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Initial and follow-up MR imaging findings in AIDS-related progressive multifocal leukoencephalopathy treated with highly active antiretroviral therapy.

BACKGROUND AND PURPOSE: Recent studies have shown the beneficial effect of highly active antiretroviral therapy (HAART) in AIDS-related progressive multifocal leukoencephalopathy (PML). The purpose of our study was to evaluate the initial and follow-up imaging findings and survival in patients with PML who were treated with HAART. METHODS: The clinical course and MR imaging findings on initial and follow-up MR studies in four consecutive AIDS patients with PML who were treated with HAART are described. RESULTS: Two patients were short-term survivors and died after 3 months. Two patients are still alive, with a survival time of 22 and 43 months, respectively. On initial MR studies, more extensive white matter changes were seen in the short-term survivors. Development of a mass effect and temporary enhancement (in one patient) was observed in two HAART responders on follow-up MR studies. Increased hypointensity on T1-weighted images with concomitant low signal on fluid-attenuated inversion-recovery fast spin-echo (FLAIR-FSE) images was seen in two responders, representing leukomalacia. Atrophic changes of the involved areas of the brain, consistent with burnt out PML lesions, were seen in two long-term survivors. In the short-term survivors, increased hypointensity was present on T1-weighted images with increased high signal on FLAIR-FSE images, representing progressive destructive disease. CONCLUSION: Our results suggest that a clinical and radiologic response can be seen in some patients with AIDS-associated PML on HAART while in others there may be no beneficial response. Development of a mass effect and temporary enhancement on MR images in the early phase of treatment might represent positive predictive factors for prolonged survival.

Acquired Immunodeficiency Syndrome↗

Progressive multifocal leukoencephalopathy in a patient with acquired immunodeficiency syndrome (AIDS) manifesting Gerstmann's syndrome.

We reported a case of acquired immunodeficiency syndrome (AIDS) via multiple blood transfusions, who manifested progressive multifocal leukoencephalopathy (PML) about 18 months after the development of AIDS. PML initiated with right hemiparesis, dysphasia, and Gerstmann's syndrome and resulted in death within 2 months after the onset. Neuroimaging examinations revealed white matter lesions mainly in the left posterior parietal lobe. The cortical gray matter also showed abnormal signal intensity. Peripheral CD4+ lymphocyte count was 81/microl. Routine cerebrospinal fluid (CSF) examinations were negative. CSF antibodies against herpes simplex virus, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus as well as serum antibody against toxoplasma gondii were negative. Though autopsy or biopsy of the brain was not performed, JC virus genomes were detected in the CSF sample by a polymerase chain reaction, and their sequencing showed unique alterations of the regulatory regions, characteristic to PML-type JC virus.

Acquired Immunodeficiency Syndrome↗

Progressive multifocal leukoencephalopathy: failure of response to transfer factor and cytarabine.

A 57-year-old woman with a 2-year history of neurologic symptoms was shown on brain biopsy to have progressive multifocal leukoencephalopathy. Although cell-mediated immune mechanisms were impaired, no underlying disease was found. The administration of transfer factor enhanced cell-mediated immunity, but the neurologic symptoms did not improve. Separate courses of glucocorticoids and cytarabine were associated with rapid neurologic deterioration.

Adrenocorticotropic Hormone↗

AIDS-associated progressive multifocal leukoencephalopathy (PML): comparison to non-AIDS PML with in situ hybridization and immunohistochemistry.

We studied brain sections from 10 patients with the acquired immunodeficiency syndrome (AIDS) and progressive multifocal leukoencephalopathy (PML) by in situ hybridization with a biotin-labeled JC virus (JCV) DNA probe and by immunohistochemistry using antibody against the JCV capsid antigen. We compared the results with brain sections studied in the same fashion from 10 PML patients without AIDS. The pathology of JCV infection in AIDS was similar to non-AIDS PML except for minor differences in degree. AIDS-associated pathologic material showed a greater tendency toward necrosis and a higher density of JCV-infected cells. Replication of JCV was restricted to glial cells in all tissue studied. Bizarre astrocytes were less frequent in the AIDS patients, and perivascular inflammatory cells were more frequent. We could not demonstrate JCV in macrophages or microglial cells known to harbor HIV infection. In situ hybridization with nonradioactive probes serves as a useful technique for the confirmation of PML in AIDS.

AIDS Dementia Complex↗

Progressive multifocal leukoencephalopathy (PML): in vitro cell-mediated immune responses to mitogens and JC virus.

