Li BS, Regal J, Soher BJ, Mannon LJ, Grossman RI, Gonen O
AJNR Am J NeuroRadiol 2003 Jan;24(1):68-74
New York University School of Medicine, Department of Radiology, New York, NY; University of California, San Francisco; VA Medical Center, San Francisco, CA
Background And Purpose
Persistent T1-HypoIntense lesions ("Black Holes") are thought to represent permanent damage of Brain Parenchyma.
We attempted to ascertain whether the metabolic profiles of these HypoIntense areas support this hypothesis and whether these profiles correlate with these HypoIntense findings.
Four patients with Relapsing/Remitting Multiple Sclerosis and four matched control volunteers underwent MR imaging and 3D proton MR Spectroscopy.
Absolute levels of N-AcetylAspartate (NAA), Creatine, and Choline (Cho) were obtained in 0.19 cm(3) Voxels containing 14 T1-HypoIntense lesions (average volume, 0.4 cm(3); range, 0.2-1.0 cm(3)) in patients.
Metabolite levels were analyzed, by using Pearson correlation, against their respective lesions' HypoIntensity relative to the surrounding Apparently-Normal White Matter.
Moderate correlation, r = 0.56, was found between the NAA level and MR imaging HypoIntensity.
Of the 14 lesions studied, 12 were deficient in NAA and 11 had excess Cho compared with corresponding Brain regions in control volunteers.
Only one lesion was significantly deficient in all three metabolites, indicative of total damage or Matrix Loss.
No relationship was found between the HypoIntensity of the lesions and their metabolic profile.
Specifically, lesions with the same HypoIntensity on T1-weighted MR images were metabolically variable (ie, displayed disparate metabolite levels and behavior).
Also, although 86% of the lesions exhibited abnormally low NAA, 71% also had increased Cho.
This indicates that although Neuronal damage had already occurred (lower NAA), these lesions were still "smoldering" with active membrane turnover (high Cho), most likely because of De- and ReMyelination, indicative of shadow plaques (ReMyelinated lesions).
Consequently, Relapsing/Remitting HypoIntense lesions represent neither final-stage nor static pathologic abnormality.
Diffusion Tensor Imaging In Early Relapsing/Remitting Multiple Sclerosis
Griffin CM, Chard DT, Ciccarelli O, Kapoor B, Barker GJ, Thompson AI, Miller DH
Mult Scler 2001 Oct;7(5):290-7
Institute of Neurology, NMR Research Unit, National Hospital for Neurology and NeuroSurgery, London, UK
Diffusion Tensor Magnetic Resonance Imaging (DTI) indices are abnormal in patients with established Multiple Sclerosis (MS).
The objective of this study was to examine the Diffusion characteristics of MS lesions, Normal Appearing White Matter (NAWM) and Normal Appearing Gray Matter (NAGM).
In MS patients with early Relapsing/Remitting disease, a further objective was to investigate the relationship between three DTI parameters:
- Fractional Anisotropy (FA)
- Mean Diffusivity (MD)
- Volume Ratio (VR)) and
Clinical Outcome Measures:
- Kurtzke Expanded Disability Status Scale (EDSS)
- MS Functional Composite Measure in early disease
DTI was performed in 28 patients and 27 controls. Analysis was carried out using a Region Of Interest (ROI) approach. ROIs were placed in 12 NAWM and nine NAGM regions.
Significant differences were found in FA, MD and VR between lesions and NAWM (P< 0.001 for all three DTI parameters).
No significant differences were found between patients and controls when examining NAWM or NAGM, although there was a trend for abnormal NAWM FA and VR in some regions.
No correlation was found between DTI parameters in lesions, NAWM or NAGM and the clinical outcome measures.
The lack of significant DTI abnormality in the NAWM and NAGM may reflect a lack of pathological change or a limited sensitivity of DTI using ROI methodology.
Previous studies have shown abnormalities in T1 relaxation time, Magnetization Transfer Ratio (MTR) and N-AcetylAspartate (NM) in this cohort of patients.
And as such, DTI using a Region Of Interest (ROI) approach may not be as sensitive as other MR techniques in detecting subtle changes in Normal Appearing Brain.
