Progressive multifocal leukoencephalopathy developed in incomplete Heerfordt syndrome,a rare manifestation of sarcoidosis,without steroid therapy responding to cidofovir

Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the central nervous system caused by the JC virus; the mortality rate is high and it is usually refractory to treatment. In non-HIV patients, PML occurs as a late consequence of hematologic malignancies or during prolonged immunosuppression for transplantation or autoimmune disease. We describe a 34-year-old PML patient with incomplete Heerfordt syndrome, a rare type of sarcoidosis, who had not received any immunosuppressants, including steroids, at the onset and who was clinically and radiologically responsive to the antiviral drug cidofovir.     

Progressive multifocal leukoencephalopathy: a review of the neuroimaging features and differential diagnosis

Progressive multifocal leukoencephalopathy (PML) is an uncommon and often fatal demyelinating disease of human central nervous system, which is caused by reactivation of the polyomavirus JC (JCV). PML generally occurs in patients with profound immunosuppression such as AIDS patients. Recently, a number of PML cases have been associated with administration of natalizumab for treatment of multiple sclerosis (MS) patients. Diagnosis and management of PML became a major concern after its occurrence in multiple sclerosis patients treated with natalizumab. Diagnosis of PML usually rests on neuroimaging in the appropriate clinical context and is further confirmed by cerebrospinal fluid polymerase chain reaction (PCR) for JCV DNA. Treatment with antiretroviral therapies in HIV-seropositive patients or discontinuing natalizumab in MS patients with PML may lead to the development of immune reconstitution inflammatory syndrome (IRIS) which presents with deterioration of the previous symptoms and may lead to death. In patients under treatment with monoclonal antibodies in routine practice, or new ones in ongoing clinical trials, differentiating PML from new MS lesions on brain MRI is critical for both the neurologists and neuroradiologists. In this review, we discuss the clinical features, neuroimaging manifestations of PML, IRIS and neuroimaging clues to differentiate new MS lesions from PML. In addition, various neuroimaging features of PML on the non-conventional MR techniques such as diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI), and MR spectroscopy (MRS) are discussed.     

Overview of the cellular immunity against JC virus in progressive multifocal leukoencephalopathy

The human polyomavirus JC (JCV) infects most healthy adults without causing any disease. In the setting of severe deficit of cell-mediated immunity, such as in acquired immunodeficiency syndrome (AIDS), malignancies or in organ transplant recipients, JCV can reactivate and cause progressive multifocal leukoencephalopathy (PML), a deadly demyelinating disease of the central nervous system. The humoral immune response, measured by the presence of virus-specific immunoglobulin G (IgG) in the blood or by intrathecal synthesis of IgG in the cerebrospinal fluid (CSF), is unable to contain the progression of PML. CD4+ T lymphocytes recognize extracellular viral proteins that have been degraded into peptides through the exogenous pathway and presented on major histocompatibility complex (MHC) class II molecules at the surface of antigen-presenting cells. Consistent with their underlying immunosuppression, the proliferative response of CD4+ T lymphocytes to mitogens or JCV antigens is reduced in PML patients. CD8+ cytotoxic T lymphocytes recognize intracellularly synthesized viral proteins that have been degraded into peptides through the endogenous pathway, and presented on MHC class I molecules at the surface of virus-infected cells. One of such JCV peptide, the VP1(p100) ILMWEAVTL, has been characterized as a cytotoxic T lymphocyte (CTL) epitope in HLA-A *0201 + PML survivors. Staining with the corresponding A *0201/JCV VP1(p100) tetrameric complex showed that VP1(p100)-stimulated peripheral blood mononuclear cells (PBMCs) of 5/7 (71%) PML survivors had JCV-specific CTL, versus none of 6 PML progressors (P = .02). This cellular immune response may therefore be crucial in the prevention of PML disease progression and the tetramer staining assay may be used as a prognostic marker in the clinical management of these patients.     

