Clinical-MRI correlations in a European trial of interferon beta-1b in secondary progressive MS.

BACKGROUND: The recently completed placebo-controlled multicenter randomized trial of interferon beta-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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Brain atrophy and magnetization transfer ratio following methylprednisolone in multiple sclerosis: short-term changes and long-term implications

BACKGROUND: The short-term effect of corticosteroids on MRI measures of multiple sclerosis (MS) is not well understood and may have a significant impact when using these quantitative measures to evaluate disease activity and changes following other therapeutic interventions. OBJECTIVE: To determine the impact of a course of intravenous methylprednisolone (IVMP) on quantitative measures of disease activity and tissue injury in MS patients. METHODS: We prospectively measured brain parenchymal fraction (BPF), magnetization transfer ratio (MTR, lesional and whole brain), and lesion volumes on nine weekly brain MRI studies in ten MS patients receiving a course of IVMP. A group of nine MS patients not receiving IVMP served as controls. RESULTS: In comparison to untreated controls, BPF declined over the eight weeks following IVMP treatment (P <0.02). BPF decline was most prominent in patients with secondary progressive MS (SPMS, P <0.03), and was not seen in relapsing-remitting (RR) MS patients. Short-term change in BPF correlated with baseline BPF (r =0.62, P =0.05) and short-term change in lesional MTR (r = -0.55, P =0.03), but not with change in enhancing lesion volume. Short-term change in lesional MTR inversely correlated with baseline lesional and whole brain MTR (r = -0.79, P =0.04 for both). There was no significant difference between treated and control patients in measures of MTR or T2, T1 or enhancing lesion volumes. CONCLUSIONS: Patients with SPMS showed a greater decline in BPF following IVMP than RRMS patients. A correlation between changes in BPF and MTR suggest that these changes are secondary to altered water content within MS lesions. Differential response to a standardized therapeutic intervention in RRMS and SPMS suggests that responses to therapy may differ due to a fundamental pathologic difference between early and late stage MS.     

Correlation of neuropsychological and MRI findings in chronic/progressive multiple sclerosis

Sixty patients with chronic/progressive MS received a newly assembled neuropsychological screening battery (NSB) and a brain MRI. A neuroradiologist blinded to NSB findings quantified cerebral lesions on MRI. We developed weighted brain area lesion scores according to number and size of cerebral lesions. Patients who were impaired on NSB testing had a significantly higher mean bihemispheric lesion score (X = 26.1) than those who were unimpaired (X = 17.4); this MRI lesion rating score correlated significantly with the cognitive summary score of the NSB (r = 0.35, p less than 0.01). However, we did not find a significant correlation between the Kurtzke Expanded Disability Status Scale and any MRI or NSB summary measures. Compared with the Mini-Mental State Exam (MMSE), the NSB cognitive summary score yielded a prevalence estimate for cognitive impairment that is more consistent with previous findings in chronic/progressive MS. The NSB is a useful screening test for cognitive dysfunction in chronic/progressive MS because of its relationship to cerebral lesions on MRI and its greater sensitivity than the frequently used MMSE.     

Brain atrophy in relapsing-remitting multiple sclerosis: relationship with 'black holes', disease duration and clinical disability

Recent MRI studies in multiple sclerosis have highlighted the potential role of brain atrophy evaluation as a putative marker of disease progression. In the present study, we evaluated the supratentorial and infratentorial brain volume in patients with relapsing remitting multiple sclerosis (RR MS) and in healthy subjects. Moreover, we determined whether brain volumes of MS patients are associated with different aspects of brain MRI abnormalities and clinical findings. Two-dimensional acquired MRI was performed on 52 relapsing-remitting multiple sclerosis and 30 healthy subjects. The volume of supratentorial and infratentorial structures was measured in selected representative slices. Gd-enhancement, T2 hyperintense, T1 hypointense (i.e. 'black holes') total lesion load, as well as the area of corpus callosum was calculated in the MS group and related to brain volume measures. Correlations between MRI parameters and clinical features were also considered. MS patients had significantly lower supratentorial, infratentorial brain volume and corpus callosum area than healthy subjects (P<0.01). Supratentorial brain volume was significantly related to corpus callosum area (r=0.58; P<0.01) and T1 hypointense lesion load (r=0.48; P<0.01), but not with T2 hyperintense lesion load. Infratentorial/supratentorial ratio was significantly associated with disease duration and EDSS score (r=-0.34; P=0.02 and r=-0.49; P<0.01, respectively). This study documents that brain atrophy is an early MRI finding in RR MS and it is closely related to 'black holes' burden. The use of relative values (infratentorial/supratentorial ratio) may increase the conspicuity of correlation between clinical and MRI findings.     

