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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
CASE REPORT  
Year : 2019  |  Volume : 30  |  Issue : 2  |  Page : 526-530
Biopsy-proven progressive multifocal leukoencephalopathy in a renal transplant patient


1 Department of Critical Care Medicine, Mayo Clinic, Florida, USA
2 Department of Dermatology, Mayo Clinic, Florida, USA
3 Department of Laboratory Medicine and Pathology, Mayo Clinic, Florida, USA

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Date of Submission16-May-2018
Date of Acceptance07-Aug-2018
Date of Web Publication23-Apr-2019
 

   Abstract 


Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease that affects immunocompromised hosts. Most often the disease is reported in association with leukemia, lymphoma, and AIDS. With recent advancements in immunosuppressive medications and subsequent rise in solid organ transplantations, it is becoming more prevalent in this population. Both the diagnosis and treatment of PML remains a challenge to the transplant community. The disease remains mostly underreported and undertreated. The diagnostic uncertainty in a renal transplant patient leads us to do the brain biopsy for suspicion and confirmation of PML.

How to cite this article:
Guru PK, Vissing MB, Agarwal A, Krishna M. Biopsy-proven progressive multifocal leukoencephalopathy in a renal transplant patient. Saudi J Kidney Dis Transpl 2019;30:526-30

How to cite this URL:
Guru PK, Vissing MB, Agarwal A, Krishna M. Biopsy-proven progressive multifocal leukoencephalopathy in a renal transplant patient. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2019 May 20];30:526-30. Available from: http://www.sjkdt.org/text.asp?2019/30/2/526/256862



   Introduction Top


Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease caused by infection of an immunocompromised host with John Cunningham (JC) virus. It was first described in 1958 in patients with Hodgkin’s lymphoma and chronic lymphocytic leukemia.[1] Years later, in 1971, its association with JC polyomavirus was discovered.[2] However, its most notable association came with the AIDS pandemic of the 1980s when the prevalence of PML drastically increased. Since then it has been been reported in association with immunomodulatory medications used for hematologic malignancies, autoimmune and inflammatory diseases, and solid organ transplant. However, the diagnostic challenges in patients are primarily responsible for underreporting of the disease. While brain biopsy remains the gold standard for diagnosis of PML, it is rarely performed due to obvious morbidity associated with the procedure.


   Case Report Top


A 60-year-old Caucasian male with a deceased donor renal transplant in 2011 presented to our facility in August 2016. He had a gradual 9-month decline with personality changes, fatigue, and muscle weakness when rising from a seated position. Six weeks before presentation, he had reduced conversational engagement, decreased appetite, and worsening ambulation. Transplant was performed in 2011 for end-stage renal disease due to hypertensive and diabetic nephropathy. His maintenance immunosuppressive regimen included tacrolimus, prednisone, and mycophenolic acid. He had prior medication noncompliance and diagnosed to have chronic graft rejection with a baseline creatinine varying between 2.0 and 2.3 mg/dL. Initial neurologic examination was significant for deficits in attention and short-term memory, absent color sensation and decreased visual acuity in the right eye, mild weakness involving upper and lower extremities, right upper extremity intention tremor, and decreased sensation in a length-dependent manner. Computerized tomography (CT) of the head showed diffuse white matter disease with hypodense lesions involving subcortical bi-frontal and left posterior parietal lobes. Magnetic resonance imaging (MRI) of the brain was significant for generalized cerebral and cerebellar atrophy, out of proportion to age, with extensive foci of abnormal fluid-attenuated inversion recovery (FLAIR) and T2 hyperintensity within cerebral white matter in the frontal, parietal, and temporal lobes. [Figure 1] Possibilities of acute/ subacute encephalitis, central nervous system (CNS) lymphoma, or PML were considered in the differential.
Figure 1: Brain magnetic resonance imaging showing hyper-intense changes in the frontal and parietal region.

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He was treated with antimicrobials and fluids for septic shock secondary to extended-spectrum β-lactamase Enterobacter bacteremia in the intensive care unit (ICU). His condition stabilized, and he had symptomatic improvements in the ICU. Workup for CNS pathology included cerebrospinal fluid (CSF) studies which were negative for infectious serology, including JC virus, paraneoplastic disease, and malignancy. Serum fungal studies, infectious serology, autoimmune serology, cryptococcal antigen, and human immunodeficiency virus (HIV) were negative.

