Meningeal Inflammation on 7T MRI as a Tool for Measuring and Predicting Ocrelizumab Response in Multiple Sclerosis
Condition: Multiple Sclerosis
MeSH terms: Multiple Sclerosis; Sclerosis; Inflammation
Study type: Observational

Summary: 
      Multiple Sclerosis (MS) is an autoimmune disorder of the central nervous system. In MS,
      inflammation is known to attack areas of the brain, spinal cord, and optic nerves; resulting
      in disability. Current MRI technology provides an adequate view of the impact of MS on the
      "white matter" of the brain, which contains many of the connections between neurons.
      Quantification of lesions in the white matter due to MS are a standard part of clinical
      trials and clinical care in MS. However, it has long been known that MS not only can affect
      the white matter, but also the "gray matter," which contains the majority of the nerve cells
      in the brain and can cause inflammation in the meninges (the protective tissue that surrounds
      the brain and spinal cord). Autopsy studies have shown that the inflammation seen in the
      meninges is driven by a B-cells, a subset of white blood cells and that meningeal
      inflammation may be responsible for damage to the gray matter of the brain.

      Ocrelizumab is a new treatment for multiple sclerosis. This medication works by targeting and
      destroying circulating B-cells. It is thought that this may reduce the level of meningeal
      inflammation in patients with multiple sclerosis. By reducing meningeal inflammation, this
      medication may result in less damage to the gray matter and subsequently less disability in
      MS patients.

      In this study, the investigators will evaluate the use of a method on 7 tesla (7T) MRI to
      identify inflammation in the meninges as a potential predictor of response to ocrelizumab
      treatment for multiple sclerosis. Further, the investigators will evaluate if this MRI
      technique can be used to monitor the long-term effect of the medication on meningeal
      inflammation and the development of damage to the gray matter of the brain.
    

Detailed description: 
      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.
    

Intervention name(s): Gadoteridol
Intervention type(s): Drug
Intervention description(s): gadolinium MRI contrast
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Patients with multiple sclerosis who have been prescribed ocrelizumab
      
Keywords: multiple sclerosis; 7T MRI; Meningeal inflammation