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CASE COMMUNICATIONS
321
IMAJ • VOL
15
• June
2013
MRI showing changes
consistent with PML. Diffuse
bilateral hemispheric
changes in white matter are
prominent on DW1 without
enhancement or mass effect
medical history included chronic renal
failure, ischemic heart disease, bipolar
disorder, and a 1 year history of stage IV
diuse large B cell lymphoma. He had
received ve cycles of chemotherapy
with the R-CHOP protocol (rituximab,
cyclophosphamide, adriamycin, oncovin,
prednisone) 7 months prior to his current
admission with a good clinical and radio-
logical response. A sixth cycle of chemo-
therapy was withheld due to persistent
and prolonged neutropenia.
His physical examination was remark-
able for confusion without focal neuro-
logical decits. Laboratory examination
revealed pancytopenia (white blood cells
0.92 K/µl, hemoglobin 8.9 g/dl, platelets
102 K/µl) and mild renal failure (cre-
atinine 1.4 mg/dl, urea 52 mg/dl). Blood
electrolytes, thyroid-stimulating hormone
and B12 levels were within normal limits.
An HIV test was negative and a computed
P
rogressive multifocal leukoencepha-
lopathy is a rare and lethal demy-
elinating disease of the central nervous
system. It is associated with reactivation
of the JC virus in immunocompromised
patients. PML
1
may aect HIV
2
/AIDS
patients but can also result from the use of
potent immunosuppressive regimens and
novel biological therapies. is observa-
tion raises concerns about the safety
prole of these agents.
Rituximab is a chimeric anti-CD20
monoclonal antibody commonly used
in the treatment of lymphoproliferative
malignancies. e development of PML
following rituximab treatment has been
reported rarely. We report here a case of
PML in an HIV-negative patient with
diuse large B cell lymphoma following
treatment with rituximab. Diagnosis was
based on clinical ndings as well as imag-
ing and direct demonstration of the JC
virus in the cerebrospinal uid.
PATIENT DESCRIPTION
A 66 year old man presented to the hos-
pital with progressive confusion, agitation
and functional deterioration. His past
PML = progressive multifocal leuko-
encephalopathy
HIV = human immunodeficiency virus
tomography scan of the brain was normal.
CSF
3
analysis was normal and showed no
cells. Bone marrow biopsy revealed mild
hypocellularity. A PET scan (positron
emission tomography) showed no signs
of active hematological disease. ree
weeks later further deterioration was
noted in the patient’s mental status and
he became non-responsive. Polymerase
chain reaction for JC virus from the CSF
returned positive. Magnetic resonance
imaging of the brain showed white matter
abnormalities consistent with progressive
multifocal leukoencephalopathy [Figure].
e patient died a few days later.
COMMENT
PML is a white matter disease caused by
reactivation of the JC virus. e JC virus
CSF = cerebrospinal fluid
progressive multifocal
leukoencephalopathy (PML), human
immunodeficiency virus (HIV), JC
virus, rituximab
IMAJ
2013; 15: 321–322
KEY WORDS:
Progressive Multifocal Leukoencephalopathy in an
HIV-Negative Patient following Treatment with Rituximab
Shafik Khoury MD
1
, Shirley Shapira MD
1
, Tal Zilberman MD
1
, Yoseph A. Mekori MD
1,2
and Alon Y. Hershko MD PhD
1,2
1
Department of Internal Medicine B, Meir Medical Center, Kfar Saba, Israel
2
Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel
322
IMAJ • VOL
15
• June
2013
CASE COMMUNICATIONS
is a double-stranded DNA virus named
for John Cunningham, the individual
from whom the virus was rst isolated.
Between 66% and 92% of the adult popu-
lation is seropositive for the JC virus. e
primary infection is thought to occur in
childhood through the respiratory and
gastrointestinal tracts. Aer the primary
asymptomatic infection, the virus remains
latent in dierent sites including the kid-
ney, bone marrow and B lymphocytes.
Despite its presence in multiple sites, only
severe immunosuppression can enable the
virus to translocate into the brain, infect-
ing oligodendrocytes and causing PML.
e history of PML has been charac-
terized by three distinct landmarks. In
the past, PML was a disease of patients
with hematological malignancies treated
with chemotherapy. en, in the 1980s,
it emerged predominantly as a complica-
tion in AIDS patients, prior to the era of
the highly active antiretroviral therapy. In
recent years, however, the observation of
PML aer using biological therapies has
been of special concern.