Primary and transitional progressive MS: a clinical and MRI cross-sectional study

BACKGROUND: Ten percent of patients with MS have a progressive course from onset with no history of relapses or remissions. A smaller subgroup follow a similar progressive course but have a single relapse at some point (transitional progressive [TP] MS). To date these patients have been excluded from receiving licensed treatments for MS and from most therapeutic trials. OBJECTIVE: To document the clinical and MRI characteristics of a large cohort of progressive patients, including 158 with primary progressive (PP) MS and 33 with TPMS. Data from a small reference group of 20 patients with secondary progressive (SP) MS are also presented for reference. METHODS: Patients were recruited from six European centers. All underwent a clinical assessment including scoring on the Expanded Disability Status Scale (EDSS) and MRI of the brain and spinal cord. RESULTS: The men-to-women ratio was 81:77 (51% men) in the PP group, 14:19 (42% men) in the TP group, and 5:15 (25% men) in the SP group. The mean age at disease onset was significantly higher in the PP group than it was in the other two groups (PP 40.2 years, TP 34.9 years, SP 28.7 years). On MRI the PP group had lower mean brain T2 and T1 hypointensity lesion loads than the SP group (T2 12.02 versus 27.74 cm3, p = 0.001; T1 4.34 versus 7.04 cm3, p = 0.015). The SP and TP cohorts had significantly more T2-weighted lesions in the spinal cord than the PP patients, and the SP cohort had the greatest degree of atrophy. There was a correlation in the PP and TP patients between EDSS score and brain and spinal cord atrophy (r = 0.3, 0.2, p < or = 0.006) but not with brain lesion load. The PP and TP patients who presented with spinal cord pathology had significantly lower brain T2 and T1 lesion loads than those with non-spinal cord presentations (p = 0.002). CONCLUSIONS: The monitoring of disease progression in PPMS is difficult, although measures of atrophy correlate with the EDSS and appear most promising. This study increases our understanding of this unique patient group, which will be further expanded with the acquisition of serial data.     

Diffusion tensor magnetic resonance imaging in multiple sclerosis

OBJECTIVES: To quantify, using diffusion tensor imaging (DTI), the tissue damage in lesions and normal-appearing white matter (NAWM) from a large cohort of patients with MS and to investigate the magnitude of the correlation between DTI-derived metrics and clinical disability. METHODS: Dual-echo and DTI scans were obtained from 78 patients with relapsing-remitting, secondary progressive, or primary progressive MS and from 20 normal control participants. Post-contrast T1-weighted images were also obtained from the patients. After creating mean diffusivity (D) and fractional anisotropy (FA) images and image coregistration, D and FA values were measured for 4846 lesions (3207 nonenhancing T1-isointense, 1511 nonenhancing T1-hypointense, and 128 enhancing), 497 NAWM areas from patients, and 160 white matter areas from the controls. RESULTS: The average lesion D was higher and the average lesion FA was lower than the corresponding quantities of the NAWM (p < 0.001). The values of enhancing and nonenhancing lesions were not different, whereas enhancing lesions had lower FA (p < 0.001). T1-hypointense lesions had higher D and lower FA than T1-isointense lesions (p < 0.001). NAWM of patients had higher and lower FA than white matter of controls (p = 0.01). Significant correlations were found between T1 and T2 lesion volume and and FA of lesions and NAWM. In the overall patient sample, a moderate correlation was also found between lesion D and the Expanded Disability Status Scale score (r = 0.28, p = 0.01). However, the r value of this correlation was 0.48 in patients with secondary progressive MS, whose disability was also correlated with average lesion FA (r = -0.50). CONCLUSIONS: The results of this study show that DTI is able to identify MS lesions with severe tissue damage and to detect changes in the NAWM. They also indicate that DTI-derived measures are correlated with clinical disability, especially in patients with secondary progressive MS, thus suggesting a role for DTI in monitoring advanced phases of the disease.     

