Final Diagnosis -- Progressive Multifocal Leukoencephalopathy


Progressive Multifocal Leukoencephalopathy (PML) associated with Immune Reconstitution Inflammatory Syndrome (IRIS).


SV40 antibody decorated the enlarged cells with bizarre, hyperchromatic nuclei (Fig. 8). JC virus was also detected in his CSF by PCR prior to surgery, but radiologically a primary CNS lymphoma was suspected. Following the histological diagnosis, the patient was treated with a tapering dose of dexamethasone and he subsequently recovered. A repeat MRI scan revealed temporal resolution of the contrast enhancing areas in the white matter.

IRIS is a relatively uncommon complication of HAART in HIV patients and may pose a diagnostic challenge to both clinician and pathologist due to its ability to mimic other space occupying brain lesions, such as an astrocytic tumor or a lymphoma in this case.

IRIS presents as a paradoxical clinical deterioration in a patient's pre-existing condition despite increasing CD4 counts and decreasing HIV-1 viral load following a recent initiation of HAART (6). Its occurrence has been reported with infections by mycobacteria, VZV, HSV and JC virus (5) IRIS can present in early or late phase of HAART. Although IRIS is a now recognized entity, its exact pathogenesis remains to be elucidated (5, 6).

On the other hand, PML is a viral induced demyelination disease caused by reactivation of latent JC polyomavirus (7). This can occur in both untreated and treated HIV patients, the latter being a result of "unmasking" latent infection by a recuperating immune system. HAART has been implicated in initiating JC virus replication or uncovering subclinical PML as well as increasing the production of cytokines (8). PML usually appears as a non-contrast enhancing area on MRI scans and the presence of contrast enhancement reflects an increased inflammatory response with breakdown of the blood brain barrier (8). Reports of PML-IRIS presenting as a pseudotumor with mass effect on the MRI have been documented (1) as seen in our case.

IRIS associated with PML has been characterised on histology as having abundant perivascular CD8 T lymphocytes and macrophages within the brain parenchyma (3). Bizarre pleomorphic, multinucleated cells whose origins may be astrocytic or histiocytic can be seen (2). These usually represent JC virus transformed cells (4). Although PML by itself can present with similar histological features i.e., abundant foamy macrophages, bizarre anaplastic cells and perivascular infiltrate of lymphocytes, the inflammatory response is usually less exuberant and is not a prominent feature (4) as compared to IRIS associated with PML.

On histology, the presence of an intense lymphocytic infiltrate associated with markedly reactive cells in the wall of the blood vessels as seen in our case could potentially mislead the uninitiated into diagnosing a lymphoma. Understandably, the discrimination between a lymphoma and a markedly reactive lymphoid infiltrate can be problematic, especially if the clinical history is not provided or if the pathologist is not familiar with IRIS associated with PML's ability to manifest as a pseudotumor featuring dense inflammation and bizarre glial cells. Careful attention to the presence of a mixed inflammatory infiltrate (containing T cells, B cells, plasma cells and histiocytes in conjunction with the bizarre glial cells) and clinical input are pivotal in arriving at the correct diagnosis. As the management differs for these 2 entities, a correct and timely diagnosis is crucial to prevent further deterioration in the patient.


  1. Gonzalez-Duarte, A, Sullivan S, Sips GJ, Naidich T, Kleinman G, Murray J, Morgello S., Germano I, Mullen M and Simpson D (2009). Inflammatory pseudotumor associated with HIV, JCV, and immune reconstitution syndrome. Neurology 72: 289-290.
  2. Gray F, Bazille C, Adle-Biassete H, Mikol J, Moulignier A and Scaravilli F (2005). Central nervous system immune reconstitution disease in acquired immunodeficiency syndrome patients receiving highly active antiretroviral treatment. J Neurovirol 11:16-22.
  3. Martinez JV, Mazziotti JV, Efron ED, Bonardo P and Jordan R and Sevlever G and Martinez M and Verbanaz SC and Salazar ZS and Pardal MF et al (2006). Immune reconstitution inflammatory syndrome associated with PML in AIDS: a treatable disorder. Neurology 67: 1692-1694.
  4. Mckeever PE. The brain, spinal cord and meninges. In: Sternberg SS, Mills SE and Carter D (eds) (2010), Sternberg's diagnostic surgical pathology. Lippincott Williams and Williams, 5th edition:376-377.
  5. Murdoch DM, Venter WD, Van Rie A and Feldman C (2007). Immune reconstitution inflammatory syndrome (IRIS): review of common infectious manifestations and treatment options. AIDS Res Ther 4: 1-10.
  6. Shelburne SA, Visnegarwala F, Darcourt J, Graviss E, Giordano TP, White Jr AC and Hamill RJ (2005). Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS 19:399-406.
  7. Sidhu N and McCutchan JA (2010). Unmasking of PML by HAART: Unusual clinical features and the role of IRIS. J Neuroimmunol 219:100-104.
  8. Tan K, Roda R, Ostrow L, Arthur J and Nath A (2009). PML-IRIS in patients with HIV infection. Neurology 72. 1458-1646.

Contributed by Yee Lin Tang, MBBS, Wai Hoe Ng, MBBS, MD, FRACS, Yih Yian Sitoh, MBBS, FRCR, Hwei Yee Lee, MBBS, FRCPath, Wai Ming Yap, MBBS, FRCPath, Khoon Leong Chuah, MBBS, FRCPA

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