ Jr, Brown BA, Onyi GO. Skin, soft tissue, and bone infections
due to Mycobacterium chelonae: importance of prior corticosteroid therapy,
frequency of disseminated infections, and resistance to oral antimicrobials
other than clarithromycin. J Infect Dis 1992;166:405-12.
THE CAT AND THE CATHETER
To the Editor: Pasteurella multocida is part of the normal flora
of many domestic animals and can produce infection in hu-
mans. Although the infection is often acquired through a bite,
we describe a patient with P. multocida bacteremia acquired in
an unusual manner.
A 35-year-old man with poorly differentiated rhabdomyo-
sarcoma had undergone placement of a Hickman catheter for
adjuvant chemotherapy. He was sleeping at home and woke
up to find fresh blood on his chest. His Hickman catheter was
damaged and had bite marks on it. It appeared to have been
chewed. He had a cat, which was in the room where the pa-
tient had been sleeping. He went to the emergency room and
was admitted, and the Hickman catheter was removed. On
the second day in the hospital, he had a temperature of
38.3C, and blood cultures grew P. multocida. The organism
was sensitive to penicillin, and the patient had a prompt re-
sponse to treatment with intravenous penicillin G.
P. multocida occurs in the respiratory and gastrointestinal
tracts of many domestic and wild animals worldwide. It is
perhaps the most common organism found in human wounds
from bites by cats and dogs. This patient was cautioned to
keep the cat away from his new catheter.
HASHIM MAJEED, M.D.
ABRAHAM VERGHESE, M.D.
RAGENE R. RIVERA, M.D.
Texas Tech University
El Paso, TX 79905 Health Sciences Center