Igor J. Koralnik

Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis

Progressive multifocal leukoencephalopathy (PML) is a rare but often fatal brain disease caused by reactivation of the polyomavirus JC. Knowledge of the characteristics of PML has substantially expanded since the introduction of combination antiretroviral therapy during the HIV epidemic and the development of immune reconstitution inflammatory syndrome (IRIS) in patients with PML. Recently, the monoclonal antibodies natalizumab, efalizumab, and rituximab--used for the treatment of multiple sclerosis, psoriasis, haematological malignancies, Crohns disease, and rheumatic diseases--have been associated with PML. Additionally, the JC virus can also lead to novel neurological disorders such as JC virus granule cell neuronopathy and JC virus encephalopathy, and might also cause meningitis. The increasingly diverse populations at risk and the recent discovery of the presence of the JC virus in the grey matter invite us to reappraise the pathogenesis of this virus in the CNS.

PML diagnostic criteria: Consensus statement from the AAN Neuroinfectious Disease Section

Objective: To establish criteria for the diagnosis of progressive multifocal leukoencephalopathy (PML). Methods: We reviewed available literature to identify various diagnostic criteria employed. Several search strategies employing the terms “progressive multifocal leukoencephalopathy” with or without “JC virus” were performed with PubMed, SCOPUS, and EMBASE search engines. The articles were reviewed by a committee of individuals with expertise in the disorder in order to determine the most useful applicable criteria. Results: A consensus statement was developed employing clinical, imaging, pathologic, and virologic evidence in support of the diagnosis of PML. Two separate pathways, histopathologic and clinical, for PML diagnosis are proposed. Diagnostic classification includes certain, probable, possible, and not PML. Conclusion: Definitive diagnosis of PML requires neuropathologic demonstration of the typical histopathologic triad (demyelination, bizarre astrocytes, and enlarged oligodendroglial nuclei) coupled with the techniques to show the presence of JC virus. The presence of clinical and imaging manifestations consistent with the diagnosis and not better explained by other disorders coupled with the demonstration of JC virus by PCR in CSF is also considered diagnostic. Algorithms for establishing the diagnosis have been recommended.

JC virus DNA load in patients with and without progressive multifocal leukoencephalopathy

Objective: To determine the clinical value of JC virus (JCV) detection in various anatomic compartments for the diagnosis of progressive multifocal leukoencephalopathy (PML). Methods: CSF, peripheral blood mononuclear cells (PBMC), plasma, and urine samples were evaluated from HIV-infected and uninfected individuals. JCV DNA was detected by PCR and was quantified using a competitive PCR ELISA. Results: JCV DNA was detected in one-third of the urine samples, regardless of HIV serostatus or clinical evidence of PML. JCV DNA was detected in five of eight PBMC and three of seven plasma samples of HIV-positive PML patients, in 13 of 103 PBMC and 7 of 32 plasma samples of HIV-positive persons without PML, but in 0 of 18 PBMC and 0 of 13 plasma samples of HIV-negative control subjects. There was no correlation between the presence of JCV DNA in the PBMC and plasma, but the detection of JCV in either compartment was associated with low CD4+ lymphocyte counts. JCV DNA was not detected in the CSF of 27 of 27 HIV-negative persons and 64 of 65 HIV-positive persons without PML, but was found in the CSF of three of three HIV-negative immunosuppressed individuals and 10 of 11 HIV-positive individuals with clinical and radiologic evidence of PML, confirmed by biopsy in four of four tested patients. PBMC harbored 10 to 90 JCV copies/μg DNA, and the CSF of the PML patients contained 3.65 × 104 to 2.04 × 105 JCV copies/mL CSF. Conclusions: JCV viruria was found as frequently in HIV-positive individuals as in control subjects, suggesting that its detection has no clinical value. JCV detection in the blood correlates with immunosuppression and not with PML. The presence of JCV in the CSF is highly sensitive and specific for PML, and a high CSF JC viral load was associated with poor clinical outcome in patients receiving antiretroviral therapy. JCV quantification in the CSF constitutes a potentially important tool for monitoring clinical PML treatment trials.

Progressive multifocal leukoencephalopathy revisited: Has the disease outgrown its name?

