Treatment of AIDS-associated progressive multifocal leukoencephalopathy with highly active antiretroviral therapy

OBJECTIVES: To evaluate the efficacy of highly active antiretroviral therapy (HAART) in 12 patients with AIDS-associated progressive multifocal leukoencephalopathy (PML). PATIENTS AND METHODS: The diagnosis of PML was established by brain biopsy in six patients and by neuroimaging findings and PCR detection of JC virus in cerebrospinal fluid (CSF) in six patients. We also studied 13 consecutive AIDS patients with biopsy-proven PML cared for in the same institution before HAART was available. Eleven patients of the HAART group and eight patients of the control group received intravenous arabinoside cytosine cycles. RESULTS: With HAART, the median decrease in the HIV viral load was 3.58 log10 copies/ml and the median increase in the CD4 cell count was 74x10(6)/l. The median survival time after PML diagnosis was 545 days in the HAART group and 60 days in the control group (P<0.001, log-rank test). In the HAART group, the neurological deficits improved substantially in six patients and stabilized in six patients. Eleven patients underwent follow-up cranial computed tomography or magnetic resonance scan that showed improvement of PML lesions in 10 patients and stabilization in one patient. Follow-up CSF analysis showed clearance of JC virus in six out of seven patients who had an initial positive result. CONCLUSIONS: This study shows that HAART may increase the survival, clinical status and radiological features of AIDS patients with PML. Clearance of JC virus from CSF has been found, suggesting that immune reconstitution can interrupt the JC virus lytic cycle.     

Cytarabine therapy for progressive multifocal leukoencephalopathy in patients with AIDS

To evaluate the efficacy and safety of intravenous cytarabine in the treatment of AIDS-associated progressive multifocal leukoencephalopathy (PML), we reviewed the charts of all human immunodeficiency virus-infected patients with PML who were seen during a 28-month period at our institution. Patients with biopsy-proven PML were offered therapy with intravenous cytarabine (2 mg/[kg.d] for 5 days every 4 weeks). The diagnosis of PML was histologically confirmed for 13 patients. The median CD4 cell count was 91 x 10(6)/L. A median of three courses of cytarabine was administered to eight patients. Two patients developed mild drug-related toxicities. Clinical and/or radiological signs of improvement were observed for three patients treated with cytarabine; no signs of improvement were noted for the untreated patients. Median survival time after the diagnosis of PML was 102 days (range, 46-220 days) for patients who received cytarabine and 60 days (range, 28-72 days) for untreated patients matched for Karnofsky scores (P = .06, logrank test). Although cytarabine is well tolerated by patients with AIDS and PML, only modest short-term clinical improvement in the conditions of patients treated with the drug has been observed, with no significant impact on survival.     

Progressive multifocal leukoencephalopathy in a patient with hypogammaglobulinemia

Baker's yeast reduction of methyl and ethyl (2-oxocyclohexyl) acetates proceeded with enantio- and diastereo-selectivity, affording the corresponding (2S)-trans-alcohols (major), (2S)-cis-alcohols (minor), and the unaltered (1S)-ketones with high optical purity.     

Magnetization transfer imaging in progressive multifocal leukoencephalopathy

We report a patient with biopsy-proven progressive multifocal leukoencephalopathy (PML) who was serially imaged with MRI and magnetization transfer imaging. The magnetization transfer ratio (MTR) was profoundly and significantly diminished when compared with normal control subjects. The pattern of MTR was distinct from that of MS and periventricular ischemic white matter disease. Magnetization transfer imaging techniques may aid in the differential diagnosis of PML.     

Progressive multifocal leukoencephalopathy in a patient with acquired immunodeficiency syndrome

We report a 28 year old heterosexual male with AIDS that presented with progressive motor disturbances and malaise. Light and transmission electron microscopy of a stereotaxic brain biopsy demonstrated a progressive multifocal leukoencephalopathy. This is a demyelinating infectious cerebral disease attributed to JC virus and must be considered in the differential diagnosis of central nervous system disturbances in AIDS patients.     

Successful treatment of progressive multifocal leukoencephalopathy with low-dose interleukin-2

A patient with low-grade lymphoma presented 8 months after autologous marrow transplantation with dizziness, aphasia and hemiparesis. Magnetic resonance imaging (MRI) showed an abnormal T2 signal in the frontoparietal region unilaterally. Biopsy of the area demonstrated progressive multifocal leukoencephalopathy positive for JC virus and p53. Treatment with interleukin-2 at 0.5 MU/m2/day i.v. continuous infusion resulted in near complete resolution of symptoms and MRI abnormalities. The absolute number of CD3+CD4+ and CD3-CD56+ cells in the peripheral blood also increased, and the CD4/CD8 ratio normalized. She remains free of evidence of progressive multifocal leukoencephalopathy 1 year off therapy.     

