Journal of NeuroVirology https://doi.org/10.1007/s13365-019-00742-1 CASE REPORT A 41-year-old female with progressive multifocal leukoencephalopathy after liver transplant Zahra Ahmadinejad 1 & Fatemeh Talebi 2 & Niloofar Ayoobi Yazdi 3 & Fereshteh Ghiasvand 1 Received: 7 August 2018 / Accepted: 21 March 2019 # Journal of NeuroVirology, Inc. 2019 Abstract Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease caused by JC virus reactivation. Its occurrence is very rare after solid organ transplantation, especially liver transplantation. We report a patient who received liver transplantation due to liver failure resulting from autoimmune hepatitis and advanced PML presenting with aphasia. A 41-year-old female with a history of liver transplantation who received a usual immunosuppression regimen was admitted with a stroke attack resulting in right hemiplegia 2 months after liver transplantation. Surprisingly, she gradually developed dysarthria and left central facial paresis. A brain MRI showed an abnormal multifocal area with a high T2/flair signal in the deep subcortical white matter of the left hemisphere as well as the splenium of the corpus callosum. PCR evaluation of CSF for JCV was positive while other PCR results were negative. A liver transplant recipient receiving immunosuppressive treatment for a long time could develop PML due to JCV reactivation. Only eight cases of JCV infection were reported after liver transplantation by the time of reporting this case. Unfortunately, there is no definite treatment for PML. Keywords Liver transplant . Progressive multifocal leukoencephalopathy . JC virus Introduction The (JC) virus is a DNAvirus without an envelope that belongs to the Polyomaviridae family. It might reactivate leading to severe demyelinating CNS diseases in patients with immunodeficiency. After primary infection, which often occurs in childhood (Chesters et al. 1983; Tan and Koralnik 2010; Sabath and Major 2002), progressive multifocal leukoencephalopathy (PML) is a demyelinating disease caused by reactivation of JC virus. The occurrence of PML has increased due to the HIV pandemic (Verhelst et al. 2011). However, PML could be found in other immunocompromised conditions like multiple sclerosis, Crohn’s disease, rheumatoid arthritis, and psoriasis (Chesters et al. 1983). PML manifestations usually include subacute neurological disorders such as altered mentalstatus,motordisorder,ataxia,visualsymptoms,andseizure. PML is usually progressive and fatal (Chesters et al. 1983). The 1yearsurvivalrateofPMLmightbetoopoor,around10%,especially in non-associated HIV PML (Neff et al. 2008). Its occurrence is very rare after solid organ transplantation, especially liver transplantation.Wereportapatientwithahistoryoflivertransplantation due to liver failure resulting from autoimmune hepatitis and advanced PML presenting with aphasia. PCR evaluation of the CSF for JCV showed positive results while other PCR results were negative. * Fatemeh Talebi talebi.fatemeh5018@yahoo.com Case report 1 Liver transplantation Research Center, Department of Infectious Diseases, Imam Khomeini Hospital complex, Tehran University of Medical Sciences, Tehran, Iran 2 Department of Infectious Diseases, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran 3 Department of Radiology, Advanced Diagnostic and Interventional Radiology (ADIR) Research Center, Tehran University of Medical Science, Tehran, Iran A 41-year-old female underwent orthotopic liver transplantation for autoimmune hepatitis in 2016. She received a usual immunosuppression regimen in the Liver Transplant Center of Imam Khomeini Hospital. Two months after liver transplantation, she experienced a stroke attack resulting in right hemiplegia. Her immunosuppressive regimen included CellCept in combination with tacrolimus. Primary follow-up after transplantation was unremarkable. In August 2016, the patient J. Neurovirol. gradually developed dysarthria and left central facial paresis and could not express the words correctly. Therefore, she was admitted to the transplantation ward for further examinations. A mild right paresis was noticed on admission. The patient’s vital signs were as follows: oral temperature 36.8 °C, blood pressure 120/85 mmHg, respiratory rate 13/min, and heart rate 85/min. On neurological examinations, the muscle force of the left and right limbs was normal and 3/5, respectively. The reflexes, gait, and sensation were also. The results of ocular examination were unremarkable but speech was unclear. The remaining physical examinations were normal. The laboratory data were as follows: WBC 2400/micl, Hb 9.5 g/dl, Plt 15,000/micl, Cr 0.9 mg/dl, blood urea 24 mg/dl, Na 140 mmol/l, K 