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PubMed2006

Multiple sclerosis, natalizumab therapy, and progressive multifocal leukoencephalopathy.

PURPOSE OF REVIEW: Multiple sclerosis affects many people, often in early adulthood, and causes significant disability. Natalizumab is a novel agent to be evaluated for multiple sclerosis and Crohn's disease that has demonstrated unique efficacy but has unfortunately been implicated in three cases of progressive multifocal leukoencephalopathy. This review covers the mechanism of action of natalizumab and efficacy for multiple sclerosis, the three cases of natalizumab-associated progressive multifocal leukoencephalopathy, our understanding of progressive multifocal leukoencephalopathy, and the mechanisms that may account for these events. RECENT FINDINGS: Natalizumab, an anti-alpha4-integrin antibody, binds to T-cell surface receptors to prevent migration from the circulation into the brain tissue. Phase II and III trials have been completed and demonstrate previously unseen efficacy in preventing relapses and disease progression. The cases of progressive multifocal leukoencephalopathy, two fatal and one disabling, resulted in the voluntary suspension of natalizumab and bring this entire class of agents into doubt. It is important to determine what led to the development of progressive multifocal leukoencephalopathy in the natalizumab-associated cases and to advance understanding and continue to develop therapies for the treatment of multiple sclerosis. SUMMARY: With ongoing safety evaluations, natalizumab is being reevaluated by the US Food and Drug Administration for possible reapproval and return to the market. If natalizumab is reapproved, challenging questions and issues will remain in treating patients with multiple sclerosis.

Adult↗
PubMed1980

Progressive multifocal leukoencephalopathy and malignant lymphoma of the brain in a patient with immunosuppressive therapy.

Progressive multifocal leukoencephalopathy and malignant lymphoma of the brain were noted at postmortem examination in a 68-year-old white woman who was treated with immunosuppressive agents after renal transplantation. The two diseases are not uncommon in patients with immunodeficiency, but their occurrence in the same patient is extremely rare. This association suggests the oncogenicity of papova viruses in man. However, no papovavirus was demonstrated in the tumor by electron microscopy and immunohistochemical staining. The immunohistochemical staining of routine histology sections for the common antigen of polyomaviruses by the peroxidase anti-peroxidase technique is shown to be simple and specific for the detection of polyomaviruses in the demyelinated areas of progressive multifocal leukoencephalopathy.

Aged↗
PubMed1988

Age distribution of progressive multifocal leukoencephalopathy.

The age distribution is given of 79 cases of progressive multifocal leukoencephalopathy confirmed as JC virus infection. The data are compared with a published age distribution of multiple sclerosis onset in Vestfold County, Norway, and with published data from Rochester, Minnesota of the age distribution of viral encephalitis. In contrast to viral encephalitis, 61% of which occurs in children under the age of 10, PML has been identified only once in this age group. PML, like MS, is a disease of adult onset, peaking in the sixth decade of life. The reason for this late onset of a CNS disease caused by a ubiquitous childhood infection is still uncertain, but it may be related to maturation of susceptible cells in the brain, as well as to declining immunity associated with chronic disease and age.

Adolescent↗
PubMed2000

Progressive multifocal leukoencephalopathy: JC virus induced demyelination in the immune compromised host.

Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the central nervous system that predominantly affects immunocompromised individuals. The etiologic agent, JCV, is a widespread polyomavirus with a very specific target, the myelin-producing oligodendrocytes of the brain. During periods of immune suppression, the virus can be reactivated from lymphoid tissues and kidney, causing targeted myelin destruction and corresponding neurological deficits. The incidence of PML has increased in recent years, due in large part to the advent of AIDS and the growing number of immunodeficient individuals. Furthermore, previous serological studies have shown that greater than 80% of the human population has antibodies to JCV in circulation. When combined, these statistics highlight an increasing need to establish effective treatment regimens for infected individuals as well as strategies to identify those at risk for developing PML.

