To report the clinical course of PML in an apparently immunocompetent patient treated with cidofovir

A De Luca

A Egli

A Langer-Gould

Anette Storstein

CB Drachenberg

Christine H Rinaldo

CM Marra

G Meintjes

H Linda

Halvor Naess

Hans Hirsch

J Berenguer

JF Viallard

JR Berger

K Tan

Kjell-Morten Myhr

KR Carson

L Kappos

MT Roberts

N Khanna

P Cinque

RL Cardenas

RW Price

Solveig Glad

Sverre J Mørk

English

PubMed

Abstract Background To report the clinical course of PML in an apparently immunocompetent patient treated with cidofovir. Case Presentation A 35-year-old immunocompetent man who developed progressive hemianopsia, aphasia, and limb weakness underwent repeated MRI scans of the brain, spinal fluid analyses, and brain biopsy. Before diagnosis was established based on brain biopsy, he was consecutively treated with methylprednisolone, acyclovir, ceftriaxone and plasmapheresis, but he deteriorated rapidly suggestive of the immune reconstitution inflammatory syndrome (IRIS). He started to recover two weeks after the initiation of treatment with cidofovir and has had no relapse at 3 1/2 years of follow-up. MRI has shown marked improvement. Conclusions PML should be considered in immunocompetent patients with a typical clinical course and MRI findings compatible with PML. Treatment with cidofovir should be considered as early as possible in the disease course.</p

Mørk Sverre J

Rinaldo Christine H

Storstein Anette

Glad Solveig

Naess Halvor

Myhr Kjell-Morten

Hirsch Hans

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BMC Neurology

Progressive multifocal leucoencephalopathy in an immunocompetent patient with favourable outcome. A case report

Naess, Halvor

Glad, Solveig

Storstein, Anette

Rinaldo, Christine H.

Mørk, Sverre J.

Myhr, Kjell-Morten

Hirsch, Hans

edoc

Progressive multifocal leucoencephalopathy in an immunocompetent patient with favourable outcome : a case report

