The clinical features of PML

DIAGNOSIS

The most reliable and accurate method for the diagnosis of PML remains brain biopsy that demonstrates the characteristic triad of histopathologic findings (demyelination, bizarre astrocytes, and enlarged oligodendrocyte nuclei) coupled with evidence of JCV infection. With respect to the latter, in situ hybridization or immunocytochemistry can be employed. In situ DNADNA hybridization is a method of annealing JCV DNA to complementary strands either in paraffin-embedded tissue or in frozen sections from biopsy samples.

In immunocytochemistry, antibodies to both T antigen and the common polyomavirus capsid antigen are used to detect cells undergoing productive viral infection. Cells that are positive by in situ hybridization are in a stage of active viral replication. Cells positive by immunocytochemistry that are expressing viral capsid antigens are in a stage of viral transcription and translation (ie, undergoing productive infection). In addition to their utility in confirming a diagnosis of PML, these techniques have demonstrated the presence of JCV in perivascular locations and at sites distant from foci of demyelination. Alternatively, PCR may be used to demonstrate JCV in brain tissue.

In the absence of biopsy, which few deem necessary today, a widely employed approach to diagnosis requires the demonstration of:

• JCV in the CSF by PCR
• Compatible clinical presentation
• An MRI finding consistent with PML
• No other alternative diagnosis.

With an ultrasensitive PCR technique, sensitivities should approach or may exceed 95%, but PCR sensitivity remains at 75% in some laboratories. Because the viral copy numbers in the CSF may be low, particularly in a patient treated with a monoclonal antibody such as natalizumab, the CSF PCR may be falsely negative.

If clinical suspicion of the disease remains high in the face of an initially negative CSF JCV, the CSF analysis should be repeated. CSF analysis for JCV is approximately 99% specific, but recent studies demonstrating low copy numbers of JCV in the CSF of patients with MS have raised concerns about potential pitfalls of this assay.²⁰

PROGNOSIS

Until recently, PML was regarded as virtually universally fatal. The mean survival in the pre-AIDS era was approximately 6 months, and mortality was 80% within 9 months of disease onset. Rarely, patients had long survivals that ranged from 5 years to 19 years.

In the early years of the AIDS era, survival with PML did not appear to differ significantly from that observed in the pre-AIDS years. In the largest study of HIV-associated PML in the era prior to HAART, the median survival was 183 days.² However, the majority of individuals were dead within 3 months of diagnosis. Only 8% to 10% of patients survived longer than 12 months, which has been regarded as “prolonged survival.” This long survival skewed the mean and median survival rates in this population.

Several factors have since been identified that correlate with prolonged survival in HIV-associated PML, including PML as the heralding manifestation of HIV, CD4 counts exceeding 300 cells per mm³, contrast enhancement of the lesions on radiographic imaging, low copy number or decreasing JCV titers in CSF,^21–24 and the presence of JCV-specific cytotoxic T cells.²⁵ A better prognosis has also been postulated for higher CSF levels of macrophage chemoattractant protein-1²⁶ and PML associated with JCV VP1 loop-specific polymorphisms.²⁷

Prognosis of HIV-associated PML improves with immune system restoration

In the era of HAART, not only has the incidence of HIV-associated PML declined, but the prognosis of affected patients has improved as well. This development highlights the importance of restoration of the immune system in both disease prevention and survival. Some estimate that as many as 50% of HAART-treated patients with PML exhibit prolonged survival. In one study of 25 patients, the median survival was more than 46 weeks.²⁸

Nonetheless, PML continues to have the worst prognosis of any AIDS-related cerebral disorder, with those having advanced immunosuppression being most susceptible to the disorder. For AIDS patients with PML, those who were HAART-naïve at the time of diagnosis appear to have better survival than treatment-experienced patients.²⁹ Survival also correlates with reduced JCV load in the CSF³⁰ and improved CD4 lymphocyte counts (CD4 counts > 100 cells/mm³).³¹

Prognosis of natalizumab-associated PML is different

The prognosis of natalizumab-associated PML differs from that of HIV-associated PML. In a series of 35 patients, 25 (71%) patients were alive on average 6 months after diagnosis.³² Prognosis was worse with a longer time to diagnosis and the presence of widespread disease.

Most deaths in patients taking natalizumab who developed PML have occurred during IRIS. Steroid treatment of IRIS appears to improve prognosis,⁸ but no scientifically rigorous study has been undertaken to demonstrate this recommendation.⁷ Among the survivors, neurologic deficit was mild in one-third, moderate in one-third, and severe in one-third of patients.

CONCLUSION: DISPELLING SOME MYTHS

Several assumptions about PML are not necessarily true. For example, although PML implies the presence of multifocal lesions as a characteristic of the disease, the lesions may be monofocal, especially with natalizumab-associated PML. The lesions of PML may show early gadolinium enhancement on neuroimaging. Although lesions typically are seen in subcortical white matter, cortical involvement also may be observed. Cerebellar granular cell degeneration may occur in association with PML or in isolation. Disease progression and death are not inevitable, even in the absence of treatment. The most important determinant for survival is restoration of the immune system.

DISCUSSION

Dr. Calabrese: Why are sensory deficits so common?

Dr. Berger: We don’t know. Because we see involvement in the parietal lobe, we would anticipate observing sensory deficits. I think that a lot of sensation occurs deep in the thalamic area, which is not often involved in PML. Also, we often don’t test for some of the deficits that may occur.

Dr. Rudick: Do you know of any cases of natalizumab-associated PML detected as an incidental finding on MRI, making a case for screening MRI in patients without clinical symptoms?

Dr. Berger: There have been a handful of cases, including one of the seminal cases of natalizumab-associated PML, in which MRI abnormalities were observed in advance of clinically recognized symptomatology.

Dr. Calabrese: The correlate question is, if a patient with a risk factor—be it HIV or treatment with a biologic agent—has a common neurocognitive sign or perhaps some subtle motor findings, does a normal MRI have 100% negative predictive value?

Dr. Berger: I have yet to see somebody with PML who has a normal MRI.

Dr. Simpson: What you may see are lesions that are not typical MRI lesions of white matter hypointensity. In some cases, as Dr. Berger mentioned in his summary, we’ll see cerebellar degeneration—atrophy—but not necessarily white matter lesions.