Progressive multifocal leukoencephalopathy in an HIV patient receiving successful long-term HAART

Progressive multifocal leukoencephalopathy (PML) has been traditionally associated to severe immunosuppression and described mainly in highly active antiretroviral therapy (HAART)-naïve patients with a low lymphocyte CD4+ count. In the last years, some cases of PML have been described in HIV patients with a higher CD4+ count shortly after initiation of HAART and in association with the immune reconstitution inflammatory syndrome (IRIS). We report on a rare case of PML, not IRIS associated, that occurred in a HIV-positive patient with a lymphocyte CD4+ count greater than 700/µl and with an undetectable HIV viral load resulting from a long-term HAART. We describe the pathological and the ultrastructural features of the brain lesion. This case confirms that a severe immunosuppression or an IRIS is not required for the development of PML in HIV positives. The diagnosis of PML should always be considered in patients with consistent neurological symptoms, even with a high lymphocyte CD4+ level and a full viral suppression resulting from a long-term HAART.     

Cellular and humoral immune response in progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a fatal, demyelinating disease caused by JC virus (JCV) in patients with severe immunosuppression. We studied the JCV-specific cellular and humoral immune response in 7 healthy donors (HD), 6 human immunodeficiency virus-1 (HIV-1)-infected patients without PML (HIV), 4 HIV-1-negative patients with PML (PML), and 8 HIV-1-positive patients with PML (HIV/PML). As antigens, recombinant virus-like particles of the major structural protein VP1 (VP1-VLP) of JCV, tetanus toxoid (TT), or the mitogen phytohemagglutinin (PHA) were used. Proliferation of peripheral blood mononuclear cells (PBMC) after stimulation with the VP1-VLP was significantly suppressed in PML and HIV/PML patients compared to HD. After antigen stimulation the production of interferon-gamma (IFN-gamma) was reduced in PML, in HIV/PML, and in HIV patients. The production of interleukin-10 (IL-10), however, was elevated in HIV/PML patients. Neither proliferation nor cytokine production correlated with the presence of JCV DNA in PBMC. The immunoglobulin G serum antibody titer to the VP1-VLP was slightly elevated in HIV, elevated in PML, and highly elevated in HIV/PML patients compared to HD. The development of PML appears to coincide with a general impairment of the Th1-type T-helper cell function of cell-mediated immunity.     

The spectrum of progressive multifocal leukoencephalopathy: a practical approach

John Cunningham virus (JCV) infection of the central nervous system causes progressive multifocal leukoencephalopathy (PML) in patients with systemic immunosuppression. With the increased application of modern immunotherapy and biologics in various immune‐mediated disorders, the PML risk spectrum has changed. Thus, new tools and strategies for risk assessment and stratification in drug‐associated PML such as the JCV antibody indices have been introduced. Imaging studies have highlighted atypical presentations of cerebral JCV disease such as granule cell neuronopathy. Imaging markers have been developed to differentiate PML from new multiple sclerosis lesions and to facilitate the early identification of pre‐clinical manifestations of PML and its immune reconstitution inflammatory syndrome. PML can be diagnosed either by brain biopsy or by clinical, radiographic and virological criteria. Experimental treatment options including immunization and modulation of interleukin‐mediated immune response are emerging. PML should be considered in any patient with compromised systemic or central nervous system immune surveillance presenting with progressive neurological symptoms.     

Role of immunity in the development of progressive multifocal leukoencephalopathy: a report of three patients with type B lymphoma and humoral immunodeficiency and six others with acquired immunodeficiency syndrome