3.4 mmol/l, CRP 1.3 mg/l, ESR 9 mm/h, and normal liver function tests. The results of CSF analysis were as follows: clear appearance, glucose 49 mg/dl, protein 10 g/ dl, LDH 13 units/l, RBC 0–1 cell/micl, WBC 4 cell/micl, and ADA 9 units/l. CSF culture and smear were normal. A brain MRI showed an abnormal multifocal area with a high T2/flair signal in the deep subcortical white matter of the left hemisphere as well as the splenium of the corpus callosum (Fig. 1). No abnormal enhancement on post contrast images or restriction diffusion was seen. MRI findings were suggestive of PML. After a few days, her neurological deficit progressed resulting in complete aphasia and paresis. Considering the progressive nature of the disease and the presence of multifocal lesions in the white matter on brain MRI in an immunodeficient patient, PML, CMV encephalitis, cryptococcal meningoencephalitis, post-transplant lymphoproliferative disorder, mycobacterial meningitis, and neuro vasculitis were included on the list of differential diagnosis. Accordingly, the following CSF analyses were ordered: CMV PCR, EBV PCR, JCV PCR, MTB PCR, cryptococcus PCR, and cytology. PCR evaluation of the CSF for JCV was positive while other PCR results were negative. The immunosuppressive regimen was Fig. 1 A brain MRI showing an abnormal multifocal area with a high T2/flair signal in the deep subcortical white matter of the left hemisphere as well as the splenium of the corpus callosum then gradually decreased. CellCept was tapered and tacrolimus was discontinued, and sirolimus 2 g/day was introduced. During the following weeks, neurological deficits including aphasia and facial hemiparesis improved. One month later, the patient was discharged from the transplantation ward with adjustment of the immunosuppressive drug dose insisting on following up neurological symptoms improvement. She was still alive after 6 months following discharge. Her speech and muscle forces improved significantly. Discussion PML is a demyelination neurologic disorder caused by JCV. This disease is usually found in immunocompromised patients including organ transplant recipients, cancerpatients, and patientsreceiving lymphocyte-targeted drug treatment for autoimmune disorders and HIVinfection. This rare disease occurs after solid organ transplantation, especially liver transplantation. The first reported cases of PML were diagnosed after kidney transplantation (Worthmann etal. 1994).Until now, eight casesof PML havebeenreported after liver transplantation (Aksamit Jr. and Groen 1995; Bronster et al. 2000; Bronster et al. 1995; Boulton-Jones et al. 2001; Lima et al. 2017; Alibert et al. 2006; Stracciari and Guarino 2001). It seems unlikely that there is any association between the cause of liver failureandPML.Theprimarydiagnosisofthepatientwascirrhosis secondary to autoimmune hepatitis. The post-transplant neurologicalmanifestationwasaphasia.TheincidenceofCNScomplication afterlivertransplantationis13to23%.Neurologicalcomplications occur during the first 2 months after transplant. It has been reported that it takes 27 months for PML symptom to emerge in the case of solidorgantransplantation,butittakesnearly11monthsinindividuals withbone marrow transplantation. These complicationscould result from metabolic disorders, infection, or side effects of drugs (Yiannoutsos et al. 1999). The CNS white matter lesions in J. Neurovirol. immunocompromisedpatientscouldbeduetoopportunisticinfections, toxic effects of medicines, and metabolic disorders. It has been shown that PML has a very poor prognosis, particularly in non-HIV-related cases and untreated HIV patients with a 1-year survival rate of 10%. These lesions could be accompanied by leukoencephalopathy. Considering the sequence and timing of clinical manifestations, some differential diagnoses could be proposed for this clinical scenario. It has also been reported that PML could develop even a long time after liver transplant. Moreover, its outcome is very variable after immunosuppressive therapy cessation.PMLseemstobeconsideredasadifferential diagnosissinceit could occur in liver transplantation recipients during early and late post transplantation stages (Neff et al. 2008). This disease usually starts with neurological deficits, including altered mental status, motility disorders, extremity ataxia, gait ataxia, seizure, and visual signsashemianopsiaanddiplopia(StracciariandGuarino2001).In the present case, the first neurological findings were aphasia and facial hemiparesis. Various methods are used to diagnose PML but the gold standard is brain biopsy. Although, there could be a neurological disorder with white matter lesions in MRI and positive polymerase