Fatal Progressive Multifocal Leukoencephalopathy in a Kidney Transplant Recipient 19 Years After Successful Renal Allograft Transplantation N. Carlson* and J.M. Hansen Department of Nephrology, Copenhagen University Hospital Herlev, Herlev, Denmark
ABSTRACT Background. Progressive multifocal leukoencephalopathy (PML) is a rare, demyelinating disease caused by viral infection of glial cells by JC polyomavirus (JCV) in immunocompromised patients. JCV is a member of the Polyomaviridae family. Infection is usually latent and reactivation only occurs in circumstances of extreme immunodeficiency. Development of fulminant PML is rare and treatment options are limited. Case Report. We have presented a case of JCV reactivation resulting in PML 19 years after renal allograft transplantation and after recent conversion of immunosuppressive treatment. One year after conversion of immunosuppressive therapy owing to biopsyproven acute humoral rejection, our patient presented with symptoms of deteriorating neurologic status. Cerebral computed tomography showed abnormal signals in the frontal lobe suspect for PML. Diagnosis was confirmed by qualitative polymerase chain reaction analysis of the cerebrospinal fluid. Owing to severe renal insufficiency, treatment options were limited to tapering of immunosuppressive treatment in hopes of achieving host clearance of the viral infection. Despite prompt termination of immunosuppressive treatment, the patient suffered rapid progressive neurologic decline and death rapidly ensued. Conclusion. Development of PML in transplant recipients remains rare. Despite advances in our understanding of JCV infection and PML, treatment options remain limited and prognosis is often poor.
P
ROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) is a rare demyelinating disorder caused by lytic infection of glial cells by JC polyomavirus (JCV) with secondary oligodendrocyte destruction. JCV is a member of the Polyomaviridae family. PML is associated with immunodeficiency and occurs in the setting of AIDS, treatment with monoclonal antibodies (natalizumab, rituximab, efalizumab, and infliximab), hematologic malignancies, and solid organ transplantation [1]. PML presents at a median of 37 months after renal transplantation [2]. PML most commonly presents with symptoms that include motor weakness (42%), speech abnormalities (40%), cognitive abnormalities (36%), headache (32%), visual field deficits (32%), ataxia (21%), aphasia (17%), cranial nerve deficits (13%), sensory deficits (9%), and seizures (rare) [3]. Treatment options are limited to discontinuation of immunosuppressive treatment and
ineffective, experimental antiviral medication [4]. Prognosis is frequently poor and PML remains a devastating and often fatal central nervous system infection. We have presented a case of delayed onset of PML 19 years after renal allograft transplantation. CASE REPORT A 60-year-old female renal allograft recipient was admitted to the hospital in January 2013 on suspicion of uremic encephalopathy. Symptoms included recent onset of latency, mild cognitive impairment, and altered diurnal rhythm. Estimated glomerular filtration rate was 8 mL/min/1.73 m2 (CKD-EPI). Her medical history *Address correspondence to Nicholas Carlson, MD, Department of Nephrology, Copenhagen University Hospital Herlev, Herlev Ringvej 75, Herlev 2730, Denmark. E-mail: nicholas. [email protected]
ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.12.072
Transplantation Proceedings, 46, 2403e2405 (2014)
2403
2404 included kidney failure in January 1993 owing to autosomaldominant polycystic kidney disease with initiation of continuous ambulatory peritoneal dialysis until renal allograft transplantation in September 1993. In addition, she developed posttransplant diabetes mellitus and hypertension. The primary immunosuppressive treatment included cyclosporine, azathioprine, and methylprednisolone. First renal allograft biopsy was done in October 1993, demonstrating acute rejection. Initial treatment with high-dose methylprednisolone was ineffective, necessitating treatment with the monoclonal antibody muromonabCD3 before induction of remission. An uneventful course followed from 1993 to 2011. Owing to a rapid decline of kidney function in July 2011, a second renal allograft biopsy was done with pathology demonstrating chronic allograft nephropathy, acute humoral rejection, and no histologic evidence of polyomavirus nephropathy. Using Luminex technology donor specific HLA-A1 and -DQ antibodies were found. Treatment included plasmapheresis, immunoglobulin therapy, and conversion of immunosuppressive therapy to mycophenolic acid, tacrolimus, and methylprednisolone. No antibody treatment of any kind was administered. Subsequently, renal function stabilized until the end of 2012, when renal insufficiency developed and a peritoneal catheter was placed. Upon admittance in January 2013, uremic encephalopathy was suspected and dialysis was initiated. Despite declining azotemia, cerebral impairment persisted. Biochemistry demonstrated normal