Emergence of thalamic magnetization transfer ratio abnormality in early relapsing-remitting multiple sclerosis

While there is now evidence for thalamic abnormality in established secondary progressive and relapsing-remitting multiple sclerosis (MS), it remains unclear when such abnormality begins. This study investigated the emergence of thalamic abnormality in relapsing-remitting MS by assessing the thalamic magnetization transfer ratio (MTR) in a cohort with clinically early disease. Twenty-three patients with early relapsing-remitting MS (mean age 37; mean disease duration 1.9 years; Expanded Disability Status Scale (EDSS) range 0-3) and 19 healthy controls (mean age 34) were imaged yearly with a magnetization transfer imaging sequence. Twenty-two MS patients and 14 controls completed two-year follow-up. Regions of interest were placed in both thalami and mean thalamic MTR calculated. At baseline, significant differences between patient and control thalamic MTR were not observed. However, at years one and two, the thalamic MTR in patients was significantly lower than control MTR. Although baseline lesion volume did not correlate with baseline thalamic MTR, at year one, an association between baseline lesion volume and year one thalamic MTR emerged. There was also a significant inverse correlation between EDSS and thalamic MTR (r = -0.47, P = 0.02). The study suggests that thalamic involvement occurs within the first five years of MS onset, when most patients are still minimally disabled.     

Correlations of brain MRI parameters to disability in multiple sclerosis

OBJECTIVES: The objective was to correlate magnetic resonance imaging (MRI) T2-weighted lesion load and measures of white matter atrophy in the brain to disability in a population-based sample of patients with multiple sclerosis (MS). MATERIAL AND METHODS: A well defined cohort of patients was drawn at random from the general MS population by using the Danish Multiple Sclerosis Registry. A semi-automated local thresholding technique was used to quantify T2-weighted lesions on MRI; whereas manual tracing was applied to measure the corpus callosum brain ratio (CCR) and the ventricle brain ratio (VBR). RESULTS: A sample of 86 patients with a mean age of 43.3 years (SD 4.3), mean disease duration of 13.6 years (SD 4.4) and a median Expanded Disability Status Score (EDSS) of 6.0 was identified. The correlation between total lesion area of the brain (TLA) and disability (EDSS) for the whole sample was moderate (Spearman rank correlation coefficient r=0.48, P<0.001). Also correlations of CCR and VBR to disability (r=0.32-0.46) were significant. CONCLUSIONS: Correlations of TLA and disability in this study were rather strong. Hence, T2-weighted MRI lesion load in the brain still plays an important role as a surrogate marker of disease and as a secondary outcome measure in phase III treatment trials.     

多发性硬化患者的认知功能障碍及其与头颅MRI病灶的相关性

目的　研究多发性硬化 (MS)患者认知功能障碍的特点及其与头颅MRI病灶的相关性。方法　对 70例MS患者进行韦氏智力量表 (WAIS)测试及头颅MRI检查 ,并用多元回归分析方法对各相关因素进行分析。结果　MS组全量表智商 (FIQ)异常 (<90分 )率为 4 0 %(2 8/70 ) ,与对照组比较差异有显著性 (P <0 0 1)。对智商成绩影响最显著的因素为病变部位 (脑部病变 )。MRI显示病灶的等级与病程呈显著正相关(r=0 348,P <0 0 5 ) ,胼胝体病灶数与FIQ呈负相关 (r=- 0 2 8,P <0 0 5 ) ,其他均无显著相关性 (均P >0 0 5 )。结论　MS患者存在认知障碍 ,MS的病变部位 (脑部病变 )对智能影响最显著 ,头颅MRI所示病灶与MS患者的认知障碍的相关性大多不显著。     

N-acetylaspartic acid in cerebrospinal fluid of multiple sclerosis patients determined by gas-chromatography-mass spectrometry