The Effect Of IFN-ß-1b On The Evolution Of Enhancing Lesions In Secondary/Progressive MS
The European Study Group on Interferon beta-1b in Secondary/Progressive MS
Brex PA, Molyneux PD, Smiddy P, Barkhof F, Filippi M, Yousry TA, Hahn D, Rolland Y, Salonen O, Pozzilli C, Polman CH, Thompson AJ, Kappos L, Miller DH
Neurology 2001 Dec 26;57(12):2185-90
Institute of Neurology, NMR Research Unit, University College London, UK
After the resolution of contrast enhancement, the majority of new MS lesions become IsoIntense with surrounding White Matter on T1-weighted MRI.
Less commonly, a HypoIntense T1 lesion develops, representing the development of more severe focal tissue damage.
Interferon-beta (IFN-ß) reduces both the number of new enhancing lesions and the duration of contrast enhancement.
To determine if IFN-ß affects the degree of tissue damage within new lesions and if its effects are related to lesion size.
One hundred twenty-five patients with Secondary/Progressive MS from seven European sites
were randomized to receive either IFN-ß-1b or placebo.
Monthly, contrast-enhanced T1-weighted MR images were acquired at baseline, at months 1 to 6, and at months 19 to 24. The size of all new enhancing lesions developing between months 1 and 6 was recorded and their appearance at follow-up documented.
In the first 6 months, fewer new enhancing lesions occurred in the IFN-ß-1b arm. This difference was greater for small (70% decrease) than for large (46% decrease) lesions.
HypoIntense T1 lesions were more likely to form from large (25%) than from small (9%) enhancing lesions in both treatment arms.
Patients taking IFN-ß-1b developed fewer HypoIntense T1 lesions; however, the proportion of enhancing lesions developing into HypoIntense T1 lesions was similar in both arms.
IFN-ß-1b reduced the number of new enhancing lesions, with a greater effect on small lesions. However, when a new enhancing lesion did become established, treatment with IFN-ß-1b did not alter its subsequent course.
Clinical-MRI Correlations In A European Trial Of Interferon-ß-1b In Secondary/Progressive MS
The European Study Group on Interferon Beta-1b in Secondary/Progressive MS
Molyneux PD, Barker GJ, Barkhof F, Beckmann K, Dahlke F, Filippi M, Ghazi M, Hahn D, MacManus D, Polman C, Pozzilli C, Kappos L, Thompson AJ, Wagner K, Yousry T, Miller DH
Neurology 2001 Dec 26;57(12):2191-7
Institute of Neurology, NMR Research Unit, London, UK
The recently completed placebo-controlled multicenter randomized trial of Interferon-ß-1b (Betaferon) in 718 patients with Secondary/Progressive MS shows significant delay of disease progression and reduction of relapse rate.
This study provides an opportunity to assess the level of relationship between clinical and MRI outcomes in this cohort of patients with Secondary /Progressive MS.
Brain T2-weighted lesion volume was measured annually in all available patients, with visual analysis to identify any new or enlarging (active) T2 lesions at each annual time point.
A subgroup of 125 patients had monthly Gadolinium-enhanced, T1-weighted imaging at months 0 to 6 and 18 to 24. Relapses were documented and Expanded Disability Status Scale (EDSS)was measured every 3 months.
For the annual MRI outcomes, a significant but modest correlation was identified between the change in T2 lesion volume from baseline to the final scan and the corresponding change from baseline in EDSS (r = 0.17, p < 0.0001).
There were significant correlations between the cumulative number of active T2 lesions and 1) change in EDSS (r = 0.18, p < 0.0001) and 2) relapse rate (r = 0.24, p < 0.0001).
In the subgroup of 125 patients undergoing monthly imaging, MRI lesion activity was correlated with relapse rate over months 0 to 24 (r = 0.24, p = 0.006) but not with change in EDSS.
These results confirm that the clinical-MRI relationships previously identified in Relapsing/Remitting MS still are apparent in the Secondary/Progressive phase of the disease and support the use of MRI as a relevant outcome measure.
In view of the relatively modest nature of the correlations, it seems unwise to rely on such MRI measures alone as primary efficacy variables in Secondary/Progressive MS trials.