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Progressive Multifocal Leukoencephalopathy: What's New?
Abstract
Progressive multifocal leukoencephalopathy (PML), a severe demyelinating disease that is caused by human JC polyomavirus, was first described as a complication of immune suppression 50 years ago and emerged as a major complication of HIV infection in the 1980s. The prognosis has remained dismal since then, with discouraging results from clinical trials of various therapeutic approaches, including immunomodulation and/or inhibition of viral replication. PML is caused by reactivation of latent JC virus, and serotonergic 5-HT(2a) receptors have been identified as being critical for viral infection of glial cells. In recent years, immunosuppressive therapeutic antibodies have been associated with an increased incidence rate of PML. Here, the authors review findings on the pathogenesis of PML and the encouraging case reports of novel treatments.
... Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system (CNS) first described in 1958. A polyomavirus was identified as the etiological agent in 1967, named in 1971 as JC Virus (JCV), after the initials of the patient where the virus was first isolated (John Cunningham) [1,2]. It occurs in immunocompromised patients, nowadays mainly in HIV infected ones. ...
... It occurs in immunocompromised patients, nowadays mainly in HIV infected ones. HIV infection accounts for 85% of all cases of PML, with a prevalence estimated of 4-5% in this population [1,3]. The probability of an HIV patient developing neurological symptoms and PML lesions is higher amongst the ones with a lower immunological status, expressed by a CD4 T cell count lower than 200/mm 3 [4,5]. ...
... Cidofovir is a deoxycytidine monophosphate analogue that inhibits viral DNA synthesis by interfering with viral DNA polymerase. There have been some positive reports concerning the use of cidofovir in HIV patients with PML in the past [1]. However, a recent paper concludes that cidofovir does not influence mortality or morbidity related to PML in HIV infected patients [17]. ...
Progressive multifocal leukoencephalopathy is an AIDS defining disease often arising in HIV patients with low CD4 T cell count, and rarely among those with more than 500 CD4 T cell/mm³. Definite diagnosis requires JC Virus (JCV) isolation in cerebrospinal fluid (CSF) or in brain tissue. JCV PCR sensitivity in highly active antiretroviral therapy (HAART) era is lower, making progressive multifocal leukoencephalopathy (PML) definite diagnosis difficult. A 48-year-old woman was diagnosed with HIV1 in 1998, never having had any AIDS-defining illness. Combined antiretroviral therapy was started in 2004. In January 2009 she presented a tandem gait and gait ataxia. Her HIV viral load was undetectable and the CD4 T cell count was of 533/mm³. Brain CT scan was normal. In the following months a bilateral cerebellar syndrome installed and brain MRI was done showing asymmetrical demyelinating lesions. Normal cerebrospinal fluid (CSF) findings other than mononuclear pleocytosis and a negative JCV PCR were documented. PML was suspected, combined antiretroviral therapy (cARV) was altered, and cidofovir and mirtazapine were prescribed, associated with physiotherapy. She was clinically stable for some months. Almost one year later her neurological state got worse, CD4 T cell count was of 478/mm³, brain lesions progressed, and finally, JCV PCR became positive (5th determination). PML definite diagnosis was made. The patient died in June 2010 due to PML progression. Sensitivity of JCV PCR in CSF lowers under HAART with high CD4 T cell count, making definite PML diagnosis difficult even when a high grade of suspicion exists, based on clinical presentation and magnetic resonance imaging (MRI) findings. Differential diagnosis of demyelinating diseases should be considered, and HIV-leukoencephalitis should be taken in consideration when HIV replication exists in the brain. PML may arise in a patient under cARV and good immunological status. Treatment should not be delayed when a probable diagnosis exists even if CD4 T cell count is above 500/mm³. Repeated lumbar puncture with JCV determinations should be done in the advent of new/worsen neurological symptoms and evidence of demyelination showed in MRI. Sensitivity of JCV PCR increases with lower CD4 T cell count.
doi:10.4021/jmc78w
... Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system (CNS) first described in 1958. A polyomavirus was identified as the etiological agent in 1967, named in 1971 as JC Virus (JCV), after the initials of the patient where the virus was first isolated (John Cunningham) [1,2]. It occurs in immunocompromised patients, nowadays mainly in HIV infected ones. ...
... It occurs in immunocompromised patients, nowadays mainly in HIV infected ones. HIV infection accounts for 85% of all cases of PML, with a prevalence estimated of 4-5% in this population [1,3]. The probability of an HIV patient developing neurological symptoms and PML lesions is higher amongst the ones with a lower immunological status, expressed by a CD4 T cell count lower than 200/mm 3 [4,5]. ...
... Cidofovir is a deoxycytidine monophosphate analogue that inhibits viral DNA synthesis by interfering with viral DNA polymerase. There have been some positive reports concerning the use of cidofovir in HIV patients with PML in the past [1]. However, a recent paper concludes that cidofovir does not influence mortality or morbidity related to PML in HIV infected patients [17]. ...
Progressive multifocal leukoencephalopathy is an AIDS defining disease often arising in HIV patients with low CD4 T cell count, and rarely among those with more than 500 CD4 T cell/mm3. Definite diagnosis requires JC Virus (JCV) isolation in cerebrospinal fluid (CSF) or in brain tissue. JCV PCR sensitivity in highly active antiretroviral therapy (HAART) era is lower, making progressive multifocal leukoencephalopathy (PML) definite diagnosis difficult. A 48-year-old woman was diagnosed with HIV1 in 1998, never having had any AIDS-defining illness. Combined antiretroviral therapy was started in 2004. In January 2009 she presented a tandem gait and gait ataxia. Her HIV viral load was undetectable and the CD4T cell count was of 533/mm3. Brain CT scan was normal. In the following months a bilateral cerebellar syndrome installed and brain MRI was done showing asymmetrical demyelinating lesions. Normal cerebrospinal fluid (CSF) findings other than mononuclear
pleocytosis and a negative JCV PCR were documented. PML was suspected, combined antiretroviral therapy (cARV) was altered, and cidofovir and mirtazapine were prescribed, associated with physiotherapy. She was clinically stable for some months. Almost one year later her neurological state got worse, CD4 T cell count was of 478/mm3, brain lesions progressed, and finally, JCV PCR became positive (5th determination). PML definite diagnosis was made. The patient died in June 2010 due to PML progression. Sensitivity of JCV PCR in CSF lowers under HAART with high CD4 T cell count, making definite PML diagnosis difficult even when a high grade of suspicion exists, based on clinical presentation and magnetic resonance imaging (MRI) findings. Differential diagnosis of demyelinating diseases should be considered, and HIV-leukoencephalitis should be taken in consideration when HIV replication exists in the brain. PML may arise in a patient under cARV and good immunological status. Treatment should not be delayed when a probable diagnosis exists even if CD4 T cell count is above 500/mm3. Repeated lumbar puncture with JCV determinations should be done in the advent of new/worsen neurological symptoms and evidence of demyelination showed in MRI. Sensitivity of JCV PCR increases with lower CD4 T cell count.
... Despite of JCV ubiquity, with a seroprevalence range from 66% to 92% in worldwide adult population, PML is rare and almost always seen in association with an underlying immunosuppressive condition, such as lymphoproliferative disorders, autoimmune diseases, cancer, and organ transplantation (Maginnis and Atwood 2009). The prognosis is still poor, with discouraging results from clinical trials of various therapeutic approaches, including immunomodulation and/or inhibition of viral replication (Focosi et al. 2010). ...
... JCV has a restricted cellular tropism, infecting oligodendrocytes, astrocytes, kidney epithelial cells, and peripheral blood cells, such as granulocytes and B lymphocytes. This tropism is, at least in part, defined by the cellular presence of both receptor components: in fact, recently Focosi and colleagues speculated that the 5-HT 2a receptor for JCV could be a N-linked glycoprotein, which would simplify the current understanding of JCV receptors (Focosi et al. 2010). ...
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.
... Despite of JCV ubiquity, with a seroprevalence range from 66% to 92% in worldwide adult population, PML is rare and almost always seen in association with an underlying immunosuppressive condition, such as lymphoproliferative disorders, autoimmune diseases, cancer, and organ transplantation (Maginnis and Atwood 2009). The prognosis is still poor, with discouraging results from clinical trials of various therapeutic approaches, including immunomodulation and/or inhibition of viral replication (Focosi et al. 2010). ...
... JCV has a restricted cellular tropism, infecting oligodendrocytes, astrocytes, kidney epithelial cells, and peripheral blood cells, such as granulocytes and B lymphocytes. This tropism is, at least in part, defined by the cellular presence of both receptor components: in fact, recently Focosi and colleagues speculated that the 5-HT 2a receptor for JCV could be a N-linked glycoprotein, which would simplify the current understanding of JCV receptors (Focosi et al. 2010). ...
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.
... PML was first described in 1958 [4] and the etiological agent, polyomavirus JC (JCV) isolated in 1971 [5]. Interest in PML remains high as shown by the publication of a number of recent reviews [1][2][3][6][7][8][9]. Even so, PML remains an incurable and often fatal disease. ...
... Even so, PML remains an incurable and often fatal disease. The directions of molecular studies of the virus may benefit from guidance from clinical observations from PML patients while the results of molecular studies may yield new insights into the life cycle of the virus, which may aid the development of novel therapeutic strategies [1,2,[6][7][8][9][10]. ...
The fatal CNS demyelinating disease, progressive multifocal leukoencephalopathy (PML), is rare and appears to occur almost always as a consequence of immune dysfunction. Thus, it is associated with HIV/AIDS and also as a side effect of certain immunomodulatory monoclonal antibody therapies. In contrast to the rarity of PML, the etiological agent of the disease, the polyomavirus JC (JCV), is widespread in populations worldwide. In the 40 years since JCV was first isolated, much has been learned about the virus and the disease from laboratory and clinical observations. However, there are many aspects of the viral life cycle and of the pathogenesis of the disease that remain unclear, and our understanding is constantly evolving. In this review, we will discuss our current understanding of the clinical features of PML and molecular characteristics of JCV and of how they relate to each other. Clinical observations can inform molecular studies of the virus, and likewise, molecular findings concerning the life cycle of the virus can guide the development of novel therapeutic strategies.
