The n e w e ng l a n d j o u r na l of m e dic i n e

have been desirable but not essential to the deter-

monitoring and movement of persons with potential Ebola
v irus exposure. October 2015 (http://www.cdc.gov/vhf/ebola/
mination of initial care. Severe malaria requiring
exposure/monitoring-and-movement-of-persons-with-exposure
.html). intravenous antimalarial therapy is distinguished
from uncomplicated malaria primarily by the
3. Centers for Disease Control and Prevention. Guidance for
malaria diagnosis in patients suspected of Ebola infection in
presence of dysfunction of vital organs.2 Smear
the United States. 2014 (http://www.cdc.gov/malaria/new_info/
2014/malaria_ebola.htm). preparation unnecessarily increases not only the
risk of a laboratory accident (glass slides are
4. Centers for Disease Control and Prevention. Malaria diag-
nosis (United States) (http://www.cdc.gov/malaria/d iagnosis_
sharp and can break) but also the complexity of
treatment/d iagnosis.html).
diagnosis, lengthening diagnostic turnaround
DOI: 10.1056/NEJMc1512873 time and diminishing the pool of adequately
trained technologists who can be available to
The discussants reply: After EVD had been perform testing 24 hours a day, 7 days a week.
ruled out in this case, blood smears were exam- JohnA. Branda, M.D.
ined to confirm the diagnosis of falciparum ma- GregoryK. Robbins, M.D., M.P.H.
laria and to assess the parasite burden. There DavidC. Hooper, M.D.
was no evidence of a mixed plasmodium infec- Massachusetts General Hospital
tion; thus, the patients relapse with nonfalci- Boston, MA
parum malaria would not have been predicted or Since publication of their article, the authors report no fur-
prevented if microscopy had been used initially. ther potential conflict of interest.
Our decision to rely on a rapid diagnostic test for
malaria at the time of initial presentation, which 1. Centers for Disease Control and Prevention. Guidance for
malaria diagnosis in patients suspected of Ebola infection in the
is acceptable according to CDC guidance,1 bal- United States. 2014 (http://www.cdc.gov/malaria/new_info/2014/
anced clinical needs with laboratory safety. After malaria_ebola.htm).
falciparum malaria was diagnosed with a rapid 2. White NJ, Pukrittayakamee S, Hien TT, et al. Malaria. Lancet
2014;383:723-35.
diagnostic test, measurement of the parasite
count or the detection of mixed infection would DOI: 10.1056/NEJMc1512873

More on PML in Patients Treated with Dimethyl Fumarate

To the Editor: Balak and Hajdarbegovic (Aug. 6
issue)1 discuss an old case of Kaposis sarcoma2
in a patient with psoriasis who was treated with
Fumaderm, a drug containing different fumaric
acid esters (FAE). The authors claim that the pa-
tient had normal total lymphocyte counts before
the diagnosis of Kaposis sarcoma, whereas the
original publication shows counts of 500 to 800
per cubic millimeter for more than 18 months.2
In the same issue of the Journal, van Kester
et al.3 report a case of suspected generalized
varicellazoster virus (VZV) infection in a
23-year-old patient with psoriasis who was treat-
ed with a compounded Dutch FAE preparation
for 2 months, without the development of lym-
phocytopenia. The authors conclude that FAE
treatment may reactivate VZV infection in the
absence of lymphocytopenia. However, from the
clinical picture and in the absence of IgG anti-
bodies to VZV, other interpretations need to be
considered, including adult chickenpox and
generalized zoster related to preexisting im-
mune deficiencies or irrespective of immunosup-
pression.
Both letters reference a report previously pub-
lished in the Journal of a case of progressive
multifocal leukoencephalopathy (PML) in a pa-
tient with psoriasis who was treated with a com-
pounded Dutch FAE preparation for approxi-
mately 2 years, which was reported to have
occurred without severe lymphocytopenia.4 Such
a conclusion is questionable, because lympho-
cytes were not monitored for 19 months before
the diagnosis of PML, and the extent of lympho-
cytopenia during that period is unknown.
We conclude that PML and other opportunis-
tic infections have not been observed during FAE
therapy without lymphocytopenia and in the
presence of appropriate monitoring and drug-
discontinuation rules.

