correspondence

n engl j med 368;17 nejm.org april 25, 2013

1657
Since publication of the article, Dr. Kasmar reports no further
potential conflict of interest. Dr. Turner reports no potential
conflict of interest relevant to this letter.
1. Global tuberculosis report 2012 (http://www.who.int/tb/
publications/global_report/en).
2. Fang J-T, Chen Y-C, Chang M-Y. Ethambutol-induced optic
neuritis in patients with end stage renal disease on hemodialy-
sis: two case reports and literature review. Ren Fail 2004;26:
189-93.
3. Conde MB, Efron A, Loredo C, et al. Moxifloxacin versus
ethambutol in the initial treatment of tuberculosis: a double-blind,
randomised, controlled phase II trial. Lancet 2009;373:1183-9.
4. Zumla A, Raviglione M, Hafner R, von Reyn CF. Tuberculo-
sis. N Engl J Med 2013;368:745-55.
DOI: 10.1056/NEJMc1302312
PML in a Patient Treated with Fumaric Acid
To the Editor: Fumaric acid is considered effec-
tive and safe in the treatment of psoriasis vul-
garis
1
and is licensed for this use in Germany.
We diagnosed progressive multifocal leukoen-
cephalopathy (PML) in a 74-year-old man who
had received monotherapy for psoriasis with oral
fumaric acid for 3 years (2007 through 2010) in
doses of up to 120 mg of dimethyl fumarate and
95 mg of monoethyl fumarate, each taken two
times a day. The patient had had psoriasis for
more than 5 years and had been treated topically
with glucocorticoids (January through May 2005)
and orally with acitretin (maximum dose of 50 mg
once daily, May 2005 through June 2006) and
methotrexate (maximum dose of 22.5 mg once
weekly, July 2006 through July 2007). In July 2010,
progressive sensory aphasia developed. Magnetic
resonance imaging (MRI) of the brain (see Fig. S1
in the Supplementary Appendix, available with
the full text of this letter at NEJM.org), neuro-
pathological investigations of specimens of the
brain obtained during biopsy (Fig. S2 in the Sup-
plementary Appendix), and positive results on
polymerase-chain reaction (PCR) assays for the JC
virus in the cerebrospinal fluid (CSF) (90 copies
per milliliter) and brain tissue (88,800,000 copies
per microgram of DNA) led to the diagnosis
of PML.
A differential blood count revealed grade 3 lym-
phocytopenia (Fig. 1, and Tables S1 and S2 in the
Supplementary Appendix). Retrospective analysis
revealed that the lymphocytopenia had reached
grade 3 status within 1 year after the initiation
of treatment with fumaric acid. Although it was
the manufacturers recommendation to discon-
tinue treatment with fumaric acid in patients with
severe lymphocytopenia, treatment was contin-
ued in this patient until the diagnosis of PML
was made 2 years later.
Before implicating fumaric acidassociated
lymphocytopenia as the probable cause of im-
munodeficiency, we ruled out other causes of
immunodeficiency and cancer. Flow-cytometric
immunophenotyping of peripheral blood and
bone marrow aspirate did not reveal any myelo-
dysplastic syndrome. Tests for markers of para-
neoplastic tumors were negative, and computed
tomographic scans of the chest, abdomen, and
pelvis were normal. PCR assays of the CSF for
neurotropic viruses were negative, as were the
results of HIV testing. At the time of diagnosis,
the only other medication the patient was taking
was tamsulosin, for the treatment of prostate
hyperplasia.
When PML was diagnosed in August 2010,
fumaric acid was discontinued and treatment
with mefloquine and mirtazapine was started.
2

Within 5 weeks, an immune reconstitution in-
flammatory syndrome (IRIS) developed, mani-
fested by clinical worsening and detected in areas
of enhancement on MRI of the brain after the
administration of gadolinium (Fig. S3 in the Sup-
Leukocytes
Lymphocytes
L
e
u
k
o
c
y
t
e
s