INTRODUCTION: Progressive multifocal leukoencephalopathy (PML) caused by JC virus (JCV) mostly occurs in different conditions of impaired cellular immunity like acquired immunodeficiency syndrome (AIDS) and rarely when humoral immunity is involved. PML remains unusual although there is a high prevalence of JCV among the population and immunosuppression is not rare because of chemotherapies. METHODS: We present two groups of patients: first, we studied reports of three patients suffering from lymphoma type B who developed a PML, proved by cerebral biopsy. The second group included six HIV-infected patients who developed a PML. No biopsy was made but MRI and the physical examination suggested strong arguments for the diagnosis. RESULTS: In the first group, PML was furthered by humoral immunosuppression (rate of immunoglobulin G under 4 g/l). Average survival was five months. In the second group, HIV-infected patients had a survival range from 2 to 58 months after the first PML symptoms and one of them is still alive. CONCLUSION: Humoral immunosuppression in lymphoma can contribute to the development of PML. PML prognosis is often severe but prolonged survivals were described. So it is necessary to restore a sufficient immunity level. But immunity failure may be insufficient to lead to PML. In the case of lymphomas, the role of malignant lymphocytes in multiplication and mutation of JCV might be an interesting pathophysiological hypothesis.     

Progressive multifocal leukoencephalopathy

Before the AIDS epidemic, progressive multifocal leukoencephalopathy (PML) was a rare disorder occurring most often in association with leukemia and lymphoma. Current estimates indicate that PML ultimately develops in up to 5% of all patients with AIDS. This demyelinating disease results from infection with JC virus, a papova virus, that most of the world's population is exposed to prior to adulthood. Although PML commonly occurs in the setting of advanced immunosuppression, it may be observed in patients with CD4 lymphocyte counts in excess of 200 cells/mm3. Focal neurological symptoms and signs coupled with hyperintense signals abnormalities of the white matter on T2-weighted cranial magnetic resonance imaging are highly suggestive of the disease. In this setting, a positive CSF polymerase chain reaction for JCV DNA has been felt to be sufficiently diagnostic to eliminate the need for brain biopsy. Survival of AIDS-associated PML is poor with median survivals averaging just 6 months. However, as many as 10% of AIDS patients with PML will have prolonged (>12 months) survival and partial recovery. Highly active antiretroviral therapy (HAART) has been demonstrated to have a salutary effect on survival.     

Inflammatory reaction in progressive multifocal leukoencephalopathy: harmful or beneficial?

Progressive multifocal leukoencephalopathy (PML) occurs in patients with profound immunosuppression. Although lesions are usually devoid of lymphoplasmocytic infiltrates, inflammatory forms of PML have been described, in both human immunodeficiency virus (HIV)-seropositive (HIV+) and -seronegative (HIV-) patients. In addition, PML has been shown to develop in HIV+ patients shortly after introduction of highly active antiretroviral therapy (HAART), despite a recovery of the immune system. Therefore, one could postulate that PML might arise in the context of an immune reconstitution syndrome. To examine the clinical and neuroradiological characteristics of inflammatory forms of PML, the authors performed a retrospective analysis of the patients seen at their institution since 1996 as well as a review of the literature. Of 39 HIV+ and HIV- PML patients, 5 (13%) presented with an inflammatory form of this disease. Two HIV+ patients developed PML soon after the onset of HAART, concomitant to immune recovery, as demonstrated by a decrease of HIV viral load (VL) and an increase of CD4+ T-cell count. Three patients (2 HIV+ and 1 HIV-) had signs of inflammation in the central nervous system (CNS) characterized by contrast-enhancing lesions on neuroimaging studies, and/or inflammatory infiltrates on brain biopsy. The presence of JC virus-specific cytotoxic T lymphocytes was demonstrated in 4/4 patients tested and the outcome was favorable in 3 of them. In agreement with previously published case reports, the data indicate that inflammatory reactions in PML are not infrequent, and that they are generally associated with a favorable prognosis. Therefore clinicians should not disregard the diagnosis of PML in presence of contrast-enhancing brain lesions, and should use caution before treating these immunosuppressed individuals with steroids.     

Inflammatory reaction in progressive multifocal leukoencephalopathy: Harmful or beneficial?