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Naess et al. BMC Neurology 2010, 10:32
http://www.biomedcentral.com/1471-2377/10/32
Open AccessC A S E  R E P O R TCase reportProgressive multifocal leucoencephalopathy in an 
immunocompetent patient with favourable 
outcome. A case report
Halvor Naess*1, Solveig Glad1, Anette Storstein1, Christine H Rinaldo2, Sverre J Mørk3, Kjell-Morten Myhr1 and 
Hans Hirsch4
Abstract
Background: To report the clinical course of PML in an apparently immunocompetent patient treated with cidofovir.
Case Presentation: A 35-year-old immunocompetent man who developed progressive hemianopsia, aphasia, and 
limb weakness underwent repeated MRI scans of the brain, spinal fluid analyses, and brain biopsy. Before diagnosis was 
established based on brain biopsy, he was consecutively treated with methylprednisolone, acyclovir, ceftriaxone and 
plasmapheresis, but he deteriorated rapidly suggestive of the immune reconstitution inflammatory syndrome (IRIS). He 
started to recover two weeks after the initiation of treatment with cidofovir and has had no relapse at 3 1/2 years of 
follow-up. MRI has shown marked improvement.
Conclusions: PML should be considered in immunocompetent patients with a typical clinical course and MRI findings 
compatible with PML. Treatment with cidofovir should be considered as early as possible in the disease course.
Background
Progressive multifocal leukoencephalopathy (PML)
which is caused by the JC virus (JCV), is a rare and usu-
ally fatal demyelinating disease of the central nervous sys-
tem typically occurring in severely immunosuppressed
patients [1]. The diagnosis of PML is presumptive when
based on clinical or radiological evidence and the detec-
tion of JCV DNA by polymerase chain reaction (PCR) in
the cerebrospinal fluid (CSF). The diagnosis is definitive
by detection of viral protein or DNA by immunohis-
tochemistry or in situ hybridisation of brain biopsies,
respectively. While the JCV genomes of urine isolates
usually have an archetypal regulatory region, genomes
detected in the CSF and brains from PML patients have
always a rearranged viral regulatory region. Even though
the majority of PML cases are found in HIV infected
patients, cases have been diagnosed in patients with other
cellular immunodeficiencies due to haematological
malignancy, chemotherapy, organ transplantation, lym-
phocyte depletion as well as systemic lupus erythemato-
sus [1]. Increasing occurrence of PML in patients exposed
to monoclonal antibody therapy such as natalizumab [2],
rituximab [3], and efalizumab have been reported [4].
PML is often fatal [5], but prolonged survival has been
reported during antiviral treatment with cidofovir [6-10].
No definitive guidelines for treatment of PML have been
established. The treatment is often complicated by the
immune reconstitution inflammatory syndrome (IRIS)
[11,12]. We report an immunocompetent man with PML
probably complicated with IRIS who was successfully
treated with cidofovir.
Case presentation
A 35-years-old man was admitted to the Department of
Neurology, Haukeland University Hospital in Bergen,
Norway because of increasing problems with reading
during the last four weeks. Apart from surgery for appen-
dicitis 16 years earlier the patient was previously healthy.
On admission, the neurological examination was normal
except for a bilateral lower right-sided quadrant anopsia.
Magnetic resonance imaging (MRI) showed occipital
white matter lesions mainly on the left side (Figure 1A).
CSF analyses were normal (PCR on JCV was not per-
* Correspondence: haln@haukeland.no
1 Department of Neurology, Haukeland University Hospital, N-5021 Bergen, 
Norway
Full list of author information is available at the end of the articleBioMed Central
© 2010 Naess et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
Naess et al. BMC Neurology 2010, 10:32
http://www.biomedcentral.com/1471-2377/10/32
Page 2 of 4formed). Extensive haematological and immunological
blood analyses were performed including electrolytes,
creatinine, liver enzymes, and CRP and they were all nor-
mal. The patient remained HIV negative on repeated
tests.
Ten days after admission the patient had developed a
complete bilateral right-sided hemianopsia and slight
bilateral left-sided quadrant anopsia. A new MRI showed
progression of the white matter lesions (Figure 1B). The
patient was consecutively treated with high dose methyl-
prednisolone, acyclovir, ceftriaxone and plasmapheresis.
However, the vision disturbances progressed and he also
developed aphasia and paresis of the right arm. Four
weeks after admission brain biopsy was taken from the
left occipital lobe lesion. Histology showed demyelination
and atypical astrocytes suggestive of PML (Figure 2A-D).
PCR performed on extracted DNA from brain biopsy
