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Progressive multifocal leukoencephalopathy from JC virus in a patient with advanced mycosis fungoides
CASE
REPORTS
Progressive multifocal leukoencephalopathy from JC virus in a patient with advanced mycosis fungoides Jin Lee, MD,a Stephen K. Richardson, MD,a Elias R. Melhem, MD,b Alain H. Rook, MD,a and Ellen J. Kim, MDa Philadelphia, Pennsylvania Progressive multifocal leukoencephalopathy is a central nervous system disease due to reactivation of the human polyoma JC virus in immunocompromised patients. Advanced mycosis fungoides patients are intrinsically immunosuppressed and susceptible to infections, but only rarely have been reported to develop progressive multifocal leukoencephalopathy. We report a case of progressive multifocal leukoencephalopathy developing in an advanced mycosis fungoides patient without prior history of immunosuppressive therapy. ( J Am Acad Dermatol 2007;57:893-5.)
P
rogressive multifocal leukoencephalopathy (PML) infection with the human polyoma JC virus (JCV) is an uncommon white matter demyelinating disease as a result of virus reactivation in immunocompromised patients. It has been reported in patients with HIV/AIDS, postchemotherapy, and, more recently, after treatment with rituximab and natalizumab. Patients with advanced mycosis fungoides (MF) and Se´zary syndrome (SS) have depressed cell-mediated immunity and are susceptible to bacterial/viral infections, yet PML has been rarely reported and only in patients treated with chemotherapy. We report a case of PML in a patient with advanced MF without prior immunosuppressive therapy. A 64-year-old Caucasian man with MF (stage IIIB) presented with increasing confusion and fatigue. He inadvertently backed his car into bushes near his house. Since then he experienced poor memory, disorientation, decreased interest in activities, poor appetite, and weight loss. He denied psychomotor retardation, suicidal ideation, hallucinations, headaches, dysarthria, dysmetria, weakness, numbness,
From the Departments of Dermatologya and Radiology,b University of Pennsylvania. Dr Lee is currently affiliated with Boston University/Tufts University Dermatology Training Program. Funding sources: None. Conflicts of interest: None declared. Reprints not available from the authors. Correspondence to: Ellen J. Kim, MD, Department of Dermatology, University of Pennsylvania Health System, 2 Maloney Bldg, 3600 Spruce St, Philadelphia, PA 19104. E-mail: Ellen.kim@ uphs.upenn.edu. Published online August 30, 2007. 0190-9622/$32.00 ª 2007 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2007.06.025
Abbreviations used: FLAIR: JCV: MF: PML: SS:
fluid-attenuated inversion recovery JC virus mycosis fungoides progressive multifocal leukoencephalopathy Se´zary syndrome
or difficulty with comprehension. He had been taking combination therapy with low-dose interferon alfa-2b, low-dose bexarotene, isotretinoin, and monthly extracorporeal photopheresis for several months prior without problems. On examination he had patches/plaques covering 50% of his body surface area and palpable axillary/inguinal lymphadenopathy. He was alert, oriented, and attentive but with depressed affect. No aphasia, apraxia, or neglect was observed. Extraocular muscles, facial symmetry, and extremity musculoskeletal strength were intact. Routine blood work revealed normal findings except for decreased hemoglobin of 8.4 g/dL (normal range 13.5-17.5 g/dL). Rapid plasma reagin and HIV test produced negative results. Se´zary count was 7% to 12% and peripheral blood flow cytometry revealed a CD4:CD8 ratio of 7.75:1, with 7% CD41 CD7e cells. The patient was initially given the diagnosis of anemia of chronic disease and received a transfusion. However, a brain magnetic resonance imaging scan revealed multiple foci of abnormal signal intensity involving the subcortical and deep white matter (Fig 1). There were foci in the subcortical white matter of the right frontal lobe, the splenium of the corpus callosum extending into right parietooccipital subcortical white matter, the right centrum 893
894 Case reports
J AM ACAD DERMATOL NOVEMBER 2007
Fig 1. Axial FLAIR (A to C) and corresponding contrast-enhanced T1-weighted (D to F) magnetic resonance images of brain demonstrate abnormal hyperintense foci on FLAIR and hypointense foci on contrast-enhanced T1-weighted in subcortical white matter of right frontal lobe (arrows in A and D), splenum of corpus callosum extending into right parieto-occipital subcortical white matter (arrows in B and E), and both middle cerebellar peduncles (arrows in C and F). Importantly, no abnormal foci demonstrated contrast enhancement or mass effect.
