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Successful Treatment of Progressive Multifocal Leukoencephalopathy With Interferon

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Progressive multifocal leukoencephalopathy is usually a fatal demyelinating disease of the central nervous system caused by the John Cunningham (JC) virus with a median survival time of less than 5 months. We report about a patient that had typical clinical and radio- logical signs of progressive multifocal leukoencephalopathy, as well as positive in situ hybridization for JC virus of brain tissue, that was successfully treated with interferon >. The patient did largely outlive the usual prognosis of the disease, and no progress of clinical symp- toms or radiological findings could be found after treatment.
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Successful Treatment of Progressive Multifocal
Leukoencephalopathy With Interferon
Andreas Horn, MD*Þand John N. Greene, MD, FACPþ§
Abstract: Progressive multifocal leukoencephalopathy is usually a
fatal demyelinating disease of the central nervous system caused by the
John Cunningham (JC) virus with a median survival time of less than
5 months. We report about a patient that had typical clinical and radio-
logical signs of progressive multifocal leukoencephalopathy, as well
as positive in situ hybridization for JC virus of brain tissue, that was
successfully treated with interferon >. The patient did largely outlive
the usual prognosis of the disease, and no progress of clinical symp-
toms or radiological findings could be found after treatment.
Key Words: progressive multifocal leukoencephalopathy, PML, JC
virus, interferon, leukemia
(Infect Dis Clin Pract 2012;20: 345Y348)
Progressive multifocal leukoencephalopathy (PML) is a rare
and usually fatal demyelinating disease of the central ner-
vous system
1
that is caused by the polyomavirus JC.
2,3
The JC
virus was discovered in 1971 and was named after the 2 ini-
tials of a patient with PML.
4
Asymptomatic primary JC virus
infection is found in 86% of adults.
5
Latent JC virus resides
in kidneys and lymphoid organs. Most exclusively in immuno-
compromised patients, the virus can reactivate, spread to the
brain, and induce a lytic infection of oligodendrocytes called PML.
The median survival of patients affected by PML without HIV
infection is only 2.6 months. Treatment options for PML include
cytarabine, cidofovir, topotecan, and interferon >-2b, and all
have failed to demonstrate clear benefit in clinical studies.
6Y10
Here, we present a case of successful treatment of PML with
interferon in a leukemia patient without HIV infection.
CASE REPORT
A 66-year-old white female was on maintenance therapy
with 6-mercaptopurine and methotrexate for biphenotypic leu-
kemia. In August 2005, she presented with a 5-month history
of slightly progressive speech and writing difficulty as well as
‘trouble collecting thoughts.’’ In the last 3 weeks, she devel-
oped nearly complete aphasia and significant weakness of the
right arm.
She was initially diagnosed with breast cancer in 1985, which
required a right mastectomy followed by radiation therapy. She
was diagnosed with biphenotypic leukemia in April 2003. She
achieved a complete remission after being treated with 2 induc-
tion courses of chemotherapy ending in December 2003 followed
by consolidation chemotherapy.
She developed a nodular pneumonia and underwent an
open lung biopsy on August 2004 that was found to be histo-
plasmosis (which was successfully treated with itraconazole).
Her family history is positive for breast, lung, and colon
cancer, as well as non-Hodgkin lymphoma. Her social history
is positive for a 2 pack-years history of tobacco use, she quit
30 years ago. She lives with her husband.
On physical examination, she was in no immediate distress,
with stable vital signs, and was afebrile. The only pertinent find-
ing was on neurologic examination. She was alert and able to
follow simple commands, such as opening and closing her eyes,
but was unable to follow more complex commands such as
sticking her tongue out. She had both aphasia and apraxia of
speech. Nonverbal apraxia was also present as she was unable to
imitate blowing and coughing after numerous attempts. Exami-
nation of the cranial nerves was normal, except the range of motion
of the lips were mildly reduced for retraction and pucker on the
right, as well as a possible visual field defect on the right.
There were components of both pyramidal and extrapyra-
midal findings resulting in a hemiparesis on the right, particu-
larly affecting the right hand. She was unable to show 2 fingers
on the right hand. She had a poor coordination of the right upper
extremity and increased reflexes, predominantly in the right
extremities.
By September 15, 2005, her speech worsened but she could
still communicate. On September 17, 2005, she was only able to
say ‘‘yes’’ and ‘‘no’’ but otherwise unable to communicate fur-
ther, nor write. She was able to point at things and still managed
daily life with her husband at home. She had a mildly hemipa-
retic gait pattern on the right.
A magnetic resonance imaging (MRI) of the head on August
2005 demonstrated multifocal white matter demyelination consist-
ent with PML (Fig. 1). A spinal fluid analysis for JC virus poly-
merase chain reaction (PCR) was negative as well as negative
cytology for evidence of malignancy. By October 2005, a third
MRI showed extensive white matter abnormalities involving the
left cerebral hemisphere as well as multifocal changes involving
the right frontal area and an enhancing abnormality involving the
right frontoparietal area (Fig. 2). On October 13, 2005, a stereo-
tactic biopsy of the frontal intracranial lesion was performed.
