Background

Until the advent of AIDS, this disease was extremely rare, usually reported in immunocompromised patients. Now, it is understood to be a viral infection by the JC virus. The prognosis was once uniformly grim, made more dismal by the association with AIDS. Now with combined HAART therapy for AIDS, patients have improved survival.

Outline

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/Immunohistochemistry/Electron Microscopy
Differential Diagnosis
Prognosis and Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
Progressive multifocal leukoencephalopathy in persons infected with human immunodeficiency virus, San Francisco, 1981-1989. Gillespie SM, Chang Y, Lemp G, Arthur R, Buchbinder S, Steimle A, Baumgartner J, Rando T, Neal D, Rutherford G, et al. Division of Viral and Ricketssial Diseases, Centers for Disease Control, Atlanta, GA.	Ann Neurol 1991 Oct;30(4):597-604 Abstract quote Progressive multifocal leukoencephalopathy (PML), a rare neurological disease, has been sporadically reported in persons infected with human immunodeficiency virus (HIV), the causative agent of acquired immune deficiency syndrome (AIDS). From January 1981 through February 1989, in San Francisco, we identified 94 HIV-infected persons with PML, of whom 48 (51%) were pathologically confirmed (as required for AIDS case reporting). These 48 patients were significantly older when diagnosed with AIDS (20% older than 50 years) than patients with AIDS without PML. The remaining 46 (49%) patients, diagnosed clinically and by neuroimaging, did not differ significantly from definitive patients in demographic or survival characteristics after PML diagnosis. We detected antibodies to JC virus, the causative agent of PML, in 9 of 14 (64%) AIDS-related patients with PML, and in 9 of 14 (64%) matched control subjects, suggesting that determination of JC virus antibody status before AIDS diagnosis does not reliably indicate which patients will contract PML. Our study shows that the proportion of patients with AIDS who contracted PML remained stable between 1981 and 1988, but increased in the first 2 months of 1989. Our findings further indicate that PML in HIV-infected patients may be underestimated by as much as 50%.
Progressive multifocal leukoencephalopathy in the United States, 1979-1994: increased mortality associated with HIV infection. Holman RC, Torok TJ, Belay ED, Janssen RS, Schonberger LB. Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Atlanta, Ga., USA.	Neuroepidemiology 1998;17(6):303-9 Abstract quote To examine trends in progressive multifocal leukoencephalopathy (PML) mortality in the United States, we analyzed PML death rates and deaths for 1979 through 1994, using US multiple cause-of-death data. During the 16-year study period 3,894 PML deaths were reported. The age-adjusted death rate increased more than 20-fold, from less than 0.2 per million persons before 1984 to 3.3 per million persons in 1994. The increase was attributable to infection with human immunodeficiency virus (HIV) which was recorded on 2,267 (89.0%) of 2.546 death records from 1991 through 1994. PML age-adjusted death rates increased abruptly for all males beginning in 1984 and for black females in 1990. Only a small increase was observed for white females. In 1994, PML was reported in 2.1% of white males who died with HIV-associated disease compared with 1.2% of white females and 1.0% of black males and females who died of similar causes. The epidemic of PML deaths is increasing in parallel with the AIDS epidemic. The increase in HIV-associated PML deaths, first noted among males, has also become apparent among females and probably reflects the increasing importance of drug use and heterosexual transmission of HIV. The reason for the higher prevalence of PML among white males with HIV infection is unknown.

 

DISEASE ASSOCIATIONS	CHARACTERIZATION
Progressive multifocal leukoencephalopathy in AIDS: a clinicopathologic study and review of the literature. von Einsiedel RW, Fife TD, Aksamit AJ, Cornford ME, Secor DL, Tomiyasu U, Itabashi HH, Vinters HV. Department of Pathology (Neuropathology), UCLA Medical Center 90024.	J Neurol 1993 Jul;240(7):391-406 Abstract quote We reviewed the clinical, radiographic, and pathologic features of 15 patients with the acquired immune deficiency syndrome (AIDS) and progressive multifocal leukoencephalopathy (PML). Brain tissue from 10 autopsy and 6 biopsy specimens was studied using: in situ hybridization (ISH) for JC virus (JCV), immunohistochemistry for human immunodeficiency virus (HIV) p24 antigen, and electron microscopy. Thirteen patients presented with focal neurologic deficits, while 2 presented with a rapid decline in mental status. PML was commonly the initial opportunistic infection of AIDS and produced hemiparesis, dementia, dysarthria, cerebellar abnormalities, and seizures. Magnetic resonance imaging was more sensitive than computed tomography in detecting lesions, and often showed multifocal areas of PML. CD4+ T-cell counts were uniformly low (mean 84/mm3), except in 1 patient who improved on 3'-azido-3'-deoxythymidine (AZT). PML involved the cerebral hemispheres, brain stem, cerebellum, and cervical spinal cord. The distribution of brain involvement was consistent with hematogenous dissemination of the virus. In 2 brain specimens, multiple HIV-type giant cells were present within the regions involved by PML. When co-infection by HIV and papovavirus was present, PML dominated the pathological picture. ISH for JCV showed virus in the nuclei of oligodendrocytes and astrocytes. Occasionally there was staining for JCV in the cytoplasm of glial cells and in the neuropil, the latter possibly a correlate of papovavirus spread between myelin sheaths, as seen by electron microscopy. ISH demonstrated more extensive foci of PML than did routine light microscopy.
Progressive multifocal leukoencephalopathy in a patient with acquired immunodeficiency syndrome (AIDS) manifesting Gerstmann's syndrome. Saito H, Sakai H, Fujihara K, Fujihara K, Itoyama Y. Department of Neurology, Tohoku University School of Medicine, Sendai, Japan.	Tohoku J Exp Med 1998 Nov;186(3):169-79 Abstract quote 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.