semiovale, the white matter lateral to the temporal horn, and both middle cerebellar peduncles, which were hypointense on the T1-weighted images, and hyperintense on fluid-attenuated inversion recovery (FLAIR) and T2-weighted images. Importantly, none of the abnormal foci demonstrated contrast enhancement or mass effect. These findings were thought to be consistent with PML, with a differential diagnosis that included toxic demyelination, toxic exposure, or an infiltrating glioma. JCV was detected on cerebrospinal fluid by polymerase chain reaction. Two weeks later, his fatigue and lethargy increased and he was admitted to the hospital after a fall. Cidofovir treatment for his PML was initiated. The patient subsequently developed chronic renal failure, Staphylococcus aureus bacteremia, hypernatremia, and worsening mental status, and died. An autopsy was not performed.
DISCUSSION PML was first described in 1958 in immunosuppressed patients as a result of hematologic malignancies, antineoplastic therapies, organ transplantation, or certain inflammatory conditions.1 PML occurs in
up to 5% of patients with HIV and AIDS and, more recently, as a rare but serious adverse event during natalizumab treatment (a monoclonal antibody to alpha4-integrin that inhibits lymphocyte/monocyte adhesion to endothelium) for multiple sclerosis and Crohn’s disease,1 and during rituximab treatment of lymphoproliferative disorders and systemic lupus.2,3 These recent observations have triggered renewed interest into the pathogenesis and treatment of PML. Primary JCV infection commonly occurs during childhood, where healthy individuals are asymptomatic and the virus becomes latent in renal cells and B lymphocytes. A total of 70% to 90% of adults have JCV antibodies. JCV can spread across the bloodbrain barrier when activated B cells transmit the reactivated virus to oligodendrocytes within the brain, resulting in plaquelike demyelinated lesions in the deep cortical layers at the gray-white junction within the white matter itself. PML can affect any part of the central nervous system white matter and, thus, present with a variety of subacute neurologic deficits including weakness, change in mental status, ataxia, visual symptoms, aphasia, seizures, or more rarely with cerebellar
J AM ACAD DERMATOL
Case reports 895
VOLUME 57, NUMBER 5
ataxia or meningitis-like symptoms. Brain magnetic resonance imaging reveals typical white matter lesions and diagnosis is confirmed by either brain biopsy or polymerase chain reaction detection of JCV DNA in the cerebrospinal fluid (sensitivity of 72%-92%, specificity of 92%-100%). JCV infection is associated with decreased cellmediated immunity. Major histocompatibility complex class I and II molecules are expressed at high levels within PML lesions, however, they are insufficient to stimulate a significant immune response. Recent studies of survivors of PML suggest that the cytolytic activity mediated by class I restricted CD81 T cells against either T antigen or the VP1 capsid protein is associated with either recovery from or lack of progression of PML. Proliferation of peripheral blood mononuclear cells from patients with PML and from patients with PML/AIDS was suppressed compared with healthy control subjects.4 Weber et al4 also showed that interferon-g production from VP1-stimulated peripheral blood mononuclear cells of patients with PML and PML/AIDS was suppressed in comparison with healthy control subjects. Thus, active JCV infection may cause a disturbance in cytokine levels, leading to a strong antibody response while dramatically reducing cellular immunity needed to kill the virus. Peripheral blood mononuclear cells from patients with PML and AIDS had increased interleukin 10 production in response to VP1 protein in comparison with control subjects, thus, further pushing the switch to production of T helper type 2 cells. Patients with advanced MF/SS are susceptible to infections such as pneumonia and bacterial sepsis, which are the leading cause of