Pathological analysis of the brain biopsy was consistent with a
nonneoplastic inflammatory process of the white matter. In situ
hybridization for JC virus of the brain tissue was positive, there-
fore supporting the diagnosis of PML.
In the beginning of November, she was treated with intra-
venous cidofovir 5 mg/kg weekly for 8 weeks. A follow-up MRI
scan in late December 2005 demonstrated even more extensive
white matter abnormalities (but no enhancement). Interferon >
5 million units 3 times weekly subcutaneously was begun in
December 2005. She developed symptoms of fatigue and 6-lb
weight loss but tolerated the interferon treatment well. Her neu-
rological symptoms gradually improved. On March 2006, she ex-
hibited an unsteady gait and aphasia. Her speech became much
clearer after having complete aphasia for 4 months. She was able
to speak single words and answer appropriately. She was able
to walk and do most things in daily life without assistance (eg,
CASE REPORT
Infectious Diseases in Clinical Practice &Volume 20, Number 5, September 2012 www.infectdis.com 345
From the *Department for Neurology, University Hospital, Albert-Ludwigs-
Universita¨t Freiburg, Freiburg; Bernstein Center for Computational Neu-
roscience Berlin, Humboldt-Universita¨t zu Berlin, Berlin, Germany; H. Lee
Moffitt Cancer Center; and §Departments of Internal Medicine and Onco-
logical Sciences, University of South Florida College of Medicine, Tampa, FL.
Correspondence to: John N. Greene, MD, FACP, H. Lee Moffitt Cancer
Center, 12902 Magnolia Dr, FOB-3, Tampa, FL 33612-9497.
E-mail: john.greene@moffitt.org.
The authors have no funding or conflicts of interest to disclose.
Copyright *2012 by Lippincott Williams & Wilkins
ISSN: 1056-9103
Copyright © 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
dressing and eating). Her facial droop resolved. An MRI scan on
April 6, 2006 showed that the white matter lesions regressed over
the earlier study from December 2005 (Fig. 3). An MRI of the
brain done in July 2006 was stable without further change. The
hemiparesis on the right as well as a mild aphasia was noted on
January 2009.
Unfortunately, the patient developed a relapse of the leu-
kemia after 4 years of remission on October 2007. She received
chemotherapy from January 2008 through June 2009. A month
later, she died from refectory leukemia. Her neurological symp-
toms remained unchanged until her death, and there was no evi-
dence of recurrence of the PML.
DISCUSSION
Progressive multifocal leukoencephalopathy is a severe dis-
ease of the white matter of the brain that is caused by reactivation
of latent JC virus. Usually, the infection develops exclusively in
immunocompromised adults, although there are some excep-
tional isolated reports of PML in the immunocompetent.
11Y13
Reactivation of the JC virus resulting in PML is described with
chronic lymphoid leukaemia, chronic myelogenous leukemia, and
Hodgkin lymphoma,
14Y19
PML was also a major opportunistic
infection associated with acquired immunodeficiency syndrome
in adults before the widespread use of highly active antiretroviral
therapy (HAART).
20Y23
Progressive multifocal leukoencephalo-
pathy is also associated with the use of the following immuno-
suppressive therapies: efalizumab,
24
fludarabine,
14Y16,18,19
rituximab,
25Y27
mycophenolate,
28
as well as natalizumab (used
to treat Crohn disease and multiple sclerosis).
29
Glucocorticoids
alone, or in combination with other immunosuppressants
30
can also
cause PML. Our patient was on a long treatment course of che-
motherapy which included dexamethasone, cyclophosphamide,
cytarabine, doxorubicin, methotrexate (hyper-CVAD); before that
daunorubicin and cytarabine.
Progressive multifocal leukoencephalopathy classically mani-
fests with neurologic deficits including altered mental status,
motor deficits, limb and gait ataxia, as well as visual symptoms
such as hemianopsia and diplopia. However, depending on the
location of lesions in the brain, symptoms can greatly vary be-
tween patients. Our patient presented with motor deficits such
as weakness of the right extremities, facial droop, and speech
apraxia, aswell as gait ataxia and hemianopsia. Cortical symptoms
such as aphasia (the neurological chief complaint of our patient)
are frequently found caused by white matter lesions that develop
in areas involved in language. All 7 MRI scans done for initial
diagnosis and progress of the disease showed slowly evolving and
finally decreasing signal intensity diffusely spread through the
left cerebrum and in the right frontal and parietal lobesVthe most
important areas for language processing.
31
Modern neurologi-
cal networking studies emphasize not only gray but especially
white matter tracts being important for language processing.
