MRI finds PML in some natalizumab-treated patients despite negative CSF, no symptoms


Some multiple sclerosis patients who are treated with natalizumab can have small progressive multifocal leukoencephalopathy (PML) lesions seen on MRI yet have undetectable JC virus DNA in their cerebrospinal fluid, a cross-sectional, retrospective study has revealed.

The findings show that for some people with MS, PML diagnosis could be delayed if cerebrospinal fluid (CSF) sampling is negative and patients are asymptomatic, potentially resulting in worse functional outcomes and survival rates, according to the authors, led by Martijn T. Wijburg, MD, of the MS Center at VU University Medical Center in Amsterdam.

The study also described a potential correlation between PML lesion volume and John Cunningham virus (JCV) copy numbers. “To our knowledge, this is the first study that shows an association between total PML lesion volume measured by brain MRI and CSF JCV PCR [polymerase chain reaction] results in patients with [natalizumab-associated PML]. This may have considerable implications for patient care,” the research team wrote in JAMA Neurology .

PML, a lytic infection of glial and neuronal cells by the JCV, can be diagnosed when a patient exhibits clinical symptoms, JC virus DNA is detected in CSF by PCR, and specific brain lesions are seen on MRI, according to a consensus statement from the Neuroinfectious Disease section of the American Academy of Neurology.

Dr. Wijburg and his coinvestigators reviewed data from Dutch and Belgian patients considered to have natalizumab (Tysabri)-associated PML during January 2007 and December 2014.

Patients were required to meet one of the following criteria:

• Definite or probable PML, based a positive PCR and MRI findings suggestive of PML, with or without PML symptoms.

• In the absence of a positive PCR, the presence of all four of the following features: high risk of PML development, such as positive anti-JCV serostatus and natalizumab treatment duration greater than 12 months; no MS disease activity prior to PML suspicion; MRI lesions highly suggestive of PML, with lesion characteristics as previously reported and absence of lesion characteristics suggestive of other diseases, as judged by an experienced neuroradiologist; and a lesion evolution on follow-up MRI scans suggestive of PML, including development of immune reconstitution inflammatory syndrome.

In the study of 56 patients (37 women), 9 patients (16.1%) had undetectable JCV DNA in CSF and 14 (25%) were asymptomatic for PML. At the time of PML diagnosis, the median age was 45 years, and the median natalizumab treatment duration was 43 months. Results showed that patients with a positive PCR had larger total PML lesion volumes than did those with undetectable JCV DNA (median volume, 22.9 mL vs. 6.7 mL; P = .008). Logistic regression showed that a lower PML lesion volume significantly increased the probability for undetectable JCV DNA.

The research team also observed a positive correlation between PML lesion volume and JCV copy numbers (Spearman’s rho, 0.32; P = .03). PML lesion volume was also higher in patients with PML symptoms and in patients with more widespread lesion dissemination. But no association was found between PCR results and PML lesion dissemination, signs of inflammation, or PML symptoms.

The findings appear to show that patients with a smaller PML lesion volume were more likely to have a negative test result for JCV, which may lead to a delayed diagnosis of PML. Patients with smaller lesion volume were also more likely to be asymptomatic, which may further delay a diagnosis.

“This can result in a therapeutic dilemma. Unjustly excluding PML may have serious consequences (e.g., when switching from [natalizumab] to even more potent immunosuppressive treatments, such as alemtuzumab),” they wrote.

“In patients with [natalizumab-associated PML], both the probability for a positive CSF JCV PCR result and the JCV viral load are associated with the total PML lesion volume … as a consequence, patients with smaller PML lesion volumes are more likely to have undetectable JCV DNA, and PML can thus not reliably be excluded based on a negative PCR,” they concluded.

They warned that strict pharmacovigilance by MRI “will lead to identification of smaller [PML] lesions that associate with a higher likelihood of negative polymerase chain reaction results, which hampers a formal diagnosis of [PML] and may complicate patient treatment.”

Meticulous clinical and MRI follow-up in combination with repeated CSF JCV PCR testing was warranted in these patients, the researchers advised.

They suggested that complementary PML diagnostic approaches, such as assessing intrathecal antibody synthesis to JCV by determining the CSF JCV antibody index, may also be of additional value.

“Furthermore, undetectable JCV DNA does not completely preclude the presence of JCV DNA. Further development and improvement of ultrasensitive PCR assays may improve the diagnostic accuracy in the future,” they added.

The study was supported by the Dutch Foundation for MS Research. Individual authors reported support for the research from the Charcot Foundation, the Hertie Foundation, and the National Institutes of Health. Several of the authors reported receiving consultancy fees from pharmaceutical companies.

SOURCE: Wijburg M et al. JAMA Neurol. 2018 Mar 12. doi: 10.1001/jamaneurol.2018.0094


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