... Innate injury responses resulting from tissue preparation must be considered when Box 2 | Progressive multifocal leukoencephalopathy JC virus is a human virus that, similarly to HIV-1, thrives in non-neuronal cells in the central nervous system (CNS). It infects oligodendrocytes and astrocytes and can cause progressive multifocal leukoencephalopathy (PML) 109,114,115 . Mutations in the JC virus caspid protein have been associated with PML and may be a crucial aspect of disease development 116 . ...
... During HIV infection, enhanced blood-brain barrier breakdown and global immunosuppression may facilitate JC virus entry and replication within the CNS. Furthermore, because JC virus is cytopathic, it can cause a primary demyelinating disorder by destroying myelin-producing oligodendrocytes 115,119,120 . In general, this human virus represents an excellent example of a pathogen that is normally controlled by an intact immune system, but has the potential to cause a severe, potentially fatal neurological disorder if CNS immune surveillance is disturbed. ...
Viral infections are a major cause of human disease. Although most viruses replicate in peripheral tissues, some have developed unique strategies to move into the nervous system, where they establish acute or persistent infections. Viral infections in the central nervous system (CNS) can alter homeostasis, induce neurological dysfunction and result in serious, potentially life-threatening inflammatory diseases. This Review focuses on the strategies used by neurotropic viruses to cross the barrier systems of the CNS and on how the immune system detects and responds to viral infections in the CNS. A special emphasis is placed on immune surveillance of persistent and latent viral infections and on recent insights gained from imaging both protective and pathogenic antiviral immune responses.
... First, our experience mainly with Brazilian AIDS patients has recently demonstrated how prevalent PML could be as a neurological complication in HIV-1 seropositive patients, as PML cases are only exceeded by those of cerebral toxoplasmosis, cryptococcal meningoencephalitis, and CNS tuberculosis [12]. To date, the presentation of JCV-driven CNS manifestation is not restricted to multiple foci in the subcortical white matter [13], but also to multiple or unifocal lesions in a variety of sites, including the white matter of the cerebellar peduncles [8], the deep grey matter [14], neuronal cells in the cerebellum (granule cell neuronopathy) [3], or the cortical pyramidal neurons in the gray/white matter interface, recently termed as JCV encephalopathy [15]. These novel presentations of polyomavirus-associated diseases occur primarily in patients under HAART and highlight the relevance of performing biopsies and molecular studies to genotype and identify mutations altering the behavior and tropism of the JC virus in all HIV-1/AIDS patients with radiological observable brain lesions [13,16,17]. ...
... To date, the presentation of JCV-driven CNS manifestation is not restricted to multiple foci in the subcortical white matter [13], but also to multiple or unifocal lesions in a variety of sites, including the white matter of the cerebellar peduncles [8], the deep grey matter [14], neuronal cells in the cerebellum (granule cell neuronopathy) [3], or the cortical pyramidal neurons in the gray/white matter interface, recently termed as JCV encephalopathy [15]. These novel presentations of polyomavirus-associated diseases occur primarily in patients under HAART and highlight the relevance of performing biopsies and molecular studies to genotype and identify mutations altering the behavior and tropism of the JC virus in all HIV-1/AIDS patients with radiological observable brain lesions [13,16,17]. Noteworthy, the JCV-associated spectrum of neurological diseases currently constitutes a variety of syndromes recently classified as classic PML, inflammatory progressive multifocal leukoencephalopathy, JCV granule cell neuronopathy, and JCV meningitis [18]. ...
Human polyomavirus JC is the causative agent of a deadly form of sudden onset dementia, progressive multifocal leukocoencephalopathy (PML). PML is highly prevalent in immunodeficient populations, specially those undergoing chemotherapy, immunosuppressive treatments for autoimmune conditions, and HIV-1/AIDS patients.
In fact, before the highly active antiretroviral therapy (HAART) regimens became available, PML was a leading cause of death in HIV-1 seropositive individuals. However, patients under HAART show increased survival times with better prognoses. In this report we described the main differences between PML before and after the HAART era; highlighting the new patterns of presentation, the neurotropism of other human polyomaviruses, and the increased prevalence of immune reconstitution inflammatory syndrome (IRIS), as a complication of PML in patients under HAART. Lastly, we propose a revised classification of human poliomavirus-associated cerebral disorders that may reflect more accurately what clinicians encounter in their everyday practice.
... Progressive multifocal leuko-encephalopathy (PML) is an opportunistic infection of the central nervous system (CNS) caused by reactivation of JC polyomavirus (JCV) infection characterized by focal demyelination in the CNS. [1,2] It is almost always seen in the setting of profound immunodeficiency states, with acquired immunodeficiency syndrome (AIDS) being the most common predisposing condition responsible for approximately 80%-85% of all PML cases. [3] In the prehighly active antiretroviral therapy (HAART) era, the disease has been diagnosed in approximately 2%-5% of the human immunodeficiency virus (HIV) infected patients, as documented in data from developed countries mostly. ...
Background and objectives:
Progressive multifocal leukoencephalopathy (PML) is a viral infection affecting the central nervous system (CNS) seen mostly in advanced human immunodeficiency virus (HIV) infection. There is limited data on the epidemiology and disease course of these patients from India. This study was aimed to determine the frequency of PML in patients with HIV/acquired immunodeficiency syndrome (AIDS) and the clinical presentation and prognosis of these patients.
Materials and methods:
The study was conducted at a tertiary care HIV center in New Delhi. Data of 765 patients from our anti-retroviral therapy (ART) clinic during a span of 4 years were retrospectively analyzed and reviewed. The diagnosis was based on the clinical and radiological picture and exclusion of other differential diagnosis by cerebrospinal fluid and serological studies.
Results:
Of 765 patients with HIV/AIDS, 12 (1.56%) were diagnosed with PML on the basis of consistent clinical and radiological features after ruling out other differential diagnosis. PML was the initial presentation of HIV infection in 8 (55.5%) patients. 11 (89%) patients had CD4 count <200/μl. Insidious onset focal limb weakness (50%) and dysarthria (50%) were common symptoms. Magnetic resonance imaging of the brain revealed characteristic white matter lesions in all the patients. The estimated median survival was 40 months (95% confidence interval, 23.88-53.19 months).
Interpretation and conclusions:
Our results show that PML is associated with high morbidity despite the institution of highly active ART (HAART), but mortality has significantly declined if ART is started early. Key to good response is early diagnosis and HAART.
... Progressive multifocal leukoencephalopathy (PMLE) is a demyelinating disease of the central nervous system. A polyomavirus was identified as the etiological agent in 1967, named in 1971 as JC Virus (JCV), after the initials of the patient where the virus was first isolated (John Cunningham) [1,2]. It occurs in immunocompromised patients; nowadays mainly in HIV infected ones. ...
... PML is a demyelinating disease of the CNS characterized by extensive lesions ascribed to the infection of oligodendrocytes by the JC virus. It occurs almost exclusively in patients with immunosuppression, and its prevalence in HIV-infected individuals is around 4-5% [43,44]. A considerable amount of studies have described PML as a crucial cause of seizures in such a population, and the incidence of seizures was found to be 18% [4,12,45,46]. ...
Seizures or epilepsy is one of the common serious complications in patients with advanced human immunodeficiency virus (HIV) infection or diagnosed with immune deficiency syndrome, with higher incidence and prevalence than in the general population. Generalized seizures are the most common type in the patients. Opportunistic infections are a stereotypical predisposing factor for seizures in HIV patients, but a variety of pathogenic factors can also be found in these patients, such as metabolic perturbation and drug-drug interactions. The diagnostic criteria for seizures in these patients are the same as those in the general population. As HIV patients with seizures need to take both antivirals and antiepileptic drugs, the risk of drug-drug interactions is greatly increased, and the side effects of drugs may also become more prominent. At present, most experience in antiepileptic drug usage has come from the general population, and there is still a lack of guidance of antiepileptic drug use in special groups such as the HIV-infected people. Unlike the old-generation drugs that involve metabolisms through CYP450, the first-line antiepileptic drugs usually bypass CYP450, thus having less drug-drug interactions. In this review, we summarize the recent research progress on the above-mentioned widely discussed topics and make a prospect on future research direction.
... CMV and EBV can cause chronic encephalitis in immunosuppressed patients and EBV has also been recorded as an inducer of chronic fatigue syndrome in the Northern hemisphere [21,27]. JCV (a polyomavirus) is implicated in progressive multifocal leukoencephalopathy (PML), a fatal neurological demyelinating disease of the CNS related to the destruction of oligodendrocytes by lytic infection of myelin producing cells [22][23][24][25][26]. A capsid protein mutation of JCV is related to PML [27] and in addition, motor neuronal loss, muscle atrophy, denervation and interstitial inflammatory cells have been seen in patients with PPS [28]. ...
Background and Objective
Infectious diseases are amongst the leading causes of death in the world and central nervous system infections produced by viruses may either be fatal or generate a wide range of symptoms that affect global human health. Most antiviral plants contain active phytoconstituents such as alkaloids, flavonoids, and polyphenols, some of which play an important antiviral role. Herein, we present a background to viral central nervous system (CNS) infections, followed by a review of medicinal plants and bioactive compounds that are effective against viral pathogens in CNS infections.
Method
A comprehensive literature search was conducted on scientific databases including: PubMed, Scopus, Google Scholar and Web of Science. The relevant key words used as search terms were: “myelitis”, “encephalitis”, “meningitis”, “meningoencephalitis”, “encephalomyelitis”, “central nervous system”, “brain”, “spinal cord”, “infection”, “virus”, “medicinal plants” and “biological compounds”.
Results
The most significant viruses involved in central nervous system infections are: Herpes simplex virus (HSV), Varicella zoster virus (VZV), West Nile virus (WNV), Enterovirus 71 (EV71), Japanese encephalitis virus (JEV) and Dengue virus (DENV). The inhibitory activity of medicinal plants against CNS viruses are mostly active through prevention of viral binding to cell membranes, blocking viral genome replication, prevention of viral protein expression, scavenging reactive oxygen species (ROS) and reduction of plaque formation.
