Progressive Multifocal Leukoencephalopathy
This patient, presenting with subacute memory loss complicated by acute delirium and clinical evidence of predominantly left hemisphere dysfunction, was found to have radiographic evidence of highly asymmetric, multifocal white matter disease. As the differential diagnosis for causes of acquired leukoencephalopathy in adults includes opportunistic infections, a search for causes of immunosuppression was undertaken, demonstrating HIV infection with a high viral RNA load and low CD4+ lymphocyte count. Diagnosis of progressive multifocal leukoencephalopathy was established by demonstrating JC virus DNA in the CSF by a PCR study, together with a typical appearance of lesions on MR imaging. No other cause of his acquired, multifocal white matter disease was detected on screening studies.
Progressive Multifocal Leukoencephalopathy (PML) is a demyelinating disease that predominantly affects immunocompromised hosts. Descriptions of this disease were made as early as 1930 by the German neuropathologist Hallervorden. However, PML did not become recognized as a distinct syndrome until its cardinal histopathological features were defined. These cardinal features were defined by Astrom et al. (1958), as: demyelination, enlarged nuclei of oligodendrocytes, and bizarre appearing astrocytes. The cause(s) of such changes were unclear at the time, but presence of inclusion bodies in the nuclei of damaged oligodendrocytes suggested the possibility of a viral cause. The possibility of a polyoma virus as the causative factor in PML was proposed by ZuRhein (1967), and subsequently confirmed by isolation of a papovavirus using human fetal brain cell cultures. The virus was named JC after the index patient from whose brain tissue the virus was isolated.
The JC virus is part of the Polyomavirus genus, in the Papovaviridae family. JC virus has a DNA genome of 5.1 kilobases in a double-stranded supercoiled form, encapsulated in an icosahedral protein structure measuring 40 nm in diameter. The JC viral DNA codes for one nonstructural but multifunctional protein (T), and three capsid proteins (VP1, VP2, and VP3). The role of the T protein is unclear in humans. The VP1 protein is the major capsid protein that contains epitopes responsible for antibody induction and recognition. It is also the protein used for virion attachment to cell membranes to initiate infection, and has the ability to agglutinate human type O erythrocytes (1). The JC virus can attach and gain entry to many types of cells, but does not transcribe or replicate its own DNA. Although other members of this genus have been suggested as etiologic agents in PML (e.g., SV40 and BK virus), the JC virus appears to be responsible for almost, if not all cases of PML.
Seroepidemiologic studies show that IgG antibodies to the JC virus can be detected in 80-90% of the population by middle adulthood. However, no illness has been proven to result from initial JC virus infection in an immunocompetent host. After initial infection, the JC virus remains latent in the reticuloendothelial system and the kidney. Evidence to date suggests that the JC virus may not be latent in the brain, but instead may appear only after reactivation.
Historically, PML was a rare disease. The number of reported cases of PML did not begin to rise until the start of the AIDS epidemic in the 1980s. Prior to the AIDS epidemic, PML was seen mainly in patients with chronic lymphocytic leukemia or lymphoma. In a review published in 1984 by Brooks and Walker, the most common cause of PML was lymphoproliferative disease, associated with up to 62% of cases. The first description of PML complicating AIDS was in 1981 (9). By the late 1980s, AIDS was reported to be the most common underlying disorder predisposing to development of PML in New York and Miami. Currently, HIV infection is the most common underlying cause of immunosuppression associated with PML. It mostly affects homosexual or bisexual men between the ages of 25-50 years. The male:female ratio is 7.6 to 1. PML is the heralding AIDS-defining illness in approximately 1% of all HIV-infected persons.
When the JC virus begins to replicate in the brain, it rapidly forms lesions that affect various brain functions. The particular functions disturbed appear to depend upon the regions of the brain affected, rather than reflecting distant effects of viral infection. PML usually presents with rapidly progressing, focal neurological deficits due to demyelination of white matter. Weakness and speech disturbances are among the most common symptoms reported by patients. Over 50% of individuals who have HIV-associated PML will develop weakness of their arms or legs. Other symptoms and signs of PML may include altered mental status or delirium, personality changes, memory loss, dementia, headache, ataxia, and sensory loss. "Cortical" signs, such as aphasia, may develop if demyelination occurs in white matter tracts beneath the language areas, while apraxia may occur if the supplementary motor area is involved. Visual field defects may develop due to involvement of the geniculo-calcarine projections of the optic tract, but optic nerve involvement has not been reported. Seizures are seen in 10% of patients and may reflect either involvement of the cortex by the JC virus, HIV infection of the brain, or some other process. Brainstem involvement also occurs, and may result in dysphagia, limb weakness, sensory loss, diplopia, and other cranial nerve abnormalities, based on which ones are affected. Cerebellar dysfunction may dominate in some cases of PML.
