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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.
JC virus (JCV) is the etiological agent of progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease of the central nervous system (CNS). During the acquired immunodeficiency syndrome (AIDS) epidemic, it was the cause of the death in up to 8% of AIDS patients. The genomic organization of JCV and, in particular, the hypervariability of the transcriptional control region (TCR), a regulatory noncoding region, are well known. Given that the TCR plays a central role in the viral replication of JCV, a crucial role in the determination of the neurotropism and in the pathogenic capabilities of the virus is also suspected. Here the authors describe a case of PML that did not respond to highly active antiretroviral therapy (HAART) therapy. There was a simultaneous presence of JCV strains with four different TCR structures in urine, peripheral blood cells, serum, and cerebrospinal fluid (CSF) samples. These data confirmed that the presence of the archetype TCt is restricted to urine, while also suggesting that the degree of the rearrangement varies and increases from the peripheral blood to CSF.
The case of a 40-year-old homosexual male with A.I.D.S. (Acquired Immune Deficiency Syndrome) and P.M.L. (Progressive Multifocal Leukoencephalopathy) is described. The importance of a brain biopsy for diagnostic procedures, especially in the case of a patient with A.I.D.S. is stressed. The diagnosis P.M.L. has been made by means of light- and electronic microscopical examination, and the presence of JCV-DNA in the brain tissue has been confirmed by dot hybridization. Various antiviral treatments did not show any effect on the course of the P.M.L.
OBJECTIVE: To evaluate the presence of thallium-201 brain uptake determined by thallium-201 brain SPECT (Tl-201 SPECT) in patients with progressive multifocal leukoencephalopathy (PML) and AIDS. MATERIAL AND METHODS: Six AIDS patients with stereotactic biopsy diagnosis of PML were prospectively evaluated with Tl-201 SPECT, Magnetic Resonance Imaging (MRI), and proton magnetic resonance spectroscopy (1H-MRS). Tl-201 SPECT results were compared with 2 patients with AIDS and biopsy proven primary CNS lymphoma. RESULTS: In all patients with PML, Tl-201 SPECT studies showed lack of uptake while MRI demonstrated subcortical white matter focal brain lesions and 1H-MRS disclosed metabolic abnormalities. Intense thallium uptake (uptake ratios of 3.2 and 5.6) was demonstrated in the 2 patients with primary CNS lymphoma. CONCLUSIONS: The present study shows that PML lesions are not detectable on Tl-201 SPECT while MRI and 1H-MRS demonstrate abnormalities, and intense thallium-201 uptake may be detected in primary CNS lymphoma. These results suggest that Tl-201 SPECT is a method which, combined with other non-invasive techniques such as MRI and 1H-MRS, may help in the diagnostic approach of PML and to differentiate PML from other high proliferative brain lesions characterized by positive thallium uptake.
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-naïve 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.
BACKGROUND: The clinical, neuroimaging, virologic and evolutive characteristics of progressive multifocal leukoencephalopathy (PML) in 35 AIDS patients are studied. PATIENTS AND METHODS: PML was diagnosed by clinical and neuroimaging criteria in 32 patients and by autopsy in other three. The detection of JC virus (JCV) was done by PCR and further hybridization of the amplified DNA in peripheral blood lymphocytes, urine and CSF. RESULTS: 127 of 930 HIV positive patients were admitted by neuropsychiatric symptoms and of them 35 (SD 27.6%) by PML. The PML patients had a mean CD4 lymphocytes count of 75.3 (82.0)/x 10(6)/l and a HIV viral load of 330,698 (538,971) copies of RNA/ml. Thirty patients did not receive any anti-retroviral therapy or only transcriptase inhibitors monotherapy and five triple anti-retroviral therapy, including a proteases inhibitor. Multiple hypodense lesions on CT (53.1%) and T2 hyperintense lesions on MRI (58.3%) were the most frequent neuroimaging findings. JCV was detected in 20/21 (95.2%) LMP patients: 18/19 detections in lymphocytes, 6/8 in CSF and 4/6 in urine. The mean survival without and with antiretroviral therapy were 3.0 (0.47) and 21.4 (4.4) months (p < 0.001) in 34 patients followed. PML progressed to death in 31/34 patients (91.2%), and remained stable in 3/34 (8.8%). A patient was lost for follow-up. CONCLUSIONS: The application of clinical and neuroimaging criteria and the detection of JCV in CSF are useful for high presumption diagnosis of PML without brain biopsies. JCV detection in lymphocytes and in urine have a much lower predictive value. The evolution and survival of this disease can improve with triple anti-retroviral therapy including a protease inhibitor.