With the strong suspicion for CNS lymphoma or PML, a right frontal stereotactic brain biopsy was performed. Postprocedure, he experienced a focal seizure with secondary generalization and ventricular fibrillation cardiac arrest. Return of spontaneous circulation was achieved after 10 min of cardiopulmonary resuscitation. His neurologic status returned to the admission baseline after 72 h of cardiac arrest. JC virus polymerase chain reaction (PCR) obtained from the repeat CSF studies on the day of brain biopsy reported to be positive. The brain biopsy results were confirmatory showing tissue demyelination with many lipid-laden macrophages and bizarre hypertrophic astrocytes, many oligo-dendroglias with swollen nuclei and clearing of chromatin consistent with intra-nuclear viral inclusions [Figure 2]a. BK virus immunohisto-chemistry confirmed the presence of viral antigen in the nuclei of oligodendrocytes [Figure 2]b. With a diagnosis of PML, the prognosis was discussed with the patient and family. As per the patient and family wishes, his care was transferred to hospice. The patient passed away 10 days after his transition to hospice.


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   Discussion Top


PML is caused by JC virus infection involving the CNS. HIV is the most common immunocompromised state leading to PML (80%), with hematologic malignancies (8.4%), solid cancers (2.83%), and rheumatologic diseases (<1.0%) presenting much less frequently.[3] Despite its increased frequency among solid tumor transplants, the overall risk of development of PML is very low in renal transplant, 0.027%.[4] While immunosuppression remains the greatest risk factor for the infection, no single antirejection agent has been found to be associated with a higher risk compared to the other. JC virus asymptomatically infects more than 50% of the healthy general population, and in contrast to the BK virus, its seroprevalence increases with age.[5] Asymptomatic viremia after initial infection leads to latent infection in the renal epithelial cells until an immuno-suppressive insult, such as HIV or medication, causes virus reactivation. Viral replication then takes place within glial cells resulting in diffuse demyelination. Although rare, viral replication within the kidney can lead to polyomavirus-associated nephropathy (PVAN). PVAN is most often associated with another strain of polyomavirus, BK, but there have been a small number of cases published on JC virus associated PVAN.[6],[7],[8] Rarely, JC virus causes both PML and PVAN in the same patient.[9]

PML can affect any area of the brain, and its clinical manifestations are extremely variable. Cognitive and behavioral changes along with motor weakness are present in approximately one-third to one-half of patients. Gait abnormalities, sensory loss, and speech difficulties are more common in AIDS-related PML, whereas visual field defects are more common in nonAIDS related PML.[10] Symptoms onset is variable, but on average most occur around one year out from transplant.[4] Diagnosis is often delayed due to variable clinical presentations and other competing etiologies in immuno-compromised transplant patients. The diagnosis of PML is made with a combination of clinical, laboratory, and radiologic data. However, definitive diagnosis can only be established with tissue biopsy. Imaging findings, although nonspecific, can raise suspicion for PML. Hypodense lesions that rarely contrast enhances are evident on CT in areas of affected white matter. MRI is the imaging test of choice as it is more sensitive than CT. On MRI, there are multi-focal, hyperintense lesions on T2 and FLAIR that most often affect the frontal and parieto-occipital regions.[10] CSF fluid studies are often helpful in both confirmations of diagnosis, and to rule out other causes. JC virus CSF PCR has a sensitivity of up to 95% and specificity of 95%–100%.[11],[12],[13] A diagnosis can be made without the need for biopsy in the proper clinical settings, with characteristics imaging and positive JC viral DNA in the CSF. However, initial CSF PCR can be negative, as in our case, despite the clinical and radiologic evidence of disease. If repeated CSF studies are negative, brain biopsy is the next step. The brain biopsy in PML is characterized by triad findings of: (1) multi-focal demyelination with frequent involvement of the cerebellum, cerebrum, and brain stem, (2) hyperchromatic, enlarged oligoden-droglial nuclei, and (3) bizarre astrocytes.[14] In addition, PCR amplification of brain tissue will be positive JC virus.

Posttransplant PML is often rapidly progressive and fatal with limited options for definitive treatment. Median survival in transplant patients is approximately 6.4 months from symptom onset with overall mortality of 84%.[15] Reconstitution of the immune system, with complete withdrawal or significant reduction in immunosuppression, is the only definitive modality to treat PML. Although, it has not been shown to provide a substantial survival benefit.[15] In addition, there is a risk of graft rejection with reduction of immunosuppression. Other less frequently used treatment options include mirtazapine, antivirals such as meflo-quine and cidofovir, and the antimetabolite cytarabine.[15],[16]


   Conclusion Top


With recent advancements in immunosuppression, transplant patients are increasing in number and living longer causing many to believe the incidence of PML will only increase in this population. It is important to always have PML on the differential in any patient presenting with a change, no matter how small or nonspecific, in neurologic status. JC virus PCR has improved our ability to detect the virus early in the CSF leading to a less invasive diagnostic approach. However, as in our case, a negative result with suggestive clinical and imaging characteristics should not rule out the disease. If clinical suspicion is high, repeat CSF testing and brain biopsy are warranted.