Cell-mediated immunity was studied by in vitro tests in seven patients with progressive multifocal leukoencephalopathy (PML). Lymphocyte proliferation in response to mitogenic stimulation was reduced to a variable degree in all patients, indicating a general impairment of cell-mediated immune responsiveness, although mitogen-induced production of the lymphokine migration inhibitory factor (LIF) was normal in most cases. Cell-mediated immunity to JC virus (JCV) was assessed by LIF production in response to JCV antigen. In the six PML patients tested, LIF production with JCV antigen was absent despite the presence of antibody to JCV in serum. This contrasted with positive LIF production in seropositive normal individuals and patients and patients with other diseases. These results provide the first in vitro evidence of a depressed cell-mediated immune response to JCV in patients with PML, and support the hypothesis that PML is accompanied by a selective marked deficiency in cellular response to this virus in association with a general depression of cell-mediated immunity of variable severity.

Adult↗

Clinical course and prognostic factors of progressive multifocal leukoencephalopathy in patients treated with highly active antiretroviral therapy.

We analyzed survival rates, neurologic function, and prognostic factors for 118 consecutive patients with acquired immunodeficiency syndrome-associated progressive multifocal leukoencephalopathy (PML) treated with highly active antiretroviral therapy (HAART) in 11 hospitals throughout Spain. Seventy-five patients (63.6%) remained alive for a median of 114 weeks (2.2 years) after diagnosis of PML. Neurologic function of the survivors was categorized as cure or improvement in 33, stabilization or worsening in 40, and unknown in 2. The baseline CD4+ cell count was the only variable found with prognostic significance. The odds ratio of death was 2.71 (95% confidence interval, 1.19-6.15) for patients with CD4+ cell counts of <100 cells/microL, compared with patients who had CD4+ cell counts of > or =100 cells/microL. One-third of patients with PML died despite receipt of HAART; neurologic function improved in approximately one-half of the survivors. A CD4+ cell count of <100 cells/microL was associated with higher mortality.

Acquired Immunodeficiency Syndrome↗

JC virus load in progressive multifocal leukoencephalopathy: analysis of the correlation between the viral burden in cerebrospinal fluid, patient survival, and the volume of neurological lesions.

JC virus (JCV) is the causative agent of progressive multifocal leukoencephalopathy (PML), a demyelinating central nervous system infection that mainly affects patients with acquired immunodeficiency syndrome. The diagnostic value of the detection of JCV DNA in cerebrospinal fluid (CSF) has been proved. A correlation between the JCV burden in CSF and the PML prognosis has been proposed. To our knowledge, the present study is the first to examine JCV burden in CSF in relation to the magnitude of neurological damage. An in-house quantitative polymerase chain reaction assay was used for measurement of the JCV burden in CSF samples from 12 patients with PML. A wide variation in JCV load (6.4 log) was found among the patient CSF samples, a finding that makes JCV load measurements worthwhile. Virus load values of >4.68 log were associated with shorter patient survival time. No correlation was found between the virus load values and the global volume of brain tissue damaged. Our data suggest that factors other than the volume of neurological lesions influence the shedding of JCV in the CSF.

Adult↗

Association of prolonged survival in HLA-A2+ progressive multifocal leukoencephalopathy patients with a CTL response specific for a commonly recognized JC virus epitope.

The role of JC virus (JCV)-specific CTL was explored in the immunopathogenesis of progressive multifocal leukoencephalopathy (PML). We identified a 9-aa epitope of the JCV capsid protein VP1, the VP1(p100) peptide ILMWEAVTL, which is recognized by CTL of HLA-A2+ HIV+/PML survivors. We then constructed an HLA-A*0201/VP1(p100) tetrameric complex that allowed us to assess by flow cytometry the PBMC of 13 PML patients and 11 control subjects for the presence of JCV-specific CTL. VP1(p100)-specific CTL were detected by tetramer binding in VP1(p100)-stimulated PBMC of five of seven (71%) PML survivors and zero of six PML progressors (p = 0.02). Two of three HIV+ patients with a leukoencephalopathy resembling PML, but with no virologic evidence of JCV infection, also had detectable VP1(p100)-specific CTL in their PBMC. PBMC of eight HIV+ patients with other neurologic diseases and healthy control subjects had no detectable JCV-specific CTL. These data suggest that the JCV-specific cellular immune response may be important in the containment of PML, and the tetramer-staining assay may provide a useful prognostic tool in the clinical management of these patients.

Antigens, Viral↗

Progressive multifocal leukoencephalopathy. Diagnosis by in situ hybridization with a biotinylated JC virus DNA probe using an automated Histomatic Code-On slide stainer.