Ninety-one brain tissue sections taken at autopsy from 33 elderly patients (63-100 years old) without progressive multifocal leukoencephalopathy were examined for the presence of JC virus DNA by the polymerase chain reaction and Southern hybridization analysis after DNA extraction. JC virus DNA was detected in 15 sections from 10 patients. These results suggest that JC virus is frequently present in the brains of aged patients.
JC virus (JCV) DNA was detected by polymerase chain reaction (PCR) amplification in the cerebrospinal fluid (CSF) of 10 of 13 patients with a diagnosis of progressive multifocal leukoencephalopathy (PML) previously confirmed by histological and virological techniques. It was not found in 42 CSF samples from 41 patients who did not have PML. Four sets of primers were used to amplify polyomavirus DNA. One was from the region of the genome coding the T antigen, a conserved region common to JC and BK viruses. A second set nested to these was used as a confirmatory test in a secondary PCR. The remaining two were from the region of the genome coding VP1, one specific for JCV and the other for BKV. CSF did not inhibit the PCR and preliminary DNA extraction was not considered necessary.
In the era of the AIDS pandemic, progressive multifocal leukoencephalopathy (PML) has ceased being a rare disease. Prevalence estimates from clinical and pathological series suggest that up to 5% of all HIV-infected persons will develop PML. The extraordinary frequency with which PML attends HIV infection vastly exceeds its appearance in association with other predisposing conditions and has resulted in it no longer being considered a rare disorder. Why PML appears to be far more common with AIDS than with other underlying immunosuppressive conditions remains unexplained. Potential explanations include an alteration of the CNS milieu by HIV facilitating JC viral entry into the brain and activation of the JCV by HIV proteins, e.g., tat, and by inflammatory byproducts of HIV infection. It is quite likely that multiple diverse mechanisms are at play.
A 46-year-old woman with relapsing-remitting multiple sclerosis died from progressive multifocal leukoencephalopathy (PML) after having received 37 doses of natalizumab (300 mg every four weeks) as part of a clinical trial of natalizumab and interferon beta-1a. PML was diagnosed on the basis of the finding of JC viral DNA in cerebrospinal fluid on polymerase-chain-reaction assay and was confirmed at autopsy. Nearly every tissue section from bilateral cerebral hemispheres contained either macroscopic or microscopic PML lesions. There was extensive tissue destruction and cavitation in the left frontoparietal area, large numbers of bizarre astrocytes, and inclusion-bearing oligodendrocytes, which were positive for JC virus DNA on in situ hybridization.
This case report describes a 78-year old female patient with chronic lymphocytic leukaemia and neurological symptoms due to progressive multifocal leukoencephalopathy (PML). At autopsy the histopathology was characteristic, the involvement of JC virus was established. PML occurs in immunocompromised patients and is caused by infection with JC papova virus. Epidemiology, clinical course, diagnostic procedures with special reference to the use of the polymerase chain reaction, and therapy are briefly reviewed.
This study was carried out to determine clinical features, abnormalities on CT scan and MRI, and course in patients with HIV-I-related progressive multifocal leukoencephalopathy (PML). There were 14 patients with a presumptive diagnosis of PML among 500 HIV-I infected patients with neurological complaints, examined between September 1982 and May 1991 in the University Medical Centre in Amsterdam by a neurologist. In these 14 patients clinical features, imaging abnormalities and course of the disease were analysed retrospectively. All patients presented with progressive focal neurological abnormalities. Cerebrospinal fluid analysis revealed aspecific abnormalities in 5/13 patients. CT scanning of the brain showed hypodense areas in the white matter, without mass effect and with contrast enhancing in only one patient. MR Imaging of the brain showed high signal intensity areas in white matter and in gray matter (10/13), without mass effect, and with contrast enhancement in two. Specimens for neuropathological examination were obtained from 7 patients; in all these cases the diagnosis of PML was confirmed. In patients with AIDS a presumptive diagnosis of PML can be based on clinical features, brain imaging abnormalities and course. However neuropathological confirmation remains the gold standard. Usually the course in these patients was steadily progressive. Most patients died within one year.
Cerebrospinal fluid (CSF) from 12 AIDS patients with clinical signs consistent with progressive multifocal leukoencephalopathy (PML) was examined by the polymerase chain reaction (PCR) for the presence of JC virus (JCV). A specific JCV target sequence was amplified in the CSF from 9 of the 12 patients and also in brain tissue from all nine JCV-positive patients. The clinical course, neuroimaging features, and, in four cases, histopathology of brain tissue proved that the nine patients had PML. In the other three patients with central nervous system disorders, the JCV genome was undetectable by PCR and Southern blot analysis in CSF and brain tissue. The clinical course and neuroimaging features ruled out PML in these three patients. Five CSF samples and five brain tissue specimens from 10 PML-free AIDS patients with central nervous system disorders were all negative for the JCV genome by PCR and Southern blot analysis. These results show that detection of JCV in CSF by PCR is a good alternative to brain tissue studies for the virological diagnosis of PML in AIDS patients.