Progressive multifocal leukoencephalopathy (PML) occurs in patients with profound immunosuppression. Although lesions are usually devoid of lymphoplasmocytic infiltrates, inflammatory forms of PML have been described, in both human immunodeficiency virus (HIV)-seropositive (HIV+) and-seronegative (HIV?) patients. In addition, PML has been shown to develop in HIV+ patients shortly after introduction of highly active antiretroviral therapy (HAART), despite a recovery of the immune system. Therefore, one could postulate that PML might arise in the context of an immune reconstitution syndrome. To examine the clinical and neuroradiological characteristics of inflammatory forms of PML, the authors performed a retrospective analysis of the patients seen at their institution since 1996 as well as a review of the literature. Of 39 HIV+ and HIV?PML patients, 5 (13%) presented with an inflammatory form of this disease. Two HIV+ patients developed PML soon after the onset of HAART, concomitant to immune recovery, as demonstrated by a decrease of HIV viral load (VL) and an increase of CD4+ T-cell count. Three patients (2 HIV+ and 1 HIV?) had signs of inflammation in the central nervous system (CNS) characterized by contrast-enhancing lesions on neuroimaging studies, and/or inflammatory infiltrates on brain biopsy. The presence of JC virus-specific cytotoxic T lymphocytes was demonstrated in 4/4 patients tested and the outcome was favorable in 3 of them. In agreement with previously published case reports, the data indicate that inflammatory reactions in PML are not infrequent, and that they are generally associated with a favorable prognosis. Therefore clinicians should not disregard the diagnosis of PML in presence of contrast-enhancing brain lesions, and should use caution before treating these immunosuppressed individuals with steroids.     

Human demyelinating disease and the polyomavirus JCV

Many human neurological diseases involve demyelination of the central and/or peripheral nervous systems. These include the hereditary leukodystrophies--which have a genetic basis; multiple sclerosis (MS)--where the underlying cause of demyelination remains unknown; and progressive multifocal leukoencephalopathy (PML)--where the etiology is well-established as being viral. The human neurotropic polyomavirus--JC virus (JCV)--is the etiologic agent of PML, a fatal demyelinating disease of the central nervous system that occurs mainly in immunosuppressed patients, especially those with HIV/AIDS. JCV belongs to the polyomavirus family of tumor viruses that are characterized by non-enveloped icosahedral capsids containing small, circular, double-stranded DNA genomes. Serological studies have shown that JCV is widespread throughout the human population, but infections are usually restricted by the immune system, particularly cell-mediated immunity, causing the virus to enter a latent phase. An important corollary of this is that situations of severe immunosuppression may permit JCV to replicate and are thus a risk factor for PML.     

Progressive multifocal leukoencephalopathy (PML) in chronic lymphatic leukemia (CLL). Review of the literature and case report

Progressive multifocal leukoencephalopathy (PML) is an infectious disease of the central nervous system caused by the JC virus. Progressive multifocal leukoencephalopathy represents a reactivation of the JC virus after long-standing immunosuppression. Also, PML plays an important role as an opportunistic infection in patients with AIDS. The average time of survival in patients with PML in combination with chronic lymphatic leukemia (CLL) (n = 17 in the literature) is 4.3 months, and therapeutic options are not established. We report the case of a patient with CLL and PML. Clinical symptoms are slight hemiparesis of the right side, mainly appearing as a disturbance of motor function. In MRI, a typical subcortical lesion was shown, and JC virus DNA was positive in the CSF by PCR. Because of first positive results in treatment of PML in patients with AIDS, therapy with cidofovir was started. After treatment for 16 months, symptoms are stable, the PML-induced lesions in MRI are in regression, and JC virus DNA is not detectable in the CSF.     

"Thinking without thinking" about natalizumab and PML

The novel multiple sclerosis (MS) therapeutic natalizumab has taken neurologists and their MS patients on a roller-coaster ride: initial encouraging efficacy data led to expedited release in the United States, followed by suspension of dosing with the unexpected occurrence of progressive multifocal leukoencephalopathy (PML) in three clinical trial participants. The drug was re-released in 2006, in a restricted distribution format. Aside from PML, natalizumab treatment was not associated with opportunistic infections, suggesting the possibility that PML in these individuals was mechanism-based, and was not a consequence of generalized immunosuppression. This commentary proposes a hypothesis to account for PML in natalizumab-treated patients.     

