Progressive multifocal leukoencephalopathy caused by polyoma JC virus is a rare and severe demyelinating disease of the central nervous system. It occurs in immunocompromised patients and is scarcely reported in liver transplant recipients. Brain biopsy demonstrating demyelination with presence of foamy macrophages, relative preservation of axons, astrogliosis, and typical polyomavirus inclusions in the enlarged oligodendroglial nuclei is essential for diagnosis. Here, we report a case of JC virus-associated progressive multifocal leukoencephalopathy in a living-donor liver transplant recipient who was transplanted for hepatitis C virus-related decompensated cirrhosis. Brain biopsy with immunohistochemistry confirmed the diagnosis of progressive multifocal leukoencephalopathy secondary to JC virus. JC virus related-progressive multifocal leukoencephalopathy is associated with extremely poor prognosis. Awareness and consideration of this entity in liver transplant recipients who present with sudden progressive neurologic manifestations can help in prompt diagnosis and timely treatment.
Key words : Brain biopsy, Immunohistochemistry, Polyoma virus inclusions
Progressive multifocal leukoencephalopathy (PML) caused by polyoma JC virus is a rare and severe demyelinating disease of the central nervous system. It typically occurs in immunocompromised patients and is rarely seen in liver transplant recipients. Here, we report a case of JC virus-associated PML in a living-donor liver transplant recipient.
A 59-year-old man with hepatitis C virus-related cirrhosis, which was treated with interferon and ribavirin and who had a sustained viral response for 6 years, presented with refractory ascites. He was diagnosed to have multifocal hepatocellular carcinoma with high α-fetoprotein (AFP) levels. He underwent orthotopic living-donor liver transplant in October 2015. The immunosuppressive regimen consisted of triple therapy with tacrolimus, mycophenolate mofetil, and steroids. However due to the frequent altered behavior with persistent high trough tacrolimus levels, immunosuppression was stopped, although it was again started later in the course. Graft function and the remainder of the hospital stay were otherwise uneventful during the immediate posttransplant period.
In December 2015 (2.5 mo after transplant), he developed persistent cognitive deficits in the form of drowsiness, altered behavior, and poor oral intake. An initial screening noncontrast computed tomography of the brain revealed absence of intracranial bleed. In view of persistence of neuropsychiatric manifestations, brain magnetic resonance imaging (MRI) with contrast was performed, which showed multiple round to oval space-occupying lesions with diffusion restriction in bilateral cerebral and cerebellar hemisphere. A possibility of metastatic deposits of hepatocellular carcinoma was raised. However, the AFP level was normal and imaging of the abdomen and chest revealed no abnormalities. Hepatitis C virus RNA was undetectable, and liver function tests were grossly normal, with serum bilirubin level of 0.8 mg/dL, aspartate aminotransferase and alanine aminotransferase levels of 56 and 82 IU/L, and serum alkaline phosphatase of 120 IU/L. Over the subsequent days, the sensorium worsened to a Glasgow Coma Scale of 8/15, with neurologic deficits in the form of complete left hemiparesis of upper motor neuron type. No cranial nerve or meningeal involvement was shown on clinical examination. On day 12 of admission, a repeat brain MRI was performed with contrast, which revealed multiple round to oval mildly ring-enhancing lesions of varying sizes in bilateral cerebral and cerebellar hemispheres (Figure 1). Differential diagnoses based on MRI were tumefactive demyelination, lymphoma, and metastasis.
In view of a normal AFP, no other site of involvement, lymphoma being too early for a liver transplant patient, and no evidence of invasive fungal or tubercular pathology, MRI-guided stereotactic brain biopsy was performed in January 2016 (3 mo after transplant). Sections from the brain biopsy showed cortical tissue with swollen astrocytes. These showed enlarged processes, with some revealing multilobated hyperchromatic nuclei (also known as bizarre astrocytes) (Figure 2). Oligodendrocytes were also swollen and demonstrated enlarged densely basophilic nuclei, with a few filled with eosinophilic inclusion bodies and with minimal inflammation in the biopsy (Figure 3).
Immunohistochemistry was performed by streptavidin-biotin method, using polyclonal antibody against simian virus 40 based on the principle that it cross-reacts with the JC virus (Figure 4). Diaminobenzidine was used as the chromogen to detect the reaction. Several oligodendrocyte nuclei showed nuclear reaction for JC virus protein. A diagnosis of PML secondary to JC virus was rendered. Biopsy was negative for malignancy. However, the patient continued to remain critical with progressive worsening of sensorium requiring mechanical ventilation. During the 2 weeks of hospital stay, tacrolimus and mycophenolate mofetil were tapered and then stopped. He was maintained only on prednisolone at 20 mg. There was gradual deterioration in clinical condition, with features of raised intracranial pressure and bradycardia; therefore, the patient was put on deep sedation and tracheostomy with mechanical ventilation. However, the patient subsequently developed sepsis with multiorgan failure and succumbed to his illness 3 weeks after diagnosis.