Demyelinating Diseases↗
PubMed1975

Atypical progressive multifocal leukoencephalopathy with plasma-cell infiltrates.

In rare cases of progressive multifocal leukoencephalopathy (PML) the lesions are atypical in that the characteristic alteration of oligodendrocytic nuclei is infrequent or absent, and the demyelinated foci contain mononuclear inflammatory infiltrates including numerous plasma cells. Otherwise these cases, both as to the topographic features of the lesions, and the background of chronic lymphoproliferative or myeloproliferative disease or immunosuppressive treatment, conform to the usual pattern. In the case here reported, that of a 54-year-old man receiving immunosuppressive drugs for chronic polymyositis, electron microscopy showed papovavirions in astrocytic nuclei and fluorescent antibody studies indicated that these represented JC virus. In this and the 3 previously reported similar cases of atypical PML, the neurologic illness was less devastating than generally occurs in classic PML. Possibly these cases represent instances of unusually strong host-resistance against the disease.

Astrocytes↗
PubMed2002

Autopsy case of the cerebellar form of progressive multifocal leukoencephalopathy without immunodeficiency.

A case of the cerebellar form of progressive multifocal leukoencephalopathy (PML) without remarkable immune depression or immune deficiency is reported here. The patient was a 74-year-old-woman who had complications of chronic renal failure and renal anemia for several years. Seven months before her death she had symptoms of general fatigue, gait disturbance and articulation disorder. During her hospitalization period her neurological disorder gradually progressed irreversibly with failure of consciousness and she died of respiratory failure. She did not have remarkable clinical signs of immunodeficiency nor did she receive immunosuppressive therapy. Clinically she had not been diagnosed with PML. At the post-mortem examination different degrees of demyelination were observed in the brain white matter: diffuse and severe in the cerebellum, moderate and coalescent in the brainstem, and light and patchy in the cerebrum. JC virus antigen-positive cells were frequently observed in the demyelinated lesions in the cerebrum and sometimes observed in the brainstem, but were rarely found in the cerebellum. These findings suggest that PML lesions may be present with different degrees of demyelination that are inversely correlated with the number of JC virus-infected cells. This fact should be considered when evaluating the brain biopsies of PML patients.

Aged↗
PubMedDate not supplied

Fine needle aspiration biopsy of progressive multifocal leukoencephalopathy in a patient with AIDS. A case report.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is one of the most common opportunistic infections, with a range of 4-7% in acquired immunodeficiency syndrome (AIDS) patients. Clinical diagnosis is often difficult, and the specific pathologic agent requires cytologic and pathologic confirmation. CASE: A 38-year-old, Haitian male was admitted with a new-onset seizure disorder. On computed tomography (CT), there were right frontoparietal cortex, right external capsule and right basal ganglia lucencies. Fine needle aspiration biopsy (FNAB) of the radiolucent area revealed foci of white matter demyelination and a few eosinophilic inclusions in oligodendrocytes plus abnormal giant astrocytes. Ultrastructurally, JC virions were observed in the nuclei and cytoplasm of the oligodendrocytes. CONCLUSION: Diagnostic cranial CT-guided FNAB, with cytologic and histologic studies, is extremely valuable in evaluating the nature of central nervous system demyelinated and space-occupying lesions in AIDS.

AIDS-Related Opportunistic Infections↗
PubMed2003

Progressive multifocal leukoencephalopathy: analysis of lesion development with diffusion-weighted MRI.

Progressive multifocal leukoencephalopathy (PML), caused by replication of JC virus in oligodendrocytes of immunocompromised patients, is diagnosed by polymerase chain reaction-based demonstration of JC virus DNA. We investigated whether MRI might be used to assess disease activity. Diffusion-weighted imaging (DWI) was obtained in two patients with PML, in whom it was the only MRI sequence on which we could identify areas of progressive disease. The extent of abnormal diffusion appeared to correlate with the speed of clinical progression. DWI would thus seem to be of value in patients with PML.