Abstract Background Axonal degeneration is considered to play a major role in the development of clinical disability in multiple sclerosis (MS). N-AcetylAspartic Acid (NAA) is a neuron-specific marker constantly identified in MR-spectroscopy studies of the normal and MS brain. To our knowledge there are no studies available that evaluated NAA in cerebrospinal fluid (CSF) as a possible marker for disease severity. Objective To evaluate CSF concentrations of NAA in MS in relation to disease phenotype, clinical measures of disability and MRI markers of disease burden. Methods NAA concentrations were determined in CSF of 46 patients with MS (26 relapsing remitting (RRMS), 12 secondary progressive (SPMS) and 8 primary progressive (PPMS)). Prior to lumbar puncture, MS-patients underwent MRI and clinical examination, including the Expanded Disability Status Scale (EDSS) and the MS Functional Composite (MSFC). Additionally, CSF concentrations of NAA were determined in 12 patients with other neurological diseases (OND). Results Median CSF NAA concentration was 0.74 (IQR: 0.59–0.94) in RRMS , 0.54 (IQR: 0.35–0.73) in SPMS and 0.83 μmol/l (IQR: 0.56–1.03) in PPMS patients. SPMS patients had a significantly lower NAA concentration than RRMS patients. NAA concentrations correlated with EDSS (r = )0.37, p = 0.016), MSFC (r = 0.41, p = 0.010), normalised brain volume (r = 0.49, p = 0.001), T2 lesion load (r = )0.35, p = 0.021) and black hole lesion load (r = )0.47, p = 0.002). No differences were observed between OND (median: 0.57 IQR: 0.28–0.73) and MS patients. Conclusion CSF NAA concentration in MS patients is related to clinical performance and MRI measures of disease burden and may therefore be an important neuron specific marker of disease severity and possibly progression.     

Cognitive dysfunction in patients with mildly disabling relapsing-remitting multiple sclerosis: an exploratory study with diffusion tensor MR imaging

Neuronal damage seems to be a major source of disability in multiple sclerosis (MS) patients and at present magnetic resonance imaging (MRI) is a sensitive method to evaluate lesion and disease activity. We studied the potential correlation between changes in MS patients' disability after relapse, the degree of T1 lesion hypointensity on MRI in vivo and neuronal apoptosis induced by cerebrospinal fluid (CSF) on neuron cultures. In this study, we included 24 MS patients with relapsing disease. Clinical recovery from relapse was measured by the Expanded Disability Status Scale (EDSS). T1-weighted MRI studies were done according to established standards and neuronal apoptosis was induced by treatment of neuronal cultures with CSF from patients while relapsing. Recovery after relapse is inversely correlated with neuronal apoptosis (r=-0.725, p<0.0001). A correlation was found between T1 lesion hypointensity and a poor recovery from relapse (r=0.656, p=0.0005) and such hypointensity correlated strongly with neuronal apoptosis (r=-0.779, p<0.0001). CSF from all patients with hypointense T1 lesions caused significantly increased neuronal apoptosis, whereas all CSF that did not induced such effects corresponded to patients without T1 lesions. The recovery from an acute MS relapse is significantly worse in patients with hypointense T1 lesions in MRI and in those whose CSF damaged neurons on cultures in vitro, phenomena that closely correlated each other.     

Whole brain volume changes in patients with progressive MS treated with cladribine

OBJECTIVE: To compare changes in whole brain volume measured using MRI scans in patients with progressive MS enrolled in a double-blind, placebo-controlled trial assessing the efficacy of two doses of cladribine (0.7 and 2.1 mg/kg) and to assess the correlations between change in whole brain volume and change in other conventional MRI measures. BACKGROUND: Measuring brain parenchymal volumes is an objective and reliable surrogate for the destructive pathologic process in MS. The dynamics and the mechanisms of tissue loss in progressive MS are unclear. METHODS: Whole brain volumes were measured using postcontrast T1-weighted scans with 3 mm slice thickness from 159 patients with progressive MS (70% secondary progressive and 30% primary progressive) enrolled in a double-blind, placebo-controlled trial of 12-month duration. RESULTS: Whole brain volumes were similar in the placebo and cladribine-treated patients on the baseline scans. A significant decrease of brain volume over time was observed both in the entire population of patients (p = 0.001) and in the placebo patients in isolation (p = 0.04). No significant treatment effect of either dose of cladribine on brain volume changes over time was found. In the 54 patients who received placebo, the change in brain volume was not significantly correlated with other MRI measures at baseline (enhancing lesion number and volume and T2-hyperintense and T1-hypointense lesion volumes) or at follow-up (cumulative number of enhancing lesions and absolute and percentage changes of enhancing T2- and T1-hypointense lesion volumes). CONCLUSIONS: This study shows in a large cohort of patients that brain parenchymal loss occurs, even over a short period of time, in progressive MS and that cladribine is not able to alter this process significantly. It also suggests that MRI-visible inflammation and new lesion formation has a marginal role in the development of brain atrophy in patients with progressive MS.     