specimens was strongly positive for JCV. Retrospective
quantitative PCR analysis of the original CSF was per-
formed [13] and showed 2500 JCV genome copies/ml.
Sequencing analysis of the JCV genome [14] showed a
highly rearranged unique non-coding control region
denoted PML HL (Figure 3). Retrospective enzyme
immunoassay serum analysis (EIA) [14] showed JCV IgG
antibodies at the time of hospitalization and the titres
gradually increased at 3-months of follow-up. However,
the JCV IgM levels were low and constant (Figure 4).
Treatment with intravenous cidofovir was initiated five
weeks after admission. The patient received 350 mg once
a week for three weeks and thereafter every fortnight for
6 months. Two weeks after onset of treatment with cido-
fovir the patient reported some improvement of the pare-
sis in his right arm. Yet the MRI (Figure 1C) performed
after 3 1/2 weeks treatment showed further progression
compared with the MRI performed 2 weeks prior to
onset of treatment with cidofovir. However, the patient
continued to improve clinically, and he recovered com-
pletely from the paresis of his right arm and aphasia.
After two months of treatment he also reported slight
improvement of his vision.
MRI performed after 4 months of treatment showed
marked regression of the white matter lesions. The
patient's vision improved slightly during the next months,
and the MRI (Figure 1D) showed further improvement
after 6 months. The white matter lesions remained unal-
tered on further MRI investigations, the last one being
performed 30 months after onset of treatment with cido-
Figure 1 MRI on admission and follow-up. A. MRI (flair T2) per-
formed on admission showing a white matter lesion in the parieto-oc-
cipital region on the left side. B. MRI (flair T2) showing progression of 
the white matter lesion 10 days after admission. C. MRI (flair T2) show-
ing progression of the white matter lesions in both hemipheres 3 1/2 
weeks after onset of treatment with cidofovir. D. MRI (flair T2) shower 
regression of the white matter lesions in both hemispheres 6 months 
after onset of treatment with cidofovir.
A B
C D
Figure 2 Brain biopsy. The biopsy specimen contained cortical grey 
and subcortical white matter with loose tissue texture (edema), fine 
caliber vacuolization, swollen, reactive astrocytes (pink cytoplasm in 
Panel A, hematoxylin and eosin), microglia and lipid macrophages 
(transformed microglia). Large pleomorphic nuclei of some astrocytes 
are clearly evidenced. Immunohistochemical staining for myelin basic 
protein (Panel B, immunoperoxidase (brown)) shows loss of myelin in 
the white matter lesion. Pleomorphic cells are immunopositive for as-
trocyte marker glial fibrillary acidic protein (Panel C, immunoperoxi-
dase for GFAP). In-situ-hybridization of the demyelinated lesion (Panel 
D, original magnification ×400) shows enlarged irregular nuclei posi-
tive for JC virus.
Naess et al. BMC Neurology 2010, 10:32
http://www.biomedcentral.com/1471-2377/10/32
Page 3 of 4fovir. Follow-up PCR analysis of the CSF was JCV nega-
tive seven months after onset of treatment with cidofovir.
The patient developed epilepsy 9 months after onset of
symptoms.
Antinuclear antibodies, quantification of immunoglob-
ulins (IgG 17.3 g/liter, IgA (.55 g/liter), IgM (1,3 g/liter),
electrophoresis, as well as complement (C3, C4) were all
normal, except for moderate reduced levels of IgA (0.55
g/L). The number of CD4 T-cells was 994 × 106/liter (nor-
mal range 516 - 1494 × 106/liter), the number of CD8 T-
cells was 271 × 106/liter (normal range 306 - 1184 × 106/
liter), and the number of natural killer cells (CD56) was
2.9 × 106/liter (normal range 5.0 - 26.0 × 106/liter). The
moderately reduced numbers of CD8 T-cells and natural
killer cells (CD56) were probably secondary to the treat-
ment with methylprednisolone. It was concluded by
immunologiststhat immunodeficiency was unlikely.
At the last follow-up which was 46 months after the
onset of treatment with cidofovir, the patient had experi-
enced no relapse.
Conclusion
This case report of PML highlights several interesting
points. Firstly, apparently immunocompetent persons
may develop PML, and secondly, treatment with cidofo-
vir may be successful. Thirdly, the increased progression
of symptoms after initiating antiviral and antibiotic ther-
apy, methylprednisolone and plasmapheresis, was sug-
gestive of immune reconstitution inflammatory
syndrome (IRIS). This complication may therefore follow
PML treatment in apparently immunocompetent per-
sons.
Clinical improvement within 2 weeks of the onset of
cidofovir therapy suggests that cidofovir was effective.
However, spontaneous recovery cannot be ruled out [15].
The progression of the MRI white matter lesions detected
3 1/2 weeks after onset of cidofovir treatment may have