death.5 In addition, they develop a higher rate of secondary lymphomas than the general population.6 The inherent immunosuppression in MF/SS is likely a result of several factors, including depressed cell-mediated immunity from increased T helper type 2 cytokines and decreased T helper type 1 cytokines7 and impaired/ narrowed T-cell repertoire observed even in patients with early MF/SS.8 Two previous case reports of PML in MF have been published. In 1970, Caldwell and Dayan9 described a patient with MF and PML who had receive chlorambucil earlier. In 1982, Tremblay et al10 reported a patient with MF and PML who received superficial radiotherapy and cyclophosphamide. In contrast, our patient had not received any prior immunosuppressive therapy, which suggests that the intrinsic immune abnormalities in advanced MF alone made the patient susceptible. Treatment options for PML are limited.1 Decrease or cessation of all immunosuppressive agents is uniformly recommended. In HIV-/AIDS-associated
cases of PML, highly active antiretroviral therapy is the treatment of choice, although clinical worsening, usually transient, can be observed with highly active antiretroviral therapy initiation as part of an immune reconstitution inflammatory syndrome. Cytarabine and cidofovir (an antiviral effective against cytomegalovirus and in vitro against murine and simian polyomavirus) were not found effective in multicenter HIV/PML clinical trials. Other agents used without consistent success include topetecan, interferon alfa2b, and corticosteroids (for the inflammatory PML subtype). Recombinant interferon gamma has been used in the treatment of MF/SS and may be useful for PML patients given their impaired interferon-gamma production. Potential future treatments include serotonin receptor antagonists such as mirtazipine (to down-regulate 5-hydroxytryptamine-2a serotonin receptors, recently identified as a cellular receptor of JCV) and dendritic cell-based immunotherapy. For patients with advanced MF/SS and mental status or other neurologic abnormalities, in addition to evaluation for central nervous system lymphoma, infectious, metabolic, psychiatric, and drug-induced causes, PML should be considered.
REFERENCES 1. Koralnik IJ. Progressive multifocal leukoencephalopathy revisited: has the disease outgrown its name? Ann Neurol 2006;60:162-73. 2. Garcia-Suarez J, de Miguel D, Krsnik I, Banas H, Arribas I, Burgaleta C. Changes in the natural history of progressive multifocal leukoencephalopathy in HIV-negative lymphoproliferative disorders: impact of novel therapies. Am J Hematol 2005;80:271-81. 3. Freim Wahl S, Folvik M, Torp S. Progressive multiforce leukoencephalopathy in a lymphoma patient with complete remission after treatment with cytostatics and rituximab: case report and review of literature. Clin Neuropathol 2007;26:68-73. 4. Weber F, Goldmann C, Kramer M, Kaup FJ, Pickhardt M, Young P, et al. Cellular and humoral immune response in progressive multifocal leukoencephalopathy. Ann Neurol 2001;49:636-42. 5. Axelrod PI, Lorber B, Vonderheid EC. Infections complicating mycosis fungoides and Se´zary syndrome. JAMA 1992;267:1354-8. 6. Huang KP, Weinstock MA, Clarke CA, McMillan A, Hoppe RT, Kim YH. Second lymphomas and other malignant neoplasms in patients with mycosis fungoides and Se´zary syndrome: evidence from population-based and clinical cohorts. Arch Dermatol 2007;143:45-50. 7. Kim EJ, Hess S, Richardson SK, Newton S, Showe LC, Benoit BM, et al. Immunopathogenesis and therapy of cutaneous T cell lymphoma. J Clin Invest 2005;115:798-812. 8. Yawalkar N, Ferenczi K, Jones DA, Yamanaka K, Suh KY, Sadat S, et al. Profound loss of T-cell receptor repertoire complexity in cutaneous T-cell lymphoma. Blood 2003;102:4059-66. 9. Caldwell I, Dayan AD. Mycosis fungoides and progressive multifocal leukoencephalopathy. Br J Dermatol 1970;82: 176-81. 10. Tremblay GF, Anderson JM, Davidson DL. Brain biopsy in the diagnosis of cerebral mycosis fungoides. J Neurol Neurosurg Psychiatry 1982;45:175-8.