Conclusion
Due to the increased resistance of microorganisms (bacteria, viruses and parasites) to antimicrobial therapies, alternative treatments, especially using plant sources and their bioactive constituents, appear to be more fruitful.
... Furthermore, based on the finding that CD57 is expressed on regulatory CD8 + T-cells [25], we analyzed the expression of CD57 on CD8 + CD28 − T-cells in HD and observed a coexpression of CD57 on LFA-1 high T-cells (Fig. 2g). We concluded that the CD8 + CD28 − LFA-1 high and previously described [26,27] regulatory CD8 + CD57 + population are identical. For visualization, we sorted CD8 + CD28 − LFA-1 high T-cells and CD8 + CD28 − LFA-1 + T-cells by FACS and stained the sorted cells after cytospin preparation according to the Wright staining protocol (supplementary Fig. 1a). ...
Abstract
Tumor-mediated immunosuppression via regulatory T-cells is a key player among the various immune-escape mechanisms in multiple myeloma. We analyzed the generation, distribution, function and immunophenotype of CD8+CD28− regulatory T-cells in patients with multiple myeloma. Functionality of CD8+CD28− T-cells was assessed by immunological assays using ex vivo generated antigen-specific T-cells from patients with plasma cell dyscrasias and healthy donors. Detailed analysis of distribution, immunophenotype and cytotoxic potential of CD8+CD28− T-cells was performed by flow cytometry and ELISA. We found that the amount of CD8+CD28− T-cells was directly correlated with the suppression of antigen-specific T-cell responses in patients with plasma cell dyscrasia. Analyzing the CD8+CD28− T-cells in detail, increased numbers of these cells were observed in the bone marrow (i.e., tumor microenvironment) of patients with plasma cell dyscrasia. Furthermore, we identified the expression of lymphocyte function-associated antigen 1 (LFA-1) as a marker of immunosuppression and defined the CD8+CD28−CD57+LFA-1high population as the relevant immunosuppressive compartment. These regulatory T-cells act as immunosuppressors via soluble factors and incubation with IL-10 augmented their immunosuppressive capacity. The immunosuppressive regulatory network of IL-10 and the CD8+CD28−CD57+LFA-1high regulatory T-cells show unique characteristics and contribute to the tumor immune escape mechanism in patients with multiple myeloma.
... Reactivation and CNS replication occur in patients with acquired deficiencies in cell-mediated immunity, and lead to progressive demyelination and neuronal death [2]. Despite its rising incidence, attributed to the growing use of new immunomodulatory therapies developed for conditions like multiple sclerosis [3], PML prognosis has remained dismal and therapeutic approaches targeting immunomodulation and viral replication have been futile [4]. ...
Progressive multifocal leukoencephalopathy (PML) is a life-threatening opportunistic infection of immunomodulatory therapies. PML cases reported in PubMed (1995–2017) following stem-cell transplantation (HSCT) or chemoimmunotherapy (CIT) for hematologic malignancies were reviewed. We found 107 cases, 40% were HSCT recipients (32 allogeneic, 11 autologous) and 40% indolent lymphomas receiving monoclonal antibodies (mAbs). HSCT cases had longer time to PML diagnosis (10.8 vs. 4 months, p < .001), higher proportion of PML therapy response (58% vs. 25%, p = .019), lower mortality rate (56% vs. 88%, p < .001), and longer median survival (8 vs. 2 months, p < .001). Outcome differences might be caused by selection bias as HSCT patients are most likely treated aggressively; however, time-dependent immune reconstitution might also contribute to their better prognosis. Increased use of mAbs and HSCT are associated with rising PML incidence in hematological malignancies, currently constituting the second largest vulnerable population after HIV-infected patients; further research is needed for its optimal treatment.
... The rate of reactivation in KT patients of this study is 12.5%. Although in PML patients the rate is threetimes greater, the reactivation cases in the KT patients are considerable because they are at risk of developing PML [33]. Therefore, this group of patients needs more care in terms of JCV reactivation. ...
Aim: Infection of John Cunningham virus (JCV) usually occurs in early childhood and can lead to progressive multifocal leukoencephalopathy in immunosuppressed individuals. In this study, prevalence, reactivation and genotypes of JCV were evaluated. Materials & methods: Overall, 128 sex-matched individuals, including 64 patients with end-stage renal disease (ESRD) and 64 kidney transplant (KT) patients were evaluated using PCR and reverse transcriptase-PCR. Results: JCV DNA was detected in the urine samples of 17.2% of KT recipients and 1.6% of ESRD patients. Reactivation of JCV was determined in 12.5% of KT patients. All JCV-DNA-positive samples belonged to Af2 genotype (subtype b). Conclusion: Rare excretion of JCV in the ESRD urine samples can be associated with kidney function. JCV shedding and reactivation occur more frequently in the first 2 years following kidney transplantation. The genotype of Af2-b is circulating among the population of Iran.
... JCV infects the majority of the human population during childhood, and establishes a life-long latent/persistent infection in healthy individuals (Weber T., 2008;Moens et al., 2008). Between 3 to 5% of HIV-infected individuals develop PML (Focosi et Al., 2010;Zheng et al., 2009;San-Andres et al., 2003,). PML has also been diagnosed in patients with autoimmune diseases treated with immunomodulatory therapies, such as the monoclonal antibodies natalizumab and efalizumab, which bind to alpha-integrin molecules on the surface of B and T cells, respectively, and prevent their entry into the brain. ...
Progressive multifocal leukoemcephalopathy (PML) is a fatal demyelinating disease caused by the human neurotropic JC virus (JCV). JCV infects the majority of the human population during childhood and establishes a latent/persistent life-long infection. The virus reactivates under immunosuppressive conditions by unknown mechanisms, resulting in productive infection of oligodendrocytes in the central nervous system (CNS). Given the fact that the natural occurrence of PML is strongly associated with immunosuppression, the functional and molecular interaction between glial cells and neuroimmune signaling mediated by soluble immune mediators is likely to play a major role in reactivation of JCV and the progression of the lytic viral life cycle leading to the development of PML. In order to explore the effect of soluble immune mediators secreted by peripheral blood mononuclear cells (PBMCs) on JCV transcription, primary human fetal glial (PHFG) cells were treated with conditioned media from PBMCs. We observed a strong suppression of JCV early as well as late gene transcription in cells treated with conditioned media from induced PBMCs. Using a variety of virological and molecular biological approaches, we demonstrate that immune mediators secreted by PBMCs induce the expression of SRSF1, a strong inhibitor of JCV gene expression, and inhibit the replication of JCV. Our results show that downregulation of SRSF1 in glial cells overcomes the suppression of JCV gene expression and its replication mediated by soluble immune mediators. These findings suggest the presence of a novel immune signaling pathway between glial cells and PBMCs that may control JCV gene expression during the course of viral reactivation.
... Classically, JCV association with human pathology has been limited to immunosuppressed patients such as in AIDS and organ transplantation. In the immunosuppressed setting, reactivation of JCV occurs and can induce the fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML) as well as polyomavirus-associated nephropathy [7,8]. More recently, there has been mounting evidence for a potential role of JCV in human cancers in the absence of immunosuppression or PML. ...
Anal carcinoma is thought to be driven by human papillomavirus (HPV) infection through interrupting function of cell regulatory proteins such as p53 and pRb. John Cunningham virus (JCV) expresses a T-antigen that causes malignant transformation through development of aneuploidy and interaction with some of the same regulatory proteins as HPV. JCV T-antigen is present in brain, gastric, and colon malignancies, but has not been evaluated in anal cancers. The authors examined a cohort of anal cancers for JCV T-antigen and correlated this with clinicopathologic data.
Archived anal carcinomas were analyzed for JCV T-antigen expression. DNA from tumor and normal tissue was sequenced for JCV with viral copies determined by quantitative polymerase chain reaction and Southern blotting. HPV and microsatellite instability (MSI) status was correlated with JCV T-antigen expression.
Of 21 cases of anal cancer (mean age 49 years, 38% female), 12 (57%) were in human immunodeficiency virus (HIV)-positive individuals. All 21 cancers expressed JCV T-antigen, including 9 HPV-negative specimens. More JCV copies were present in cancer versus surrounding normal tissue (mean 32.54 copies/μg DNA vs 2.98 copies/μg DNA, P = .0267). There was no correlation between disease stage and viral copies, nor between viral copies and HIV-positive or -negative status (28.7 vs 36.34 copies/μg DNA, respectively, P = .7804). In subset analysis, no association was found between JCV T-antigen expression and HPV or MSI status.
Anal carcinomas uniformly express JCV T-antigen and contain more viral copies compared with surrounding normal tissue. JCV and its T-antigen oncogenic protein, presumably through interruption of cell regulatory proteins, may play a role in anal cancer pathogenesis. Cancer 2011. © 2010 American Cancer Society.
... Several supportive immunomodulatory approaches have been tested, but to date there is no convincing evidence for the efficacy of treatments with immunoglobulin, interleukin-2 (IL-2), or IL-a [159]. Therapeutic regimens aimed at inhibiting JCV replication have also been attempted, but as yet relevant evidence supporting the clinical use of drugs such as cytosine arabinoside is not available [153,160]. ...
There was a growing need for practical guidelines for the most common OIs in Germany and Austria under consideration of the local epidemiological conditions.
The German and Austrian AIDS societies developed these guidelines between March 2010 and November 2011. A structured Medline research was performed for 12 diseases, namely Immune reconstitution inflammatory syndrome, Pneumocystis jiroveci pneumonia, cerebral toxoplasmosis, cytomegalovirus manifestations, candidiasis, herpes simplex virus infections, varizella zoster virus infections, progressive multifocal leucencephalopathy, cryptosporidiosis, cryptococcosis, nontuberculosis mycobacteria infections and tuberculosis. Due to the lack of evidence by randomized controlled trials, part of the guidelines reflects expert opinions. The German version was accepted by the German and Austrian AIDS Societies and was previously published by the Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF; German Association of the Scientific Medical Societies).