Thalamic Involvement in Multiple Sclerosis: A Diffusion-Weighted Magnetic Resonance Imaging Study

BACKGROUND AND PURPOSE: Injury to deep gray matter structures in multiple sclerosis (MS) has been suggested by recent neuro-imaging and neuropathology studies. Diffusion-weighted magnetic resonance imaging (MRI) can assess tissue damage with greater sensitivity than conventional MRI. The authors' objective was to assess thalamic gray matter damage by diffusion-weighted imaging in MS patients. METHODS: This was a retrospective study performed at a tertiary care, university-affiliated comprehensive MS center of 82 MS patients and 43 controls. The main outcome measures were thalamic apparent diffusion coefficients (ADCs), whole-brain atrophy (brain parenchymal fraction), fluid-attenuated inversion recovery (FLAIR) hypertense lesion volume, and clinical course. RESULTS: ADCs in the left thalamus were higher in MS patients (0.741 +/- 0.044 x 10(-3) mm2/s) than controls (0.723 +/- 0.036 x 10(-3) mm2/s) (P = .027) and higher in secondary progressive MS patients (0.761 +/- 0.044 x 10(-3) mm2/s) than relapsing-remitting MS patients (0.735 +/- 0.032 x 10(-3) mm2/s) (P = .029). ADCs in the right thalamus were higher in secondary progressive MS patients (0.784 +/- 0.069 x 10(-3) mm2/s) than controls (0.757 +/- 0.038 x 10(-3) mm2/s) (P = .033). In the MS group, left thalamus ADCs correlated negatively with brain parenchymal fraction (r = -0.30, P = .008), total left hemispheric FLAIR lesion volume correlated with ADCs in the left (r = 0.35, P = .001) and right (r = 0.39, P < .001) thalami, and total right hemispheric FLAIR lesion volume correlated with ADCs in the left (r = 0.31, P = .006) and right thalami (r = 0.22, P = .048). CONCLUSION: MS patients have increased water diffusion in the thalamus that is partly associated with clinical course, lesion load, and whole-brain atrophy. Both indirect and direct mechanisms of gray matter injury may play a role in the pathophysiology of MS.     

A semiautomated measure of whole-brain atrophy in multiple sclerosis

Brain atrophy is a proposed MRI marker of irreversible pathologic damage in multiple sclerosis (MS). The brain parenchymal fraction (BPF) is the ratio of brain parenchymal volume to the total volume within the surface contour. We developed a semiautomated measure of BPF using commercially available edge-finding and thresholding software (30-min analysis time per patient). We measured BPF in 78 patients with MS and 17 healthy controls. BPF was lower in a cohort of patients with MS (n=50) (0.843+/-0.042, range 0.743-0.906) age-matched to controls (0.877+/-0.020, range 0.835-0.901) (p<0.001). BPF correlated inversely with third ventricular width (r=-0.785, p<0.001), and total T1 hypointense lesion volume (r=-0.347, p=0.011), but not with total T2 hyperintense lesion volume (r=-0.213, p=0.13). BPF correlated negatively with expanded disability status scale (EDSS) score (r=-0.391, p=0.0006) and disease duration (r=-0.281, p=0.01). Stepwise regression compared the relative abilities of MRI variables to predict clinical data. By regression of age, BPF, third ventricular width, T2 lesions, and T1 lesions, BPF was the best predictor of disability score (R(2)=0.204, p<0.001). Third ventricular width was the best predictor of disease duration (R(2)=0.316, p<0.001). None of the MRI variables differed between relapsing-remitting (RR) (n=60) and secondary progressive (SP) (n=18) disease course (p>0.05). The intrarater, interrater, and scan-rescan BPF variability (COV) was 0.31%, 0.34%, and 0.41% and the accuracy against a phantom was 99.1%. We conclude that whole-brain atrophy in MS can be reliably and readily quantified by a semiautomated approach. Longitudinal studies are warranted to determine if this method provides a sensitive biologic marker of the MS disease process.     