Conflict of interest: None declared.



 
   References Top

1.
Astrom KE, Mancall EL, Richardson EP Jr. Progressive multifocal leuko-encephalopathy; a hitherto unrecognized complication of chronic lymphatic leukaemia and Hodgkin’s disease. Brain 1958;81:93-111.  Back to cited text no. 1
    
2.
Padgett BL, Walker DL, ZuRhein GM, Eckroade RJ, Dessel BH. Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy. Lancet 1971;1: 1257-60.  Back to cited text no. 2
    
3.
Molloy ES, Calabrese LH. Progressive multi-focal leukoencephalopathy: A national estimate of frequency in systemic lupus erythematosus and other rheumatic diseases. Arthritis Rheum 2009;60:3761-5.  Back to cited text no. 3
    
4.
Neff RT, Hurst FP, Falta EM, et al. Progressive multifocal leukoencephalopathy and use of mycophenolate mofetil after kidney transplantation. Transplantation 2008;86:1474-8.  Back to cited text no. 4
    
5.
Egli A, Infanti L, Dumoulin A, et al. Prevalence of polyomavirus BK and JC infection and replication in 400 healthy blood donors. J Infect Dis 2009;199:837-46.  Back to cited text no. 5
    
6.
Kazory A, Ducloux D, Chalopin JM, Angonin R, Fontanière B, Moret H. The first case of JC virus allograft nephropathy. Transplantation 2003;76:1653-5.  Back to cited text no. 6
    
7.
Wen MC, Wang CL, Wang M, et al. Association of JC virus with tubulointerstitial nephritis in a renal allograft recipient. J Med Virol 2004;72:675-8.  Back to cited text no. 7
    
8.
Kantarci G, Eren Z, Demirağ A, et al. JC virus-associated nephropathy in a renal transplant recipient and comparative analysis of previous cases. Transpl Infect Dis 2011;13:89-92.  Back to cited text no. 8
    
9.
Phillips T, Jacobs R, Ellis EN. Polyoma nephropathy and progressive multifocal leukoencephalopathy in a renal transplant recipient. J Child Neurol 2004;19:301-4.  Back to cited text no. 9
    
10.
Berger JR, Aksamit AJ, Clifford DB, et al. PML diagnostic criteria: Consensus statement from the AAN neuroinfectious disease section. Neurology 2013;80:1430-8.  Back to cited text no. 10
    
11.
Fong IW, Britton CB, Luinstra KE, Toma E, Mahony JB. Diagnostic value of detecting JC virus DNA in cerebrospinal fluid of patients with progressive multifocal leukoencephalopathy. J Clin Microbiol 1995;33:484-6.  Back to cited text no. 11
    
12.
Weber T, Turner RW, Frye S, et al. Specific diagnosis of progressive multifocal leukoence-phalopathy by polymerase chain reaction. J Infect Dis 1994;169:1138-41.  Back to cited text no. 12
    
13.
Gibson PE, Knowles WA, Hand JF, Brown DW. Detection of JC virus DNA in the cerebrospinal fluid of patients with progressive multifocal leukoencephalopathy. J Med Virol 1993;39:278-81.  Back to cited text no. 13
    
14.
Richardson EP Jr. Progressive multifocal leukoencephalopathy. N Engl J Med 1961;265: 815-23.  Back to cited text no. 14
    
15.
Mateen FJ, Muralidharan R, Carone M, et al. Progressive multifocal leukoencephalopathy in transplant recipients. Ann Neurol 2011;70:305-22.  Back to cited text no. 15
    
16.
Bauer J, Gold R, Adams O, Lassmann H. Progressive multifocal leukoencephalopathy and immune reconstitution inflammatory syndrome (IRIS). Acta Neuropathol 2015;130:751-64.  Back to cited text no. 16
    

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Correspondence Address:
Pramod Kumar Guru
Department of Critical Care Medicine, Mayo Clinic, Florida
USA
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DOI: 10.4103/1319-2442.256862

PMID: 31031391

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    Abstract
   Introduction
   Case Report
   Discussion
   Conclusion
    References
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