The accurate surgical pathological diagnosis of progressive multifocal leukoencephalopathy (PML) depends on the demonstration of pathognomonic histological features in cerebral biopsy tissue. The diagnosis may be difficult, however, if only small tissue fragments are submitted from the center of a demyelinating lesion. Previous studies by other authors have established that in situ hybridization with a biotinylated JC virus DNA probe can be a valuable diagnostic adjunct because it identifies the virally infected cells with great specificity and does not depend on the larger specimen, which may be necessary for a firm histological diagnosis. To confirm and extend these findings, we have used a commercially available biotinylated JC virus DNA probe to demonstrate the presence of viral DNA in formalin-fixed, paraffin-embedded tissues from four open biopsies, four needle biopsies, and two autopsies of patients with PML. With the goal of making this procedure applicable to the general surgical pathology laboratory, this method was adapted to the Histomatic Code-On slide stainer. The Histomatic is a programmable, robotic instrument with walk-away capability for hybridization histochemistry. Operation of this instrument requires the same expertise as execution of immunocytochemistry. With the advent of commercially available JC virus DNA probes and an automated system for hybridization histochemistry, this technology for diagnosis of PML may enter the routine diagnostic surgical pathology laboratory.

Acquired Immunodeficiency Syndrome↗

Survival improvement of AIDS-related progressive multifocal leukoencephalopathy in the era of protease inhibitors. Clinical Epidemiology Group. French Hospital Database on HIV.

OBJECTIVE: To estimate the change in survival of patients with AIDS-related progressive multifocal leukoencephalopathy (PML), in relation to the introduction of protease inhibitors (PI). DESIGN: The French Hospital Database on HIV (FHDH) is a prospective cohort of 70 224 HIV-infected subjects. This study included the patients diagnosed with PML between 1 July 1995 and 30 June 1997. PML diagnosis was both presumptive and confirmed. We compared the survival probability according to the diagnosis period (period 1 or 2, before or after introduction of PI in France on 1 April 1996). Cox's model was used to calculate the relative hazards of death according to the antiretroviral regimen. RESULTS: The study included 246 patients, 109 diagnosed during period 1 and 137 during period 2. In all, 131 patients received an antiretroviral combination that included PI. By 31 December 1997, a total of 131 deaths had been reported. The probability of survival at 6 months for patients from period 2 was nearly twice as high as for patients from period 1 (60.5 versus 34.5%). In comparison with patients receiving no treatment, the risk of death in patients on combination therapy not including PI was reduced by 38% [relative hazard (RH) 0.62, 95% confidence interval (CI) (0.41; 0.95), P = 0.026] and in patients on combination therapy with PI, by 63% [RH 0.37, 95% CI (0.22; 0.64), P = 0.0004]. CONCLUSION: This study of a large cohort of patients diagnosed with PML (n = 246), provides evidence that a combination antiretroviral regimen, especially one including PI, confers marked survival benefits.

AIDS-Related Opportunistic Infections↗

Progressive multifocal leukoencephalopathy. A cause of visual loss.

A patient had been treated for chronic lymphocytic leukemia for five years before developing visual blurring as the manifestation of occipital lobe lesions of progressive multifocal leukoencephalopathy (PML). The disease is caused by an infection of the CNS oligodendrocytes by a papovavirus, whose replication is facilitated by an impairment of the host's cell-mediated immunologic system. The multiplying virus destroys the oligodendrocytes and causes extensive demyelination of the white matter of the brain. Antiviral agents, such as cytarabine, may be beneficial in treating patients with PML.

Cytarabine↗

HAART improves prognosis in HIV-associated progressive multifocal leukoencephalopathy.

Introduction of highly active antiretroviral therapy (HAART) has been associated with many changes in the complications of human immunodeficiency virus (HIV) infection. A cohort of 25 HIV patients with progressive multifocal leukoencephalopathy (PML) treated with HAART experienced a median survival of >46 weeks. This is an improvement in prognosis compared with recent historic experience and correlated with HIV RNA viral load reductions. We conclude that current HIV therapy is important in improving the outlook of PML in the setting of HIV.

Adult↗

Progressive multifocal leukoencephalopathy in human immunodeficiency virus type 1-infected patients: absence of correlation between JC virus neurovirulence and polymorphisms in the transcriptional control region and the major capsid protein loci.