Inclusions identical to those described in multiple sclerosis (MS) brain by Prineas (1975) have been seen by ultrastructural study of cerebral tissue in two elsewhere reported cases of Progressive Multifocal Leukoencephalopathy (PML). The meaning of these formations, which have been suggested to be related to a special process of demyelination in MS, is discussed in the light of the hypotheses concerning the demyelination mechanism in PML. Whatever might be their significance, these cytoplasmic non viral inclusions are not specific for MS.
Infection of the cerebral cortical neurons with JC virus (JCV) with possible dysplastic ganglion-like alteration of the infected neurons found in a case of progressive multifocal leukoencephalopathy (PML) is described. The patient was a 21-year-old man with common variable immunodeficiency who died of PML after a 9-month clinical course. At autopsy, the white matter of the cerebrum, brainstem, cerebellum, and spinal cord exhibited extensive demyelination and necrosis. Numerous inclusion-bearing oligodendrocytes and bizarre astrocytes were found. In the occipital and temporal cortex, thick band-like aggregates of dysplastic ganglion-like cells (DGLCs) were found. These DGLCs showed immunohistochemical properties of neurons, and nuclei of some DGLCs were immunoreactive for large T antigen of SV40/JCV and p53, but not for capsid protein JCV VP1. In situ hybridization for mRNA of JCV large T antigen revealed positive signals in the nuclei of some DGLCs. These results indicate that JCV infected neurons and it is suggested that binding of the large T antigen with cellular proteins could have resulted in the dysplastic, ganglion cell-like change of the infected neurons, although the possibility that the aggregates of DGLCs represent a pre-existent malformative lesion of the cortex cannot be excluded completely.
In situ hybridization (ISH) for JC virus (JCV) is generally applied for the diagnosis of progressive multifocal leukoencephalopathy (PML). To explore the usefulness of immunohistochemistry (IHC) for JCV early proteins, 14 paraffin-embedded postmortem brain specimens with histologic features compatible with PML were tested for the presence of JCV by means of DNA-DNA ISH with a biotinylated probe corresponding to the entire JCV genome, for JCV early proteins IHC with both PAb 2003 and anti-SV40 large T antigen monoclonal antibodies, and polymerase chain reaction (PCR) amplification of JCV virion protein 3 (VP3) and transcriptional control region (TCR) sequences. ISH was positive in 13 cases and IHC in all 14 cases, the number of IHC-positive cells generally being far in excess of ISH-positive cells. Of the 2 monoclonal antibodies used, PAb 2003 proved to be more sensitive than anti-SV40 large T antigen. Occasional neuronal nuclei were positive for JCV early proteins in 5 cases. As for PCR, VP3 was amplified in all 14 cases and TCR in 9 cases. Consequently, PAb 2003 IHC for JCV early proteins seems to be a powerful tool for viral demonstration in PML and may well become the diagnostic recourse of choice in this setting.
A 34-year-old man who used intravenous drugs developed the acquired immunodeficiency syndrome with lymphadenopathy, Mycobacterium tuberculosis pneumonia, and progressive multifocal leukoencephalopathy. Early biopsy specimens of the lymph node showed hyperplasia without evidence of lymphoma. Later, immunologic analysis of peripheral blood lymphocytes showed inversion of the helper/suppressor T-lymphocyte ratio and persistent monoclonal B-cell proliferation without clinically overt lymphoma. The clinical course of this patient suggests that abnormal immune responses seen in the setting of the acquired immunodeficiency syndrome may evolve into lymphoproliferative disorders detectable by peripheral blood lymphocyte analysis.
The authors investigated the effect of highly active antiretroviral therapy (HAART) on the onset and outcome of progressive multifocal leukoencephalopathy (PML) in a group of 43 patients with histological or clinicovirological diagnosis of PML. In eight of these cases (19%), PML symptoms presented 21 to 55 days after the start of HAART, concomitantly with a CD4 cell-count increase and plasma human immunodeficiency virus type 1 (HIV-1) RNA load (VL) decrease. Four of these patients died of PML. Apart from baseline VL, we did not identify any other variable that could distinguish these forms of immune reconstitution PML from those occurring in patients either untreated or failing to respond to therapy. To compare the viroimmunological response to HAART with PML outcome, we evaluated a subgroup of 23 patients untreated at the time of PML onset. No different pattern of response to HAART was observed between patients who died or survived to PML. However, start of HAART was delayed of > or =3 months after onset of PML in half of the latter patients. In conclusion, HAART-associated immune reconstitution seems to play a role on development of a substantial number of PML cases. Although the authors could not demonstrate a directly deleterious effect of HAART on PML progression, prompt initiation of HAART after diagnosis of PML and subsequent successful response were often associated with bad PML outcome.