infectious parameters, normal immunoglobulin status, normal thyroid status, and no significant electrolyte or other metabolic derangement than uremia. Polymerase chain reaction (PCR) for BK virus and cytomegalovirus was negative. Symptoms progressed with development of focal neurologic deficits including anomia and facial nerve paralysis. Computed tomography of the brain demonstrated an uncharacteristic hypointensity in the left frontal lobe. Ensuing FLAIR and T2-weighted magnetic resonance imaging demonstrated cerebral foci of demyelination and gliosis characterized by abnormal increased signal in the left frontal lobe. A diagnosis of PML was confirmed by a clearly positive qualitative JCV DNA PCR in the cerebrospinal fluid. No brain biopsy was performed and urinary JCV PCR was negative. Treatment was initiated with discontinuation of immunosuppressive therapy. The patient was transferred to another hospital. Because of the patient’s severe renal insufficiency, no antiviral therapy was considered viable. The patient’s cerebral status deteriorated with development of progressive global aphasia, hemiparesis, partial epilepsy, and somnolence. Cerebral magnetic resonance imaging in February 2013 demonstrated unambiguous progression with extensive abnormalities in both frontal lobes and parietal lobes. Approximately 3 months after the onset of symptoms, death ensued.
DISCUSSION
The incidence and clinical significance of latent JCV remains undetermined [5]. JCV remains harbored in the kidneys after primary infection and may reactivate in circumstances of severe immune insufficiency. PML is, however, exceptional and typically related to high levels of viral DNA in the cerebrospinal fluid [3]. Occurrence of PML has previously been described in transplant recipients undergoing immunosuppressive treatment with therapies, including tacrolimus, sirolimus, azathioprine, cyclosporine, methylprednisolone, and mycophenolic acid [6e8]. In this regard, this case is the second
CARLSON AND HANSEN
example of PML after conversion of immunosuppressive treatment in a patient with a history of decades of renal graft survival [9]. It is noteworthy that the patient had not received any antibody preparations against T or B cells since 1993. However, because most patients are exposed to a plethora of immunosuppressive therapies over time, it remains unclear whether any 1 drug is primarily associated with reactivation of the JCV. Despite in vitro evidence of an effect and case reports of JCV infection response to various treatments, all controlled studies until now have failed to demonstrate any efficacy for drugs against PML [10]. Treatment options, therefore, remain limited to either simple reduction of the immunosuppressive treatment in the hope of achieving host clearance of the virus or experimental therapy with antiviral drugs without documented effect. We present a case of fatal PML in a patient with nearly 20 years of previous graft survival with a history of recent conversion of immunosuppressive therapy to mycophenolic acid and tacrolimus. Unique to the case is the occurrence of PML in a patient with severe renal insufficiency, thus limiting treatment options to discontinuation of immunosuppressive agents. Although causality remains unproven, the case underscores the possible influence of conversion of immunosuppressive treatment with reactivation of PML. In conclusion, reactivation of JCV and development of PML remains poorly understood. Seemingly, occurrence of PML is related to immunosuppressive status and possibly distinctive immunosuppressive therapy. Transplant recipients who show signs and symptoms of central nervous system infection should undergo extensive diagnosis with prompt attenuation of immunosuppressive treatment upon verification of JCV in the CSF. In our patient, PML developed 19 years after renal allograft transplantation, possibly owing to recent conversion of immunosuppressive treatment. Although diagnosis was relatively swift, the patient suffered clinical regression and ultimately death despite complete discontinuation of previous immunosuppressive treatment. REFERENCES [1] Bellizzi A, Anzivino E, Rodio DM, Palamara AT, Nencioni L, Pietropaolo V. New insights on human polyomavirus JC and pathogenesis of progressive multifocal leukoencephalopathy. Clin Dev Immunol 2013;2013:839719. [2] Neff RT, Hurst FP, Falta EM, Bohen EM, Lentine KL, Dharnidharka VR, et al. Progressive multifocal leukoencephalopathy and use of mycophenolate mofetil after kidney transplantation. Transplantation 2008;86(10):1474e8. [3] Crowder CD, Gyure KA, Drachenberg CB, Werner J, Morales RE, Hirsch HH, et al. Successful outcome of progressive multifocal leukoencephalopathy in a renal transplant patient. Am J Transplant 2005;5(5):1151e8. [4] Nath A, Tyler KL. Novel approaches and challenges to treatment of CNS viral infections. Ann Neurol 2013;74: 412e22. [5] Delbue S, Ferraresso M, Ghio L, Carloni C, Carluccio S, Belingheri M, et al. A review on JC virus infection in kidney transplant recipients. Clin Dev Immunol 2013;2013:926391.