Natalizumab discontinuation after PML risk stratification: outcome from a shared and informed decision

Multifocal progressive leukoencephalopathy (PML) is associated with JC virus (JCV) seropositivity, past immunosuppression, and natalizumab treatment for two years or more. The aim of our study was to investigate the rate of treatment discontinuation after stratifying for the three risk factors in a group of 104 natalizumab-treated patients with relapsing-remitting multiple sclerosis. We investigated JCV serological status in our population. We then divided patients into groups according to their PML risk. Treatment indication was reassessed. Of the patients, 64 (61.5%) were JCV seropositive. Amongst seropositive patients on natalizumab for 2 years or more, 10 had received immunosuppression (group A), and 38 had not (group B). After an informed and shared decision-making process, 6/10 (60%) from group A compared with 9/38 (23.7%) from group B discontinued treatment (p=0.027). In groups A and B, discontinuation also depended upon doctors' views (p=0.019, group A; p=0.010, group B) and clinical outcomes (p=0.021, group A). No-one from low-intermediate risk groups discontinued. The decision to discontinue natalizumab treatment is complex, even when clear PML risk rates are described. Clinical outcomes and doctors' idiosyncrasies play a crucial part in patients' final choice.     

Atypical radiological presentation of progressive multifocal leukoencephalopathy following liver transplantation

Progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the brain caused by JC virus (JCV), occurs following transplantation and other conditions associated with immunosuppression. On magnetic resonance imaging (MRI), PML lesions typically appear as hyperintense signal on T2-weighted and FLAIR images located in the subcortical white matter, which are devoid of contrast enhancement or mass effect. The prognosis is poor, but unusual inflammatory forms of PML characterized by contrast enhancement have been associated with a cellular immune response against JCV and a better prognosis. The authors report an atypical presentation of PML with contrast-enhancing lesions and mass effect on the MRI in a liver transplant recipient,who had a progressive course and fatal outcome.     

Progressive multifocal leukoencephalopathy and other forms of JC virus disease

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the brain caused by the JC virus (JCV). PML usually occurs via reactivation of JCV when an immune system becomes compromised. A diagnosis of PML is normally made on the basis of distinguishing neurological features at presentation, characteristic brain MRI changes and the presence of JCV DNA in cerebrospinal fluid. PML has a 3 month mortality rate of 20-50%, so prompt intervention is essential. Currently, reconstitution of the immune system affords the best prognosis for this condition. When PML is first suspected, and where possible, immunosuppressant or immunomodulatory therapy should be suspended or reduced. If PML is associated with a protein therapy that has a long half-life the use of plasma exchange to accelerate the removal of the drug from the circulation may aid the restoration of immune system function. Rapid improvements in immune function, however, might lead to transient worsening of the disease. In this Review, we critically appraise the controversies surrounding JCV infection, and provide practical management guidelines for PML.     

ISNV Meeting Supplement

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by the neurotropic human polyomavirus JC (JCV) lytic infection of oligodendrocytes. PML was first described as a complication of lymphoproliferative disorders more than 50 years ago and emerged as a major complication of human immunodeficiency virus (HIV) infection in the 1980s. Despite the ubiquity of this virus, PML is rare and always seen in association with underlying immunosuppressive condition, such as HIV infection, autoimmune diseases, cancer, and organ transplantation. JCV remains quiescent in the kidneys, where it displays a stable archetypal non-coding control region (NCCR). Conversely, rearranged JCV NCCR, including tandem repeat patterns found in the brain of PML patients, have been associated with neurovirulence. The specific site and mechanism of JCV NCCR transformation is unknown. According to one model, during the course of immunosuppression, JCV departs from its latent state and after entering the brain, productively infects and destroys oligodendrocytes. Although the majority of PML cases occur in severely immunesuppressed individuals, PML has been increasingly diagnosed in patients treated with biological therapies such as monoclonal antibodies (mAbs) that modulate immune system functions: in fact, CD4⁺ and CD8⁺ T lymphopenia, resulting from this immunomodulatory therapy, are the primary risk factor. Furthermore, JCV reactivation in nonpermissive cells after treatment with mAbs, such as intestinal epithelial cells in Crohn’s disease patients, in association with other host tumor-inducing factors, could provide valid information on the role of JCV in several malignancies, such as colorectal cancer.     

