A 58 Year‐Old Male with Hallucinations and Ataxia

Clinical History and Radiology

A 58 year old Caucasian male presented with weight and appetite loss over 2 to 3 months. He was recently diagnosed with HIV infection. His initial CD4 count was < 20 cells/mm³ (7%) with a viral load of 352000 copies/ml. He was started on highly active antiretroviral therapy (HAART) and in the third month of therapy, he presented with increasing hallucinations and ataxia. Serologies for hepatitis A, hepatitis B, CMV, toxoplasma, syphilis, tuberculosis (TB) and Cryptococcus neoformans were negative. His CSF profile was negative for Cryptococcus neoformans, TB, HSV, CMV, toxoplasma, VZV and EBV were negative. In addition, his CD4 count rose to 202 cells/mm³ with a viral load of 425 copies/ml.

MRI showed an area of heterogeneous contrast enhancement affecting the deep nuclei as well as white and grey matter tracts with extension into the deep white matter of the right frontal, temporal and parietal lobes. This area exhibited mild mass effect compressing on the left lateral and third ventricles with early midline shift to the left (Fig. 1a). In view of the radiological findings, a clinical diagnosis of lymphoma was considered and the patient underwent a brain biopsy to ascertain the nature of the brain lesion.

Figure 1.

 

Pathology

Grossly, multiple fragments of brain tissue measuring 2x1x1cm were received. On light microscopy, there was a prominent and dense perivascular infiltrate of lymphoid cells distending the walls of the blood vessels (Fig. 1b), raising the suspicion for a neoplastic lymphoid proliferation. On closer scrutiny, the inflammatory cells comprised atypical medium to large lymphoid cells with some degree of irregular nuclear outlines (Fig. 1c). Some smaller lymphoid cells accompanied the infiltrate. Significantly, the adjacent brain parenchyma showed a mixture of foam cells, similar lymphoid cells as those described above and plasma cells. Interestingly, an occasional enlarged cell with bizarre and hyperchromatic nuclei was present within the inflammatory background (Fig. 1d). Microglial nodules were also seen in some parts of the tissue. No acid fast bacilli and fungal organisms were noted on Ziehl Neelsen stain and Grocott methenamine silver stain respectively.

On immunohistochemistry, CD3 and CD20 stains highlighted the perivascular and brain parenchyma lymphoid cells with a predominance of CD 3+ T lymphocytes in the latter. CD163 confirmed the presence of histiocytes in the inflammatory lesion which assumed the appearance of foam cells in several places. Stains for toxoplasmosis and CMV were negative. Neurofilament stain confirmed the presence of the axonal processes in the areas with the histiocytes. A viral immunostain was diagnostic (Fig 1e). What is your diagnosis?

Diagnosis

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

Discussion

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.