 

PATHOGENESIS	CHARACTERIZATION
Progressive multifocal leukoencephalopathy and JC virus genotypes in West African patients with acquired immunodeficiency syndrome: a pathologic and DNA sequence analysis of 4 cases. Chima SC, Agostini HT, Ryschkewitsch CF, Lucas SB, Stoner GL. Neurotoxicology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-4126, USA.	Arch Pathol Lab Med 1999 May;123(5):395-403 Abstract quote OBJECTIVE: Progressive multifocal leukoencephalopathy is caused by polyomavirus JC in immunosuppressed patients. JC virus genotypes are identified by sequence analysis of the viral genome. Despite the prevalence of acquired immunodeficiency syndrome in sub-Saharan Africa, few cases of progressive multifocal leukoencephalopathy have been reported from this region. Here we describe 4 African cases and provide an analysis of viral genotypes. METHODS: Immunohistochemical staining by labeled streptavidin-biotin for capsid protein antigen was performed on all cases. Polymerase chain reaction amplification of viral genomic DNA was followed by direct cycle sequencing. RESULTS: JC virus type 3 was identified in 2 cases, and type 6 was isolated in 1 case. The viral regulatory region from 1 case showed an uncommon rearrangement pattern. CONCLUSIONS: Progressive multifocal leukoencephalopathy in West African patients with acquired immunodeficiency syndrome is caused by African genotypes of JC virus (types 3 and 6). The prevalence of disease in this autopsy series from sub-Saharan Africa (1.5%) was less than has been reported from Europe and the United States (4% to 10%) and may be partly due to biological differences in JC virus genotypes. Further studies will be needed to confirm this observation.
Increased frequency of JC virus type 2 and of dual infection with JC virus type 1 and 2 in Italian progressive multifocal leukoencephalopathy patients. Ferrante P, Mediati M, Caldarelli-Stefano R, Losciale L, Mancuso R, Cagni AE, Maserati R. Laboratory of Biology, Don C. Gnocchi Foundation, IRCCS (Research Hospital), University of Milan, Italy	J Neurovirol 2001 Feb;7(1):35-42 Abstract quote To verify the possibility of different role of JC virus genotypes in the etiology of progressive multifocal leukoencephalopathy, we analysed several JC virus isolates amplified from AIDS patients with and without progressive multifocal leukoencephalopathy and healthy controls by nucleotide sequencing. Cerebrospinal fluid (CSF), peripheral blood mononuclear cells (PBMCs) and urine from 52 AIDS patients suffering from various neurological diseases including 21 cases of progressive multifocal leukoencephalopathy, and PBMCs and urine from healthy subjects were evaluated by nested polymerase chain reaction (PCR) for the presence of DNA belonging to the highly conserved large T antigen (LT) of JC virus. The different JC virus subtypes were identified by nucleotide sequence analysis of the virion protein (VP1) genomic region. JC virus DNA was detected in all the CSF samples from the progressive multifocal leukoencephalopathy patients, but not in the CSF from non-progressive multifocal leukoencephalopathy cases, while the frequency of JC virus DNA detection in the PBMCs and urine did not differ among the three groups studied. JC virus type 2 was detected only in progressive multifocal leukoencephalopathy patients, and in particular in 52.4% of their CSF samples. Moreover, in the CSF of 19.0% of the progressive multifocal leukoencephalopathy cases, dual infection with both JC virus types 1 and 2 was found. The data obtained in this study indicate that the unexpected involvement of JC virus type 2, a strain not common in Italy, and the high frequency of dual infection with both JC virus types 1 and 2 in progressive multifocal leukoencephalopathy CSF, can be indications of risk factors for progressive multifocal leukoencephalopathy development.