Left vocal cord paralysis in cytomegalovirus multifocal neuropathy in a patient with HIV infection

Cytomegalovirus multifocal neuropathies (CMV-MN) in patients with AIDS are much less frequent than meningoradiculitis. We report here the case of a patient with AIDS hospitalized because of severe motor weakness and paralyzed left true vocal cord (PVC), related to a multifocal neuropathy. CSF analysis was normal with a negative PCR for CMV, but neuromuscular biopsy showed typical CMV inclusions. The patient's condition improved with high dose foscarnet therapy, followed by a combination of ganciclovir plus foscarnet, during a five-month follow-up period. Twenty three case reports of CMV-MN have been published in the literature, only 2 of them presenting with a PVC. Extraneurological CMV involvement was usually documented. PCR for CMV in CSF was most often positive. However CMV inclusions were not frequently observed. The patients were usually improved under therapy with usually ganciclovir but relapse was observed in fifty percent within 3 to 6 months despite secondary prophylaxis.     

A case of progressive multifocal leukoencephalopathy with methionine uptake demonstrated by PET]

We report here a 55-year-old man with progressive multifocal leukoencephalopathy (PML) associated with chronic adult T cell leukemia (ATL). Neurological examination revealed mild dementia, right homonymous hemianopsia and visual agnosia. Serologically anti-HTLV-I antibody was positive. Peripheral blood analysis showed ATL cells up to 23% in white blood cells. Because he did not have symptoms or signs directly related to ATL, it was considered that he had chronic ATL. T2-weighted cranial MRI demonstrated multiple hyperintensity lesions confined to the white matter from the bilateral occipital to parietal lobes, without enhancement after gadolinium administration or mass effect. We performed stereotactic biopsy of the left occipitoparietal white matter. Histological examination of the biopsied specimens showed demyelinated lesions, containing foamy macrophages and bizarre astrocytes. Oligodendrocytes contained nuclear inclusions which reacted with an antibody against the JC virus (JCV) antigen. These findings were consistent with those of PML. The genomic analysis of JCV from the biopsied brain revealed deletions in the regulatory region. We investigated cerebral blood flow, glucose and amino acid metabolism in this patient using positron emission tomography, and obtained the following three characteristic findings in the lesions: 1) luxury perfusion state, 2) decreased fluorodeoxyglucose (FDG) uptake, and 3) increased methionine (Met) uptake. These findings resembled those of low grade tumors.     

Nucleic acid detection as a diagnostic tool in polyomavirus JC induced progressive multifocal leukoencephalopathy

Procedures involved in the diagnosis of JC virus central nervous system infection range from detection of virus specific products in biopsy material to demonstration of viral DNA in cerebrospinal fluid by PCR. Despite the fact that PCR is the most sensitive method for the detection of virus in clinical specimens, diagnostic evaluation is increasingly difficult in view of the possible subclinical activation of persistent JCV infection in the central nervous system of high risk patients. Therefore, PML diagnosis by molecular detection of JCV DNA in biopsy material was compared with diagnosis by PCR on CSF of patients with and without PML. Evaluation of the diagnostic techniques revealed that stereotactic biopsy based PCR diagnosis at present combines speed and sensitivity with the highest specificity available. Although the non invasive technique of JCV detection in CSF by PCR is even more sensitive leading to detection of about 20 genome equivalents per 1 microl of CSF, the specificity of the method is limited by subclinical presence of JCV DNA in CSF of neurologically asymptomatic HIV infected patients. Additionally, autopsy proven PML cases remaining JCV negative in PCR on CSF become a common finding. Therefore, in cases where biopsy is not performed, diagnosis of PML can only be achieved in combination with neurological and radiological diagnosis.     

Failure of cytarabine in progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. AIDS Clinical Trials Group 243 Team

BACKGROUND: Progressive multifocal leukoencephalopathy affects about 4 percent of patients with the acquired immunodeficiency syndrome (AIDS), and survival after the diagnosis of leukoencephalopathy averages only about three months. There have been anecdotal reports of improvement but no controlled trials of therapy with antiretroviral treatment plus intravenous or intrathecal cytarabine. METHODS: In this multicenter trial, 57 patients with human immunodeficiency virus (HIV) infection and biopsy-confirmed progressive multifocal leukoencephalopathy were randomly assigned to receive one of three treatments: antiretroviral therapy alone, antiretroviral therapy plus intravenous cytarabine, or antiretroviral therapy plus intrathecal cytarabine. After a lead-in period of 1 to 2 weeks, active treatment was given for 24 weeks. For most patients, antiretroviral therapy consisted of zidovudine plus either didanosine or stavudine. RESULTS: At the time of the last analysis, 14 patients in each treatment group had died, and there were no significant differences in survival among the three groups (P=0.85 by the log-rank test). The median survival times (11, 8, and 15 weeks, respectively) were similar to those in previous studies. Only seven patients completed the 24 weeks of treatment. Anemia and thrombocytopenia were more frequent in patients who received antiretroviral therapy in combination with intravenous cytarabine than in the other groups. CONCLUSIONS: Cytarabine administered either intravenously or intrathecally does not improve the prognosis of HIV-infected patients with progressive multifocal leukoencephalopathy who are treated with the antiretroviral agents we used, nor does high-dose antiretroviral therapy alone appear to improve survival over that reported in untreated patients.