Progressive multifocal leukoencephalopathy: Dot‐shaped inclusions and virus‐host interactions

Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease caused by reactivation of the asymptomatic persistent pathogen human polyomavirus JC (JC virus). The pathology of affected brain tissues demonstrates oligodendroglia‐like cells with viral inclusions in their enlarged nuclei, a diagnostic hallmark of this disease. Today, the pathological features of this disease are expanding, partly due to an unsteady balance between viral virulence and host immunity. Intranuclear viral inclusions were initially thought to be amphophilic materials comprising the entire enlarged nucleus, based on HE staining (full inclusions). Howevewr, recent immunohistochemical analyses detected the presence of intranuclear viral inclusions in dots (dot‐shaped inclusions). The dot‐shaped inclusions reflect clustered progeny virions at punctuated subnuclear domains called promyelocytic leukemia nuclear bodies, and are indicative of early‐stage viral infection or suppressed viral proliferation. Second, the JC virus is usually reactivated in patients with impaired immunity, and therefore the inflammatory reactions are poor. However, the causes of immunosuppression are divergent, as seen with the frequent use of immunosuppressive drugs, including natalizumab. Therefore, the degree of host immunity is variable; some patients show marked anti‐viral inflammatory reactions and a good prognosis, indicating that a strong resistance against viral infection remains. Recovery of the immune system may also induce paradoxical clinical worsening, known as immune reconstitution inflammatory syndrome, the mechanism of which has not been clarified. The virus‐host interactions have increased in complexity, and the pathology of PML is diverging. In this review, the pathology of PML will be described, with a focus on the intranuclear target of JC virus infection and host inflammatory reactions.     

Progressive multifocal leukoencephalopathy in the absence of immunosuppression

A 69-year-old woman presented with a cortical hand syndrome progressing over several weeks. MRI brain showed characteristic appearances of progressive multifocal leukoencephalopathy (PML), confirmed by detection of the JC virus in CSF, despite the absence of any evidence of immunosuppression. Treatment with mirtazapine, mefloquine and cidofovir did not affect the progression of the disease, which was fatal within 7 months of presentation. This report adds to the small case literature that suggests that PML can occur in immunocompetent people, albeit extremely rarely.     

Natalizumab and progressive multifocal leukoencephalopathy: migrating towards safe adhesion molecule therapy in multiple sclerosis

Natalizumab, a humanized monoclonal antibody against alpha4beta1 integrin, was shown in clinical trials to dramatically reduce the relapse rate, development of new magnetic resonance imaging (MRI) lesions and progression of disability in patients with relapsing multiple sclerosis. Following its expedited approval, sales of the drug were discontinued owing to the emergence of two cases of progressive multifocal leukoencephalopathy (PML), a rare but deadly viral infection of the central nervous system (CNS) associated with immunosuppression. Owing to the effect of natalizumab on central nervous system leukocyte recruitment, the emergence of PML has been attributed to diminished immunosurveillance. The lack of additional opportunistic or CNS infections among natalizumab-treated patients, however, suggests that alternate mechanisms may contribute to the infectious risk. This review examines how the inhibition of alpha4beta1-mediated adhesion might establish a unique milieu for the development of PML and how future approaches to selective adhesion molecule therapy in multiple sclerosis might avoid a similar fate.