Studies performed under 89-N-0045 are designed to examine the natural history of multiple
sclerosis (MS) using MRI and immunological measures. In addition to studying the natural
history of untreated patients, the natural history of patients receiving approved
disease-modifying therapies of MS will be examined. In both cohorts of patients levels of
disease activity on MRI will be compared with immunological characteristics in order to help
identify disease mechanism. Patients with either definite MS (based either on clinical or
combined clinical and MRI criteria) or with an initial presentation of neurological
dysfunction consistent with MS will be studied longitudinally by MRI. Disease activity on MRI
will be assessed using several MRI measures of disease activity including the number of
contrast enhancing lesions, the overall burden of disease, brain atrophy and measures to
assess axonal damage. Patients will be assessed clinically and correlations between
immunological and genetic factors and disease activity as seen clinically or by MRI will be
A second cohort of patients starting the use of approved therapy will also be examined.
Patients referred to NIH prior to beginning approved therapy will be assessed with a series
of three monthly MRIs to determine the level of pretreatment disease activity. After
beginning approved therapy under the direction of their private physician, patients will be
followed similarly to the natural history cohort. Immunological and genetic findings will be
accessed before and during therapy in order to help establish the mechanisms of action of the
therapies and to identify mechanisms accounting for either a response or lack of response to
therapy. Part of the collected samples willl be cryopreserved to provide respository for
further studies focusing on detection of biomarkers indicative of disease state, disease
stage or repsonse to therapies.
Additionally, a cohort of normal volunteers will be studied. The studies in the normal
volunteers will be used to establish the most appropriate imaging sequences for studying
normal white matter in MS patients using magnetization transfer (MT) imaging sequences for
studying normal white matter in MS patients using magnetization transfer (MT) imaging and to
provide normative immunological measures.
Studies performed under 89-N-0045 are primarily designed to examine the natural history of
multiple sclerosis (MS) and its mimickers, viewed through the window of imaging (especially
magnetic resonance imaging or MRI). The protocol has four other important objectives: (1)
Screening prospective participants in selected Neuroimmunology Branch clinical trials; (2)
Performing studies to help define the mechanism of action and cause of side effects of
disease modifying therapies (DMT); (3) Studying healthy volunteers for comparison with
patients and for development of new experimental technologies; and (4) Comparing MS to other
neurological diseases that share imaging features.
Disease activity on MRI will be assessed using several MRI measures, focusing on the number
of new on-study lesions but also including the number of contrast-enhancing lesions, the
total number of MRI-visible lesions, brain atrophy, and more recently defined MRI measures of
tissue damage, such as quantitative magnetic relaxation mapping, diffusion-weighted imaging
(DWI), magnetization transfer imaging (MTI), and MR spectroscopy (MRS). Additionally,
participants will be assessed with other imaging modalities, specifically optical coherence
tomography (OCT) and fluorescein angiography of the eye, and they will also be studied
clinically and with neurophysiologic tests.
In order to obtain comparative data for proper interpretation of the results in MS, two
control cohorts one consisting of patients, the other of healthy volunteers will be studied.
The patient control cohort will have three subcohorts: (1) patients with other disorders who
are receiving DMT used in MS and are experiencing similar side effects (e.g. progressive
multifocal encephalopathy (PML) in patients with systemic lupus erythematosus (SLE) or
rheumatoid arthritis (RA)), (2) patients who are receiving DMT not used in MS but in whom
MS-like illness is suspected (e.g. TNF-alpha inhibitors in patients with rheumatological
diseases) and (3) patients with neurodegenerative diseases that may share pathophysiological
processes with MS patients (e.g. oxidative stress in patients with Parkinson s disease or
mitochondrial dysfunction in patients with mitochondrial diseases) and who do not qualify for
the enrollment to the 09-N-0032 protocol. Enrollment of patients with different diseases who
are experiencing identical side effects on DMTs as those studied in MS cohort will help to
answer the question of whether the identified mechanism of action of the side effect is MS
specific or generalizable. The other neurological disease cohort will provide data to assess
the specificity of the MRI findings in the MS cohort.
- INCLUSION CRITERIA:
Inclusion criteria for all populations:
- Diagnosis of MS based on combined MRI and clinical criteria (Polman et al., 2005) OR
presentation with a clinically isolated syndrome consistent with MS and at least two
abnormalities on MRI consistent with MS OR diagnosis of another neurological disease
of the CNS (see Section 6.1.2) OR patients with other diseases who are receiving
identical DMTs as the MS cohort OR patients who acquire an MS-like disease while
receiving immunomodulatory agents for a different indication.
- For patients with neuroimmunological disorders, treatment with any available
- Age greater than or equal to 18.
- Able to give informed consent.
Exclusion criteria for all cohorts:
- Contraindication to MRI.
- Fulfills inclusion criteria for 09-N-0032 protocol, i.e. any untreated
neuroimmunological or CNS white matter disease that requires diagnostic work-up.
- Unwilling to allow coded samples to be processed offsite or unwilling to have coded
samples used in other studies.