Claudio Gasperini

Predictive value of gadolinium-enhanced magnetic resonance imaging for relapse rate and changes in disability or impairment in multiple sclerosis: a meta-analysis

BACKGROUND Reliable prognostic factors are lacking for multiple sclerosis (MS). Gadolinium enhancement in magnetic resonance imaging (MRI) of the brain detects with high sensitivity disturbance of the blood-brain barrier, an early event in the development of inflammatory lesions in MS. To investigate the prognostic value of gadolinium-enhanced MRI, we did a meta-analysis of longitudinal MRI studies. METHODS From the members of MAGNIMS (European Magnetic Resonance Network in Multiple Sclerosis) and additional centres in the USA, we collected data from five natural-course studies and four placebo groups of clinical trials completed between 1992 and 1995. We included a total of 307 patients, 237 with relapsing disease course and 70 with secondary progressive disease course. We investigated by regression analysis the relation between initial count of gadolinium-enhancing lesions and subsequent worsening of disability or impairment as measured by the expanded disability status scale (EDSS) and relapse rate. FINDINGS The relapse rate in the first year was predicted with moderate ability by the mean number of gadolinium-enhancing lesions in monthly scans during the first 6 months (relative risk per five lesions 1.13, p=0.023). The predictive value of the number of gadolinium-enhancing lesions in one baseline scan was less strong. The best predictor for relapse rate was the variation (SD) of lesion counts in the first six monthly scans which allowed an estimate of relapse in the first year (relative risk 1.2, p=0.020) and in the second year (risk ratio=1.59, p=0.010). Neither the initial scan nor monthly scans over six months were predictive of change in the EDSS in the subsequent 12 months or 24 months. The mean of gadolinium-enhancing-lesion counts in the first six monthly scans was weakly predictive of EDSS change after 1 year (odds ratio=1.34, p=0.082) and 2 years (odds ratio=1.65, p=0.049). INTERPRETATION Although disturbance of the blood-brain barrier as shown by gadolinium enhancement in MRI is a predictor of the occurrence of relapses, it is not a strong predictor of the development of cumulative impairment or disability. This discrepancy supports the idea that variant pathogenetic mechanisms are operative in the occurrence of relapses and in the development of long-term disability in MS.

Randomized placebo-controlled trial of mitoxantrone in relapsing-remitting multiple sclerosis: 24-month clinical and MRI outcome

Abstract We designed a randomized, placebo-controlled, multicentre trial involving 51 relapsing-remitting multiple sclerosis patients to determine the clinical efficacy of mitoxantrone treatment over 2 years. Patients were allocated either to the mitoxantrone group (27 patients receiving IV infusion of mitoxantrone every month for 1 year at the dosage of 8 mg/m2) or to the placebo group (24 patients, receiving IV infusion of saline every month for 1 year) using a centralized randomization system. Disability at entry and at 12–24 months was evaluated by four blinded neurologists trained in the application of the Kurtzke Expanded Disability Scale (EDSS). In addition, the number and clinical characteristics of the exacerbations over the 24 months were recorded by the local investigators. MRI, at 0,12 and 24 months, was performed with a 0.2 T permanent unit. MRI data were analysed by two blinded neuroradiologists. All patients underwent a clinical evaluation. A statistically significant difference in the mean number of exacerbations was observed between the mitoxantrone group and placebo group both during the 1st and the 2nd year. Although there was no statistically significant benefit in terms of mean EDSS progression over 2 years, the proportion of patients with confirmed progression of the disease, as measured by a one point increase on the EDSS scale, was significantly reduced at the 2nd year evaluation in the mitoxantrone group. Forty-two (23 mitoxantrone, 19 placebo) patients underwent all MRI examinations during the 24-month period. We observed a trend towards a reduction in the number of new lesions on T2-weighted images in the mitoxantrone group. Our study suggests that mitoxantrone might be effective in reducing disease activity, both by decreasing the mean number of exacerbations and by slowing the clinical progression sustained by most patients after 1 year from the end of treatment.