Brain↗
PubMed1998

An unusual course of progressive multifocal leukoencephalopathy in a patient with idiopathic CD4+ T lymphocytopenia.

A case is reported of idiopathic CD4+T lymphocytopenia with progressive multifocal leukoencephalopathy and cervical lymph node tuberculosis. A 57 year old Japanese man presented with cervical lymphadenopathy and progressive neurological deficits, and six months later he developed akinetic mutism. He had a persistent severely depressed number of circulating CD4+T lymphocytes in the absence of human immunodeficiency virus infection. T1 weighted MRI showed a diffuse decreased signal intensity limited to the white matter without mass effect. A brain biopsy specimen had a morphology similar to that of progressive multifocal leukoencephalopathy. Polyomavirus antigen was detected in the brain lesion, and viral DNA was identified in nucleated blood cells and urine. Unusually this serious medical condition has lasted for more than three years without remission. To our knowledge this is the first patient with CD4+T lymphocytopenia with progressive multifocal leukoencephalopathy, suggesting that similar opportunistic infections should be considered even in previously normal people.

Antigens, Viral↗
PubMed1994

Differential expression of mRNAs for JC virus large and small tumor antigens in brain tissues from progressive multifocal leukoencephalopathy patients with and without AIDS.

JC virus (JCV) causes progressive multifocal leukoencephalopathy (PML), the fatal demyelinating infection of oligodendrocytes, in up to 5% of AIDS patients. An intron-differential RNA PCR was developed to study the expression of alternately spliced JCV early mRNAs in brain tissues from PML patients with and without AIDS and in JCV-induced hamster brain tumors. The method utilizes primers that span the large tumor (T) and small tumor (t) antigen introns allowing amplification of specific cDNAs in the presence of contaminating viral genomic DNA. Hybridization with specific junctional probes and DNA sequence analysis confirmed the identity of the PCR products. Sequencing showed that JCV early mRNA is alternatively spliced as previously predicted by analogy to simian virus 40. Large T antigen mRNA was detected in all the brain tissues from PML patients with and without AIDS. The expression of small t antigen mRNA varied depending upon the association of PML with AIDS and upon other unknown factors. Of the 12 PML/AIDS brain tissue samples, 11 (92%) expressed small t antigen mRNA, whereas only 8 of 13 (62%) brain samples from patients with PML alone showed detectable levels of small t antigen mRNA. Human immunodeficiency virus 1 proviral DNA was detected in 10 of 12 PML/AIDS brain samples. The results indicate that alternative splicing of JCV early mRNA is regulated in the human brain and that the production of small t antigen may not be essential for the pathogenesis of PML.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Angiographic abnormalities in progressive multifocal leukoencephalopathy: an explanation based on neuropathologic findings.

BACKGROUND AND PURPOSE: Progressive multifocal leukoencephalopathy (PML) is typically occult at angiography and fails to enhance on MR images. After observing angiographic abnormalities characterized by arteriovenous shunting and pathologic parenchymal blush in patients with AIDS-related PML, often in the absence of contrast enhancement on MR images, we hypothesized that there might be distinct changes in the cerebral microvasculature that account for the reduction in vascular transit time (arteriovenous shunting) in the absence of blood-brain barrier dysfunction. METHODS: The imaging studies and neuropathologic specimens of six patients with biopsy-proved PML were reviewed retrospectively. In all patients contrast-enhanced MR imaging and CT, followed by cerebral angiography, were performed before stereotactically directed biopsy. The angiograms were evaluated for the presence of vascular displacement, pathologic parenchymal blush, arteriovenous shunting, and neovascularity. The CT and MR studies were reviewed for the presence of enhancement of the PML lesions. Biopsy specimens were examined for the presence of necrosis, perivascular inflammation, and neovascularity. RESULTS: All patients had oligodendrocytic intranuclear inclusions diagnostic of PML, together with perivascular inflammation and neovascularity to a varying extent; no other neuropathologic processes were identified. Angiographic abnormalities, characterized by a pathologic parenchymal blush and arteriovenous shunting, were identified in four of the six patients. In only one of these cases, however, was abnormal enhancement identified on cross-sectional imaging studies (MR and CT), and this patient had florid perivascular inflammatory infiltrates histologically. CONCLUSION: The pathologic parenchymal blush and arteriovenous shunting seen angiographically in some patients with PML reflect small-vessel proliferation and perivascular inflammatory changes incited by the presence of the JC virus in infected oligodendrocytes.