The diagnosis of PML can sometimes be tricky, as several other conditions can present in a similar fashion. In the differential diagnosis of PML, one should include the other disorders associated with severe immunosuppression or with HIV infection: toxoplasmosis, AIDS-dementia complex, cryptococcal meningitis, lymphoma, CMV, and herpes infections. Metastatic Kaposi's sarcoma, acute stroke, and tuberculous or fungal abscesses, although typically presenting differently, have been misdiagnosed as PML, and should be included in the differential. In individuals with HIV and PML, the CD4 lymphocyte counts tend to be below 200 cells/mm3. The mean CD4 count at the time of diagnosis is approximately 85.
Computed tomography (CT) of the brain shows hypodense lesions of the white matter, without associated mass effect and only rare enhancement. These lesions may have a "scalloped" appearance when they are located near the gray-white junction. This scalloped appearance is due to involvement of the subcortical arcuate fibers (which are often spared in syndromes of altered myelin formation or in some leukoencephalopathies due to enzyme deficiencies). MRI is much more sensitive for detecting these white matter lesions than CT, and also provides superior visualization of the anatomy. T2-weighted images on MRI show hyperintense lesions in the affected areas. These lesions enhance with contrast in only 5-10% of cases. Recent data suggest that enhancement of these lesions may have some long-term prognostic value (Arbusow et al., 2000). It is proposed that contrast enhancement of CT or MRI may indicate a more robust immune response to the viral antigens, thus favoring long-term survival.
Definitive diagnosis of PML is based on demonstrating the presence of the JC virus within the brain of the affected individual, usually following stereotactic needle biopsy, open biopsy, or autopsy. Presence of the JC virus in the sampled brain lesions is suggested by demonstrating oligodendrocytes containing eosinophilic inclusions by histologic stains. Immunoperoxidase stains for the SV40 virus-related antigen can also be used to identify the virus in sampled brain tissue, along with viral tissue cultures, and electron microscopic identification of viral particles in oligodendroglia.
CSF studies have become increasingly important in the diagnosis of PML. CSF examination usually shows fewer than 20 cells/mm3, and elevated protein (highest recorded value was 208 mg/dL). Hypoglycorrhachia was observed in fewer than 15% of cases. The JC virus can now be identified in the CSF by polymerase chain reaction (PCR) techniques. PCR techniques for detection of the JC virus in CSF have been found to be highly sensitive and specific for this illness (e.g., Berger and Major, 1999). Many authorities feel that positive JC PCR assays, along with appropriate clinical and radiologic features, is sufficient to reliably diagnose PML, and that brain biopsy is not necessary in most cases.
The median survival of PML complicating AIDS is six months and the mode is only one month, indicating substantial heterogeneity in outcomes. Recovery of neurologic function, improvement of PML lesions in radiographic imaging and survival exceeding 12 months have been observed in as many as 10% of patients with AIDS-associated PML. In individuals who have improved with PML, biopsy has shown prominent inflammation within the lesions, and enhancement on MRI was seen in a few cases. These findings suggest that some individuals were able to mount an effective JC virus-directed immune response, which proved to be beneficial.
A few additional findings may suggest a better prognosis in individuals with PML. PML presenting as the initial manifestation of AIDS, higher CD4 counts (>300 cells/mm3), and contrast enhancement on radiographic imaging have been associated with prolonged survival. The longest reported survival to date has been 92 months from onset of illness.
Treatment of PML has been historically poor. In vitro studies of cytosine arabinoside (Ara-C) showed inhibition of JC virus replication, but ara-C failed to show marked benefit in a large randomized trial. Interferon-alpha has also been used, but its efficacy for PML has yet to be proven. Presently, only highly aggressive antiretroviral therapy (HAART) has been shown to improve both neurologic conditions and survival of individuals with AIDS-associated PML (e.g., Domingo et al., 1997). Clinical improvements have been observed after 3-8 weeks of therapy in some cases. These reports are generally consistent with successful treatment of the predisposing immunosuppressive condition.
Of the antiretroviral agents, cidofovir has been found to have considerable direct activity against polyomaviruses, including JC, using in vitro studies. Several anecdotal reports of improvement of PML with cidofovir treatment have been published (e.g., Brambilla and Castagna, 1999). Its true effectiveness, however, has not yet been proven in large-scale trials.
The topoisomerase inhibitor, topotecan hydrochloride, may also be of some benefit in PML. In infected glial cells in culture, topotecan has been shown to inhibit the replication of the JC virus and suppress replication of HIV. A clinical trial is currently underway to test its effectiveness.
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