SUMMARY An international group of neurologists and radiologists developed revised guidelines for standardized brain and spinal cord MR imaging for the diagnosis and follow-up of MS. A brain MR imaging with gadolinium is recommended for the diagnosis of MS. A spinal cord MR imaging is recommended if the brain MR imaging is nondiagnostic or if the presenting symptoms are at the level of the spinal cord. A follow-up brain MR imaging with gadolinium is recommended to demonstrate dissemination in time and ongoing clinically silent disease activity while on treatment, to evaluate unexpected clinical worsening, to re-assess the original diagnosis, and as a new baseline before starting or modifying therapy. A routine brain MR imaging should be considered every 6 months to 2 years for all patients with relapsing MS. The brain MR imaging protocol includes 3D T1-weighted, 3D T2-FLAIR, 3D T2-weighted, post-single-dose gadolinium-enhanced T1-weighted sequences, and a DWI sequence. The progressive multifocal leukoencephalopathy surveillance protocol includes FLAIR and DWI sequences only. The spinal cord MR imaging protocol includes sagittal T1-weighted and proton attenuation, STIR or phase-sensitive inversion recovery, axial T2- or T2*-weighted imaging through suspicious lesions, and, in some cases, postcontrast gadolinium-enhanced T1-weighted imaging. The clinical question being addressed should be provided in the requisition for the MR imaging. The radiology report should be descriptive, with results referenced to previous studies. MR imaging studies should be permanently retained and available. The current revision incorporates new clinical information and imaging techniques that have become more available.

Recent studies indicate that functional connectivity using low-frequency BOLD fluctuations (LFBFs) is reduced between the bilateral primary sensorimotor regions in multiple sclerosis. In addition, it has been shown that pathway-dependent measures of the transverse diffusivity of water in white matter correlate with related clinical measures of functional deficit in multiple sclerosis. Taken together, these methods suggest that MRI methods can be used to probe both functional connectivity and anatomic connectivity in subjects with known white matter impairment. We report the results of a study comparing anatomic connectivity of the transcallosal motor pathway, as measured with diffusion tensor imaging (DTI) and functional connectivity of the bilateral primary sensorimotor cortices (SMC), as measured with LFBFs in the resting state. High angular resolution diffusion imaging was combined with functional MRI to define the transcallosal white matter pathway connecting the bilateral primary SMC. Maps were generated from the probabilistic tracking employed and these maps were used to calculate the mean pathway diffusion measures fractional anisotropy FA, mean diffusivity MD, longitudinal diffusivity lambda(1), and transverse diffusivity lambda(2). These were compared with LFBF-based functional connectivity measures (F(c)) obtained at rest in a cohort of 11 multiple sclerosis patients and approximately 10 age- and gender-matched control subjects. The correlation between FA and F(c) for MS patients was r = -0.63, P < 0.04. The correlation between all subjects lambda(2) and F(c) was r = 0.42, P < 0.05. The correlation between all subjects lambda(2) and F(c) was r = -0.50, P < 0.02. None of the control subject correlations were significant, nor were FA, lambda(1), or MD significantly correlated with F(c) for MS patients. This constitutes the first in vivo observation of a correlation between measures of anatomic connectivity and functional connectivity using spontaneous LFBFs.

Magnetic resonance imaging (MRI) has been a valuable tool to understand the pathophysiology and natural history of multiple sclerosis (MS), and increasing attention is focusing on the use of MRI findings as outcome measures in treatment trials in MS. The recently completed trial of interferon-beta-1b (IFN-beta 1b) demonstrated a decrease in accumulation of diseased tissue on T2-weighted images and a reduction in new lesions on T2-weighted images. To examine the effect of IFN-beta 1b on blood-brain barrier (BBB) breakdown, and to provide additional insights into the usefulness of MRI in the evolution of effectiveness of experimental treatments in MS, we used the contrast-enhanced lesion frequency of 7-month baseline MRIs compared with the enhanced lesion frequency for 6-month treatment period MRIs in 14 relapsing-remitting (RR) MS patients. Longer baselines were also available for analysis in a subset of 8 patients, as these patients had been followed by monthly MRI in a natural history study for up to 4 years prior to the current study. A significant reduction in the total or new enhancing lesion frequency was detected in the patients analyzed as a whole, and 13 of 14 of the patients demonstrated a reduction in enhancing lesion frequency on treatment over the 6 months studied. These findings suggest that IFN-beta has a mechanism of action that at least temporarily inhibits the opening of the BBB in RRMS patients. This trial also illustrates the usefulness of a baseline versus treatment trial design to evaluate the effect of drug therapy in MS.

It is now well established that clinically stable patients with relapsing-remitting multiple sclerosis have ongoing disease activity when evaluated by serial gadolinium-enhanced (Gd-DTPA) magnetic resonance imaging (MRI) scans. Despite this, the relationship between clinical disease and MRI lesions, though suspected, has not been extensively documented. The relationship between Gd-DTPA MRI lesions and clinical disease was examined in this study of 9 patients with mild relapsing-remitting multiple sclerosis (Expanded Disability Status Scale [EDSS] < 3.5) who had 24 to 37 monthly Gd-DTPA MRI scans, neurological examinations, and EDSS score assignments. The area and frequency of Gd-DTPA lesions were examined during months with and without clinical worsening as measured by EDSS. Forty-one episodes of clinical worsening were noted during the study. A significant association was observed between these periods of clinical worsening and MRI parameters, including increases in total number, number of new lesions, and the total area of enhancement. Logistic regression analysis showed a significant effect of the number and area of Gd-DTPA MRI lesions on both the onset and continuation of clinical worsening, confirming an important relationship between clinical disease and an increase in cerebral Gd-DTPA MRI activity. A relationship with long-term disability was suggested, but cannot be confirmed without longer follow-up of these patients.

A phase 1, randomized, placebo-controlled, five-level dose escalation safety and tolerability and pharmacokinetic study of a single IV dose of natalizumab was performed. Doses of 0.03 to 3.0 mg/kg natalizumab or placebo were studied in 28 stable relapsing-remitting or secondary-progressive MS. All doses were safe and well tolerated in MS. Serum concentrations of natalizumab are detectable for 3 to 8 weeks after a single 1- or 3-mg/kg IV dose and justify controlled efficacy studies.