The review presented here is a translation of a short version of the German-Austrian Guidelines of opportunistic infections in HIV patients. These guidelines are well-accepted in a clinical setting in both Germany and Austria. They lead to a similar treatment of a heterogeneous group of patients in these countries.
... Interferons are often associated with injection-site reactions and flu-like symptoms (Patti, 2010), with other less commonly reported events including liver dysfunction and cytopenias (Rice et al., 2001). Of greater concern with the efficacious agent natalizumab is the increasing incidence of progressive multifocal leukoencephalopathy (PML), a rare but serious infection associated with immunosuppression (Berger and Major, 1999;Focosi et al., 2010;Steinman, 2005) that has resulted in multiple fatalities in MS patients receiving this therapy (Weissert, 2011). Another example is the cytostatic agent mitoxantrone that has a cumulative dose-dependent cardiac toxicity with additional risk of leukemia, both of which limit its long-term use (Kingwell et al., 2010). ...
Multiple sclerosis (MS) is a chronic autoimmune disorder affecting the central nervous system (CNS) through demyelination and neurodegeneration. Until recently, major therapeutic treatments have relied on agents requiring injection delivery. In September 2010, fingolimod/FTY720 (Gilenya, Novartis) was approved by the FDA as the first oral treatment for relapsing forms of MS. Fingolimod is a novel compound produced by chemical modification of a fungal precursor. Its active metabolite, formed by in vivo phosphorylation, modulates sphingosine 1-phosphate (S1P) receptors that are a subset of a larger family of cell-surface, G protein-coupled receptors (GPCRs) mediating the effects of bioactive lipids known as lysophospholipids. Fingolimod's mechanism of action in MS is not completely understood; however, its relevant biology indicates a fundamentally different mechanism compared to all previously approved MS therapies, with evolving research supporting both immunological and nervous system activities. This duality may herald a paradigm shift in the treatment of MS and other neurological disorders.
... 1 It was first described as a complication of immune suppression 50 years ago and emerged as a major complication of HIV infection in the 1980s. 6 PML has recently become topical because it is a side effect of some newly developed immunomodulatory drugs for autoimmune diseases, including natalizumab for multiple sclerosis and Crohn's disease, rituximab for systemic lupus erythematosus, and efalizumab for psoriasis. 1 4 6 PML has had a dramatic effect on the use of these drugs-efalizumab was withdrawn from the market in April 2009 and natalizumab was transiently withdrawn in February 2005 after three confirmed cases of PML. 7 New neurological disorders-including granule cell neuropathy, encephalopathy, and meningitis-have also been recently attributed to JC virus, 1 and the virus has also been associated with some tumours. ...
Is highly prevalent, and can be fatal in immunocompromised people
The recent discovery of new neurological syndromes that result from neuronal infection with polyomavirus JC, also known as JC virus, and the presence of this virus in the grey matter are currently under debate.1 It has been suggested that JC virus is associated with cognitive decline, dementia, strokes, and brain tumours,2 and this hypothesis has been commented on in the BMJ .3
JC virus is a causal agent implicated in a rare but often fatal infection known as progressive multifocale leucoencephalopathy (PML).4 JC virus was first isolated in 1971 from the brain of a patient with PML; JC are the patient’s initials.5
PML is a demyelinating disease of the central nervous system that results from lytic JC virus infection of glial cells in immunosuppressed patients.1 It was first described as a complication of immune suppression 50 years ago and emerged as a major complication of HIV infection in the 1980s.6 PML has recently become topical because it is a side effect of some newly developed immunomodulatory drugs for autoimmune diseases, including natalizumab for multiple …
Hintergrund - Die Multiple Sklerose (MS) ist bis heute eine nur teilweise verstandene Autoimmunerkrankung des zentralen Nervensystems (ZNS). Das Tiermodell der experimentellen autoimmunen Enzephalomyelitis (EAE) ermöglicht die Erforschung von Teilaspekten der Pathogenese der MS und kann zur Etablierung von Therapeutika herangezogen werden. Die MP4-abhängige EAE ermöglicht als Mausmodell die gezielte Erforschung der Rolle der B-Zelle als Akteur in der Pathogenese der MS. Diese Dissertation untersuchte den Effekt des S1P1-Rezeptor-Modulators FTY720 (Fingolimod) auf die Immunantwort der autoreaktiven B-Zellen in der Peripherie sowie im ZNS. Methoden - MP4-immunisierte Mäuse erhielten 50 Tage nach dem EAE-Krankheitsbeginn oral appliziertes FTY720 über einen Zeitraum von 30 Tagen. Die Tiere wurden nach dem Auftreten der Krankheitssymptome täglich klinisch evaluiert. Die MP4-spezifische B-Zell-Immunantwort und die MP4-spezifische humorale Immunreaktion wurden mittels ELISPOT und ELISA ausgewertet. Die Verteilung der T- und B-Zell-Anteile im peripheren Blut der Mäuse sowie die Aufteilung der B-Zell-Subsets in der Milz wurden mittels Durchflusszytometrie quantifiziert. Mittels Immunhistochemie wurden die B- und T-Zell-Ansammlungen im ZNS der Mäuse hinsichtlich ihrer Entwicklung in tertiär lymphatische Organe (TLOs) untersucht. Ergebnisse - In diesem Versuchsaufbau zeigte FTY720 keine signifikante Verbesserung des klinischen Krankheitsverlaufes der Tiere. Der Anteil von T-Zellen im peripheren Blut der Mäuse war unter der Therapie mit FTY720 signifikant reduziert, während die Anzahl an B-Zellen nicht-signifikant beeinflusst wurde. Bei der Untersuchung der B-Zell-Subtypen in der Milz fiel zunächst ein erhöhter Anteil an B220+-B-Zellen auf, während die Verteilung der weiteren Subsets nicht-signifikant verändert war. Unter der Therapie mit FTY720 zeigte sich keine Reduktion bereits etablierter B-Zell-Aggregate im ZNS, allerdings ist eine inhibierte Entwicklung in TLOs zu diskutieren. Zusammenfassung - Diese Arbeit impliziert unterschiedliche Effekte von FTY720 auf die B-Zellen in einem B-Zell-abhängigen chronischen Mausmodell der MS.
Central nervous system (CNS) infections—i.e., infections involving the brain (cerebrum and cerebellum), spinal cord, optic nerves, and their covering membranes—are medical emergencies that are associated with substantial morbidity, mortality, or long-term sequelae that may have catastrophic implications for the quality of life of affected individuals. Acute CNS infections that warrant neurointensive care (ICU) admission fall broadly into three categories—meningitis, encephalitis, and abscesses—and generally result from blood-borne spread of the respective microorganisms. Other causes of CNS infections include head trauma resulting in fractures at the base of the skull or the cribriform plate that can lead to an opening between the CNS and the sinuses, mastoid, the middle ear, or the nasopharynx. Extrinsic contamination of the CNS can occur intraoperatively during neurosurgical procedures. Also, implanted medical devices or adjunct hardware (e.g., shunts, ventriculostomies, or external drainage tubes) and congenital malformations (e.g., spina bifida or sinus tracts) can become colonized and serve as sources or foci of infection. Viruses, such as rabies, herpes simplex virus, or polioviruses, can spread to the CNS via intraneural pathways resulting in encephalitis. If infection occurs at sites (e.g., middle ear or mastoid) contiguous with the CNS, infection may spread directly into the CNS causing brain abscesses; alternatively, the organism may reach the CNS indirectly via venous drainage or the sheaths of cranial and spinal nerves. Abscesses also may become localized in the subdural or epidural spaces. Meningitis results if bacteria spread directly from an abscess to the subarachnoid space. CNS abscesses may be a result of pyogenic meningitis or from septic emboli associated with endocarditis, lung abscess, or other serious purulent infections. Breaches of the blood–brain barrier (BBB) can result in CNS infections. Causes of such breaches include damage (e.g., microhemorrhage or necrosis of surrounding tissue) to the BBB; mechanical obstruction of microvessels by parasitized red blood cells, leukocytes, or platelets; overproduction of cytokines that degrade tight junction proteins; or microbe-specific interactions with the BBB that facilitate transcellular passage of the microorganism. The microorganisms that cause CNS infections include a wide range of bacteria, mycobacteria, yeasts, fungi, viruses, spirochaetes (e.g., neurosyphilis), and parasites (e.g., cerebral malaria and strongyloidiasis). The clinical picture of the various infections can be nonspecific or characterized by distinct, recognizable clinical syndromes. At some juncture, individuals with severe acute CNS infections require critical care management that warrants neuro-ICU admission. The implications for CNS infections are serious and complex and include the increased human and material resources necessary to manage very sick patients, the difficulties in triaging patients with vague or mild symptoms, and ascertaining the precise cause and degree of CNS involvement at the time of admission to the neuro-ICU. This chapter addresses a wide range of severe CNS infections that are better managed in the neuro-ICU. Topics covered include the medical epidemiology of the respective CNS infection; discussions of the relevant neuroanatomy and blood supply (essential for understanding the pathogenesis of CNS infections) and pathophysiology; symptoms and signs; diagnostic procedures, including essential neuroimaging studies; therapeutic options, including empirical therapy where indicated; and the perennial issue of the utility and effectiveness of steroid therapy for certain CNS infections. Finally, therapeutic options and alternatives are discussed, including the choices of antimicrobial agents best able to cross the BBB, supportive therapy, and prognosis.
The advent of effective immunosuppressive regimens has improved the prognosis for many patients with neoplasms and autoimmune diseases. However, the resulting extended duration of impaired B- and T-lymphocyte function predisposes these patients to viral infections whose course may be unusually virulent. This chapter discusses the presentation, differential diagnosis, clinical consequences, and therapy of common central nervous system viral infections, including human herpesviruses-6 and 7, herpes simplex virus, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus, and JC virus (JCV). Particular patient groups covered in detail include hematopoietic stem cell and solid-organ transplant recipients, patients receiving intensive chemotherapy for malignancies without transplantation, and patients with primary brain tumors, multiple sclerosis, and a diverse group of rheumatologic and autoimmune conditions for which intensive immunosuppression is a consequence of effective therapies.