Rituximab is a chimeric anti-CD20
monoclonal antibody widely used in
the treatment of lymphoproliferative
malignancies. e development of PML
following treatment with rituximab is
exceedingly rare. It has been hypothesized
that rituximab facilitates the development
of PML through the depletion of mature
B cells. Consequently, the decrease in
mature B cells induces expansion of pre-B
cells infected with latent JC virus. ese
lymphocytes carry the virus to the cen-
tral nervous system where it infects and
destroys oligodendrocytes [1].
e diagnosis of PML is based on clini-
cal neurological ndings, positive PCR
4
for
the JC virus from CSF, characteristic nd-
ings on MRI, and brain biopsy. e latter,
however, is seldom required for the diag-
nosis. Neurological signs and symptoms
may be either focal or diuse. e PCR for
PCR = polymerase chain reaction
JC virus should be obtained from cerebro-
spinal uid. Fong et al. [2] showed that the
sensitivity and specicity for JC virus DNA
by PCR were 74% and 96%, respectively.
MRI of the brain has a strong negative
predictive value. Typical radiographic
characteristics of PML on MRI include
subcortical white matter hyperintense areas
on T2-weighted images. On T1-weighted
images hypointense lesions can be seen that
usually do not enhance [3].
e management of PML depends on
the clinical setting. In HIV patients not
treated with an antiviral agent, initiation
of HAART
5
is essential. In patients receiv-
ing immunosuppressive medications,
immune reconstitution should be accel-
erated primarily by withdrawal of immu-
nosuppressive therapy. Nevertheless, PML
remains an incurable disease. Dierent
treatments have been tried over the years
with no signicant success [3].
Carson et al. [4] reviewed 57 cases
reported during the years 1997–2008. ey
analyzed PML case descriptions among
patients treated with rituximab. e clini-
cal data were provided by the Food and
Drug Administration, the manufacturer,
physicians and a literature review. ey
reported a 5.5 months median time from
the last retuximab dose to diagnosis of
PML and a 2 months median time from
PML diagnosis to death [4]. In the patient
described here, the diagnosis of PML was
made 8 months aer completion of ritux-
imab treatment and his death occurred
soon aerwards.
is communication highlights the
awareness required for a possible diagno-
sis of PML in individuals receiving ritux-
imab. e relevant dierential diagnosis
for the behavioral changes in this case
also included central nervous system lym-
phoma and a non-organic etiology (given
his psychiatric background). However,
detection of JC virus in the CSF in the
relevant clinical setting was diagnostic
HAART = highly active antiretroviral therapy
for PML and magnetic resonance imaging
conrmed the diagnosis.
Although PML in this patient could be
hypothetically related to other chemothera-
peutic agents or lymphoma, we believe that
rituximab remains a more likely cause. First,
the presentation of PML occurred 8 months
aer the last treatment, which is compatible
with the previously reported time for this
complication. Second, the patient attained
complete remission and was disease-free at
the time of PML diagnosis.
In this era of widespread use of bio-
logical agents it is prudent to keep the
diagnosis of PML in mind and to actively
seek JC virus in the appropriate clinical
setting. Recently, a study on risk factors
for PML aer treatment with natali-
zumab, a monoclonal antibody against
alpha-4 integrin, was published in the
New England Journal of Medicine [5], and
it is anticipated that the number of reports
will continue to grow with the accumula-
tion of additional data on these drugs.
Corresponding author:
Dr. A. Hershko
Dept. of Medicine B, Meir Medical Center, Kfar
Saba 44281, Israel
Phone: (972-9) 747-1576
Fax: (972-9) 747-1301
email: alon.hershko@clalit.org.il
References
1. Bellizzi A, Nardis C, Anzivino E, et al. Human
polymovirus JC reactivation and pathogenetic
mechanisms of progressive multifocal leukoen-
cephalopathy and cancer in the era of monoclonal
antibody therapies. J Neurovirology 2012; 18: 1-11.
2. Fong IW, Britton CB, Luinstra KE, Toma E, Mahony
JB. Diagnostic value of detecting JC virus DNA in
cerebrospinal uid of patients with progressive
multifocal leukoencephalopathy. J Clin Microbiol
1995; 33: 484-586.
3. Calabrese L. A rational approach to PML for
clinicians. Cleve Clin J Med 2011; 78: S38-41.
4. Carson KR, Evens AM, Richey EA, et al. Progressive
multifocal leukoencephalopathy aer retuximab
therapy in HIV-negative patients: a report of 57
cases from research on adverse drug events and
report project. Blood 2009; 113: 4834-40.
5. Bloomgren G, Richman S, Hoterman C, et al. Risk
of natalizumab-associated progressive multifocal
leukoencephalopathy. N Engl J Med 2012; 366:
1870-80.
“Common sense is the fountainhead of Justice”
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