Monitoring disease activity and progression in primary progressive multiple sclerosis using MRI: sub-voxel registration to identify lesion changes and to detect cerebral atrophy

Objective To explore the potential usefulness of two new magnetic resonance imaging (MRI) analysis techniques for assessment of progressive cerebral atrophy and T2 lesion activity in primary progressive multiple sclerosis (PPMS), and thereby assess the relationship between MRI activity and atrophy in this patient group. Background Measurements of cerebral atrophy and net change in T2 lesion volumes are currently used as surrogate markers of disease progression in multiple sclerosis (MS). However, manual implementation of these techniques is time-consuming and the pathological specificity of T2 lesion change is low. Advances in serial scan registration have facilitated the development of a new, fully-automated technique to measure cerebral volume (SIENA; Structural Image Evaluation, using Normalisation, of Atrophy), and a technique to measure the total new T2 lesion volume selectively (MRI difference imaging). Method SIENA measures changes in cerebral size based on sub-voxel detection of shifts in edge contours. The lesion difference imaging method measures differences in lesion volumes over time as defined by a semi-automated outlining technique. The two new methods were validated against the T2 lesion volume contour technique and a previously described measure of partial brain volume (which uses six slices centred on the presumed area of greatest change around the lateral ventricles). All were applied to serially acquired MR images from a cohort of 39 patients with PPMS, who also underwent scoring on the expanded disability status scale (EDSS) twice, two years apart. Results The two measures reflecting cerebral atrophy correlated strongly (r = 0.58, p < 0.001). T2 lesion load measurements using the two techniques correlated very highly (r = 0.999, p < 0.001). 91 % of the total new T2 lesion volume was from enlargement of pre-existent lesions and only 9 % from new, discrete, lesions. No relationship was seen between the traditional measure of net gain in T2 lesion load and either measure of atrophy. However, the fully-automated measure of total new T2 load correlated with both measures of atrophy (SIENA technique, r= −0.37, p= 0.02; six slice measure, r = −0.41, p = 0.01). There was no relationship between the MRI measures and changes in the EDSS. Conclusion Both of the new image analysis techniques appear to be promising as sensitive markers for disease progression in PPMS. The correlation of total new T2 lesion volume with the progression of cerebral atrophy (which is known to be a consequence of axonal loss in progressive disease), compared with a lack of correlation with the traditional net gain in T2 lesion load is interesting and suggests that the total new T2 lesion volume may ultimately be the most useful measure. Received: 24 November 2000, Received in revised form: 23 April 2001, Accepted: 11 June 2001     

Magnetic resonance imaging measures of brain and spinal cord atrophy correlate with clinical impairment in secondary progressive multiple sclerosis

BackgroundNeuroaxonal loss is a pathological substrate of disability in progressive multiple sclerosis (MS) and can be estimated in vivo by measuring tissue atrophy on magnetic resonance imaging (MRI). While there is some evidence that brain atrophy correlates better with disability than T2 lesion load in secondary progressive MS, the clinical relevance of atrophy within specific regions of the central nervous system requires further evaluation.MethodsClinical and MRI examinations were performed in 117 subjects with secondary progressive MS. MRI analysis included measures of normalized brain volume (NBV), normalized grey matter (NGMV) and white matter volume (NWMV), central cerebral volume (CCV), spinal cord cross-sectional area (SCCA), and brain T2 and T1 lesion volume. Clinical assessments included the expanded disability status scale (EDSS) and MS functional composite (MSFC).ResultsAll MRI measures correlated significantly with the MSFC score, with the strongest correlation being for the NBV (r = 0.47; P < 0.001). NBV and SCCA were the only significant independent predictors of the MSFC score in a stepwise regression model containing all the MRI measures, and SCCA was the only MRI measure to show a significant association with the EDSS. While NGMV had stronger correlations with the clinical variables than NWMV, NBV was more correlated with clinical impairment than either measure.ConclusionsThis data suggests that measures of atrophy, particularly of the whole brain and spinal cord, are relevant and useful disease markers in secondary progressive MS.     

T cell vaccination in multiple sclerosis: results of a preliminary study

Myelin basic protein (MBP)-reactive T cells are potentially involved in the pathogenesis of multiple sclerosis (MS), and can be depleted by subcutaneous inoculations with irradiated autologous MBP-reactive T cells (T cell vaccination). This preliminary open label study was undertaken to evaluate whether depletion of MBP-reactive T cells would be clinically beneficial to patients with MS. Fifty-four patients with relapsing-remitting (RR) MS (n=28) or secondary progressive (SP) MS (n=26) were immunized with irradiated autologous MBP-reactive T cells and monitored for changes in rate of relapse, expanded disability scale score (EDSS) and MRI lesion activity over a period of 24 months. Depletion of MBP-reactive T cells correlated with a reduction (40 %) in rate of relapse in RR-MS patients as compared with the pre-treatment rate in the same cohort. However, the reduction in EDSS was minimal in RR-MS patients while the EDSS was slightly increased in SP-MS patients over a period of 24 months. Serial semi-quantitative MRI examinations suggest stabilization in lesion activity as compared with baseline MRI. The findings suggest some potential clinical benefit of T cell vaccination in MS and encourage further investigations to evaluate the treatment efficacy of T cell vaccination in controlled trials. Received: 27 November 2000, Received in revised form: 10 May 2001, Accepted: 11 June 2001     