Nothing is more disappointing for patients than when a promising new treatment hits a roadblock because of unexpected side effects. This is what happened when natalizumab (Tysabri) was associated with a few cases of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis and Crohns disease patients, caused by the reactivation of the polyomavirus JC. These dramatic events drew PML squarely into the spotlight and generated considerable interest from the medical community, the pharmaceutical industry, financial markets, and regulatory agencies alike. This scrutiny, in turn, helped crystallize areas of consensus and expose gaps in our understanding of PML pathogenesis. Indeed, since its initial description, there has been a considerable evolution in both the epidemiology and clinical presentations of this disease, and new manifestations of central nervous system infection by polyomavirus JC have been characterized. To keep pace with this opportunistic pathogen, we are therefore forced to reexamine the foundations of our knowledge of virus–host interactions, reappraise our investigational approaches, and in short, rethink PML down to its very name. Hopefully, this crisis will be instrumental in helping us define novel avenues of research, develop predictive tests for PML in populations at risk, and challenge us to find a treatment for this deadly disease. Ann Neurol 2006; 60: 162–173

Asymptomatic Reactivation of JC Virus in Patients Treated with Natalizumab

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

JC virus granule cell neuronopathy: A novel clinical syndrome distinct from progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) typically affects the CNS white matter of the central nervous system. We present an human immunodeficiency virus–infected patient with polyomavirus JC infection restricted to granule cell neurons of the cerebellum and with corresponding neurological symptomatology. Magnetic resonance imaging demonstrated cerebellar atrophy without white matter lesions and stereotactic biopsy showed selective infection of the cerebellar granular cell layer, with preservation of Purkinje cells and absence of classic progressive multifocal leukoencephalopathy histopathology in underlying white matter. Evolution over 8 years was marked by symptomatic improvement corresponding to highly active antiretroviral therapy (HAART), with modest increase in CD4+ T‐cell counts. We propose to call this novel syndrome JCV granule cell neuronopathy (JCV GCN). Ann Neurol 2005;57:576–580

Progressive multifocal leukoencephalopathy in HIV-1 infection

Progressive multifocal leukoencephalopathy is caused by the JC polyomavirus (JCV) and is one of the most feared complications of HIV-1 infection. Unlike other opportunistic infections, this disease can present when CD4 counts are higher than those associated with AIDS and when patients are receiving combined antiretroviral therapy, either shortly after starting or, more rarely, during long term successful treatment. Clinical suspicion of the disease is typically when MRI shows focal neurological deficits and associated demyelinating lesions; however, the identification of JCV in cerebrospinal fluid or brain tissue is needed for a definitive diagnosis. Although no specific treatment exists, the reversal of immunosuppression by combined antiretroviral therapy leads to clinical and MRI stabilisation in 50-60% of patients with the disease, and JCV clearance from cerebrospinal fluid. A substantial proportion of patients treated with combined antiretroviral therapy develop inflammatory lesions, which can be associated with either a favourable outcome or clinical worsening. The reasons for variability in the natural history of progressive multifocal leukoencephalopathy and treatment responses are largely undefined, and more specific and rational approaches to management are needed.

New insights into progressive multifocal leukoencephalopathy.

Purpose of reviewProgressive multifocal leukoencephalopathy is a deadly demyelinating disease of the central nervous system, which occurs in immunosuppressed individuals. It is caused by a reactivation of the polyomavirus JC, which induces a lytic infection of oligodendrocytes. This review covers recent developments in the clinical and pathological presentations of progressive multifocal leukoencephalopathy, and advances in the understanding of JC virus biology. Recent findingsThe availability of highly active antiretroviral therapy has changed the clinical spectrum of progressive multifocal leukoencephalopathy in HIV-infected individuals; although the incidence has not diminished, mortality has decreased from 90% to approximately 50% during the first 3 months as a result of recovery of the immune system. More progressive multifocal leukoencephalopathy patients are now negative for JC virus in the cerebrospinal fluid by polymerase chain reaction, which calls for a new consensus terminology. Inflammatory forms of the disease are also becoming more frequent, and are associated with a strong cellular immune response mediated by JC virus-specific CD8 cytotoxic T lymphocytes, which are instrumental in preventing disease progression. SummaryAdvances in the understanding of JC virus biology have shed new light on the pathogenesis of progressive multifocal leukoencephalopathy, and on its possible role in cerebellar atrophy in HIV-infected individuals. Findings on the cellular immune response against the virus have direct implications for patient management, and may lead to new forms of immunotherapies for progressive multifocal leukoencephalopathy. An animal model of progressive multifocal leukoencephalopathy in non-human primates will facilitate the development of novel therapeutic strategies.