Progressive multifocal leukoencephalopathy (PML) is a rapidly fatal demyelinating disease of the central nervous system related to JC polyomavirus (JCV) replication in oligodendrocytes. PML usually occurs in immunocompromised individuals, especially in the setting of AIDS. Administration of highly active anti-retroviral therapy (HAART) may improve survival prognosis in some, but not all, patients with AIDS-related PML. This observation might be explained by the outgrowth of some JCV variants of increased fitness. To evaluate this hypothesis, two subgroups of five patients with AIDS-related PML, started on HAART after PML diagnosis, were analysed. The non-responder (NR) patients died rapidly despite HAART, while responders (R) had a positive outcome and were still alive. JCV DNA was extracted from cerebrospinal fluid biopsies and two regions of the genome were analysed, the transcriptional control region (TCR) and the major capsid protein gene (VP1). Both regions show different degrees of polymorphism and are recognized as evolving independently. Sequence analysis demonstrated that (i) extensive TCR rearrangements were present in both subgroups of patients, (ii) VP1 sequence polymorphisms could be identified in the BC loop, suggesting the absence of immune selection, and (iii) no genomic marker for JCV specific neurovirulence could be identified in the TCR and VP1 loci.

Acquired Immunodeficiency Syndrome↗

Detection of JC virus in cerebrospinal fluid (CSF) samples from patients with progressive multifocal leukoencephalopathy but not in CSF samples from patients with herpes simplex encephalitis, enteroviral meningitis, or multiple sclerosis.

JC virus (JCV) DNA was detected in cerebrospinal fluid (CSF) samples from patients with progressive multifocal leukoencephalopathy (PML) but not in CSF samples from patients with herpes simplex encephalitis, enteroviral meningitis, or multiple sclerosis. This suggests that inflammatory processes in the brain do not necessarily reactivate JCV, which further supports the proposal that the presence of JCV DNA in the CSF is diagnostic for PML.

Adult↗

JC virus type 2B is found more frequently in brain tissue of progressive multifocal leukoencephalopathy patients than in urine from controls.

OBJECTIVES: Previous studies have shown that strains of human polyomavirus JC (JCV) of Asian origin (type 2) are much more highly represented in progressive multifocal leukoencephalopathy (PML) brain than would be expected from their frequency of excretion in urine samples of a comparable control group. The present studies were designed to test whether one subtype of type 2 was preferentially elevated. STUDY DESIGN/METHODS: The statistical relation between JCV subtypes represented in PML brain tissue from 51 probands and those in urine samples from 115 control individuals was examined. RESULTS: The proportion of the JCV subtype 2B in PML brain (36%) was highly significantly increased relative to its occurrence in control urine samples (5.9%; P < .001). Type 1 and its subtypes were not different in the PML brain and control urine cohorts. The number of type 4 strains in PML brains was reduced, although the difference did not reach statistical significance (P = .08). CONCLUSIONS: The results predict that the human immunodeficiency virus (HIV)-positive individuals at highest risk of PML infection are those carrying the JCV genotype known as type 2B. Prospective studies will be required to confirm this finding.

Adult↗

[Progressive multifocal leukoencephalopathy (PML). Report of a case diagnosed by amplification of JC virus DNA from cerebrospinal fluid (CSF)].

We report a 54-year-old Japanese man who was diagnosed as progressive multifocal leukoencephalopathy (PML). He had been maintained on regular hemodialysis for 10 years. He was admitted to our hospital with chief complaints of visual disturbance and disorientation. On neurological examination, he was somnolent, and showed mild weakness in the right upper and lower limbs. Deep tendon reflexes were brisk on the right upper and bilateral lower limbs. Sensory examination revealed no abnormal findings. The cerebrospinal fluid (CSF) showed five mononuclear cells/mm3, protein 39 mg/dl and glucose 38 mg/dl. Brain MRI revealed multiple hyperintense lesions in T2-images, which were confined to the white matter of bilateral occipital and the left frontal lobes without an enhancement after gadolinium administration. Using polymerase chain reaction, we amplified the JCV regulatory region from the CSF of the patient. The amplified product contained a rearranged regulatory region that could have been generated from the archetype by deletion and amplification. PML was diagnosed on the basis of these findings. The patient died 7 months after onset of the symptoms. The diagnosis of PML was confirmed by the postmortem findings. The present case indicates that PCR of JCV from CSF is very useful for definitive diagnosis of PML.

Brain↗

The effects of cidofovir on progressive multifocal leukoencephalopathy: an MRI case study.

MRI was used to study the effects of introducing cidofovir (HPMPC, Vistide) to the antiretroviral therapy of a 33-year-old white man diagnosed as having progressive multifocal leukoencephalopathy (PML) secondary to AIDS. In response to combined cidofovir and antiretroviral therapy he showed significant clinical improvement. MRI showed a decrease in extent of existing lesions, without new ones. Blood chemistry information obtained indicated some involvement of immunologic mechanisms: the CD4:8 ratio showed improvement from an average of 0.08 before treatment to 0.13 during therapy.

Adult↗