FATAL PML 19 YEARS AFTER RENAL ALLOGRAFT TRANSPLANTATION [6] Mateen FJ, Muralidharan RN, Carone M, van de Beek D, Harrison DM, Aksamit AJ, et al. Progressive multifocal leukoencephalopathy in transplant recipients. Ann Neurol 2011;70: 305e22. [7] Weber SC, Uhlenberg B, Raile K, Querfeld U, Müller D. Polyoma virus-associated progressive multifocal leukoencephalopathy after renal transplantation: regression following withdrawal of mycophenolate mofetil. Pediatr Transplant 2011;15(2):E19e24. [8] Schmedt N, Andersohn F, Garbe E. Signals of progressive multifocal leukoencephalopathy for immunosuppressants: a
2405
disproportionality analysis of spontaneous reports within the US Adverse Event Reporting System (AERS). Pharmacoepidemiol Drug Saf 2012;21(11):1216e20. [9] Manfro RC, Vedolin L, Cantarelli M, Oppitz P, Antunes ACM, Rieder CRM. Progressive multifocal leukoencephalopathy in a kidney transplant recipient after conversion to mycophenolic acid therapy. Transpl Infect Dis 2009;11:189e90. [10] De Gascun CF, Carr MJ. Human polyomavirus reactivation: disease pathogenesis and treatment approaches. Clin Dev Immunol 2013;2013:373579.
ABSTRACT Background. Progressive multifocal leukoencephalopathy (PML) is a rare, demyelinating disease caused by viral infection of glial cells by JC polyomavirus (JCV) in immunocompromised patients. JCV is a member of the Polyomaviridae family. Infection is usually latent and reactivation only occurs in circumstances of extreme immunodeficiency. Development of fulminant PML is rare and treatment options are limited. Case Report. We have presented a case of JCV reactivation resulting in PML 19 years after renal allograft transplantation and after recent conversion of immunosuppressive treatment. One year after conversion of immunosuppressive therapy owing to biopsyproven acute humoral rejection, our patient presented with symptoms of deteriorating neurologic status. Cerebral computed tomography showed abnormal signals in the frontal lobe suspect for PML. Diagnosis was confirmed by qualitative polymerase chain reaction analysis of the cerebrospinal fluid. Owing to severe renal insufficiency, treatment options were limited to tapering of immunosuppressive treatment in hopes of achieving host clearance of the viral infection. Despite prompt termination of immunosuppressive treatment, the patient suffered rapid progressive neurologic decline and death rapidly ensued. Conclusion. Development of PML in transplant recipients remains rare. Despite advances in our understanding of JCV infection and PML, treatment options remain limited and prognosis is often poor.