A Controlled Study of Early Neurologic Abnormalities in Men with Asymptomatic Human Immunodeficiency Virus Infection

BACKGROUND Although neurologic complications are frequent in the acquired immunodeficiency syndrome, their incidence and progression in early human immunodeficiency virus (HIV) infection remain controversial. The goal of this study was to assess neurologic manifestations in asymptomatic carriers of HIV. METHODS We studied 29 HIV-seropositive homosexual men and 33 seronegative homosexual controls by means of neurologic and neuropsychological examinations, magnetic resonance imaging (MRI), and electrophysiologic tests (electroencephalography, multimodal evoked-potential tests, and otoneurologic tests). After six to nine months, the tests were repeated in 27 seropositive men and 30 controls. The investigators were blind to the serologic status of the subjects. RESULTS The seropositive subjects had a mean CD4+ lymphocyte count of 635 X 10(6) per liter. Neurologic and neuropsychological examination, MRI, and measurements of pattern visual evoked potentials did not show significant differences between the two groups. The latencies of the median-nerve somatosensory evoked potentials were slightly prolonged in the seropositive men. The initial electroencephalogram was judged abnormal in 8 of 27 of the seropositive subjects (30 percent) as compared with none of the controls, with a slowing of fundamental activity, anterior spread [corrected] of alpha rhythm, subnormal reactivity, and unusual anterior theta activities. These findings were confirmed by computerized spectral analysis. The second electroencephalogram was abnormal in 10 of 25 of the seropositive men (40 percent). The otoneurologic evaluation identified abnormalities in the central auditory or vestibulo-ocular pathways in 34 percent of the seropositive men (10 of 29), as compared with 6 percent of the controls (2 of 33), on the first examination and in 44 percent (12 of 27) and 7 percent (2 of 30), respectively, on the second examination. Altogether, electrophysiologic abnormalities were found in 67 percent of the seropositive men (18 of 27) and 10 percent of the controls (3 of 30) (P less than 0.00005). CONCLUSIONS In persons with asymptomatic HIV infection, electrophysiologic tests may be the most sensitive indicators of subclinical neurologic impairment. Electrophysiologic abnormalities are far more common in asymptomatic carriers of HIV than in controls and tend to progress over time.

Determinants of survival in progressive multifocal leukoencephalopathy

Background: We sought to characterize the role of immunologic, virologic, and radiologic determinants of survival in patients with progressive multifocal leukoencephalopathy (PML). Methods: We recorded the clinical outcome of 60 patients with PML (73% HIV+) who were prospectively evaluated between 2000 and 2007 for the presence of JC virus (JCV)-specific CD8+ cytotoxic T-lymphocytes (CTL) in blood. Results: Estimated probability of survival at 1 year was 52% for HIV+/PML and 58% for HIV− patients with PML. Patients with PML with detectable CTL within 3 months of diagnosis had a 1-year estimated survival of 73% compared to 46% for those without CTL (hazard ratio [HR] for death = 0.47, 95% confidence interval [CI] 0.13-1.75, p = 0.26). Patients with CTL response had an increased likelihood of having contrast enhancement of PML lesions and immune reconstitution inflammatory syndrome (odds ratio 3.7 and 7.8). Estimated 1-year survival was 48% in HIV+ patients with PML with CD4 count <200/μL at PML diagnosis compared to 67% in those with CD4 >200/μL (HR for death 1.41, 95% CI 0.27-7.38, p = 0.68). JCV DNA was detected in the urine of 48% and in the blood of 56% of patients with PML, but viruria and viremia were not associated with survival. Conclusions: The presence of JC virus (JCV)-specific cytotoxic T-lymphocytes (CTL) was associated with a trend toward longer survival in patients with progressive multifocal leukoencephalopathy (PML), which was more pronounced than the impact of CD4 count in HIV+ patients with PML early after diagnosis. Despite the association of contrast enhancement and immune reconstitution inflammatory syndrome with JCV-specific CTL, these cannot be considered as surrogate markers for the prognostic value of the CTL. Strategies aiming at improving the cellular immune response may improve the course of PML. CE = contrast enhancement; CI = confidence interval; CTL = cytotoxic T-lymphocytes; HR = hazard ratio; IQR = interquartile range; IRIS = immune reconstitution inflammatory syndrome; JCV = JC virus; PBMC = peripheral blood mononuclear cells; PML = progressive multifocal leukoencephalopathy.