MRI criteria for the diagnosis of multiple sclerosis: MAGNIMS consensus guidelines

Summary In patients presenting with a clinically isolated syndrome (CIS), magnetic resonance imaging (MRI) can support and substitute clinical information for multiple sclerosis (MS) diagnosis demonstrating disease dissemination in space (DIS) and time (DIT) and helping to rule out other conditions that can mimic MS. From their inclusion in the diagnostic work-up for MS in 2001, several modifications of MRI diagnostic criteria have been proposed, in the attempt to simplify lesion-count models for demonstrating DIS, change the timing of MRI scanning for demonstrating DIT, and increase the value of spinal cord imaging. Since the last update of these criteria, new data regarding the application of MRI for demonstrating DIS and DIT have become available and improvement in MRI technology has occurred. State-of-the-art MRI findings in these patients were discussed in a MAGNIMS workshop, the goal of which was to provide an evidence-based and expert-opinion consensus on diagnostic MRI criteria modifications.

The prevalence of pain in multiple sclerosis A multicenter cross-sectional study

In a multicenter cross-sectional study, the authors assessed pain in patients with multiple sclerosis (MS) using a symptom-oriented approach. Out of 2,077 questionnaires, we used 1,672 for data analysis. Pain and frequencies included trigeminal neuralgia 2%, Lhermitte’s sign 9%, dysesthetic pain 18.1%, back pain 16.4%, and painful tonic spasms 11%. Comparison between different groups showed significant differences for age, Expanded Disability Status Scale, disease duration, and disease course, but not for sex. This study underlines the relevance of pain in the clinical history of MS.

Magnetic resonance imaging changes with recombinant human interferon-beta-1a: a short term study in relapsing-remitting multiple sclerosis.

OBJECTIVE: To evaluate whether recombinant human interferon-beta-1a significantly affects disease activity as measured by a reduction in the number and volume of Gd enhancing lesions on monthly MRI. The study also evaluated the effect on six-monthly T2 weighted abnormality and relapse frequency. METHODS: After a baseline scan and a six month pretreatment period, 68 patients were randomly assigned to receive either 3 MIU or 9 MIU of interferon-beta-1a by subcutaneous injection three times a week for six months. All patients were examined by Gd enhanced MRI every month in both pretreatment and treatment periods. The evaluation of Gd enhancing lesions was performed blind at the end of the study. RESULTS: The mean number of Gd enhancing lesions was higher during the pretreatment period than during treatment. This difference was statistically significant for the two different dose subgroups (3.5 v 1.8, P < 0.001 for the 3 MIU group and 2.4 v 0.9, P < 0.001 for the 9 MIU group, corresponding to a reduction of 49% and 64% respectively). The mean volume of Gd enhancing lesions also significantly decreased by 61% (3 MIU group) and 73% (9 MIU group). These reductions were evident only after the first month of treatment. The six-monthly rate of new lesions as seen in T2 weighted images showed a similar trend of reduction with treatment (65% and 70% respectively). Lesion volume on T2 scans significantly increased during the pretreatment period whereas it remained almost stable during the treatment period in both groups. Clinical relapse rate was significantly reduced by treatment (53% for the 3 MIU group, P < 0.001; 69% for the 9 MIU group, P < 0.001). CONCLUSION: Interferon-beta-1a seemed effective in reducing disease activity in relapsing-remitting multiple sclerosis at both the doses used.

'Gender gap' in multiple sclerosis: Magnetic resonance imaging evidence

The authors evaluated the gender difference in the magnetic resonance imaging characteristics of the lesions occurring in the brain of 413 multiple sclerosis (MS) patients. Men had fewer contrast‐enhancing lesions (P = 0.01), but a higher proportion of lesions evolving into ‘black holes’ (P = 0.001), when compared with women. Thus, our data indicate that men with MS are prone to develop less inflammatory, but more destructive lesions than women. This study results provides support for a modulation of the MS pathological changes by gender.

Fatigue and magnetic resonance imaging activity in multiple sclerosis.

Abstract Fatigue is a frequent and often severe symptom in multiple sclerosis. Pathogenic mechanisms proposed for fatigue include the release of proinflammatory cytokines, which is thought to have an important effect on changes in the blood-brain barrier (BBB). To investigate whether fatigue is related to BBB disruption we studied 11 relapsing-remitting MS patients participating in a multicenter longitudinal study comparing the sensitivity of monthly enhanced magnetic resonance imaging (MRI) after standard-dose and triple-dose injection of gadolinium-diethylene triaminopentoacetic acid (Gd-DTPA). Serial Gd-enhanced MRI studies were performed in two separate sessions every 4 weeks for 3 months. An expanded version of the Fatigue Severity Scale, including 29 items, was administered 24 h before each MRI examination. No relationship was found between the number and volume of Gd-enhancing lesions and fatigue scores at any monthly examination over the study period. Furthermore changes in MRI activity were not significantly related to changes in fatigue scores. These results were obtained on triple-dose delayed scanning, which is more sensitive than standard-dose scanning in detecting areas of BBB disruption. Our preliminary results thus do not support the hypothesis of a relationship between BBB alterations and fatigue severity in multiple sclerosis.