294 n engl j med 374;3nejm.org January 21, 2016

The New England Journal of Medicine

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Copyright 2016 Massachusetts Medical Society. All rights reserved.
 correspondence
Kristian Reich, M.D., Ph.D.
Dermatologikum Hamburg
Hamburg, Germany
kreich@dermatologikum.de
HansPeter Hartung, M.D.
Heinrich Heine University
Dsseldorf, Germany
Mark Lebwohl, M.D.
Icahn School of Medicine at Mount Sinai
New York, NY
Dr. Reich reports being a partner at the Dermatologikum
Hamburg, an independent institute with no financial relation-
ship to the pharmaceutical industry; receiving consulting and
lecture fees from AbbVie, consulting fees and grant support
from Amgen, Covagen, Forward Pharma, GlaxoSmithKline, Re-
generon Pharmaceuticals, Takeda Pharmaceutical, and UCB,
consulting fees, grant support, and lecture fees from Biogen,
Celgene, Eli Lilly, Janssen-Cilag, LEO Pharma, Medac, and Novar-
tis, grant support from Merck Sharp & Dohme, and consulting
fees from Boehringer Ingelheim and XenoPort; and being a
member of a data and safety monitoring board for Pfizer. Dr.
Hartung reports receiving honoraria for consulting, serving on
steering committees and advisory boards, and speaking at sci-
entific symposia from Bayer, Biogen, GeNeuro, Genzyme, Med-
Immune, Merck Serono, Novartis, Octapharma, Opexa Thera-
peutics, Roche, Teva Pharmaceutical Industries, and Sanofi, and
honoraria for consulting from Forward Pharma. Dr. Lebwohl
reports being an employee of the Mount Sinai Medical Center,
which receives research funds from AbGenomics, AbbVie, Am-
gen, Anacor Pharmaceuticals, Aqua Pharmaceuticals, Can-Fite
BioPharma, Celgene, Clinuvel Pharmaceuticals, Coronado Bio-
sciences, Eli Lilly, Ferndale Pharma Group, Janssen Biotech, LEO
Pharma, Merz, Novartis, Pfizer, Sandoz, Sun Pharmaceuticals,
and Valeant Pharmaceuticals International. No other potential
conflict of interest relevant to this letter was reported. The letter
was prepared with the editorial assistance of Forward Pharma.
1. Balak D, Hajdarbegovic E. PML in patients treated with di-
methyl fumarate. N Engl J Med 2015;373:582-3.
2. Philipp S, Kokolakis G, Hund M, et al. Immunological
changes in psoriasis patients under long-term treatment with
fumaric acid esters: risk of Kaposi sarcoma occurrence? Eur J
Dermatol 2013;23:339-43.
3. van Kester MS, Bouwes Bavinck JN, Quint KD. PML in patients
treated with dimethyl fumarate. N Engl J Med 2015;373:583-4.
4. Nieuwkamp DJ, Murk J-L, van Oosten BW, et al. PML in a
patient without severe lymphocytopenia receiving dimethyl fu-
marate. N Engl J Med 2015;372:1474-6.
DOI: 10.1056/NEJMc1512228
Drs. Balak and Hajdarbegovic reply: Reich et
al. emphasize that the case of dimethyl fumarate
(DMF)related Kaposis sarcoma was linked to a
moderate lymphocytopenia and that current
drug-monitoring rules remain applicable. We
conclude that the occurrence of immunosuppres-
sive adverse events during DMF treatment is not
restricted to lymphocytopenia in which the lym-
phocyte count is less than 500 per cubic milli-
meter. Illustratively, another case of treatment-
related PML was reported in a patient with
n engl j med 374;3nejm.org January 21, 2016
The New England Journal of Medicine
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Copyright 2016 Massachusetts Medical Society. All rights reserved.
psoriasis who was treated with DMF and had
lymphocyte counts of 500 to 1000 per cubic milli-
meter.1 In response, psoriasis guidelines have
increased the threshold for dose adjustment or
discontinuation of DMF in the event of a count of
less than 700 lymphocytes per cubic millimeter.2
These drug-discontinuation rules remain to be
validated. More important, absolute lymphocyte
counts seem to be insensitive indicators of an
increased risk of infections.1 DMF-associated
moderate lymphocytopenia with selective reduc-
tions in lymphocyte subpopulations could confer
a predisposition to PML,3,4 as is the case with
idiopathic CD4+ lymphocytopenia.5
In view of the increasing use of DMF, there is
a need for more awareness and appropriate
monitoring strategies to minimize risks of im-
munosuppression. Meanwhile, PML should be
considered in patients receiving DMF who pres-
ent with progressive neurologic symptoms, irre-
spective of the severity of lymphocytopenia.
Deepak Balak, M.D.
Enes Hajdarbegovic, M.D.
Erasmus MC
Rotterdam, the Netherlands
d.balak@erasmusmc.nl
Since publication of their letter, the authors report no further
potential conflict of interest.
1. Bartsch T, Rempe T, Wrede A, et al. Progressive neurologic
dysfunction in a psoriasis patient treated with dimethyl fuma-
rate. Ann Neurol 2015;78:501-14.
2. EDF Psoriasis guidelines working group. European S3-Guide-
lines on the systemic treatment of psoriasis vulgaris. Update
2015 (http://www.euroderm.org/edf/index.php/edf-guidelines/
category/5-guidelines-miscellaneous?download=32:guideline
-psoriasis).
3. Berkovich R, Weiner LP. Effects of dimethyl fumarate on
lymphocyte subsets. Mult Scler Relat Disord 2015;4:339-41.
4. Khatri BO, Garland J, Berger J, et al. The effect of dimethyl
fumarate (Tecfidera) on lymphocyte counts: a potential contrib-
utor to progressive multifocal leukoencephalopathy risk. Mult
Scler Relat Disord 2015;4:377-9.
5. Gheuens S, Pierone G, Peeters P, Koralnik IJ. Progressive
multifocal leukoencephalopathy in individuals with minimal or
occult immunosuppression. J Neurol Neurosurg Psychiatry 2010;
81:247-54.
DOI: 10.1056/NEJMc1512228
Dr. van Kester and colleagues reply: We
agree with Reich et al. that other interpretations
of the clinical findings in our patient are possi-
ble, but these interpretations are not very likely.
Varicella infection develops in 95% of the Dutch
population during childhood, and our patient
had reported having a previous varicella infec-
295
 The n e w e ng l a n d j o u r na l of m e dic i n e