PML is a demyelinating disease of the central nervous system caused by infection with JCV. Several cases of PML in bone marrow and solid organ transplant recipients have been reported in recent years. JCV has been isolated from the gastrointestinal mucosa of immunocompromised patients, but there are no published reports of PML associated with symptomatic gastrointestinal involvement in kidney transplant recipients. We report a case of a nine-yr-old girl with a kidney transplant who developed a severe gastrointestinal illness causing pseudo-obstruction in association with PML. JCV was suspected as the causative agent in this patient by the detection of high JCV titer through PCR analysis of the cerebrospinal fluid and blood and positive staining for simian virus 40 in the colon. JCV intestinal infection should be considered in kidney transplant recipients presenting with intestinal pseudo-obstruction.
DNA viruses with potential to cause complications after lung transplantation include the human Herpesviridae family consisting of cytomegalovirus (CMV), herpes simplex virus 1 and 2 (HSV-1, -2), varicella-zoster virus (VZV), human herpesvirus 6, 7, and 8 (HHV-6, -7, -8), and Epstein-Barr virus (EBV); the Polyomaviridae family consisting of BK virus and JC virus; and the Adenoviridae family consisting of more than 50 adenovirus subtypes. This is a diverse group of viruses with equally diverse immediate and long-term impacts on allograft function and clinical outcomes following lung transplantation. This article discusses the individual pathogens, their epidemiology and clinical manifestations, as well as treatment and preventive strategies in this era of antiviral treatment regimens.
This article provides a practical clinical approach to potential CNS infections in patients with cancer, discusses problematic presentations of posterior reversible encephalopathy syndrome and immune reconstitution inflammatory syndrome, and includes specific testing and treatment recommendations for bacterial meningitis, invasive fungal infections, and opportunistic viral infections.
The major deficits predisposing patients with cancer to CNS infection are neutropenia, barrier disruption, B-lymphocyte or immunoglobulin deficiency, and impaired T lymphocyte-mediated immunity. Evolving patterns of drug resistance and prophylactic antimicrobial regimens have altered the timing and range of organisms causing infections. Increasingly intensive immunosuppression has made new groups of patients vulnerable to infections such as progressive multifocal leukoencephalopathy. New MRI sequences offer the potential to diagnose such infections earlier, at a stage when they are more treatable.
Despite improved prophylactic and therapeutic antibiotic regimens, CNS infections remain an important source of morbidity and mortality among several cancer patient groups, particularly those patients undergoing craniotomy and those with hematologic malignancies receiving either hematopoietic cell transplantation or other intensive chemotherapy regimens.
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by the JC virus (JCV), a human papovavirus. PML is a relatively rare disease seen predominantly in immunocompromised individuals and is a frequent complication observed in AIDS patients. The significantly higher incidence of PML in AIDS patients than in other immunosuppressive disorders has suggested that the presence of human immunodeficiency virus type 1 (HIV-1) in the brain may directly or indirectly contribute to the pathogenesis of this disease. In the present study we have examined the expression of the JCV genome in both glial and non-glial cells in the presence of HIV-1 regulatory proteins. We find that the HIV-1 encoded trans-regulatory protein tat increases the basal activity of the JCV late promoter, JCV_L, in glial cells. In a reciprocal experiment, the JCV early protein, the large tumor antigen, stimulates expression from JCV_L and HIV-1 long terminal repeat promoter in both glial and non-glial cells. This trans-activation occurs at the level of RNA synthesis, as measured by the rate of transcription, stability of the message, and translation. We conclude that the presence of the HIV-1-encoded tat protein may positively affect the JCV lytic cycle in glial cells by stimulating JCV gene expression. Our results suggest a mechanism for the relatively high incidence of PML in AIDS patients than in other immunosuppressive disorders. Furthermore, our findings indicate that the HIV-1 regulatory protein tat may stimulate other viral and perhaps cellular promoters, in addition to its own.
The human JC polyomavirus (JCV) is the etiologic agent of the fatal central nervous system (CNS) demyelinating disease progressive multifocal leukoencephalopathy (PML). PML typically occurs in immunosuppressed patients and is the direct result of JCV infection of oligodendrocytes. The initial event in infection of cells by JCV is attachment of the virus to receptors present on the surface of a susceptible cell. Our laboratory has been studying this critical event in the life cycle of JCV, and we have found that JCV binds to a limited number of cell surface receptors on human glial cells that are not shared by the related polyomavirus simian virus 40 (C. K. Liu, A. P. Hope, and W. J. Atwood, J. Neurovirol. 4:49-58, 1998). To further characterize specific JCV receptors on human glial cells, we tested specific neuraminidases, proteases, and phospholipases for the ability to inhibit JCV binding to and infection of glial cells. Several of the enzymes tested were capable of inhibiting virus binding to cells, but only neuraminidase was capable of inhibiting infection. The ability of neuraminidase to inhibit infection correlated with its ability to remove both α(2-3)- and α(2-6)- linked sialic acids from glial cells. A recombinant neuraminidase that specifically removes the α(2-3) linkage of sialic acid had no effect on virus binding or infection. A competition assay between virus and sialic acid-specific lectins that recognize either the α(2-3) or the α(2-6) linkage revealed that JCV preferentially interacts with α(2.6)-linked sialic acids on glial cells. Treatment of glial cells with tunicamycin, but not with benzyl N-acetyl-α-D-galactosaminide, inhibited infection by JCV, indicating that the sialylated JCV receptor is an N-linked glycoprotein. As sialic acid containing glycoproteins play a fundamental role in mediating many virus- cell and cell-cell recognition processes, it will be of interest to determine what role these receptors play in the pathogenesis of PML.
We describe progressive multifocal leukoencephalopathy (PML) caused by infection with human polyomavirus JC virus in a patient with multiple sclerosis who was treated with natalizumab. The first PML symptoms appeared after 14 monthly infusions of the drug. Magnetic resonance imaging (MRI) showed a presumed multiple sclerosis lesion, and JC virus DNA was not detected on polymerase-chain-reaction (PCR) assay of cerebrospinal fluid. The patient's symptoms worsened, and the diagnosis of PML was established with a more sensitive quantitative PCR assay after 16 infusions of natalizumab. Plasma exchange was used to accelerate clearance of natalizumab. Approximately 3 weeks after plasma exchange, an immune-reconstitution inflammatory syndrome appeared. JC virus DNA was no longer detectable on quantitative PCR assay, and the patient's symptoms improved.
We describe the clinical and therapeutic course of a 52-year-old patient with multiple sclerosis in whom progressive multifocal leukoencephalopathy (PML) developed after 12 months of therapy with natalizumab. The patient was hospitalized 2 months after the onset of neurologic and psychiatric symptoms and was treated with plasma exchange and immunoadsorption to eliminate natalizumab. After a brief improvement, he became critically ill with an apparent episode of immune reconstitution inflammatory syndrome. Steroid-pulse therapy led to stabilization of the patient's condition and clinically significant recovery. This case illustrates that prompt diagnosis and treatment may improve the outcome in patients with severe PML associated with natalizumab therapy.
Good's syndrome (GS) is an immunodeficiency characterized by thymoma, hypogammaglobulinemia, and impaired T-cell function. The clinical manifestations of GS include recurrent or chronic infections from common or opportunistic pathogens. Encephalitis is a rare event, with only anecdotal reports of cytomegalovirus infection. Herein we report the case of a 79-year-old woman with GS who developed subacute motor deficits and cognitive changes. Magnetic resonance imaging (MRI) of the brain disclosed white- and gray-matter lesions, mostly in the right frontal and parietal areas. Polyoma virus JC, the agent of progressive multifocal encephalopathy (PML), was identified in cerebrospinal fluid samples and brain biopsy specimens. After diagnosis, the disease had a rapid fatal course. The present case represents the first reported association between GS and PML.
Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection of the central nervous system caused by the JC (John Cunningham) virus.1 This virus is common and is generally innocuous in an immunocompetent host. However, in individuals with innate, acquired, or iatrogenic immunodeficiency, the JC virus can become active and infect oligodendrocytes, leading to their lysis. Oligodendrocyte lysis leads to central nervous system demyelination, which may then result in focal neurologic deficits including hemiparesis, visual field deficits, and cognitive impairment. Progressive multifocal leukoencephalopathy is usually irreversible and fatal.
To report the clinical and radiologic features in a patient with myelofibrosis who developed atypical progressive multifocal leukoencephalopathy.
Case report.
Tertiary referral center. Patient A 72-year-old man with myelofibrosis and mild leukopenia experienced progressive limb weakness and dysarthria.
Imaging revealed almost complete sparing of the white matter with isolated involvement of the brainstem and deep gray matter. Postmortem examination led to definitive diagnosis of progressive multifocal leukoencephalopathy and demonstrated an unusual miliary pattern of disease rather than the typical confluent involvement. Genetic analysis revealed a mutation in the transcription control region of the JC polyomavirus, prompting speculation about the pathogenesis of progressive multifocal leukoencephalopathy.
Leukopenia may render patients effectively immunosuppressed. The differential diagnosis should include progressive multifocal leukoencephalopathy even in patients with atypical clinical and radiologic features.
The replication of BK virus (BKV) and JC virus (JCV) is linked to polyomavirus-associated nephropathy, hemorrhagic cystitis, and multifocal leukoencephalopathy in immunodeficient patients, but the behavior of these viruses in immunocompetent individuals has hardly been characterized.
We used EIA to study samples obtained from 400 healthy blood donors aged 20-59 years for BKV- and JCV-specific antibodies against virus-like particles. We also studied BKV and JCV loads in plasma and urine among these individuals by use of real-time polymerase chain reaction.
IgG seroprevalence was 82% (328 of 400 donors) for BKV and 58% (231 of400) for JCV. As age increased (age groups were divided by decade), the seroprevalence of BKV decreased from 87% (87 of 100) in the youngest group (aged 20-29 years) to 71% (71 of 100) in the oldest group (aged 50-59 years) (P = .006), whereas the seroprevalence of JCV increased from 50% (50 of 100) in the youngest group to 68% (68 of 100) in the oldest group (P = .06). Asymptomatic urinary shedding of BKV and JCV was observed in 28 (7%) and 75 (19%) of 400 subjects, respectively, with median viral loads of 3.51 and 4.64 log copies/mL, respectively (P < .001). Unlike urinary BKV loads, urinary JCV loads were positively correlated with IgG levels. The shedding of JCV was more commonly observed among individuals who were seropositive only for JCV, compared with individuals who were seropositive for both BKV and JCV, suggesting limited cross-protection from BKV immunity. Noncoding control regions were of archetype architecture in all cases, except for 1 rearranged JCV variant. Neither BKV nor JCV DNA was detected in plasma.