P
ROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) is a rare demyelinating disorder caused by lytic infection of glial cells by JC polyomavirus (JCV) with secondary oligodendrocyte destruction. JCV is a member of the Polyomaviridae family. PML is associated with immunodeficiency and occurs in the setting of AIDS, treatment with monoclonal antibodies (natalizumab, rituximab, efalizumab, and infliximab), hematologic malignancies, and solid organ transplantation [1]. PML presents at a median of 37 months after renal transplantation [2]. PML most commonly presents with symptoms that include motor weakness (42%), speech abnormalities (40%), cognitive abnormalities (36%), headache (32%), visual field deficits (32%), ataxia (21%), aphasia (17%), cranial nerve deficits (13%), sensory deficits (9%), and seizures (rare) [3]. Treatment options are limited to discontinuation of immunosuppressive treatment and
ineffective, experimental antiviral medication [4]. Prognosis is frequently poor and PML remains a devastating and often fatal central nervous system infection. We have presented a case of delayed onset of PML 19 years after renal allograft transplantation. CASE REPORT A 60-year-old female renal allograft recipient was admitted to the hospital in January 2013 on suspicion of uremic encephalopathy. Symptoms included recent onset of latency, mild cognitive impairment, and altered diurnal rhythm. Estimated glomerular filtration rate was 8 mL/min/1.73 m2 (CKD-EPI). Her medical history *Address correspondence to Nicholas Carlson, MD, Department of Nephrology, Copenhagen University Hospital Herlev, Herlev Ringvej 75, Herlev 2730, Denmark. E-mail: nicholas. [email protected]
ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.12.072
Transplantation Proceedings, 46, 2403e2405 (2014)
2403
2404 included kidney failure in January 1993 owing to autosomaldominant polycystic kidney disease with initiation of continuous ambulatory peritoneal dialysis until renal allograft transplantation in September 1993. In addition, she developed posttransplant diabetes mellitus and hypertension. The primary immunosuppressive treatment included cyclosporine, azathioprine, and methylprednisolone. First renal allograft biopsy was done in October 1993, demonstrating acute rejection. Initial treatment with high-dose methylprednisolone was ineffective, necessitating treatment with the monoclonal antibody muromonabCD3 before induction of remission. An uneventful course followed from 1993 to 2011. Owing to a rapid decline of kidney function in July 2011, a second renal allograft biopsy was done with pathology demonstrating chronic allograft nephropathy, acute humoral rejection, and no histologic evidence of polyomavirus nephropathy. Using Luminex technology donor specific HLA-A1 and -DQ antibodies were found. Treatment included plasmapheresis, immunoglobulin therapy, and conversion of immunosuppressive therapy to mycophenolic acid, tacrolimus, and methylprednisolone. No antibody treatment of any kind was administered. Subsequently, renal function stabilized until the end of 2012, when renal insufficiency developed and a peritoneal catheter was placed. Upon admittance in January 2013, uremic encephalopathy was suspected and dialysis was initiated. Despite declining azotemia, cerebral impairment persisted. Biochemistry demonstrated normal infectious parameters, normal immunoglobulin status, normal thyroid status, and no significant electrolyte or other metabolic derangement than uremia. Polymerase chain reaction (PCR) for BK virus and cytomegalovirus was negative. Symptoms progressed with development of focal neurologic deficits including anomia and facial nerve paralysis. Computed tomography of the brain demonstrated an uncharacteristic hypointensity in the left frontal lobe. Ensuing FLAIR and T2-weighted magnetic resonance imaging demonstrated cerebral foci of demyelination and gliosis characterized by abnormal increased signal in the left frontal lobe. A diagnosis of PML was confirmed by a clearly positive qualitative JCV DNA PCR in the cerebrospinal fluid. No brain biopsy was performed and urinary JCV PCR was negative. Treatment was initiated with discontinuation of immunosuppressive therapy. The patient was transferred to another hospital. Because of the patient’s severe renal insufficiency, no antiviral therapy was considered viable. The patient’s cerebral status deteriorated with development of progressive global aphasia, hemiparesis, partial epilepsy, and somnolence. Cerebral magnetic resonance imaging in February 2013 demonstrated unambiguous progression with extensive abnormalities in both frontal lobes and parietal lobes. Approximately 3 months after the onset of symptoms, death ensued.