31Y33
Lesions related to PML are usually bilateral and prefer-
entially localized to the periventricular areas and subcorti-
cal white matter. On MRI, these lesions are depicted as areas
of decreased signal on T1-weighted images and increased on
T2-weighted images.
34,35
They are not contrast enhancing
FIGURE 1. Magnetic resonance imaging scan of the brain
reveals white matter enhancement in the left greater than right
parieto-occipital area.
FIGURE 2. Progression of the parieto-occipital white matter
enhancement left greater than the right is noted in the MRI scan
of the brain 1 month later.
FIGURE 3. Ventricular enlargement and cortical thinning are seen
in the MRI scan of the brain 3 years later.
Horn and Greene Infectious Diseases in Clinical Practice &Volume 20, Number 5, September 2012
346 www.infectdis.com *2012 Lippincott Williams & Wilkins
Copyright © 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
nor surrounded by edema. Involvement of deep gray struc-
tures (such as the basal ganglia) is found in 17% of cases.
36
The MRI figures in our report are consistent with this usual
presentation.
The gold standard for diagnosis of PML is brain biopsy.
In neuropathological examination of brain tissue, demyelinat-
ing lesions are found together with focal cell loss of granule
cell neurons in the GC layer. Immunohistochemistry and other
special stains are usually elaborated to further differentiate the
findings. In our patient, 5 biopsies were consistent with neuro-
glial tissue, predominantly white matter and showed significant
perivascular mononuclear inflammatory infiltrates including lym-
phocytes and plasma cells. There was also a diffuse and perivas-
cular lipid-laden macrophage infiltrate present. Occasional enlarged
atypical appearing astrocytes were seen. Multiple, large nuclei
with basophilic, smudged intranuclear inclusions were scattered in
areas of inflammation. Immunohistochemistry and special stains
with appropriate positive and negative controls were performed
on sections from 1 biopsy to further define the lesion. Immuno-
histochemistry staining using glial fibrillary acidic protein anti-
body revealed a scattering of reactive, gemistocytic astrocytes,
whereas neurofilament immunohistochemistry was only focally
positive. CD68 immunoreactive macrophages were widely dis-
tributed, including in a perivascular pattern. A myelin stain (Luxol
fast blue) revealed only focal areas of myelin, with significant
loss in the areas of inflammation. Immunohistochemistry for
myelin basic protein confirmed focal loss of myelin on sections
from 2 biopsies, with scattered P53 immunoreactive cells. In situ
hybridization for JC viruswas positive. These findings support the
diagnosis of progressive multifocal leukoencephalopathy.
Diagnosis of PML can be made via lumbar puncture with
PCR detection of JC virus DNA in the cerebrospinal fluid (to-
gether with clinical findings), which was negative in our patient.
This test had a sensitivity of 72% to 92% before the HAARTera,
37
but it is now common to find negative results in PCR in HIV
patients. Our patient was HIV-negative, but even the sensitivity
before HAART therapy becoming standard showed that a nega-
tive JC virus PCR in cerebrospinal fluid can not exclude PML.
A small study showed that patients with a low JC virus burden
(50Y100 copies/mL) in the CSF had a longer survival than patients
with a higher burden.
38
This may have contributed to the suc-
cessful treatment of our patient.
For an approach to treatment of PML in the absence of HIV,
discontinuation of immunosuppressive therapy is advised. When
the diagnosis and treatment of PML began in our patient, she was
not on immunosuppressants.
As described in the Introduction, several drugs including in-
terferon >-2b, cytarabine, cidofovir, and topotecan failed to dem-
onstrate clear benefit in clinical studies.
6Y10
Our patient showed
no response to cidofovir (dosed 5 mg/kg weekly for 8 weeks) but
showed exceptional response to interferon >(5 million units 3
times weekly subcutaneously).
We report successful treatment of PML with interferon >in
a patient with slowly progressing neurologic deficits that devel-
oped after remission of leukemia. This opinion is mainly under-
pinned by 3 facts. First, neurological symptoms improved after
the episode of treatment. No new neurological symptoms were
found. Second, the findings in the follow-up MRI scans of the brain
showed no expansion of lesions but in contrast found slight de-
creased signal intensities representing evolution of inflammation in
April 2006 (4 months after treatment). Five consecutive follow-
up examinations showed that these findings were stable and the
lesions did not expand until the patient’s death. The third fact is
the patient did largely outlive (4 years) the usual prognosis of the
disease (2.6 months in patients without HIV infection).
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Article
Full-text available
Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection of the central nervous system caused by the JC (John Cunningham) virus.1 This virus is common and is generally innocuous in an immunocompetent host. However, in individuals with innate, acquired, or iatrogenic immunodeficiency, the JC virus can become active and infect oligodendrocytes, leading to their lysis. Oligodendrocyte lysis leads to central nervous system demyelination, which may then result in focal neurologic deficits including hemiparesis, visual field deficits, and cognitive impairment. Progressive multifocal leukoencephalopathy is usually irreversible and fatal.
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