 

LABORATORY/RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
Progressive multifocal leukoencephalopathy in 47 HIV-seropositive patients: neuroimaging with clinical and pathologic correlation. Whiteman ML, Post MJ, Berger JR, Tate LG, Bell MD, Limonte LP. Department of Radiology, University of Miami School of Medicine, FL.	Radiology 1993 Apr;187(1):233-40 Abstract quote The authors investigated the spectrum of radiologic findings in a large series (n = 47) of patients seropositive to human immunodeficiency virus (HIV) 1 and with pathologically proved progressive multifocal leukoencephalopathy, to determine the characteristic imaging pattern of the disease. Thirty-six computed tomographic (CT) scans and 29 magnetic resonance (MR) imaging studies obtained in the 47 patients were retrospectively reviewed and correlated with pathologic and clinical findings. Contrast agents were used in 32 CT procedures and 13 MR imaging studies. Lesions typically were hypoattenuating on CT scans and were characterized by areas of increased signal intensity without mass effect on dual-echo MR images. Lesions most often involved periventricular and subcortical white matter in parietooccipital or frontal lobes. Fifteen patients had posterior fossa lesions, and disease was limited to the posterior fossa in two. Lesions were also in the corpus callosum (seven patients), thalamus (eight patients), and basal ganglia (seven patients). In comparison with CT, MR imaging demonstrated greater sensitivity for the extent and number of lesions.
Progressive multifocal leukoencephalopathy in AIDS: initial and follow-up CT and MRI. Thurnher MM, Thurnher SA, Muhlbauer B, Hainfellner JA, Steuer A, Fleischmann D, Trattnig S, Budka H, Schindler E. Department of Radiology, University of Vienna, Austria.	Neuroradiology 1997 Sep;39(9):611-8 Abstract quote We sought to determine the value of follow-up CT and MRI in patients with acquired immuno-deficiency syndrome (AIDS) and progressive multifocal leukoencephalopathy (PML). We reviewed 50 CT and 19 MRI examinations performed in 21 biopsy- or autopsy-proven cases of PML; 17 patients had follow-up examinations (mean time 5.9 weeks). The radiological examinations were correlated with pathological findings at autopsy. On initial imaging studies, 73 lesions were found. On follow-up, the most striking feature was rapid progression in both size and number of the lesions (from a mean of 3.2 to 6.9 per patient). One third of the patients showed increasing mass effect. A central area suggesting necrosis, of variable size, was found in 12/16 patients. Autopsy revealed macroscopic necrotic changes in the lesions in 11/16 patients.
LABORATORY MARKERS
Relation of JC virus DNA in the cerebrospinal fluid to survival in acquired immunodeficiency syndrome patients with biopsy-proven progressive multifocal leukoencephalopathy. Yiannoutsos CT, Major EO, Curfman B, Jensen PN, Gravell M, Hou J, Clifford DB, Hall CD. Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, MA 02115-6017, USA.	Ann Neurol 1999 Jun;45(6):816-21 Abstract quote The detection and semiquantitation of JC virus (JCV) DNA in cerebrospinal fluid (CSF) is prognostic of survival and is a marker of the course of progressive multifocal leukoencephalopathy (PML). CSF samples from 15 acquired immunodeficiency syndrome (AIDS) patients with biopsy-proven PML were analyzed by semiquantitative polymerase chain reaction (PCR). A low JCV burden was predictive of longer survival compared with a high JCV burden (median survival from entry, 24 [2-63] vs 7.6 [4-17] weeks). Further analyses indicated a possible threshold of 50 to 100 copies/microl separating high- and moderate-risk cases. Patients with a JCV load below this level survived longer than those with a JCV load above it.
Detection and Differentiation of Human Polyomaviruses JC and BK by LightCycler PCR. Whiley DM, Mackay IM, Sloots TP. Clinical Virology Research Unit, Sir Albert Sakzewski Virus Research Centre, Royal Children's Hospital and Health Service District, University of Queensland.	J Clin Microbiol 2001 Dec;39(12):4357-4361 Abstract quote Human polyomaviruses JC and BK may cause several clinical manifestations in immunocompromised hosts, including progressive multifocal leukoencephalopathy and hemorrhagic cystitis. Molecular detection by PCR is recognized as a sensitive and specific method for detecting human polyomaviruses in clinical samples. In this study, a real-time PCR assay using the LightCycler platform was evaluated and compared to an "in-house" PCR assay using a conventional detection method. A total of 122 urine specimens were tested, and human polyomavirus was detected in 49 specimens (40%) by both conventional PCR and LightCycler PCR. The remaining 73 specimens (60%) were found negative by both assays. For 46 of the 49 positive specimens, LightCycler PCR and conventional PCR identified the same polyomavirus type. These samples included 30 samples with JC virus (JCV), 14 samples with BK virus (BKV), and 2 samples in which both viruses were detected. In the remaining three samples, both JCV and BKV were detected by the conventional assay, but only JCV was detected by the LightCycler assay. The results of this study show that the LightCycler PCR assay displays sensitivity and specificity similar to those of a conventional PCR assay. These data, combined with its rapid turnaround time for results and decreased hands-on time, make the LightCycler PCR assay highly suitable for the rapid detection and differentiation of JCV and BKV in the clinical laboratory.