been related to disease progression prior to the initiation
of cidofovir therapy. Others have reported clinical
improvement in spite of initial worsening of lesions on
MRI [16]. The MRI performed 4 months after onset of
treatment showed marked improvement.
The rapid deterioration prior to treatment with cidofo-
vir is suggestive of IRIS. IRIS is usually explained by
reconstitution of a compromised immune system, fol-
lowed by a strong immune response and inflammation.
This may lead to a paradoxical clinical worsening of an
appropriately treated infection [17]. IRIS may be seen in
HIV positive PML patients who receive antiretroviral
therapy [17]. or in PML patients with immunomodula-
tory therapy and plasmapheresis for removing the immu-
nosupressing agent [18]. Our patient received
plasmapheresis, and one might speculate whether remov-
ing the natural humoral immune response to the JCV
could influence the risk of IRIS.
There are reports that cidofovir may prolong survival
among immunocompromised patients with PML [6-9,19]
while others have failed to confirm any effect of treat-
ment with cidofovir [10,20]. One might speculate
whether cidofovir is more effective the more immuno-
competent the patient is.
In conclusion, PML should be considered in immuno-
competent patients with a typical clinical course and MRI
findings compatible with PML. Treatment with cidofovir
should be considered as early as possible in the disease
course.
Consent
Written informed consent was obtained from the patient
for publication of this case report and any accompanying
images. A copy of the written consent is available for
review by the Editor-in-Chief of this journal.
Figure 4 JCV and BKV antibody titres. JCV and BKV virus-like particle 
(VLP)-specific IgG levels from the time of patient administration and 
the following 16 months. The data were obtained retrospectively by 
EIA. OD 492 nm, optical density at 492 nm.
0,00
0,50
1,00
1,50
2,00
2,50
08
.2
00
6
10
.2
00
6
12
.2
00
6
02
.2
00
7
04
.2
00
7
06
.2
00
7
08
.2
00
7
10
.2
00
7
A
nt
ib
od
y 
A
ct
iv
ity
 (O
D
 4
82
 n
m
)
IgG JCV IgM JCV
IgG BKV IgM BKV
0              12                     30                                                   71
Weeks post admission
Figure 3 Sequencing analysis of the JCV genome. Schematic illustration of the archetype JCV regulatory regions/NCCR found in the urine of 
healthy people and the rearranged regulatory region demonstrated by the PCR in the CSF of the PML patient.
1-25 1-551-23 1-66 1-18 1-69
A B C D FE
1-25 1-551-23
16-25
1-55
1-18
58-66
1-18
1-4 6-23 58-66 1-69*
A B C D A B C FEE F D
ARCHETYPE
PML HL
Naess et al. BMC Neurology 2010, 10:32
http://www.biomedcentral.com/1471-2377/10/32
Page 4 of 4Competing interests
The authors declare that they have no competing interests.
Authors' contributions
HN investigated, treated the patient and drafted the manuscript. SG investi-
gated the patient and contributed to important revisions of the draft. AS
treated the patient and contributed to important revisions of the draft. CHR
sequenced the JVC genome, and contributed to important revisions of the
draft. SJM performed the histology examinations, selected histology images
and contributed to important revisions of the draft. KMM contributed to con-
ception, design and important revisions of the draft. HH performed the JCV
antibody analyses. All authors read and approved the final manuscript.
Author Details
1Department of Neurology, Haukeland University Hospital, N-5021 Bergen, 
Norway, 2Department of Microbiology and Infection Control, University 
Hospital of North Norway, N-9038 Tromsø, Norway, 3Department of Pathology, 
Haukeland University Hospital, N-5021 Bergen, Norway and 4Div. Molecular 
Diagnostics, Clinical & Transplantation Virology, Institute for Medical 
Microbiology, Petersplatz 10, CH-4003 Basel, Switzerland
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Pre-publication history
The pre-publication history for this paper can be accessed here:
http://www.biomedcentral.com/1471-2377/10/32/prepub
doi: 10.1186/1471-2377-10-32
Cite this article as: Naess et al., Progressive multifocal leucoencephalopathy 
in an immunocompetent patient with favourable outcome. A case report 
BMC Neurology 2010, 10:32
Received: 10 November 2009 Accepted: 18 May 2010 
Published: 18 May 2010
This article is available from: http://www.biomedcentral.com/1471-2377/10/32© 2010 Nae s et al; licensee BioMed Central Ltd. is an Open Access article distributed under th  terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.BMC Neurology 2010, 10:32


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Progressive multifocal leucoencephalopathy in an immunocompetent patient with favourable outcome. A case report

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