Grey matter magnetization transfer ratio independently correlates with neurological deficit in secondary progressive multiple sclerosis

Although there is substantial brain grey matter pathology in secondary progressive multiple sclerosis (MS), there has been limited investigation of its contribution to disability. This study investigated the correlation of magnetization transfer ratio (MTR) measures taken from brain grey matter, normal appearing white matter (NAWM) and lesions with neurological deficit and disability in 113 people with secondary progressive MS. In order to adjust for the potential effects of focal white matter lesions and global brain atrophy, T2 lesion volume and normalized brain volume (NBV) were also calculated for each subject. Clinical measures included the expanded disability status scale (EDSS) and the multiple sclerosis functional composite (MSFC) scores. Linear regression analysis was used to assess the age- and gender-adjusted correlation of MTR histogram mean, peak height and peak location with the MSFC and individual component measures. Logistic regression analysis was used to determine whether imaging measures could be used to predict if subjects were in the higher disability group (EDSS ≥ 6.5). Significant correlations were detected between MSFC composite and mean MTR in (i) normal appearing white matter (NAWM; r = 0.327, p < 0.0001), (ii) grey matter (r = 0.460, p < 0.0001) and (iii) lesions (r = 0.394, p < 0.0001). Although NBV and T2 lesion volume correlated significantly with MSFC, grey matter histogram mean emerged as the best predictor of MSFC score. None of the MRI measures significantly predicted higher EDSS. These results suggest that brain grey matter pathology plays an important role in determining neurological impairment. The apparent paucity of correlation between MRI measures and EDSS is likely to represent the relative insensitivity of the latter measure in this study group.     

Hypointense and hyperintense lesions on magnetic resonance imaging in secondary-progressive MS patients.

Cranial magnetic resonance imaging (MRI) is widely used to monitor disease activity in clinical trials in multiple sclerosis (MS). The purpose of this study is to examine lesion burden as determined from hypointense regions on postcontrast T1-weighted scans (or black holes), and lesion burden on conventional T2-weighted scans, from a cohort of secondary progressive MS patients who participated in a placebo-controlled, randomized, double-blind cross-over trial assessing the therapeutic efficacy of cladribine. T2 lesion volumes and black hole volumes are approximately normal distributed when log-transformed, and are highly correlated (adjusted R2 = 0.63). Changes in clinical scores could be predicted with a reasonable degree of precision from baseline scores and changes in T2 lesion volumes (adjusted R2 values 0.52-0.7). Stratification schemes for clinical trials should include the acute proportion of the disease (enhancing T1 lesions), degree of permanent damage (black holes), and T2 lesion volume.     

Clinical and Magnetic Resonance Imaging Changes Correlate in a Clinical Trial Monitoring Cyclosporine Therapy for Multiple Sclerosis

Magnetic resonance imaging (MRI) was used to monitor cyclosporine therapy for chronic progressive multiple sclerosis in a multicenter clinical trial and an analysis was performed to determine whether there was a correlation between clinical changes and MRI changes. MRI was performed on 163 patients at the onset and completion of the 2–year study. Burden of disease (BOD, lesion load) was quantitated by a single observer using a computer program. Active lesions were also identified. The Expanded Disability Status Scale (EDSS) score was determined every 3 months. MRI data did not show any effect of cyclosporine treatment on BOD progression (mean 24.5% increase/yr) or lesion activity. However, there was a statistically significant positive correlation between the baseline total BOD value and the baseline EDSS score (r = 0.221, p = 0.005) and a positive correlation between the percent changes in BOD from baseline to exit and EDSS score (r = 0.186, p = 0.018). The study supports the concepts that MRI is a useful technique in monitoring therapeutic trials and that MRI is a direct measure of pathology.