 

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
VARIANTS
Progressive multifocal leukoencephalopathy in HIV infection presenting as Balint's syndrome.	Neurology 1994 Jul;44(7):1339-40 Abstract quote We report a patient with AIDS presenting with Balint's syndrome. CT and MRI showed the characteristic lesions of a progressive multifocal leukoencephalopathy, which was confirmed by histologic examination.

 

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL
Stereotactic brain biopsy for diagnosis of progressive multifocal leukoencephalopathy. Prayson RA, Estes ML. Department of Pathology, Cleveland Clinic Foundation, OH 44195-5138.	South Med J 1993 Dec;86(12):1381-4, 1394 Abstract quote We describe three patients in whom the diagnosis of progressive multifocal leukoencephalopathy (PML) was made by stereotactic biopsy. All three patients had a rapidly progressive clinical course pathologically characterized by demyelination, Alzheimer I astrocytes, and basophilic intranuclear inclusions in oligodendrocytes. In each case, the diagnosis was confirmed with immunohistochemical staining of oligodendrocytes for the JC virus and in one case by electron microscopy. Determination of the adequacy of tissue received at the time of frozen section is critical and can direct the appropriate submission of tissue to maximize available diagnostic procedures.
Pathomorphological variations of the AIDS-associated progressive multifocal leukoencephalopathy. Mossakowski MJ, Zelman IB. Department of Neuropathology, Medical Research Centre, Polish Academy of Sciences, Warszawa.	Folia Neuropathol 2000;38(3):91-100 Abstract quote Pathological analysis of 20 cases of the progressive multifocal leukoencephalopathy (PML) appearing in the course of acquired immune deficiency syndrome (AIDS) is presented. PML occurred in 10% of all AIDS cases, collected in the period from 1987 to 1999. PML appeared either as the only brain pathology or accompanied HIV-related brain alterations isolated or concomitant with one or several opportunistic infections and/or neoplastic growth (malignant lymphoma). Basing on the pathomorphological picture and clinical symptomatology early, atypical and severe forms of the disease were distinguished. All of them were characterized by typical PML demyelination with oligodendroglial and astrocytic pathology. The group with early changes revealed widespread, multifocal myelin alterations of a moderate intensity with predominant oligodendroglial abnormalities and less advanced astrocytic changes. Atypical form of the disease was represented by cases with unifocal changes, although containing all key elements of PML pathology. The leading pathological feature of the severe form of the disease consisted in a particular intensity of the demyelination, resulting in tissue destruction often with its cavitation, with typical glial reaction and intense macrophage and lymphocytic infiltration. The other distinguishing feature consisted in strong topographic prevalence of the pathological process either to brain hemispheres or cerebellum. Differences of PML pathology in the course of AIDS as compared with non-AIDS cases are discussed. Due to the relatively high frequency of cases of isolated or strongly predominant involvement of cerebellum, separation of the cerebellar form of the disease has been suggested.
VARIANTS
Presence of papova-like viral particles in cerebrospinal fluid of AIDS patients with progressive multifocal leukoencephalopathy. An additional test for "in vivo" diagnosis. Orefice G, Campanella G, Cicciarello S, Chirianni A, Borgia G, Rubino S, Mainolfi M, Coppola M, Piazza M. Second Department of Neurology, Medical School, Federico II University, Naples, Italy.	Acta Neurol (Napoli) 1993 Oct;15(5):328-32 Abstract quote An "in vivo" diagnosis of progressive multifocal leukoencephalopathy (PML), a neurological opportunistic viral infection in AIDS patients, can be made only by brain biopsy. In order to identify viral particles, we examined the cerebrospinal fluid (CSF) of 15 AIDS patients with focal neurological signs by electron microscopy using negative staining technique. In 2 out of 3 patients with clinical and neuroradiological presumptive diagnosis of PML, the CSF examination revealed papova-like viral particles. Our results support the hypothesis that the severe cell-mediated immunodeficiency reactivates papovavirus from a latent state in the brain, leading to PML. Therefore, the CSF study by negative staining might be a useful test for an "in vivo" diagnosis of PML.