Our study provides important data about polyomavirus infection and replication in healthy, immunocompetent individuals. These data indicate significant differences between BKV and JCV with respect to virus-host interaction and epidemiology.
We describe the clinical course of an HIV-infected patient with progressive multifocal leukoencephalopathy who took mirtazapine for his depression. After six months of therapy the clinical symptoms had not worsened and the neuroradiological image of the brain was unchanged. Further studies are necessary to determine the effect of serotonin receptor antagonist in treating PML associated to HIV.
We investigated the incidence and outcome of progressive multifocal leukoencephalopathy (PML) in human immunodeficiency virus (HIV)-infected individuals before and after the introduction of combination antiretroviral therapy (cART) in 1996.
From 1988 through 2007, 226 cases of PML were reported to the Swiss HIV Cohort Study. By chart review, we confirmed 186 cases and recorded all-cause and PML-attributable mortality. For the survival analysis, 25 patients with postmortem diagnosis and 2 without CD4+ T cell counts were excluded, leaving a total of 159 patients (89 before 1996 and 70 during 1996-2007).
The incidence rate of PML decreased from 0.24 cases per 100 patient-years (PY; 95% confidence interval [CI], 0.20-0.29 cases per 100 PY) before 1996 to 0.06 cases per 100 PY (95% CI, 0.04-0.10 cases per 100 PY) from 1996 onward. Patients who received a diagnosis before 1996 had a higher frequency of prior acquired immunodeficiency syndrome-defining conditions (P = .007) but similar CD4+ T cell counts (60 vs. 71 cells/microL; P = .25), compared with patients who received a diagnosis during 1996 or thereafter. The median time to PML-attributable death was 71 days (interquartile range, 44-140 days), compared with 90 days (interquartile range, 54-313 days) for all-cause mortality. The PML-attributable 1-year mortality rate decreased from 82.3 cases per 100 PY (95% CI, 58.8-115.1 cases per 100 PY) during the pre-cART era to 37.6 cases per 100 PY (95% CI, 23.4.-60.5 cases per 100 PY) during the cART era. In multivariate models, cART was the only factor associated with lower PML-attributable mortality (hazard ratio, 0.18; 95% CI, 0.07-0.50; P < .001), whereas all-cause mortality was associated with baseline CD4+ T cell count (hazard ratio per increase of 100 cells/microL, 0.52; 95% CI, 0.32-0.85; P = .010) and cART use (hazard ratio, 0.37; 95% CI, 0.19-0.75; P = .006).
cART reduced the incidence and PML-attributable 1-year mortality, regardless of baseline CD4+ T cell count, whereas overall mortality was dependent on cART use and baseline CD4+ T cell count.
John Cunningham virus (JCV) constitutes a family of polyoma viruses, which plays important roles in the progressive multifocal leukoencephalopathy (PML) and tumorigenesis. However, no bibliometric investigation has been reported to guide the researchers and potential readers.
Papers were collected from database Sci-expanded and Pubmed until May 22, 2008. The highly-productive authors, institutes and countries, highly-cited authors and journals were ranked. The highly-cited articles were subjected to co-citation and chronological analysis with highly-frequent MeSH words for co-occurrence analysis.
Until now, 1785 articles about JCV were indexed in Sci-expanded and 1506 in Pubmed. The main document type was original article. USA, Japan and Italy were the largest three producers about JCV. Temple University published 128 papers and ranked the top, followed by University of Tokyo. Khalili K and Yogo Y became the core authors due to more than 20 documents produced. Journal of Neurovirology published more than 15 papers and ranked the top. Padgett BL and Berger JR were the first two highly-cited authors. Journal of Virology and Journal of Neurovirology respectively ranked to the first two highly-cited journals. These top highly-cited articles were divided into 5 aspects: (1) The correlation between JC virus and tumors; (2) Causal correlation of JCV with PML; (3) Polyoma virus infection and its related diseases in renal-allograft recipients; (4) Detection of JCV antibody, oncogene and its encoding protein; (5) Genetics and molecular biology of JCV. The MeSH/subheadings were classified into five groups: (1) JCV and virus infectious diseases; (2) JCV pathogenicity and pathological appearance of PML; (3) JCV isolation and detection; (4) Immunology of JCV and PML; (5) JCV genetics and tumors.
JCV investigation mainly focused on its isolation and detection, as well as its correlation with PML and tumors. Establishment of transgenic animal model using JCV T antigen would be a hopeful and useful project in the further study.
Progressive multifocal leukoencephalopathy (PML) is a rare but frequently fatal disease caused by the uncontrolled replication of JC virus (JCV), a polyomavirus, in the brains of some immunocompromised individuals. Currently, no effective antiviral treatment for this disease has been identified. As a first step in the identification of such therapy, we screened the Spectrum collection of 2,000 approved drugs and biologically active molecules for their anti-JCV activities in an in vitro infection assay. We identified a number of different drugs and compounds that had significant anti-JCV activities at micromolar concentrations and lacked cellular toxicity. Of the compounds with anti-JCV activities, only mefloquine, an antimalarial agent, has been reported to show sufficiently high penetration into the central nervous system such that it would be predicted to achieve efficacious concentrations in the brain. Additional in vitro experiments demonstrated that mefloquine inhibits the viral infection rates of three different JCV isolates, JCV(Mad1), JCV(Mad4), and JCV(M1/SVEDelta), and does so in three different cell types, transformed human glial (SVG-A) cells, primary human fetal glial cells, and primary human astrocytes. Using quantitative PCR to quantify the number of viral copies in cultured cells, we have also shown that mefloquine inhibits viral DNA replication. Finally, we demonstrated that mefloquine does not block viral cell entry; rather, it inhibits viral replication in cells after viral entry. Although no suitable animal model of PML or JCV infection is available for the testing of mefloquine in vivo, our in vitro results, combined with biodistribution data published in the literature, suggest that mefloquine could be an effective therapy for PML.
Accelerating the clearance of therapeutic monoclonal antibodies (mAbs) from the body may be useful to address uncommon but serious complications from treatment, such as progressive multifocal leukoencephalopathy (PML). Treatment of PML requires immune reconstitution. Plasma exchange (PLEX) may accelerate mAb clearance, restoring the function of inhibited proteins and increasing the number or function of leukocytes entering the CNS. We evaluated the efficacy of PLEX in accelerating natalizumab (a therapy for multiple sclerosis [MS] and Crohn disease) clearance and alpha4-integrin desaturation. Restoration of leukocyte transmigratory capacity was evaluated using an in vitro blood-brain barrier (ivBBB).
Twelve patients with MS receiving natalizumab underwent three 1.5-volume PLEX sessions over 5 or 8 days. Natalizumab concentrations and alpha4-integrin saturation were assessed daily throughout PLEX and three times over the subsequent 2 weeks, comparing results with the same patients the previous month. Peripheral blood mononuclear cell (PBMC) migration (induced by the chemokine CCL2) across an ivBBB was assessed in a subset of six patients with and without PLEX.
Serum natalizumab concentrations were reduced by a mean of 92% from baseline to 1 week after three PLEX sessions (p < 0.001). Although average alpha4-integrin saturation was not reduced after PLEX, it was reduced to less than 50% when natalizumab concentrations were below 1 mug/mL. PBMC transmigratory capacity increased 2.2-fold after PLEX (p < 0.006).
Plasma exchange (PLEX) accelerated clearance of natalizumab, and at natalizumab concentrations below 1 mug/mL, desaturation of alpha4-integrin was observed. Also, CCL2-induced leukocyte transmigration across an in vitro blood-brain barrier was increased after PLEX. Therefore, PLEX may be effective in restoring immune effector function in natalizumab-treated patients.
The complete DNA sequence of the human JC virus, which was found to consist of 5,130 nucleotide pairs, is presented. The amino acid sequence of six proteins could be deduced: the early, nonstructural proteins, large T and small t antigens; the late capsid proteins, VP1, VP2, and VP3; and the agnogene product encoded within the late leader sequence, called the agnoprotein in simian virus 40. The extent of homology between JC virus DNA and the genomes of simian virus 40 (69%) and BK virus (75%) confirmed the close evolutionary relationship of these three polyomaviruses. The sequences showing the greatest divergence in these viral DNAs occurred within the tandem repeats located to the late side of the replication origins.
INTRODUCTION: In their seminal report in 1958, Astrom, Mancall, and Richardson described a progressive neurological syndrome with characteristic neuropathological findings of demyelination, giant astrocytes, and oligodendrocytes with abnormal nuclei. They named the disorder progressive multifocal leukoencephalopathy (PML). The viral etiology of this neurological disease was not determined until later. PML remained a vanishingly rare disorder seen almost exclusively in individuals with underlying immunosuppressive disorders until the advent of the acquired immunodeficiency syndrome (AIDS) pandemic. In developed countries, PML occurs in approximately 1 in 20 of all human immunodeficiency virus (HIV)-infected persons and AIDS is now the predisposing disorder for 90% of all PML cases. More recently, monoclonal antibodies that result in a highly specific alteration of immune function, such as natalizumab, an α-4 integrin inhibitor, and rituximab, a chimeric monoclonal antibody directed against CD20 receptors on B cells, and whose therapeutic applications have become increasingly prevalent, have been associated with PML. JC VIRUS AND THE PATHOGENESIS OF PML. In 1965, Zu Rhein and Chou identified viral particles in glial nuclei resembling papovavirus. Subsequently, Padgett isolated polyoma virus from PML brain in glial cell cultures. This virus proved to be a double-stranded DNA virus of icosahedral symmetry. It has a simple DNA genome of 5.1 kilobases in a double-stranded, supercoiled form, encapsidated in an icosahedral protein structure measuring 40 nm in diameter. JC virus (JCV) DNA encodes for three capsid (VP1, VP2, and VP3) proteins and three regulatory proteins (agnoprotein, t, and T).
