Download Progressive Right-Sided Hemiparesis in a Man

Clinical Infectious Diseases
ANSWER TO THE PHOTO QUIZ
Anthony Amoroso, Section Editor
Progressive Right-Sided Hemiparesis in a Man With Sarcoidosis
(See pages 1141–2 for the Photo Quiz.)
Diagnosis: Progressive multifocal leukoencephalopathy (PML)
due to John Cunningham (JC) virus.
Pathologic demonstration of oligodendroglia with intranuclear inclusions, transformed astrocytes, and foamy macrophages suggested inflammatory demyelination induced by viral
infection (Figure 1A). In situ hybridization of brain biopsy tissue revealed abundant JC viral DNA in oligodendroglial nuclei,
and immunohistochemistry showed high expression of transforming T antigen in astrocytes (Figure 1B and 1C). These features are pathognomonic for PML and illustrate important
aspects of JC viral pathophysiology.
Only select cell types express the specific polysialic acid receptor for the JC virus. In the central nervous system, this receptor is found on astrocytes and oligodendroglial lineages. JC viral
entry occurs via clathrin-mediated endocytosis and can also be
facilitated by serotonin receptors (subtype 5HT2A). Cell entry is
necessary but independently insufficient for productive viral
replication. In PML, JC viral replication in glia via cellular transcription factors appears to require sequence variation (as compared to archetype virus) in the viral chromosome’s noncoding
control region (NCCR), which contains promoter and enhancer
elements [1]. NCCR variants permit early gene expression (including the large T antigen) in astrocytes, but preclude genes
needed for viral replication. Therefore, astrocytes express high
levels of the large T antigen (detected by immunohistochemistry and depicted in Figure 1C) and relatively little viral DNA
(detected by in situ hybridization and depicted in Figure 1B).
The expression of high levels of large T antigen overrides
normal cycle checkpoints, giving the infected astrocytes a
large bizarre or transformed morphology that simulates malignancy (Figure 1A and 1B). Conversely, the complement of transcription factors in oligodendroglia permits both early and late
JC viral gene expression. Oligodendroglial lineage infection
leads to a productive infection in which the virus replicates
robustly, accumulating in the nucleus. These cells contain
masses of viral DNA and label strongly by in situ hybridization
(Figure 1B), whereas their expression of large T antigen is relatively
weak (Figure 1C). The damage and death of oligodendroglia
recruit macrophages to clear the myelin debris (Figure 1A).
Diagnosis of PML is most frequently made following identification of JC virus by polymerase chain reaction (PCR) in
cerebrospinal fluid (CSF) specimens from persons with compatible clinical and radiographic findings. Brain biopsy can
provide confirmatory evidence when clinical and radiographic evidence is unconvincing [2] or when multiple pathologic
processes are simultaneously present. In our case, plasma and
CSF specimens were positive by PCR for JC virus (5393 copies/mL and 12 284 copies/mL, respectively); these results
were obtained after brain biopsy was performed. Human immunodeficiency virus (HIV) antibody by immunoassay was
negative. Prednisone was stopped and mirtazapine was initiated. Unfortunately, the patient’s neurologic symptoms progressed and he died 2 months after his brain biopsy was
performed.
Figure 1. A, Hematoxylin and eosin stain (×400 magnification) depicting oligodendroglia with intranuclear inclusions (arrowheads), transformed astrocytes (arrows), and
foamy macrophages (clear cells). B, In situ hybridization depicting JC viral DNA in oligodendroglial nuclei (arrowhead); also shown is an unstained, transformed astrocyte
(arrow). C, Immunohistochemical stain depicting transforming T antigen in astrocytes (arrows) and oligodendroglial cells (arrowheads).
1186
•
CID 2016:62 (1 May)
•
ANSWER TO THE PHOTO QUIZ
Persons with HIV infection and hematologic malignancies
are at highest risk for PML, accounting for 90% of PML cases
in one series [3]. However, in the pre-HIV era, patients with
granulomatous disease—including sarcoidosis—accounted for
an estimated 15% of all PML cases [4]. The theorized mechanism of immune depletion and resultant susceptibility to PML
among patients with sarcoidosis involves lymphocyte sequestration, monocyte exhaustion, and regulatory T-cell dysfunction.
Although iatrogenic immunosuppression likely increases the
risk of PML in individuals with sarcoidosis, there are several
reports of persons with sarcoidosis who developed PML in
the absence of immunosuppressive therapy [5].
PML can be clinically mistaken for neurosarcoidosis, as was
the case in this report. Several key characteristics distinguish the
2 conditions. Lesions due to PML tend to be subcortical and do
not typically exhibit contrast enhancement, although faint
enhancement can occasionally be seen along the margins of
PML lesions and, when present, may suggest a more favorable
prognosis. Neurosarcoid lesions can have a varied appearance,
but are frequently enhancing and often involve dural and
meningeal tissue. Pleocytosis and elevated protein are typically
absent in patients with PML, in contrast to patients with neurosarcoidosis, whose CSF tends to be inflammatory with increased
protein.
This case highlights the importance of considering PML in the
differential of neurosarcoidosis, and the accompanying neuropathology depicts important elements of JC viral pathogenesis.
Notes
Financial support. P. V. is supported by the National Center for
Advancing Translational Sciences of the National Institutes of Health
(award number KL2TR000146).
Potential conflicts of interest. All authors: No reported conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Alison L. Galdys,1 Hrishikesh A. Kale,2 David Lacomis,3 Pascalis Vergidis,1 and
Geoffrey H. Murdoch4
1
Infectious Diseases Division, 2Radiology Department, 3Neurology Department, and 4Anatomic
Pathology Division, University of Pittsburgh Medical Center, Pennsylvania
References
1. Ferenczy MW, Marshall LJ, Nelson CD, et al. Molecular biology, epidemiology, and
pathogenesis of progressive multifocal leukoencephalopathy, the JC virus-induced
demyelinating disease of the human brain. Clin Microbiol Rev 2012; 25:471–506.
2. Berger JR, Aksamit AJ, Clifford DB, et al. PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section. Neurology 2013; 80:1430–8.
3. Molloy ES, Calabrese LH. Progressive multifocal leukoencephalopathy: a national
estimate of frequency in systemic lupus erythematosus and other rheumatic diseases. Arthritis Rheum 2009; 60:3761–5.
4. Richardson EP Jr. Our evolving understanding of progressive multifocal leukoencephalopathy. Ann N Y Acad Sci 1974; 230:358–64.
5. Jamilloux Y, Neel A, Lecouffe-Desprets M, et al. Progressive multifocal leukoencephalopathy in patients with sarcoidosis. Neurology 2014; 82:1307–13.
Correspondence: A. L. Galdys, University of Pittsburgh Medical Center, 3601 Fifth Ave, Ste 150,
Pittsburgh, PA 15213 ([email protected]).
Clinical Infectious Diseases® 2016;62(9):1186–7
© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society
of America. All rights reserved. For permissions, e-mail [email protected].
DOI: 10.1093/cid/ciw011
ANSWER TO THE PHOTO QUIZ
•
CID 2016:62 (1 May)
•
1187