AIDS Dementia Complex↗
PubMed2005

Characterization of the VP1 loop mutations widespread among JC polyomavirus isolates associated with progressive multifocal leukoencephalopathy.

Recently, we found that JC polyomavirus (JCPyV) associated with progressive multifocal leukoencephalopathy (PML) frequently undergoes amino acid substitutions (designated VP1 loop mutations) in the outer loops of the major capsid protein, VP1. To further characterize the mutations, we analyzed the VP1 region of the JCPyV genome in brain-tissue or cerebrospinal fluid samples from 20 PML patients. VP1 loop mutations occurred far more frequently than silent mutations. Polymorphic residues were essentially restricted to three positions (55, 60, and 66) within the BC loop, one (123) within the DE loop, and three (265, 267, and 269) within the HI loop. The mutations at most polymorphic residues showed a trend toward a change to specific amino acids. Finally, we presented evidence that the VP1 loop mutations were associated with the progression of PML. These findings should form the basis for elucidating the biological significance of the VP1 loop mutations.

Autopsy↗
PubMed1996

Contrast-enhancing progressive multifocal leukoencephalopathy: radiological and pathological correlations: case report.

OBJECTIVE AND IMPORTANCE: Progressive multifocal leukoencephalopathy (PML), a demyelinating disease caused by the JC papovavirus, is an opportunistic infection afflicting patients with impaired cellular immunity. Although initially described in patients with hematological malignancies, PML has become associated with several other immunocompromised states, particularly human immunodeficiency virus (HIV) infection. There are numerous central nervous system manifestations in patients with acquired immunodeficiency syndrome. A major characteristic that distinguishes PML from other more common lesions, such as toxoplasmosis or non-Hodgkin's lymphoma, is the lack of contrast enhancement. We describe a case of PML that exhibits contrast enhancement, and we conclude that the diagnosis of PML must be considered in patients with HIV who have contrast-enhancing lesions. CLINICAL PRESENTATION: A 40-year-old woman presented with progressive hemiparesis, blurred vision, and ataxia. Magnetic resonance imaging revealed a contrast-enhancing lesion involving the left middle cerebellar peduncle, causing mild compression of the fourth ventricle. INTERVENTION: The patient underwent a stereotactic serial biopsy with the presumptive diagnosis of moderate- to high-grade glioma. Histological examination of the biopsy specimen revealed early PML. Subsequently, a test for HIV was obtained and the results were positive. CONCLUSION: We have reported another atypical radiographic characteristic of PML associated with HIV. We conclude that PML lesions can enhance after the administration of gadolinium. Therefore, the diagnosis of PML must be entertained in patients whose test results were positive for HIV with contrast-enhancing lesions and that a stereotactic serial biopsy may be necessary to provide a definitive diagnosis.

Adult↗
PubMed2000

Progressive Multifocal Leukoencephalopathy.