REPORTS
Progressive multifocal leukoencephalopathy from JC virus in a patient with advanced mycosis fungoides Jin Lee, MD,a Stephen K. Richardson, MD,a Elias R. Melhem, MD,b Alain H. Rook, MD,a and Ellen J. Kim, MDa Philadelphia, Pennsylvania Progressive multifocal leukoencephalopathy is a central nervous system disease due to reactivation of the human polyoma JC virus in immunocompromised patients. Advanced mycosis fungoides patients are intrinsically immunosuppressed and susceptible to infections, but only rarely have been reported to develop progressive multifocal leukoencephalopathy. We report a case of progressive multifocal leukoencephalopathy developing in an advanced mycosis fungoides patient without prior history of immunosuppressive therapy. ( J Am Acad Dermatol 2007;57:893-5.)
P
rogressive multifocal leukoencephalopathy (PML) infection with the human polyoma JC virus (JCV) is an uncommon white matter demyelinating disease as a result of virus reactivation in immunocompromised patients. It has been reported in patients with HIV/AIDS, postchemotherapy, and, more recently, after treatment with rituximab and natalizumab. Patients with advanced mycosis fungoides (MF) and Se´zary syndrome (SS) have depressed cell-mediated immunity and are susceptible to bacterial/viral infections, yet PML has been rarely reported and only in patients treated with chemotherapy. We report a case of PML in a patient with advanced MF without prior immunosuppressive therapy. A 64-year-old Caucasian man with MF (stage IIIB) presented with increasing confusion and fatigue. He inadvertently backed his car into bushes near his house. Since then he experienced poor memory, disorientation, decreased interest in activities, poor appetite, and weight loss. He denied psychomotor retardation, suicidal ideation, hallucinations, headaches, dysarthria, dysmetria, weakness, numbness,
From the Departments of Dermatologya and Radiology,b University of Pennsylvania. Dr Lee is currently affiliated with Boston University/Tufts University Dermatology Training Program. Funding sources: None. Conflicts of interest: None declared. Reprints not available from the authors. Correspondence to: Ellen J. Kim, MD, Department of Dermatology, University of Pennsylvania Health System, 2 Maloney Bldg, 3600 Spruce St, Philadelphia, PA 19104. E-mail: Ellen.kim@ uphs.upenn.edu. Published online August 30, 2007. 0190-9622/$32.00 ª 2007 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2007.06.025
Abbreviations used: FLAIR: JCV: MF: PML: SS:
fluid-attenuated inversion recovery JC virus mycosis fungoides progressive multifocal leukoencephalopathy Se´zary syndrome
or difficulty with comprehension. He had been taking combination therapy with low-dose interferon alfa-2b, low-dose bexarotene, isotretinoin, and monthly extracorporeal photopheresis for several months prior without problems. On examination he had patches/plaques covering 50% of his body surface area and palpable axillary/inguinal lymphadenopathy. He was alert, oriented, and attentive but with depressed affect. No aphasia, apraxia, or neglect was observed. Extraocular muscles, facial symmetry, and extremity musculoskeletal strength were intact. Routine blood work revealed normal findings except for decreased hemoglobin of 8.4 g/dL (normal range 13.5-17.5 g/dL). Rapid plasma reagin and HIV test produced negative results. Se´zary count was 7% to 12% and peripheral blood flow cytometry revealed a CD4:CD8 ratio of 7.75:1, with 7% CD41 CD7e cells. The patient was initially given the diagnosis of anemia of chronic disease and received a transfusion. However, a brain magnetic resonance imaging scan revealed multiple foci of abnormal signal intensity involving the subcortical and deep white matter (Fig 1). There were foci in the subcortical white matter of the right frontal lobe, the splenium of the corpus callosum extending into right parietooccipital subcortical white matter, the right centrum 893
894 Case reports
J AM ACAD DERMATOL NOVEMBER 2007
Fig 1. Axial FLAIR (A to C) and corresponding contrast-enhanced T1-weighted (D to F) magnetic resonance images of brain demonstrate abnormal hyperintense foci on FLAIR and hypointense foci on contrast-enhanced T1-weighted in subcortical white matter of right frontal lobe (arrows in A and D), splenum of corpus callosum extending into right parieto-occipital subcortical white matter (arrows in B and E), and both middle cerebellar peduncles (arrows in C and F). Importantly, no abnormal foci demonstrated contrast enhancement or mass effect.