Goldberg et al[1][1] recently reported a few unusual viral infections after high-dose chemotherapy with autologous blood stem cell rescue associated to peritransplantation rituximab. In their paper, the authors describe 4 cases of either JC papovavirus or cytomegaloviral (CMV) infections after
Cytarabine (cytosine arabinoside) was utilized in the treatment of a patient with chronic lymphocytic leukemia who developed symptomatic progressive multifocal leukoencephalopathy (PML) after a 12-year course of lymphoproliferative illness. An immediate and impressive degree of neurologic improvement occurred with the institution of antiviral chemotherapy, but clinical benefit was not sustained and the patient died of his neurologic disorder. On gross examination at postmortem, necrotic changes in the demyelinated areas of the brain were seen. Light and electron microscopic studies showed changes characteristic of PML and virus-like particles abundant in glial cells. Cytarabine may have some influence on the course of the illness, but the quality of therapeutic effect needs further investigation.
(JAMA 229:1313-1316, 1974)
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.
The effectiveness of nucleoside analogs in blocking viral multiplication was evaluated using an immortalized human neuroglial cell line capable of sustaining a persistent JCV infection, SVG-JC. Results from in situ DNA hybridization and hemagglutination assays performed on drug treated cultures were used as a measure of viral DNA replication and multiplication, respectively. Of the three drugs tested, Ara-C (cytosine arabinoside), AZT (3'-azido-3'-deoxythymidine), and cidofovir (S)-1-[3-hydroxy-2-(phosphonylmethoxypropyl] cytosine), only Ara-C showed a significant effect in decreasing active JCV replication and multiplication. In vitro data, using different cell types and virus strains have shown that specific drugs can indeed modulate viral infection. However, such modulation has not previously been demonstrated in those cells of the CNS which are specifically targeted by JCV. The SVG-JC cells represent a unique system with which further studies can be conducted on the effects of drugs on brain derived cells that are susceptible to viral infection.
We thank Vuaillat et al for reading our paper[1][1] carefully with great interest.
Within this short correspondence we hope to elucidate the questions raised:
1. All 5 untreated patients met both the McDonald and the Barkhoff criteria and were diagnosed between 2002 and 2006 with the relapsing-
The progressive multifocal leukoencephalopathy (PML), a complication of the acquired immunodeficiency syndrome (AIDS) in 4%–5% of all cases, is an encephalitis caused by the JC papovavirus. The prognosis is very poor with a mean survival time after diagnosis of 3 to 6 months. No effective therapy is known to date. Therapeutic trials in small groups of patients with a-interferon, didanosine, and arabinoside were of minor success. A controlled study with cytarabine did not show any efficacy. Single case reports on a therapy with cidofovir (Vistide®), an approved nucleotide-analogone in the therapy of cytomegalovirus-retinitis in AIDS-patients without renal dysfunction, showed positive results. We describe 2 more cases of a therapy of cidofovir in AIDS-associated PML. Out of 22 cases described in the literature, including these 2 cases, with a therapy of cidofovir in AIDS-associated PML, 16 patients improved under therapy, 2 remained stable, and only 4 patients still worsened fulminantly. These results indicate an additive antiviral effect of cidofovir against JC-virus. This may be used in the therapy of PML in AIDS-patients because no alternative antiviral therapy of PML is available at present. The efficacy of cidofovir for the therapy of PML is suggested by case reports. The exact mechanisms leading to an improvement under a therapy with cidofovir in the 16 cases described so far should be evaluated in a randomised, controlled study with an adequate size of cohorts.
The human polyomavirus JC (JCV) is a small DNA tumor virus and the etiologic agent of the progressive multifocal leukoencephalopathy. In progressive multifocal leukoencephalopathy, active JCV replication causes the lytic destruction of oligodendrocytes. The normal immune system prevents JCV replication and suppresses the virus into a state of latency so that expression of viral proteins cannot be detected. In a cellular context that is nonpermissive for viral replication, JCV can affect oncogenic transformation. For example, JCV is highly tumorigenic when inoculated into experimental animals, including rodents and monkeys. In these animal tumors, there is expression of early T-antigen but not of late capsid proteins, nor is there viral replication. Moreover, mice transgenic for JCV T-antigen alone develop tumors of neural tube origin. Detection of JCV genomic sequences and expression of viral T-antigen and agnoprotein suggest a possible association of this virus with a variety of human brain and non-CNS tumors. Here, we discuss the mechanisms involved in JCV oncogenesis, briefly review studies that do and do not support a causative role for this virus in human CNS tumors, and identify key issues for future research.
Although human polyomavirus JC (JCV) is known to cause progressive multifocal leukoencephalopathy (PML) in immunocompromised individuals, the mechanism by which JCV crosses the blood-brain barrier (BBB) remains unclear. To test our hypothesis that cell-free JCV gains entry into the brain by infecting endothelial cells, we inoculated human brain microvascular endothelial (HBMVE) cells with 50 HAU (1.33+/-0.27 x 10(7) genome copies) of JCV(Mad1) and analyzed the expression of early and late viral genes and proteins by immunocytochemistry, quantitative real-time PCR (qPCR), quantitative real-time reverse transcriptase PCR (qRT-PCR) and immunoprecipitation followed by Western blotting. JCV infected and replicated efficiently in HBMVE cells and produced infectious virions several hundred fold higher than the infecting inoculum. HBMVE cells in vitro did not express serotonin receptor 2A (5HT(2A)R), and 5HT(2A)R blockers did not prevent JCV infection of HBMVE cells. Collectively, our data indicate that the productive in vitro infection of HBMVE cells by JCV is independent of 5HT(2A)R.
Progressive multifocal leukoencephalopathy (PML) is a rare brain disease caused by reactivation of the JC virus. Herein, a case of PML in association with rituximab treatment in a patient with chronic rheumatoid arthritis (RA) and Sjögren's syndrome is described. The patient received 4 courses of rituximab (2 1,000-mg infusions administered 2 weeks apart) over a period of approximately 40 months, during a phase III trial and safety extension study. PML was diagnosed approximately 18 months after the last rituximab course, and the patient died 1 month later. Determination of the cause of PML was confounded by the fact that the patient had developed oropharyngeal cancer, which was treated with chemoradiotherapy, 9 months prior to the development of PML. Although there was no direct evidence that linked rituximab to the development of PML, this case highlights the need to consider a diagnosis of PML in patients with RA who have been treated with rituximab and who subsequently develop new neurologic symptoms.
Progressive multifocal leukoencephalopathy (PML) occurs in a fraction of patients with multiple sclerosis who were treated with natalizumab. Most adults who are infected with the JC virus, the etiologic agent in PML, do not have symptoms. We sought to determine whether exposure to natalizumab causes subclinical reactivation and neurotropic transformation of JC virus.
We followed 19 consecutive patients with multiple sclerosis who were treated with natalizumab over an 18-month period, performing quantitative polymerase-chain-reaction assays in blood and urine for JC virus reactivation; BK virus, a JC virus-related polyomavirus, was used as a control. We determined JC virus-specific T-cell responses by means of an enzyme-linked immunospot assay and antibody responses by means of an enzyme-linked immunosorbent assay and analyzed JC virus regulatory-region sequences.
After 12 months of natalizumab therapy, the prevalence of JC virus in the urine of the 19 patients increased from a baseline value of 19% to 63% (P=0.02). After 18 months of treatment, JC virus was detectable in 3 of 15 available plasma samples (20%) and in 9 of 15 available samples of peripheral-blood mononuclear cells (60%) (P=0.02). JC virus regulatory-region sequences in blood samples and in most of the urine samples were similar to those usually found in PML. Conversely, BK virus remained stable in urine and was undetectable in blood. The JC virus-specific cellular immune response dropped significantly between 6 and 12 months of treatment, and variations in the cellular immune response over time tended to be greater in patients in whom JC viremia developed. None of the patients had clinical or radiologic signs of PML.
Subclinical reactivation of JC virus occurs frequently in natalizumab-treated patients with multiple sclerosis. Viral shedding is associated with a transient drop in the JC virus-specific cellular immune response.
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the white matter of the human brain caused by lytic infection of oligodendrocytes with the human polyomavirus JCV. Although the majority of PML cases occur in severely immune-suppressed individuals, with HIV-1 infection as the predominant factor, PML has been increasingly diagnosed in patients treated with biological therapies such as monoclonal antibodies that modulate immune system functions. Monoclonal antibodies that target the cell adhesion molecules VLA-4 (natalizumab; Tysabri for multiple sclerosis and Crohn's disease) or LFA-1 (efalizumab; Raptiva for severe forms of plaque psoriasis) to prevent extravasation of inflammatory T cells into tissues, or target the cell surface marker CD20 (rituximab; Rituxan for hematologic malignancies and rheumatoid arthritis) to deplete peripheral circulating B cells, have all been associated with PML. The link between the effects of these therapies on the immune system and the occurrence of PML has prompted investigations on JCV sites of latency in the bone marrow, the migration of bone marrow derived cells into the circulation, and intracellular virus entry into the brain.
Human polyomavirus, JCV, causes fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML). It has been shown that 5HT(2A)R acts as a cellular receptor for JCV on human glial cells. In the current study, we examined the inhibitory effects of 5HT(2A)R antagonists, ketanserin and ritanserin, both on JCV infection and on propagation by using human neuroblastoma cells IMR-32 and JCI, which continuously produce JCV. Transcriptional analysis revealed that 5HT(2A)R was constitutively expressed in JCI cells. Treatments with 5HT(2A)R antagonists led to a significant reduction in the titers of progeny viruses and the population of infected JCI cells. In addition, the amount of JCV genomic DNA was decreased in JCI cells in the presence of 5HT(2A)R antagonists. These results indicate that 5HT(2A)R antagonists have an inhibitory effect on JCV infection and reproduction, and JCI cells are applicable to an experimental model for pharmacological evaluation of antiviral agents against JCV.