(

1
0

3
/
m
m
3
)
L
y
m
p
h
o
c
y
t
e
s

(

1
0

3
/
m
m
3
)
15
10
5
0
2.5
2.0
1.5
1.0
0.5
0.0
0 500 1000 1500 2000
Days after Initiation of Therapy
PML diagnosis
IRIS diagnosis
Fumaric acid treatment
Figure 1. Leukocyte and Lymphocyte Counts during
Treatment with Fumaric Acid, at the Time of Diagnosis
of PML and IRIS, and at Follow-up.
The shaded area indicates the period of treatment with
fumaric acid. IRIS denotes immune reconstitution in-
flammatory syndrome, and PML progressive multifocal
leukoencephalopathy.
The New England Journal of Medicine
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The new engl and journal o f medicine
n engl j med 368;17 nejm.org april 25, 2013
1658
plementary Appendix). Methylprednisolone was
administered at a dose of 500 mg per day for
5 days.
In January 2011, MRI studies revealed regres-
sion of T
2
-weighted hyperintensities, with almost
complete absence of gadolinium enhancement.
The patients condition had improved despite the
persistence of a marked sensory aphasia syn-
drome. PCR assays for the JC virus in the CSF
and plasma were now negative.
Fumarate, unlike other immune-based thera-
pies that may cause PML (e.g., rituximab, nata-
lizumab, efalizumab, and infliximab), does not
belong to the monoclonal antibody family. Al-
though this patient may have been at higher risk
for PML for other reasons, long-term treatment
with fumarate was probably an important factor
in its development, given the unrevealing evalu-
ation for other causes of immune deficiency, the
induction of an IRIS with 5 weeks after the with-
drawal of fumarate, and the patients clinical
improvement and survival after a follow-up of
more than 2 years. Similar to treatment with
natalizumab,
3
long-term treatment with fumaric
acid and prior treatment with other immunosup-
pressants may have increased this patients risk
of PML.
Ummehan Ermis
Joachim Weis, M.D.
Jrg B. Schulz, M.D.
RheinischWestflische Technische Hochschule Aachen
Aachen, Germany
jschulz@ukaachen.de
Disclosure forms provided by the authors are available with
the full text of this letter at NEJM.org.
1. Harries MJ, Chalmers RJG, Griffiths CEM. Fumaric acid
esters for severe psoriasis: a retrospective review of 58 cases.
Br J Dermatol 2005;153:549-51.
2. Schrder A, Lee DH, Hellwig K, Lukas C, Linker RA, Gold R.
Successful management of natalizumab-associated progressive
multifocal leukoencephalopathy and immune reconstitution syn-
drome in a patient with multiple sclerosis. Arch Neurol 2010;
67:1391-4.
3. Bloomgren G, Richman S, Hotermans C, et al. Risk of natal-
izumab-associated progressive multifocal leukoencephalopathy.
N Engl J Med 2012;366:1870-80.
DOI: 10.1056/NEJMc1211805
PML in a Patient Treated with Dimethyl Fumarate
from a Compounding Pharmacy
To the Editor: Preparations containing various
mixtures of fumaric acid esters are prescribed for
psoriasis in several countries, in many cases for
off-label use, and are regarded as safe.
1
One such
preparation is enteric-coated, slow-release Psori-
novo (compounding pharmacy, Mierlo-Hout), in
which the active agent is dimethyl fumarate and
in which copper gluconate was used as an addi-
tive until 2010 (for a profile of the drug, see the
Supplementary Appendix, available with the full
text of this letter at NEJM.org).
On November 5, 2012, a 42-year-old woman
who reported having progressive right-sided
hemiparesis since May consulted us for a second
opinion. She had been given a diagnosis of pos-
sible multiple sclerosis in September and at that
time received 3000 mg of intravenous methyl-
prednisolone over 3 days, without effect. Her
medical history was notable for psoriasis, for
which she had been taking 420 mg of Psorinovo
per day since 2007, supplemented by 1000 mg of
calcium ascorbate per day and EPA-1000 fish oil
capsules (EPA denotes the omega-3 fatty acid
eicosapentaenoic acid).
Sequential magnetic resonance imaging (MRI)
scans of the brain (Fig. 1) showed small, deep
white-matter lesions and one large progressive
lesion, which was suggestive of progressive multi-
focal encephalopathy (PML), as described in a
study of imaging findings in relation to PML
resulting from treatment with monoclonal anti-
bodies.
2
Hematologic studies revealed lympho-
penia, with a count of 200 lymphocytes per cubic
millimeter (normal range, 600 to 2900). We real-
ized in retrospect that the lymphopenia had de-
veloped after the initiation of treatment with
Psorinovo (see Table 1 in the Supplementary Ap-
pendix). The patient was seronegative for HIV,
but a semiquantitative, real-time polymerase-
chain-reaction (PCR) assay of a specimen of the
cerebrospinal fluid was positive for the JC virus.
We made a diagnosis of PML, stopped treat-
ment with Psorinovo on November 7, and then
started treatment for PML with mefloquine and
mirtazapine.
Initially, the hemiparesis remained progres-
sive, even though the lymphopenia began to
abate (Table 2 in the Supplementary Appendix).
The New England Journal of Medicine
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Copyright 2013 Massachusetts Medical Society. All rights reserved.