JC virus-associated PML is a rare disease, particularly in the posttransplant setting. The JC virus, a double-stranded circular DNA virus and a member of the polyomavirus family, is the causative agent of PML, a demyelinating disease of the central nervous system that causes lytic infection of oligodendroglial cells.1 The disease was first described in 1958 in patients with chronic lymphocytic leukemia and Hodgkin disease.2
Predisposing factors and diseases associated with JC virus reactivation-related PML include human immunodeficiency virus-induced immunodeficiency, rheumatologic conditions, Hodgkin disease, tuberculosis, sarcoidosis, primary immunodeficiency syndromes, and monoclonal antibody therapy, although it is rarely shown in transplant recipients.3,4 Reactivation of JC virus occurs with severe deficiency of cell-mediated immunity in transplant patients.5
Literature on JC virus-associated PML occurring in liver transplant recipients is scarce, with less than 10 cases reported in the published literature.6-10 Our patient is the first case in the 300 liver transplants, mainly living-donor liver transplants, performed so far at our center. Low incidence of this disease in liver transplant recipients has been shown by others as well, with 1 case in 132 liver transplant recipients11 and 1 in 463 liver transplant recipients.12 Similar to our patient, hepatitis C virus-associated cirrhosis as an indication for transplant has been reported in many published cases. However, whether JC virus-related disease has coincidental existence with hepatitis C or causal stimulatory effect between the 2 is not clear.
The central nervous system has been suggested as a potential site for JC virus persistence. The virus has a tropism for oligodendrocytes, resulting in cell lysis and myelin sheath breakdown that causes PML.
Median time to onset of the disease in transplant patients is 17 months.13 The most common clinical manifestation of JC virus is PML.4 The symptoms of PML include motor weakness (42%), speech abnormalities (40%), cognitive abnormalities (36%), headache (32%), visual ﬁeld deﬁcits (32%), ataxia (21%), aphasia (17%), cranial nerve deﬁcits (13%), and sensory deﬁcits (9%).14
Brain biopsy is considered the criterion standard for the diagnosis of PML. Pathologic features in a brain biopsy include demyelination with presence of foamy macrophages, relative preservation of axons, astrogliosis mimicking astrocytoma due to giant bizarre forms, and typical polyomavirus inclusions in the enlarged oligodentroglial nuclei. The latter 2 characteristics are considered the most important for diagnosis.2,15
Differential diagnosis in this patient included metastasis of hepatocellular carcinoma, lymphoma, calcineurin inhibitor-related leukoencephalopathy, and central nervous system infections, such as toxoplasmosis. Neoplasms and drug toxicity were excluded based on clinical and pathology features. Brain biopsy with immunohistochemistry confirmed the diagnosis of PML secondary to JC virus.
Treatment of PML due to JC virus in transplant recipients includes restoring the immune response by tapering immunosuppressants. No direct antiviral therapy is available. The prognosis is extremely poor regardless of treatment.
JC virus-related PML should always be suspected in a liver transplant recipient on immunosuppressants, who presents with sudden progressive neurologic manifestations and lesions in white matter on MRI brain scan. Awareness of this entity and prompt diagnosis are crucial considering the extremely poor prognosis.
DOI : 10.6002/ect.2016.0242
From the 1Department of Pathology, the 2Department of Hepatology, the 3Department of Radiology, and the 4Department of HPB and Liver Transplant Surgery, Institute of Liver and Biliary Sciences, Delhi, India
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare. We thank Dr. Dhiraj Gautam for immunohistochemistry support.
Corresponding author: Archana Rastogi, Institute of Liver & Biliary Sciences (ILBS),
D-1, Vasant Kunj, New Delhi, India 110070
Phone: +91 11 46300000, extension 6049
Figure 1. Day 12 Brain Magnetic Resonance Imaging Illustrating Lesions (White Arrows)
Figure 2. Brain Biopsy Showing Reactive Astrocytes Having Pleomorphic Multilobated Irregular Nuclei
Figure 3. Reactive Astrocytes With Viral Inclusion
Figure 4. Markedly Enlarged Oligodendrocyte Nucleus With Viral Particles Showing Anti-SV40 Antibody-Positive Nuclear JC Virus Proteins