Rituximab is a recombinant chimeric monoclonal antibody against CD20, a molecule expressed on cells of the B-cell lineage. A phase 2 clinical trial recently provided strong evidence of the beneficial effects of rituximab in patients with relapsing-remitting multiple sclerosis. We and other investigators previously demonstrated that rituximab therapy depletes B lymphocytes from peripheral blood and cerebrospinal fluid of patients with relapsing-remitting multiple sclerosis.
To determine the effect of rituximab on the presence of B cells in cerebral perivascular spaces. Design, Setting, and Patients Case report from a tertiary academic medical center. Cerebral white matter from autopsy material of a patient with gastrointestinal mantle-cell lymphoma who developed progressive multifocal leukoencephalopathy following rituximab therapy was evaluated by immunohistochemistry. Location-matched brain sections of patients with multiple sclerosis not treated with rituximab, patients without central nervous system disease, and patients with progressive multifocal leukoencephalopathy not associated with rituximab were used as controls.
Assessment of the number of B lymphocytes in cerebral perivascular spaces in a patient with gastrointestinal mantle-cell lymphoma treated with rituximab, patients with multiple sclerosis, patients with progressive multifocal leukoencephalopathy not associated with rituximab, and healthy control subjects.
We were unable to detect B cells in cerebral perivascular spaces of the patient who developed progressive multifocal leukoencephalopathy following rituximab therapy 8 months after her last dose. In contrast, B cells were detectable in all control brain tissues.
To our knowledge, this is the first report to show B-lymphocyte depletion from brain tissue following rituximab therapy. A reduction in B-cell numbers may be an important contributing factor in the pathogenesis of central nervous system infections.
The biological agent tocilizumab, is a humanized, anti-human interleukin-6 receptor antibody. A 72-year-old woman developed cognitive impairment during the Phase III clinical trial of tocilizumab for the treatment of rheumatoid arthritis. MRI demonstrated hyperintense dissemination throughout the white matter on T2WI. An initial diagnosis of possible progressive multifocal leukoencephalopathy was made, but the PCR for JC virus DNA was negative in the CSF. The leukoencephalopathy might have been caused by a mechanism related to tocilizumab itself. It is strongly recommended to perform MRI if a patient develops any cognitive impairment during tocilizumab therapy.
The polyomavirus JC (JCV) is the causative agent of progressive multifocal leukoencephalopathy and of JCV granule cell neuronopathy. We present a human immunodeficiency virus-negative patient who experienced development of multiple cortical lesions, aphasia, and progressive cognitive decline after chemotherapy for non-small-cell lung cancer. Brain biopsy and cerebrospinal fluid polymerase chain reaction demonstrated JCV, and she had a rapidly fatal outcome. Postmortem analysis showed diffuse cortical lesions and areas of necrosis at the gray-white junction. Immunostaining showed a productive JCV infection of cortical pyramidal neurons, confirmed by electron microscopy, with limited demyelination. This novel gray matter syndrome expands the scope of JCV clinical presentation and pathogenesis.
JC virus (JCV) is a human polyomavirus of the Polyomaviridae family, which also includes BK virus and simian vacuolating virus 40 (SV40). JC virus was first isolated in 1971 from the brain of a patient with Progressive Multifocal Leukoencephalopathy (PML). Like other polyomaviruses, JCV has a restricted host range. The virus infects the majority of the human population with seroconversion occurring during adolescence. JCV has a limited and specific tissue tropism infecting the kidney and oligodendrocytes and astrocytes in the central nervous system (CNS). Initial JCV infection is generally asymptomatic in immunocompetent hosts, and it establishes a persistent infection in the kidney and possibly bone marrow. In immunocompromised individuals JCV can cause a lytic infection in the CNS and lead to development of the fatal, demyelinating disease PML. The name polyoma is derived from the Greek terms: poly, meaning many, and oma, meaning tumors, owing to the capacity of this group of viruses to cause tumors. JCV inoculation of small animal models and non-human primates, which are not permissive to a productive JCV infection, leads to tumor formation. Given the ubiquitous nature of the virus and its strong association with cancer in animal models, it is hypothesized that JCV plays a role in human cancers. However, the role for JCV in human cancers and tumor formation is not clear. Some researchers have reported an association of JCV with human cancers including brain tumors, colorectal cancers, and cancers of the gastrointestinal tract, while other groups report no correlation. Here, we review the role of JCV in cancers in animal models and present the findings on JCV in human cancers.
Efalizumab is a recombinant, humanized IgG1 monoclonal antibody used in the treatment of plaque psoriasis. Efalizumab specifically targets T cells, leading to the subsequent inhibition of T-cell activation. The recent cases (three confirmed and one unconfirmed but suspected case) of the demyelinating disease progressive multifocal leukoencephalopathy (PML) have resulted in efalizumab being pulled from the market by European and Canadian regulatory agencies. Furthermore, manufacturer Genentech, Inc. has voluntarily withdrawn efalizumab from the United States market as of April 2009. In light of these events, this report is a practical guide to transitioning patients from efalizumab to alternative psoriasis therapies. The major consideration is the possibility for efalizumab-associated rebound of psoriasis. According to limited available literature and in the experience of the authors, the most effective agent for minimizing or preventing rebound is cyclosporine at the maximum dermatologic dose of 5 mg/kg per day.
We report an association between histologically confirmed progressive multifocal leukoencephalopathy (PML) and an extremely rare humoral immunodeficiency disease, Franklin disease. In our patient, clinical presentation has been typical and prompted us, together with radiological findings, to perform a brain biopsy to confirm the diagnosis even if there was no evidence of any other risk factor except hypogammaglobulinemia. We suggest that PML should be suspected in patients in whom immunosuppression is not obvious (i.e. not only in the setting of HIV infection or disseminated end-stage lymphomas) and involves defects in humoral immunity.
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Rituximab improves outcomes for persons with lymphoproliferative disorders and is increasingly used to treat immune-mediated illnesses. Recent reports describe 2 patients with systemic lupus erythematosus and 1 with rheumatoid arthritis who developed progressive multifocal leukoencephalopathy (PML) after rituximab treatment. We reviewed PML case descriptions among patients treated with rituximab from the Food and Drug Administration, the manufacturer, physicians, and a literature review from 1997 to 2008. Overall, 52 patients with lymphoproliferative disorders, 2 patients with systemic lupus erythematosus, 1 patient with rheumatoid arthritis, 1 patient with an idiopathic autoimmune pancytopenia, and 1 patient with immune thrombocytopenia developed PML after treatment with rituximab and other agents. Other treatments included hematopoietic stem cell transplantation (7 patients), purine analogs (26 patients), or alkylating agents (39 patients). One patient with an autoimmune hemolytic anemia developed PML after treatment with corticosteroids and rituximab, and 1 patient with an autoimmune pancytopenia developed PML after treatment with corticosteroids, azathioprine, and rituximab. Median time from last rituximab dose to PML diagnosis was 5.5 months. Median time to death after PML diagnosis was 2.0 months. The case-fatality rate was 90%. Awareness is needed of the potential for PML among rituximab-treated persons.
An efficacious treatment is needed for human immunodeficiency virus (HIV)-infected and uninfected patients with progressive multifocal leukoencephalopathy (PML).
To report clinical and magnetic resonance imaging changes in response to mirtazapine treatment in HIV-positive patients with PML.
Case series.
Outpatient neurology clinic.
Four HIV-positive patients with PML.
Mirtazapine use, 15 mg nightly.
Neurologic examinations and cranial magnetic resonance imaging.
Three patients demonstrated objective clinical improvement, and 1 patient showed improvement on magnetic resonance imaging. The patient who experienced the most significant clinical improvement was the patient who received mirtazapine therapy closest to PML symptom onset. Mirtazapine use was safe and well tolerated.
Mirtazapine use may offer some benefit as treatment or prophylaxis for PML in patients with HIV infection.
Progressive multifocal leukoencephalopathy (PML) is a demyelinating viral disease produced by the John Cunningham (JC) virus, which is ubiquitously distributed. Up to 80% of adults seroconvert to JC virus. Classically, PML is a life-threatening AIDS-defining disease of the CNS, usually occurring in severely immunocompromised individuals. Until now, and despite several therapeutic attempts, there is no specific treatment for PML. Soon after the widespread use of combination antiretroviral therapy (CART), several studies showed prolonged survival for patients with AIDS-associated PML who were treated with CART. The outcome of PML in patients receiving CART is unpredictable at disease onset. Prognostic markers are needed. The JC virus DNA detection in cerebrospinal fluid by nucleic acid amplification techniques and the CD4+ cell count are the most promising parameters. Higher levels of CD4+ cell counts were independently associated with an improved survival in different clinical observations. A summary of the main current knowledge about AIDS-related PML is presented. The most effective strategy is to optimize CART to completely suppress HIV-1 viral load and allow the best CD4+ T-cell immune recovery. Nowadays, AIDS-related PML is no longer an ultimately fatal disease. A substantial number of HIV-1-infected patients with this condition can improve with CART.
A 58-year-old Japanese man developed psychomotor excitement and hallucinatory paranoia at age 53, which gradually developed to residual schizophrenia. He was administered various common tranquilizers until death. Myelodysplastic syndrome was noted 10 months before death. A routine autopsy was performed. The brain weighed 1365 g, and macroscopic observation revealed no remarkable findings. However, microscopic examination disclosed cells with enlarged and basophilic nuclei, and unusual astrocytes in the demyelinated foci, especially at the corticomedullary junctions in the temporal and occipital lobes. On the other hand, the white matter was relatively intact. Immunohistochemical analysis using anti-JC virus protein, VP-1 antibody, demonstrated JC virus-infected cells in not only abnormal glial cells and neurons but also normal-looking cells, which are suggestive of progressive multifocal leukoencephalopathy (PML). Immunostaining for GFAP revealed severe gliosis and some scattered abnormal enlarged nuclear cells in the lesions. Some clusters of CD8-positive lymphocytes were seen, which kill infected cells. PML could be considered a short-term disease preceding death, as "incidental PML" in this case. This is a rare autopsy case of early PML occurring in a schizophrenia patient with PML.