 

SPECIAL STAINS/IMMUNOPEROXIDASE/ OTHER	CHARACTERIZATION
SPECIAL STAINS
IMMUNOPEROXIDASE
Progressive multifocal leukoencephalopathy (PML) in AIDS and in the pre-AIDS era. A neuropathological comparison using immunocytochemistry and in situ DNA hybridization for virus detection. Schmidbauer M, Budka H, Shah KV. Neurologisches Institut, Universitat Wien, Austria.	Acta Neuropathol (Berl) 1990;80(4):375-80 Abstract quote Twenty-five brains with definite, and three brains with possible, progressive multifocal leukoencephalopathy (PML), including six brains of AIDS patients, were studied with special regard to the detection of papovaviruses. Formalin-fixed serial paraffin sections were immunostained with monospecific anti-JC virus (JCV) and genus-specific anti-simian virus (SV) 40 antisera, and hybridized in situ with DNA probes for JCV and SV 40, respectively. Immunocytochemistry (ICC) and in situ hybridization (ISH) were similarly sensitive in detecting virus in classical PML lesions. In all but one definite PML cases at least one method detected virus (96%). Possible PML tissue was never labeled. Labeling patterns were generally similar in ICC and ISH: mainly oligodendroglia and, less frequently, astroglia harbored virus, whereas labeling of neurons and endothelia was absent. Bizarre giant astrocytes were occasionally labeled by ICC and ISH. Burnt-out lesions harbored JCV DNA but not virus antigens. SV 40 DNA was never detectable. PML morphology in AIDS cases did not usually differ from the disease process seen in the pre-AIDS era. However, two AIDS brains presented extremely extended and, in one case, unusually necrotizing PML damage; in the latter case, PML lesions contained large amounts not only of JCV, but also of human immunodeficiency virus (HIV) antigens. We conclude that ICC and ISH are methods of comparable sensitivity for detection of papovavirus in fluorishing PML lesions. In burnt-out PML lesions only ISH may detect virus. The possibility of an exceptional non-JCV (e.g., SV 40) etiology of PML could be neither confirmed nor disproved. In AIDS, massive coinfection by HIV of PML lesions may increase damage to tissue, resulting in unusually extended and necrotizing PML.
Diagnosis of progressive multifocal leukoencephalopathy by stereotactic brain biopsy utilizing immunohistochemistry and the polymerase chain reaction. Silver SA, Arthur RR, Erozan YS, Sherman ME, McArthur JC, Uematsu S. Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland.	Acta Cytol 1995 Jan-Feb;39(1):35-44 Abstract quote This report describes the diagnosis of progressive multifocal leukoencephalopathy (PML) in nine patients using cytopathologic and histopathologic examination of computed tomographically guided stereotactic brain biopsies in combination with immunostaining for SV-40-related antigen and the polymerase chain reaction (PCR) for the JC virus. In four patients the diagnosis of PML was based on the microscopic appearance of the biopsies and immunostaining for SV-40-related antigen. In one of these patients the diagnosis was also supported by PCR for the JC virus. In two patients whose biopsies were only suggestive of PML, a definitive diagnosis was possible utilizing immunohistochemistry and PCR. In another case the histopathologic features were atypical of PML, and the diagnosis was established with immunostaining and PCR. The diagnosis of PML was established by PCR alone in two patients whose biopsies showed only suggestive or nonspecific findings. We conclude that the accuracy of stereotactic biopsy in the diagnosis of PML is enhanced by using a combination of light microscopy, immunohistochemistry and PCR.

 

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
Demyelinating disorders

 