change reaction (PCR) for JCVin CSF. The diagnosis of PML is confirmed only by a positive brain biopsy. In this patient, PCRwaspositiveforJCVDNA.TheJCVviralloadisconsidereda prognosticfactorsuchthat apatientwithalowerviralload(50–100 copies/ml) will have a longer survival compared to a patient with a higher viral load (18). The patient’s viral load was below 100 copies/ml, which was a low viral load. Only eight cases of JCV infection were reported after liver transplantation by the time of reporting this case. Unfortunately, there is no definite treatment forPML,althoughseveralagentshavebeenevaluatedwithunproven effects on JCVinfection. Therefore, the priority of immunosuppressive treatment discontinuation is not clear yet. However, in this patient, decreasing the dose of immunosuppressive medicine improved the clinical findings ((Neff et al. 2008), Yiannoutsos et al. 1999, Crowder et al. 2005). A liver transplant recipient receiving immunosuppressive treatment for a long time could develop PML due to JCV reactivation. Principally all of the liver transplantation cases are not usually manifesting CNS lytic infection caused by JCV. Acknowledgments The authors would like to thank Dr. Mohsen Nasiritusi for editing an earlier version of this manuscript. Compliance with ethical standards Conflict of interest The authors declare that they have no conflicts of interest. References Aksamit AJ, Jr., de Groen PC. Cyclosporine-related leukoencephalopathy and PML in a liver transplant recipient. Transplantation. 1995;60(8): 874–876 Alibert S, Gerolami R, Tammam D, Borentain P, Tissot-Dupont H, Zandotty C et al (2006) Progressive multifocal leukoencephalopathy secondary to JC virus infection after liver transplantation and treatment of recurrent hepatitis C. Gastroenterol Clin Biol 30(3):473– 475 Leucoencephalopathie multifocale progressive due au virus JC au cours du traitement d’une recidive d’hepatite virale C apres transplantation hepatique Boulton-Jones JR, Fraser-Moodie C, Ryder SD (2001) Long term survival from progressive multifocal leucoencephalopathy after liver transplantation. J Hepatol 35(6):828–829 Bronster DJ, Lidov MW, Wolfe D, Schwartz ME, Miller CM (1995) Progressive multifocal leukoencephalopathy after orthotopic liver transplantation. Clin Transplant 1(6):371–372 Bronster DJ, Emre S, Boccagni P, Sheiner PA, Schwartz ME, Miller CM (2000) Central nervous system complications in liver transplant recipients–incidence, timing, and long-term follow-up. Clin Transpl 14(1):1–7 Chesters PM, Heritage J, McCance DJ (1983) Persistence of DNA sequences of BK virus and JC virus in normal human tissues and in diseased tissues. J Infect Dis 147(4):676–684 Crowder CD, Gyure KA, Drachenberg CB, Werner J, Morales RE, Hirsch HH et al (2005) Successful outcome of progressive multifocal leukoencephalopathy in a renal transplant patient. Am J Transplant : Off J Am Soc Transplant Am SocTransplant Surgeons 5(5):1151–1158 Lima MA, Silva MTT, Afonso LA, Vaz BJP (2017) Post-cART progressive multifocal leukoencephalopathy era in a Brazilian center. J Neurol Sci 381:321–324 Neff RT, Hurst FP, Falta EM, Bohen EM, Lentine KL, Dharnidharka VR et al (2008) Progressive multifocal leukoencephalopathy and use of mycophenolate mofetil after kidney transplantation. Transplantation 86(10):1474–1478 Sabath BF, Major EO (2002) Traffic of JC virus from sites of initial infection to the brain: the path to progressive multifocal leukoencephalopathy. J Infect Dis 186(Suppl 2):S180–S186 Stracciari A, Guarino M (2001) Neuropsychiatric complications of liver transplantation. Metab Brain Dis 16(1–2):3–11 Tan CS, Koralnik IJ (2010) Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol 9(4):425–437 Verhelst X, Vanhooren G, Vanopdenbosch L, Casselman J, Laleman W, Pirenne J, et al. Progressive multifocal leukoencephalopathy in liver transplant recipients: a case report and review of the literature. Transpl Int : official journal of the European Society for Organ Transplantation. 2011 ;24(4):e30–e34 Worthmann F, Turker T, Muller AR, Patt S, Stoltenburg-Didinger G (1994) Progressive multifocal leukoencephalopathy after orthotopic liver transplantation. Transplantation. 57(8):1268–1271 Yiannoutsos CT, Major EO, Curfman B, Jensen PN, Gravell M, Hou J et al (1999) Relation of JC virus DNA in the cerebrospinal fluid to survival in acquired immunodeficiency syndrome patients with biopsy-proven progressive multifocal leukoencephalopathy. Ann Neurol 45(6):816–821 Power C, Gladden JG, Halliday W, Del Bigio MR, Nath A, Ni W, et al. AIDS- and non-AIDS-related PML association with distinct p53 polymorphism. Neurology. 2000;54(3):743–6. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.