Progressive multifocal leukoencephalopathy in HIV-1 infection

Abstract

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.

Figures

Figure 1

Schematic representation of the JCV genome, composed by double-stranded circular DNA, 5,130 base pairs long - according to the JCV Mad-1 strain [24], and organized in three functional regions: regulatory, early and late. The regulatory region (RR, or non coding control region, NCCR) is a non-coding region that contains the origin of replication, viral promoter-enhancing sequences and binding sites for cell transcription factors. The early genes encode the regulatory proteins large T antigen (T-Ag) that regulates early gene transcription, initiates viral DNA replication and activates transcription of late proteins and small t antigens (t-Ag). The late genes code for the major viral capsid protein-1 (VP-1) that mediates cell attachment, and is likely the main target of both humoral and cellular immune responses, the minor capsid proteins VP-2 and VP-3, and the agnoprotein (agno).

Figure 2

Histopathological findings of PML. a. Early PML: white matter vacuolization, infected oligodendrocytes (arrows) with two to three times enlarged and basophilic nuclei; no inflammatory infiltrate (Hematoxylin-eosin, O.M. 20x). b. Demyelinating PML: foamy macrophages engulfing myelin debris (*), scattered inflammatory cells (**) and infected oligodendrocytes (arrow) with enlarged basophilic nuclei (Hematoxylin-eosin, O.M. 20x). c. An enlarged, bizarre-appearing astrocyte (arrow) with atypical multilobated nuclei and altered chromatin (Hematoxylin-eosin, O.M. 40x). d. In situ hybridization with JCV-specific probe, showing JCV DNA as brown nuclear staining of an infected oligodendrocyte (ISH, JC Virus BioProbe Labeled Probe, Enzo Diagnostics, hematoxilin counterstaining, O.M. 100x). Kindly provided by dr. Manuela Nebuloni.

Figure 3

MRI and histopathology findings in two cases of inflammatory PML. Case 1 (a-c). a. At PML diagnosis in a cART-naive patient: FLAIR hyperintense lesion in the right temporal lobe extending to the periventricular white matter (CD4+ cells 4/μL, plasma HIV-1 RNA 200,000 c/mL); b. After 11 weeks of cART: increased lesion size with extension to frontal and occipital lobes and mass effect, associated with neurological worsening (CD4+ cells 64/μL, plasma HIV-1 RNA 235 c/mL). c. Biopsy of PML lesion after 15 weeks of cART: perivascular lymphomonocytic infiltration (Hematoxylin-eosin, O.M. 20x). Kindly provided by dr. Pilar Miralles. Case 2 (d, e). d. Six months after onset of PML symptoms and 4 months after cART initiation in a cART-naive patient: Gd-T1 large hypointense lesion involving the right parietal and occipital lobes with marked peripheral contrast enhancement; patient was tetraparetic and aphasic (CD4+ cells: 79 c/μL; plasma HIV-1 RNA: <50 c/mL). e. Two weeks later, following intravenous methylprednisone (1 g per day for 5 days, tapered with oral prednisone): disappearance of the enhancement, associated with frank clinical improvement (patient could walk and speak).

Figure 4

MRI appearance of active PML lesions (a,d,g, T2; b,e,h, FLAIR; c,f,,i, Gd-T1 axial sequences). In all cases the lesions are hyperintense (white) in T2 and FLAIR sequences and hypointense (dark) on T1 sequences, showing no enhancement after Gd administration. a-c. Hemispheric localization: large white matter signal alteration in the left frontal lobe extending to the corpus callosum and left deep white matter, with additional FLAIR/T2 high intensity signal alterations in the right frontal and temporal lobes. d-f. Cerebellar localization: large signal alterations of the left middle cerebellar peduncle and hemisphere. g-i. Brain stem localization: focal signal alterations of the left bulb (arrow) and cerebellar hemispheres.

Figure 5

Active PML lesions at Diffusion Weighted Imaging (DWI), Apparent Diffusion Coefficient (ADC) map and Magnetic Resonance Spectroscopy (MRS)(same case of Figure 4, 1a-c). a. DWI, hyperintense signal (white) of the periphery and low intensity signal (dark) of the centre of the lesion. b. ADC map, hyperintense signal (white) of the centre and hypointensity (dark) of the lesion periphery. c. MRS, in correspondence of the centre of the lesion, increased choline (Cho) and creatine (Cr) and relative ratio (Cho/Cr), marked reduction of N-acetyl-aspartate (NAA) and lipid (lip) peak.

Figure 6

Sequential MRI in a case with favorable outcome following cART initiation (a-e, FLAIR; f-j, Gd-T1 axial sequences). a,f. At PML diagnosis: focal signal alteration of the frontal right white matter (a) with no mass effect or contrast enhancement (f); patient had motor deficit of left arm and leg; CD4+ cells: 495/μL, plasma HIV-1 RNA 262,000 c/mL, CSF JCV DNA 10,792 c/mL; cART was started immediately. b,g. Two months later: increase of both volume and FLAIR hyperintensity of the right frontal lesion (b), which shows T1 hypointensity and mild enhancement after Gd administration (g); neurological status was improved; CD4+ cells 619/μL, plasma HIV-1 RNA 4198 c/mL, CSF JCV-DNA 335 c/mL. c,g. Six months after diagnosis: additional extension of the right lesion to the adjacent areas and new onset of small hyperintensity in the left frontal white matter (c), with increased spot-like enhancement of the right lesion after Gd administration (h); neurological condition remained stable and improved from diagnosis; CD4+ cells 804 c/mL, plasma HIV-1 RNA <50 c/mL, CSF JCV DNA <100 c/mL. d,i. Twelve months after diagnosis: reduced lesion volume (d) and markedly reduced, but still evidence of, contrast enhancement of the right frontal lesion (i); enlarged subarachnoid spaces in proximity to the right frontal lesion (d), due to focal atrophy; CD4+ cells 1252/μL, plasma HIV-1 RNA <50 c/mL. e,j. Twenty months after diagnosis: further volume reduction (e) and no longer evidence of contrast enhancement of the right frontal lesion (j); further increase of the focal atrophy; CD4+ cells 1516/μL, plasma HIV-1 RNA <50 c/mL.