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSTIC FACTORS
Predictive factors for prolonged survival in acquired immunodeficiency syndrome-associated progressive multifocal leukoencephalopathy. Berger JR, Levy RM, Flomenhoft D, Dobbs M. Department of Neurology, University of Kentucky College of Medicine, Lexington 40536-0284, USA.	Ann Neurol 1998 Sep;44(3):341-9 Abstract quote Progressive multifocal leukoencephalopathy (PML) complicating the acquired immunodeficiency syndrome (AIDS) is typically inexorably progressive with death usually occurring within 6 months of symptom onset. Occasional patients have been observed to survive longer than 1 year, often with remission of clinical features. In this study, we identify predictive factors for prolonged survival in patients with biopsy proven, AIDS-associated PML, by comparing 7 patients with survival exceeding 12 months from symptom onset with 45 patients with shorter survivals. PML was the presenting manifestation of AIDS in 5 (71.4%) of 7 long-term survivors compared with 8 (17.8%) of 45 short-term survivors. CD4 T-lymphocyte counts were substantially higher in the long-term survivors, with 3 (42.9%) of 7 having counts exceeding 300 cells/mm3 in comparison with only 1 (4.3%) of 23 short-term survivors. Contrast enhancement on radiographic imaging was observed in 3 (50%) of 6 long-term survivors in comparison with 4 (8.9%) of 45 short-term survivors. Neurological recovery and radiographic improvement were not observed in any short-term survivors but were seen in 5 (71.4%) long-term survivors. There was no association between treatment modalities and survival. Predictors of long-term survival in AIDS patients with PML include PML as the heralding manifestation of AIDS, high CD4 T-lymphocyte count at disease onset, lesion enhancement on computed tomographic scan or magnetic resonance imaging, and evidence of recovery of neurological function.
AIDS- and non-AIDS-related PML association with distinct p53 polymorphism. Power C, Gladden JG, Halliday W, Del Bigio MR, Nath A, Ni W, Major EO, Blanchard J, Mowat M. Department of Clinical Neurosciences, University of Calgary, Alberta, Canada.	Neurology 2000 Feb 8;54(3):743-6 Abstract quote A population-based analysis of progressive multifocal leukoencephalopathy (PML) showed PML frequencies of 5.1% among patients with AIDS and 0.07% among patients with hematologic malignancies, but similar clinical features of PML in both groups. Sequencing of the p53 gene, exon 4, showed heterozygosity (Arg-Pro) at codon 72 in five of six PML patients. These findings indicate that frequencies of non-AIDS- and AIDS-related PML differ markedly but p53 polymorphisms may influence the occurrence of PML in both groups.
Epidemiology and prognosis of AIDS-associated progressive multifocal leukoencephalopathy in the HAART era. Antinori A, Ammassari A, Giancola ML, Cingolani A, Grisetti S, Murri R, Alba L, Ciancio B, Soldani F, Larussa D, Ippolito G, De Luca A. National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, Rome, Italy.	J Neurovirol 2001 Aug;7(4):323-8 Abstract quote Whereas most AIDS-related neurologic disorders have reduced incidence since HAART therapy was introduced, we find that the incidence of progressive multifocal leukoencephalopathy (PML) did not significantly differ between the pre-HAART and the HAART period (OR 0.78; 95% CI 0.41-1.50). These findings were confirmed by the preliminary results of the Italian Register Investigative Neuro AIDS (IRINA) Study, a prospective multicenter study started in January 2000, which showed that PML was the second most frequently diagnosed neurologic disorder after TE. A similar proportion of cases were found in HAART-naive and HAART-experienced patients in our experience. PML was more common in the presence of HIV RNA > 500 copies/ml. Most of the cases occurring in HAART-exposed patients developed within the first 6 months of therapy. As others have reported, we find a prolonged survival in PML subjects prescribed HAART (245 days in the group treated with HAART versus 66 days in the group not treated with HAART; P at log rank = 0.001). However despite the survival benefit, AIDS-associated PML still has a serious prognosis. In fact, PML had the lowest 1-year survival probability of any cerebral disorder in our study (P = 0.0005). Our findings also confirm that CSF JCV DNA burden at baseline is a useful prognostic indicator with a threshold of 4.7 log(10) JCV copies/ml (P at log rank = 0.01) in our experience. CSF JCV DNA load at 4 weeks of follow-up and clearance of JCV-DNA from CSF are associated with a better neurologic outcome and a longer survival.