Before embarking on experimental therapies for progressive multifocal leukoencephalopathy (PML), the diagnosis needs to be unequivocally established. Improving the underlying immunodeficiency state is the best initial approach to the management of PML. Immunosuppressive therapies should be discontinued when feasible. In the patient with AIDS, highly active antiretroviral therapy should be administered; this appears to prolong survival. At present, no therapy has been demonstrated to be effective in a well-designed prospective trial. Cytosine arabinoside, which has demonstrated efficacy in vitro against JC virus, has not been effective when administered intravenously or intrathecally to patients with AIDS and PML. The failure of regimens employing cytosine arabinoside in PML may have been the consequence of inadequate penetration of the drug to sites of infection in the brain. Other drugs with established in vitro activity against JC virus, such as topoisomerase and camptothecin, are poorly tolerated. The use of cidofovir in patients with AIDS and PML remains anecdotal, although it is currently under investigation. Interferon alfa may improve survival in patients with AIDS and PML and may have general applicability to PML regardless of the cause of the underlying immunodeficient state. Approximately 7% to 9% of patients with PML demonstrate prolonged survival (>12 months) and associated improvement in clinical and radiographic abnormalities in the absence of specific therapy. In patients with AIDS-related PML, prolonged survival correlates with PML as the presenting manifestation of AIDS, higher CD4 T-lymphocyte counts, and contrast enhancement of PML lesions on radiographic imaging. A brisk inflammatory response may also be associated with improved survival. The increased understanding of the pathophysiology of JC virus provides hope for the development of curative strategies. The growing number of persons affected with PML has allowed the organization of carefully designed therapeutic trials to address this issue.

Journal Article↗
PubMed2005

Fulminant inflammatory leukoencephalopathy associated with HAART-induced immune restoration in AIDS-related progressive multifocal leukoencephalopathy.

HAART-induced immune restoration is beneficial for patients with AIDS-related progressive multifocal leukoencephalopathy (PML). However, in rare instances, an immune-reconstitution inflammatory syndrome (IRIS) may cause paradoxical clinical deterioration. We report the neuropathological study of an AIDS patient who presented with progressive cognitive deterioration; CD4(+) count was 117 and the HIV viral load >10(4); imaging showed non-enhancing lesions consistent with PML. Following initiation of HAART, CD4(+) was 300 and HIV viral load <10(3), but his neurological symptoms continued to deteriorate. Imaging revealed an increase in the size and number of lesions and enhancement of all the lesions. A stereotactic biopsy showed severe inflammatory and demyelinating lesions with marked infiltration by macrophages and T lymphocytes in the absence of a detectable infectious agent. Despite high doses of steroids, the patient died 3 months after admission. Autopsy showed two types of lesions: (1) active inflammatory PML changes with abundant JC virus, and intraparenchymal and perivascular infiltration by T lymphocytes, and (2) acute perivenous leukoencephalitis devoid of JC virus. Most lymphocytes were CD8(+) lymphocytes; CD4(+) lymphocytes were virtually absent. Two pathological reactions were associated with the paradoxical clinical deterioration related to dysregulation of the immune response characteristic of IRIS in PML: (1) an accentuation of JCV infection, and (2) a nonspecific acute perivenous leukoencephalitis. We suggest that both these types of lesions are due to an imbalance of CD8(+)/CD4(+) T cells, with massive infiltration of the cerebral parenchyma by CD8(+) cytotoxic T lymphocytes in the absence of sufficient CD4(+) response. Better understanding of the mechanisms of the IRIS may enable prevention or cure of this severe, sometimes fatal complication of HAART.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Unusual patterns of Histoplasma capsulatum meningitis and progressive multifocal leukoencephalopathy in a patient with the acquired immunodeficiency virus.

Disseminated histoplasmosis (DH) and progressive multifocal leukoencephalopathy occur in acquired immunodeficiency syndrome (AIDS). At autopsy, DH patients with central nervous system involvement almost always show extensive involvement of the lungs and reticuloendothelial system in addition to the brain, and progressive multifocal leukoencephalopathy is manifest as multiple demyelinating lesions in several locations in the brain. We describe an AIDS patient with a long history of aggressively treated DH who died with DH in the brain only; fungus was not found elsewhere at autopsy. In addition, there was a papovavirus infection restricted to the cerebellum with predominant involvement of the internal granular cell layer; again, demyelinating lesions were not found elsewhere in the brain. Each of these patterns of brain involvement is rare. As the incidence of AIDS increases and patients are treated aggressively, the frequency of unusual neuropathologic patterns of opportunistic infections may be expected to increase.

Acquired Immunodeficiency Syndrome↗