semiovale, the white matter lateral to the temporal horn, and both middle cerebellar peduncles, which were hypointense on the T1-weighted images, and hyperintense on fluid-attenuated inversion recovery (FLAIR) and T2-weighted images. Importantly, none of the abnormal foci demonstrated contrast enhancement or mass effect. These findings were thought to be consistent with PML, with a differential diagnosis that included toxic demyelination, toxic exposure, or an infiltrating glioma. JCV was detected on cerebrospinal fluid by polymerase chain reaction. Two weeks later, his fatigue and lethargy increased and he was admitted to the hospital after a fall. Cidofovir treatment for his PML was initiated. The patient subsequently developed chronic renal failure, Staphylococcus aureus bacteremia, hypernatremia, and worsening mental status, and died. An autopsy was not performed.
DISCUSSION PML was first described in 1958 in immunosuppressed patients as a result of hematologic malignancies, antineoplastic therapies, organ transplantation, or certain inflammatory conditions.1 PML occurs in
up to 5% of patients with HIV and AIDS and, more recently, as a rare but serious adverse event during natalizumab treatment (a monoclonal antibody to alpha4-integrin that inhibits lymphocyte/monocyte adhesion to endothelium) for multiple sclerosis and Crohn’s disease,1 and during rituximab treatment of lymphoproliferative disorders and systemic lupus.2,3 These recent observations have triggered renewed interest into the pathogenesis and treatment of PML. Primary JCV infection commonly occurs during childhood, where healthy individuals are asymptomatic and the virus becomes latent in renal cells and B lymphocytes. A total of 70% to 90% of adults have JCV antibodies. JCV can spread across the bloodbrain barrier when activated B cells transmit the reactivated virus to oligodendrocytes within the brain, resulting in plaquelike demyelinated lesions in the deep cortical layers at the gray-white junction within the white matter itself. PML can affect any part of the central nervous system white matter and, thus, present with a variety of subacute neurologic deficits including weakness, change in mental status, ataxia, visual symptoms, aphasia, seizures, or more rarely with cerebellar
J AM ACAD DERMATOL
Case reports 895
VOLUME 57, NUMBER 5
ataxia or meningitis-like symptoms. Brain magnetic resonance imaging reveals typical white matter lesions and diagnosis is confirmed by either brain biopsy or polymerase chain reaction detection of JCV DNA in the cerebrospinal fluid (sensitivity of 72%-92%, specificity of 92%-100%). JCV infection is associated with decreased cellmediated immunity. Major histocompatibility complex class I and II molecules are expressed at high levels within PML lesions, however, they are insufficient to stimulate a significant immune response. Recent studies of survivors of PML suggest that the cytolytic activity mediated by class I restricted CD81 T cells against either T antigen or the VP1 capsid protein is associated with either recovery from or lack of progression of PML. Proliferation of peripheral blood mononuclear cells from patients with PML and from patients with PML/AIDS was suppressed compared with healthy control subjects.4 Weber et al4 also showed that interferon-g production from VP1-stimulated peripheral blood mononuclear cells of patients with PML and PML/AIDS was suppressed in comparison with healthy control subjects. Thus, active JCV infection may cause a disturbance in cytokine levels, leading to a strong antibody response while dramatically reducing cellular immunity needed to kill the virus. Peripheral blood mononuclear cells from patients with PML and AIDS had increased interleukin 10 production in response to VP1 protein in comparison with control subjects, thus, further pushing the switch to production of T helper type 2 cells. Patients with advanced MF/SS are susceptible to infections such as pneumonia and bacterial sepsis, which are the leading cause of