JCV-specific cellular immune response correlates with a favorable clinical outcome in HIV-infected individuals with progressive multifocal leukoencephalopathy. Du Pasquier RA, Clark KW, Smith PS, Joseph JT, Mazullo JM, De Girolami U, Letvin NL, Koralnik IJ. Department of Neurology and Division of Viral Pathogenesis, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.	J Neurovirol 2001 Aug;7(4):318-22 Abstract quote Most immunosuppressed individuals who develop progressive multifocal leukoencephalopathy (PML) have a rapid fatal outcome, whereas some become long-term survivors. We explored the impact of the cellular immune response against JC virus (JCV) on the clinical outcome of 7 HIV+ and 3 HIV- individuals with PML. Of the 4 HIV+/PML survivors, all had detectable cytotoxic T lymphocytes (CTL) specific for JCV T or VP 1 proteins compared to none of the 3 HIV+/PML progressors tested. Of the 3 HIV-/PML patients, 1 was recently diagnosed with PML and showed evidence of neurologic improvement without any treatment. This patient had CTL specific for the VP1 protein of JCV. The other 2 HIV-/PML survivors were stable 3-8 years after the diagnosis of PML. They did not have any detectable CTL against JCV. These findings suggest that JCV-specific immune response is associated with favorable outcome in HIV+ individuals with PML. The lack of detectable JCV-specific CTL in 2 HIV-/PML survivors might indicate a burnt-out disease without sufficient antigenic stimulation to maintain the cellular immune response. The detection of JCV-specific CTL in an HIV- patient recently diagnosed with PML, who was showing evidence of neurological improvement without any treatment, indicates that this finding may be used as a favorable prognostic marker of disease evolution in the clinical management of patients with PML. As the quest for an effective treatment of PML continues, JCV-specific cellular immune response deserves further attention because it appears to play a crucial role in the prevention of disease progression.
TREATMENT
Highly active antiretroviral therapy significantly improves the prognosis of patients with HIV-associated progressive multifocal leukoencephalopathy. Albrecht H, Hoffmann C, Degen O, Stoehr A, Plettenberg A, Mertenskotter T, Eggers C, Stellbrink HJ. Emory University, Atlanta, Georgia 30303, USA	AIDS 1998 Jul 9;12(10):1149-54 Abstract quote OBJECTIVE: To evaluate the impact of different antiretroviral therapies on the prognosis of AIDS patients affected by progressive multifocal leukoencephalopathy (PML). METHODS: A retrospective analysis of all HIV-infected patients admitted to hospital between 1988 and 1996 found 29 patients (25 men) with histologically or PCR-confirmed PML. Their mean age was 39.3 years. The median CD4 cell count was 40 x 10(6)/l (mean, 106 x 10(6)/l). Six patients had CD4 cell counts > 200 x 10(6)/l. Fourteen patients never received or stopped antiretroviral therapy following diagnosis (group A), 10 patients were treated with nucleoside analogues alone (group B), and five patients started highly active antiretroviral therapy (HAART) including protease inhibitors (group C). RESULTS: The median survival following the onset of symptoms was 131 days, but differed significantly between the three groups: group A, 127 days; group B, 123 days; group C, > 500 days (P < 0.0002 for the difference between group C versus group A and B, stratified log-rank test). As of July 1997, four out of five patients on HAART were still alive 391, 500, 543, and 589 days after diagnosis of PML and have either experienced a resolution of the symptoms (three patients) or had progressed very slowly (one patient). A multivariate analysis using Cox regression found younger age at diagnosis to be the only other variable associated with improved survival (P < 0.02). CD4 cell count, gender, prior AIDS diagnosis, mode of HIV transmission, and therapy with foscarnet, cytarabine, or interferon-alpha did not affect survival in this cohort (P > 0.1). CONCLUSION: This study of a large cohort of patients with confirmed PML indicates that AIDS patients with PML may benefit significantly from HAART. All patients with PML should be offered optimal antiretroviral combination therapy.
Cidofovir treatment of progressive multifocal leukoencephalopathy in a patient receiving highly active antiretroviral therapy. Razonable RR, Aksamit AJ, Wright AJ, Wilson JW. Division of Infectious Diseases and Internal Medicine, Mayo Clinic, Rochester, Minn 55905, USA.	Mayo Clin Proc 2001 Nov;76(11):1171-5 Abstract quote Progressive multifocal leukoencephalopathy (PML), a frequently fatal demyelinating disease caused by JC virus, occurs as an opportunistic infection in patients with acquired immunodeficiency syndrome. Curative therapy has been elusive, but recent reports suggest its improvement after institution of highly active antiretroviral therapy (HAART). We describe a case of PML that developed 6 months after the patient, a 55-year-old man, began to receive HAART. The PML progressed despite good virologic and immunologic response to HAART. Substantial symptomatic and radiographic improvement occurred after the addition of cidofovir to the treatment regimen. We reviewed the scientific literature on this rare occurrence of PML after institution of HAART and describe the patient characteristics, potential pathogenesis, and therapeutic options, including the successful use of cidofovir as an adjunctive agent.