DISCUSSION
The incidence and clinical significance of latent JCV remains undetermined [5]. JCV remains harbored in the kidneys after primary infection and may reactivate in circumstances of severe immune insufficiency. PML is, however, exceptional and typically related to high levels of viral DNA in the cerebrospinal fluid [3]. Occurrence of PML has previously been described in transplant recipients undergoing immunosuppressive treatment with therapies, including tacrolimus, sirolimus, azathioprine, cyclosporine, methylprednisolone, and mycophenolic acid [6e8]. In this regard, this case is the second
CARLSON AND HANSEN
example of PML after conversion of immunosuppressive treatment in a patient with a history of decades of renal graft survival [9]. It is noteworthy that the patient had not received any antibody preparations against T or B cells since 1993. However, because most patients are exposed to a plethora of immunosuppressive therapies over time, it remains unclear whether any 1 drug is primarily associated with reactivation of the JCV. Despite in vitro evidence of an effect and case reports of JCV infection response to various treatments, all controlled studies until now have failed to demonstrate any efficacy for drugs against PML [10]. Treatment options, therefore, remain limited to either simple reduction of the immunosuppressive treatment in the hope of achieving host clearance of the virus or experimental therapy with antiviral drugs without documented effect. We present a case of fatal PML in a patient with nearly 20 years of previous graft survival with a history of recent conversion of immunosuppressive therapy to mycophenolic acid and tacrolimus. Unique to the case is the occurrence of PML in a patient with severe renal insufficiency, thus limiting treatment options to discontinuation of immunosuppressive agents. Although causality remains unproven, the case underscores the possible influence of conversion of immunosuppressive treatment with reactivation of PML. In conclusion, reactivation of JCV and development of PML remains poorly understood. Seemingly, occurrence of PML is related to immunosuppressive status and possibly distinctive immunosuppressive therapy. Transplant recipients who show signs and symptoms of central nervous system infection should undergo extensive diagnosis with prompt attenuation of immunosuppressive treatment upon verification of JCV in the CSF. In our patient, PML developed 19 years after renal allograft transplantation, possibly owing to recent conversion of immunosuppressive treatment. Although diagnosis was relatively swift, the patient suffered clinical regression and ultimately death despite complete discontinuation of previous immunosuppressive treatment. REFERENCES [1] Bellizzi A, Anzivino E, Rodio DM, Palamara AT, Nencioni L, Pietropaolo V. New insights on human polyomavirus JC and pathogenesis of progressive multifocal leukoencephalopathy. Clin Dev Immunol 2013;2013:839719. [2] Neff RT, Hurst FP, Falta EM, Bohen EM, Lentine KL, Dharnidharka VR, et al. Progressive multifocal leukoencephalopathy and use of mycophenolate mofetil after kidney transplantation. Transplantation 2008;86(10):1474e8. [3] Crowder CD, Gyure KA, Drachenberg CB, Werner J, Morales RE, Hirsch HH, et al. Successful outcome of progressive multifocal leukoencephalopathy in a renal transplant patient. Am J Transplant 2005;5(5):1151e8. [4] Nath A, Tyler KL. Novel approaches and challenges to treatment of CNS viral infections. Ann Neurol 2013;74: 412e22. [5] Delbue S, Ferraresso M, Ghio L, Carloni C, Carluccio S, Belingheri M, et al. A review on JC virus infection in kidney transplant recipients. Clin Dev Immunol 2013;2013:926391.
FATAL PML 19 YEARS AFTER RENAL ALLOGRAFT TRANSPLANTATION [6] Mateen FJ, Muralidharan RN, Carone M, van de Beek D, Harrison DM, Aksamit AJ, et al. Progressive multifocal leukoencephalopathy in transplant recipients. Ann Neurol 2011;70: 305e22. [7] Weber SC, Uhlenberg B, Raile K, Querfeld U, Müller D. Polyoma virus-associated progressive multifocal leukoencephalopathy after renal transplantation: regression following withdrawal of mycophenolate mofetil. Pediatr Transplant 2011;15(2):E19e24. [8] Schmedt N, Andersohn F, Garbe E. Signals of progressive multifocal leukoencephalopathy for immunosuppressants: a
2405
disproportionality analysis of spontaneous reports within the US Adverse Event Reporting System (AERS). Pharmacoepidemiol Drug Saf 2012;21(11):1216e20. [9] Manfro RC, Vedolin L, Cantarelli M, Oppitz P, Antunes ACM, Rieder CRM. Progressive multifocal leukoencephalopathy in a kidney transplant recipient after conversion to mycophenolic acid therapy. Transpl Infect Dis 2009;11:189e90. [10] De Gascun CF, Carr MJ. Human polyomavirus reactivation: disease pathogenesis and treatment approaches. Clin Dev Immunol 2013;2013:373579.