tion when he was a child, which makes the pos-
sibility of a primary varicella infection unlikely.
Except for his psoriasis, our patient was healthy,
and he had no history of repeated infections. We
did not see an indication to exclude preexisting
immunodeficiencies or human immunodeficien-
cy virus infection, but we cannot completely rule
out this unlikely explanation for the clinical
findings in our patient. Therefore, we conclude
that reactivation of VZV infection by FAE treat-
ment is the most likely interpretation of the clin-
ical findings in our patient.
MarloesS. vanKester, M.D., Ph.D.
JanN.Bouwes Bavinck, M.D., Ph.D.
KoenD. Quint, M.D., Ph.D.
Leiden University Medical Center
Leiden, the Netherlands
m.s.van_kester@lumc.nl
Since publication of their letter, the authors report no further
potential conflict of interest.
DOI: 10.1056/NEJMc1512228
Dr. Murk and colleagues reply: Reich et al.
question our conclusion that DMF may induce
PML without severe lymphocytopenia, because
screening of lymphocytes in our patient con-
tains a 19-month gap. However, none of three
lymphocyte counts in the 6 months before
symptom onset was below 792 cells per cubic
millimeter. Moreover, three cases of FAE-asso-
ciated PML without severe lymphocytopenia
were published recently, corroborating our con-
clusion.1-3
FAEs affect lymphocyte function, the num-
ber of lymphocytes, and the ratio of CD4 cells
to CD8 cells.4 In our patient, the lymphocyte
count was just below normal, with 880 cells
per cubic millimeter; CD4 cells were reduced to
270 cells per cubic millimeter, and CD8 cells
were reduced to 40 cells per cubic millimeter.
Accordingly, a recent study showed CD4 and
CD8 lymphocytopenia with a total lymphocyte
count above 500 cells per cubic millimeter
withDMF treatment, which is relevant because
CD8 lymphocytopenia might confer a predispo-
sition to JC-virus replication.4 These new in-
sights should be taken into account when
lymphocyte counts are monitored in patients
receiving DMF.
JeanLuc Murk, M.D., Ph.D.
University Medical Center Utrecht
Utrecht, the Netherlands
DennisJ. Nieuwkamp, M.D., Ph.D.
Jeroen Bosch Hospital
Den Bosch, the Netherlands
d.nieuwkamp@jbz.nl
BobW. vanOosten, M.D., Ph.D.
VU University Medical Center
Amsterdam, the Netherlands
Since publication of their letter, the author report no further
potential conflict of interest.
1. Bartsch T, Rempe T, Wrede A, et al. Progressive neurologic
dysfunction in a psoriasis patient treated with dimethyl fuma-
rate. Ann Neurol 2015;78:501-14.
2. Dammeier N, Schubert V, Hauser TK, Bornemann A, Bischof
F. Case report of a patient with progressive multifocal leukoen-
cephalopathy under treatment with dimethyl fumarate. BMC
Neurol 2015;15:108.
3. Hoepner R, Faissner S, Klasing A, et al. Progressive multi-
focal leukoencephalopathy during fumarate monotherapy of
psoriasis. Neurol Neuroimmunol Neuroinflamm 2015; 2(3):
e85.
4. Spencer CM, Crabtree-Hartman EC, Lehmann-Horn K, Cree
BA, Zamvil SS. Reduction of CD8(+) T lymphocytes in multiple
sclerosis patients treated with dimethyl fumarate. Neurol Neu-
roimmunol Neuroinflamm 2015;2(3):e76.
DOI: 10.1056/NEJMc1512228

Cytomegalovirus Retinitis in a Patient Who Received Ruxolitinib

To the Editor: A 67-year-old man received a
diagnosis of primary myelofibrosis with extra-
medullary hematopoiesis and splenomegaly in
2009. In December 2013, treatment with ruxoli-
tinib (Jakafi) was initiated at a dose of 15 mg
twice daily. There was a palpable reduction in
spleen size.
In June 2014, the patient presented to his
ophthalmologist with unilateral anterior uveitis.
Treatment was initiated with mydriatic eyedrops
and a low-dose regimen of topical glucocorti-
coids. During follow-up, no response to this
therapy was noted, and signs of posterior in-
volvement had developed.

296 n engl j med 374;3nejm.org January 21, 2016

The New England Journal of Medicine

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