Meningeal Inflammation on 7T MRI as a Tool for Measuring and Predicting Ocrelizumab Response in Multiple Sclerosis

Twenty-two (22) participants will be recruited from the University of Maryland Center for Multiple Sclerosis Treatment and Research. Participants will be included if they are aged 18-65, have a diagnosis of relapsing or progressive multiple sclerosis per revised 2010 McDonald Criteria, and are planning to begin ocrelizumab therapy for multiple sclerosis, as prescribed by their treating physician. Participants will be excluded if they are unable to undergo an MRI due to metallic implants/devices or claustrophobia, have a history of allergy to gadolinium contrast, or are unable to provide informed consent.

All participants will undergo a baseline/screening study visit prior to initiation of ocrelizumab. This will include signing of informed consent, a clinical interview to collect demographic and clinical data, a physical examination to calculate the EDSS score, and implementation of the component tests of the Multiple Sclerosis Functional Composite (MSFC). All participants will then undergo an MRI on a 7T Philips Achieva scanner (housed at the Kennedy Krieger Institute, Baltimore, MD). This will be a whole brain MRI, including 0.7mm3 resolution magnetization prepared 2 rapid acquisition gradient echo (MP2RAGE) and MPFLAIR images acquired both pre- and post-intravenous infusion of gadolinium contrast.

MP2RAGE images will be processed to create T1 maps and T1-weighted images. All images (MPFLAIR included) will be co-registered to the pre-contrast MP2RAGE T1 map. Subtraction images will be created by subtracting the pre-contrast MPFLAIR scan from post-contrast images. Regions of hyperintensity on the subtraction image will be reviewed on anatomical images, and marked as regions of leptomeningeal enhancement if they have an amorphous appearance and are present in the leptomeningeal space.

Participants who are found to have leptomeningeal enhancement on their baseline scan will be considered as having passed screening and will proceed with further study procedures. Those that do not have meningeal enhancement on a baseline scan will not return for a follow up visit.

Participants who have passed screening (and thus have meningeal enhancement on their baseline scan) will then undergo initiation of ocrelizumab per clinical trial or commercial drug protocol as previously planned by their treating neurologists. Participants will then return for a follow up visit within 1 month after their 12 month ocrelizumab infusion. All of the above study procedures will be repeated on that date.

Follow up images for each subject will undergo co-registration to the pre-contrast MP2RAGE T1 map. This will allow co-registered review of baseline and 1 year follow up MPFLAIR images side-by-side for review of the presence or absence of enhancing foci noted at baseline on the 1 year follow up scan. Subtraction images will also be created utilizing the 1 year pre- and post-contrast MPFLAIR scan for quantification of the number of enhancing foci on the 1 year follow up scan by the same procedures as above. A semi-automated region growing painting tool will be used to create masks over areas of contrast enhancement, which will be used to quantify enhancing focus volume on the baseline and follow up scan. Further, subtraction mapping will be utilized to highlight regions of hypointensity present in the cortex on MP2RAGE T1 that were not present on baseline MP2RAGE T1, which would indicate a new cortical lesion at follow up.

Inclusion criteria

• A diagnosis of relapsing or primary progressive multiple sclerosis according to revised 2010 McDonald Criteria
• Ages 18 to 65, inclusive
• Have been prescribed ocrelizumab by their treating physician for treatment of multiple sclerosis, with the 1st infusion to occur within 30 days of enrollment

Exclusion criteria

• Inability to provide informed consent
• Inability to undergo MRI due to implantable devices or metallic foreign bodies considered unsafe in the MRI magnet
• Known severe allergic reaction (anaphylaxis) in the past to gadolinium contrast
• A current diagnosis of severe kidney failure and/or use of hemodialysis
• Currently pregnant or lactating
• History of a seizure disorder