Imaging Biomarker Diagnoses PML in Patients Taking Natalizumab for MS

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“Punctate pattern” lesions were observed in the brains of patients with PML and not in the control images.
“Punctate pattern” lesions were observed in the brains of patients with PML and not in the control images.

A group of T2 weighted hyperintensities that disseminate in what is called a “punctate pattern” (PP) may directly precede the appearance of progressive multifocal leukoencephalopathy (PML) lesions, according to a new study published in Neurology.1

When used in patients taking natalizumab (NTZ) treatment for multiple sclerosis (MS), investigators reported class II evidence that PP accurately identified patients with PML, although it does not differentiate PML from causes other than NTZ.

Investigators from multiple neuroradiological facilities in France accurately identified PP in 18 out of 20 MRIs from patients with PML, only 14 of which were NTZ associated.

The emergence of PML in patients given NTZ has been a major concern in the use of a drug that has demonstrated good efficacy in relapsing remitting MS (RRMS). Using a Biogen risk algorithm2 from 2012 to update data as of 2015, an estimated 134 600 people with MS have been treated with NTZ, with an ensuing incidence of PML of 3.87 per 100 000 patients (95% confidence interval: 3.55-4.21 per 1000 patients).1 

The algorithm showed that risks of PML are increased when a patient carries high level of anti-John Cunningham virus antibody, has a history of immunosuppressant therapy prior to NTZ treatment, and when duration of therapy exceeds 2 years.

A reassessment of PML risk published in the Journal of NeuroVirology in February showed that NTZ-PML risk in the presence of all 3 factors is 1 in 44.3

Mortality from PML is high and the disease progresses rapidly, and so early diagnosis at a presymptomatic stage while the virus may still be localized is critical to survival and functional outcomes.1,2 Investigators explained that although MRI imaging is frequently used in MS, it is difficult to distinguish PML lesions from MS lesions. The identification of PP in the vicinity of the PML in what was described as a “milky way” or “star-like” formation is the first clear MRI evidence of presymptomatic PML.

A total of 147 MRIs from 20 RRMS patients were examined for the study, including 11 images taken at the presymptomatic stage, 48 at the symptomatic stage (within 2 weeks of PML clinical diagnosis), 53 in patients diagnosed with immune reconstitution inflammatory syndrome (IRIS), and 35 taken from patients in chronic stages of disease (at least 3 months after identification of IRIS).

Another 227 images taken from a control group of 80 people without MS were randomly interspersed with the PML images for blinded review by 3 radiologists.

Punctate pattern lesions were observed in the brains of patients with PML and not in the control images. Twenty-four regions were involved, including right and left frontal and parietal regions, the pons, and the middle cerebellar peduncles. Uncontested PP was viewed on both nonenhancing and enhancing T1 weighted postcontrast images, although there was disagreement in at least 1 case on 3D FLAIR or T2 weighted images.

The clarity of PP on MRI increased with disease severity, with nonenhancing lesions more evident in earlier stages. Seven of 9 patients in early stages of PML, and 13 of 15 patients in the symptomatic stage demonstrated PP on MRI. By the IRIS stage of PML, a greater number of enhancing PP lesions was evident in a “rim-like” pattern on the MRIs of 16 out of 20 patients. The number of lesions then appeared to decrease in chronic stages of disease, and there were none of the nonenhancing type.

Investigators observed that both NTZ-PML lesions and PP tended to be found in subcortical regions of the brain, pointing to a need for consideration of the whole brain in searching for PML lesions. They also reported a benefit to diffusion-weighted imaging (DWI) in accurately identifying PP lesions in symptomatic and IRIS stages of disease. “However, due to the low spatial resolution inherent to this technique,” the authors wrote, “comparison of DWI with other 3D high-resolution MRI sequences may have introduced a substantial bias.”

PP was found to have high sensitivity and specificity for the diagnosis of NTZ-PML lesions in comparison to MS plaques, in this study—the first to demonstrate class II evidence in support of its potential use as a biomarker in patients taking NTZ for MS.


  1. Hodel J, Darchis C, Outteryck O, et al. Punctate pattern. A promising imaging marker for the diagnosis of natalizumab-associated PML. Neurology. 2016. doi: 10.1212/WNL.0000000000002586.
  2. New analysis of risk stratification for TYSABRI® published in New England Journal of Medicine [press release]. Cambridge, MA: Biogen; May 17, 2012.  Accessed April 7, 2016.
  3. Berger JR, Fox RJ.  Reassessing the risk of natalizumab-associated PML. J Neurovirol2016. doi: 10.​1007/​s13365-016-0431-x.

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