death.5 In addition, they develop a higher rate of secondary lymphomas than the general population.6 The inherent immunosuppression in MF/SS is likely a result of several factors, including depressed cell-mediated immunity from increased T helper type 2 cytokines and decreased T helper type 1 cytokines7 and impaired/ narrowed T-cell repertoire observed even in patients with early MF/SS.8 Two previous case reports of PML in MF have been published. In 1970, Caldwell and Dayan9 described a patient with MF and PML who had receive chlorambucil earlier. In 1982, Tremblay et al10 reported a patient with MF and PML who received superficial radiotherapy and cyclophosphamide. In contrast, our patient had not received any prior immunosuppressive therapy, which suggests that the intrinsic immune abnormalities in advanced MF alone made the patient susceptible. Treatment options for PML are limited.1 Decrease or cessation of all immunosuppressive agents is uniformly recommended. In HIV-/AIDS-associated
cases of PML, highly active antiretroviral therapy is the treatment of choice, although clinical worsening, usually transient, can be observed with highly active antiretroviral therapy initiation as part of an immune reconstitution inflammatory syndrome. Cytarabine and cidofovir (an antiviral effective against cytomegalovirus and in vitro against murine and simian polyomavirus) were not found effective in multicenter HIV/PML clinical trials. Other agents used without consistent success include topetecan, interferon alfa2b, and corticosteroids (for the inflammatory PML subtype). Recombinant interferon gamma has been used in the treatment of MF/SS and may be useful for PML patients given their impaired interferon-gamma production. Potential future treatments include serotonin receptor antagonists such as mirtazipine (to down-regulate 5-hydroxytryptamine-2a serotonin receptors, recently identified as a cellular receptor of JCV) and dendritic cell-based immunotherapy. For patients with advanced MF/SS and mental status or other neurologic abnormalities, in addition to evaluation for central nervous system lymphoma, infectious, metabolic, psychiatric, and drug-induced causes, PML should be considered.
REFERENCES 1. Koralnik IJ. Progressive multifocal leukoencephalopathy revisited: has the disease outgrown its name? Ann Neurol 2006;60:162-73. 2. Garcia-Suarez J, de Miguel D, Krsnik I, Banas H, Arribas I, Burgaleta C. Changes in the natural history of progressive multifocal leukoencephalopathy in HIV-negative lymphoproliferative disorders: impact of novel therapies. Am J Hematol 2005;80:271-81. 3. Freim Wahl S, Folvik M, Torp S. Progressive multiforce leukoencephalopathy in a lymphoma patient with complete remission after treatment with cytostatics and rituximab: case report and review of literature. Clin Neuropathol 2007;26:68-73. 4. Weber F, Goldmann C, Kramer M, Kaup FJ, Pickhardt M, Young P, et al. Cellular and humoral immune response in progressive multifocal leukoencephalopathy. Ann Neurol 2001;49:636-42. 5. Axelrod PI, Lorber B, Vonderheid EC. Infections complicating mycosis fungoides and Se´zary syndrome. JAMA 1992;267:1354-8. 6. Huang KP, Weinstock MA, Clarke CA, McMillan A, Hoppe RT, Kim YH. Second lymphomas and other malignant neoplasms in patients with mycosis fungoides and Se´zary syndrome: evidence from population-based and clinical cohorts. Arch Dermatol 2007;143:45-50. 7. Kim EJ, Hess S, Richardson SK, Newton S, Showe LC, Benoit BM, et al. Immunopathogenesis and therapy of cutaneous T cell lymphoma. J Clin Invest 2005;115:798-812. 8. Yawalkar N, Ferenczi K, Jones DA, Yamanaka K, Suh KY, Sadat S, et al. Profound loss of T-cell receptor repertoire complexity in cutaneous T-cell lymphoma. Blood 2003;102:4059-66. 9. Caldwell I, Dayan AD. Mycosis fungoides and progressive multifocal leukoencephalopathy. Br J Dermatol 1970;82: 176-81. 10. Tremblay GF, Anderson JM, Davidson DL. Brain biopsy in the diagnosis of cerebral mycosis fungoides. J Neurol Neurosurg Psychiatry 1982;45:175-8.