Cidofovir in AIDS-associated progressive multifocal leukoencephalopathy: A monocenter observational study with clinical and JC virus load monitoring. Gasnault J, Kousignian P, Kahraman M, Rahoiljaon J, Matheron S, Delfraissy JF, Taoufik Y. Neuro-AIDS Rehabilitation Unit, Department of Internal Medicine; INSERM E109, Faculte de Medecine Paris Sud, Le Kremlin-Bicetre.	J Neurovirol 2001 Aug;7(4):375-81 Abstract quote A monocenter observational study was conducted to determine the clinical and virological effects of cidofovir added to highly active anti-retroviral therapy (HAART) in AIDS-associated progressive multifocal leukoencephalopathy (PML). Exposure to other anti-viral drugs or late initiation of cidofovir were exclusion criteria. Of the 53 consecutive patients with virologically proven PML admitted at the NeuroAIDS Unit of Bicetre Hospital between May 1996 and July 2000 and having received HAART with or without cidofovir, 46 met the inclusion criteria. Cidofovir was initiated in most cases on compassionate grounds. The 22 patients treated with HAART only (HAART group) were compared to the 24 patients treated with HAART and cidofovir (CDV group). Survival, neurological outcome assessed by the expanded disability status scale (EDSS), and monitoring of the JC virus (JCV) load in CSF were investigated prospectively. At baseline (date of initiation or intensification of HAART), both groups were similar regarding CD4 cell count, plasma HIV load, CSF JCV load, EDSS, and demographic features. Both groups had similar response to HAART in terms of plasma HIV load and CD4 cell count. At month 6, CSF-JCV load was below the detection level in 8 out of 24 (33%) patients from the CDV group and 7 out of 18 (39%) patients from the HAART group (P = 0.71). One-year cumulative probability of being alive was 62% in the CDV group and 53% in the HAART group (P = 0.72). However, an additional benefit with respect to survival was observed in patients who were given cidofovir after adjustment to the following baseline variables (CSF-JCV load, CD4 cell count, and EDSS). Despite the addition of cidofovir to HAART, no significant benefit had been observed in neurological outcome, particularly in patients with an early worsening.
Convection-enhanced intraparenchymal delivery (CEID) of cytosine arabinoside (AraC) for the treatment of HIV-related progressive multifocal leukoencephalopathy (PML). Levy RM, Major E, Ali MJ, Cohen B, Groothius D. Department of Neurosurgery, Northwestern University Medical School, Chicago, Illinois, USA.	J Neurovirol 2001 Aug;7(4):382-5 Abstract quote AIDS-related PML continues to be a relatively common and rapidly fatal infection in patients with AIDS, and no effective therapy has been established to alleviate the effects of this disease. Through the years, isolated reports and small case studies have shown somewhat encouraging results using cytosine arabinoside (AraC) in the treatment of PML. The optimism behind the use AraC for this disease began to fade with ACTG trial 243, which suggested that AraC had no benefit in patients with HIV-related PML. In this article, we provide evidence that suggests that the failure of AraC in the ACTG trial may have been due to insufficient delivery of the drug through traditional intravenous and intrathecal routes. Furthermore, we provide evidence that convection-enhanced intraparenchymal delivery of AraC may prove to be a safe and effective means of treating this infection, and we outline a clinical trial that we have recently undertaken to test this hypothesis.
Potent anti-retroviral therapy with or without cidofovir for AIDS-associated progressive multifocal leukoencephalopathy: Extended follow-up of an observational study. De Luca A, Giancola ML, Ammassari A, Grisetti S, Cingolani A, Larussa D, Alba L, Murri R, Ippolito G, Cauda R, Monforte A, Antinori A. Department of Clinical Infectious Diseases, Universita Cattolica del S Cuore, Rome, Italy.	J Neurovirol 2001 Aug;7(4):364-8 Abstract quote To analyze the clinical efficacy of cidofovir combined with highly active anti-retroviral therapy (HAART) in AIDS-related progressive multifocal leukoencepalopathy (PML), a multicenter observational study was performed. Consecutive HIV-positive patients with histologically or virologically proven PML and at least 4 weeks of treatment after diagnosis were examined: 27 patients were treated with HAART, whereas 16 patients were treated with HAART plus cidofovir 5 mg/kg intravenously per week for the first 2 weeks and every other week thereafter. JC virus DNA was quantified in cerebrospinal fluid (CSF) by PCR. Baseline virologic, immunologic, and clinical characteristics as well as HIV RNA and CD4 responses to HAART were homogeneous between the groups. The median follow-up was 132 weeks. In one case (6%), cidofovir was permanently discontinued because of severe proteinuria. One-year cumulative probability of survival was 0.61 with cidofovir and 0.29 without (log rank test P = 0.02). After adjusting for baseline CD4 counts, JC viral load in CSF, Karnofsky, and use of HAART prior to the onset of PML, the use of cidofovir was independently associated with a reduced risk of death (hazard ratio, 0.21, 95% confidence interval, 0.07-0.65; P = 0.005). A randomized study will definitively establish whether cidofovir confers significant advantage over HAART alone in AIDS-related PML.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Eight Edition. Mosby 1996.
Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.

Brain and Spinal Cord

Last Updated 12/14/2001