Monthly corticosteroids decrease neutralizing antibodies to IFNβ1b: A randomized trial in multiple sclerosis

Abstract Neutralizing antibodies (NAB) to interferon beta (IFNβ) occur in some multiple sclerosis (MS) patients, particularly during the first year of treatment. The presence of NAB may be associated with an attenuation of the therapeutic effect. The aim of this study was to compare the frequency of NAB occurrence in patients treated with IFNβ-1 b with that in patients treated with IFNβ-1 b combined with monthly pulses of intravenous methylprednisolone (MP).One hundred and sixty-one patients with relapsing-remitting MS were randomized in two treatment arms: 8 MIU of IFNβ-1 b subcutaneously injected every other day either alone or in combination with 1000 mg of monthly intravenous MP.NAB were evaluated at baseline and at months 3, 6, 9, 12 and 15 by the MxA assay in a specialized laboratory. Positivity was defined as a titer of ≥ 20 neutralizing units according to two different definitions: I) one or more non-consecutive positive samples, II) at least two consecutive positive samples.NAB (definition I) were observed in 26.8 % of patients in the IFNβ-1 b alone arm and in 12.1 % of patients in the combination therapy arm (p=0.05 by the chi-square test), which corresponds to a relative reduction of 54.9 %, whereas according to definition II, these figures dropped to 22.5 % for the IFNβ–1 b alone arm, and 10.6 % for the combination therapy arm (relative reduction 52.9 %, p=0.10, NS). A higher probability of remaining in the NAB-free status was observed in patients treated with the combination therapy (p=0.031 for definition I and p=0.049 for definition II, by the Wilcoxon-Gehan test).Methylprednisilone combined with IFNβ-1 b reduces the incidence of neutralizing bodies to interferon-β during the first year of treatment in MS patients.

Gadolinium enhanced MRI predicts clinical and MRI disease activity in relapsing-remitting multiple sclerosis.

The aim of the study was to evaluate the predictive power of baseline gadolinium (Gd) enhanced MRI in relation to subsequent clinical and MRI activity. Sixty eight patients with clinically definite relapsing-remitting multiple sclerosis had a baseline Gd enhanced MRI and were followed up clinically and by monthly Gd enhanced MRI for six months. The occurrence of relapses during the follow up period was predicted by the presence of at least one enhancing lesion on the baseline MRI (P < 0.05). The number and volume of enhancing lesions at baseline were significantly associated with both enhancing lesions observed during the follow up period (P < 0.0001) and the accumulation of abnormality on T2 weighted images (P < 0.0001). Moreover, the presence of three or more enhancing lesions at baseline scan was consistently associated with the development of permanent abnormalities on T2 weighted images six months later. The study suggests that the number and volume of Gd enhancing lesions at a single examination are strong short term predictors of subsequent clinical and MRI activity.

Effect of training and different measurement strategies on the reproducibility of brain MRI lesion load measurements in multiple sclerosis

In this study, we evaluated the intra- and interobserver variabilities in measuring lesion load of brain MRI abnormalities present on proton-density scans from patients with MS, using using both manual outlining or a semiautomated local thresholding technique (LTT). We also evaluated how these variabilities were affected by the use of standard rules for lesion load measurements, training, and different measurement strategies. The intraobserver variabilities obtained after establishing rules for lesion load measurements and training were not significantly different from those obtained before any consensus among the observers, both for manual outlining and for the LTT. On the contrary, the interobserver variabilities obtained with manual outlining or the LTT were significantly reduced when rules for lesion load measurements were used. For manual outlining, the intraobserver variability did not significantly change when the measurements were performed after an experienced radiologist identified lesions or when using adjacent slices and the corresponding T2-weighted images as reference for lesion identification. On the contrary, for the LTT, the intraobserver variability was significantly reduced by the use of the radiologic marking. The interobserver variabilities for both manual outlining and the LTT were reduced compared with the free condition when these measurement strategies were used. Our findings demonstrate that both lesion identification and outlining are important sources of variation for MRI lesion load measurements in MS and that there are simple strategies to reduce such variation that might be useful when planning clinical trials.