Triple dose of gadolinium-DTPA and delayed MRI in patients with benign multiple sclerosis.

OBJECTIVES--To evaluate whether a triple dose of gadolinium-DTPA (Gd-DTPA) or delayed MRI increase the number, size, and conspicuousness of enhancing lesions in patients with benign multiple sclerosis. METHODS--T1 weighted brain MRI was carried out on 20 patients with benign multiple sclerosis (expanded disability status scale < 3 with a disease duration > 10 years) in two sessions. In the first session, one scan was obtained before and two scans five to seven minutes and 20-30 minutes after the injection of 0.1 mmol/kg Gd-DTPA (standard dose). In the second session, six to 24 hours later, the same procedure was repeated with 0.3 mmol/kg Gd-DTPA (triple dose). RESULTS--Nine enhancing lesions were found in seven patients (35%) using the standard dose of Gd-DTPA. The numbers of enhancing lesions increased to 13 (P = 0.03) and the number of patients with such lesions to eight (40%) on the delayed standard dose scans. On the early triple dose scans, we found 19 enhancing lesions in 10 patients (50%). The number of enhancing lesions was significantly higher (P = 0.01) than that obtained with the early standard dose. The number of enhancing lesions was 18 and the number of "active" patients 11 (55%) on the delayed triple dose scans. The enhancing areas increased progressively from the early standard dose scans to the delayed triple dose scans. The contrast ratios of the lesions detected in early standard dose scans was lower than those of lesions present in the early (P = 0.01) and delayed (P = 0.04) triple dose scans. CONCLUSIONS--More enhancing lesions were detected in patients with benign multiple sclerosis with both delay of MRI and the use of triple dose of Gd-DTPA suggesting that the amount of inflammation in the lesions of such patients is mild and heterogeneous.     

A Preliminary Study Comparing the Sensitivity of Serial Monthly Enhanced MRI After Standard and Triple Dose Gadolinium-DTPA for Monitoring Disease Activity in Primary Progressive Multiple Sclerosis

We performed this study to evaluate and compare the numbers of total and new enhancing lesions detected on serial monthly brain magnetic resonance imaging (MRI) after the injection of a standard dose (SO) and a triple dose (TO) of gadolinium-OTPA (Gd) in patients with primary progressive multiple sclerosis (PPMS). Every 4 weeks for 3 months and in two separate sessions, MRI scans were obtained from 5 patients with PPMS, 5 (early) and 20 minutes (delayed) after SO (0.1 mmol/kg) or TO (0.3 mmol/kg) Gd injection. In 2 patients, T1-weighted scans with a magnetization transfer pulse (MT) after SD and TD injection were also obtained. There were 13 enhancing lesions (5 of which were new) on the early SO scans, 15 (5 new) on the delayed SD scans, 17 (6 new) on the early TO scans and 18 (7 new) on the delayed TO scans. TO MRI scans detected more enhancing lesions than SO scans in 3 patients (two of them were those with the lowest disability). The application of the MT pulse did not change the numbers of enhancing lesions seen after the injection of SO and TO of Gd in the remaining two patients. No side effects were reported and no significant changes in blood test parameters were found throughout the study. Our results suggest that serial monthly TO MRI, delayed scanning, MT T1-weighted scans or their combination, although safe, have a limited role for monitoring disease evolution in patients with PPMS.     

Strategies for optimizing MRI techniques aimed at monitoring disease activity in multiple sclerosis treatment trials

Serial magnetic resonance imaging (MRI) detects substantial subclinical disease activity in multiple sclerosis (MS) and is presently included in most treatment trials as an objective outcome measure. Our current knowledge of the role of MRI in MS treatment trials is derived from very limited patient studies, and the aim of this paper is to identify strategies to optimize the use of MRI in monitoring disease activity in treatment trials. The number of active lesions revealed by MRI can be used as the primary outcome measure in exploratory treatment trials. With monthly scanning, the majority of active lesions will be seen by virtue of a limited number of new areas of gadolinium enhancement. The contrast between enhancing lesions and background could be increased by: (1) using higher doses of gadolinium, (2) suppressing the background signal with magnetization transfer, (3) delayed scanning, or (4) a combination of these. Following a systematic comparison of those approaches, the effect on the sensitivity in detecting active lesions should be analysed with reference to the power of treatment trials. We present preliminary results showing marked agreement between observers in reporting enhancing lesions; however, with new acquisition strategies, the observer variation should be re-established in a multicentre fashion. In definitive trials, the increase in total lesion load serves as a secondary outcome measure. Since the majority of lesions making up the total lesion load are inactive during the study, spatial resolution should be maximized in order to preclude any artificial changes in lesion load to be superimposed (noise) upon the relatively small actual change (information). Reduction in measurement error can be attempted by improved acquisition techniques with increased lesion to background contrast. More importantly, improvement in quantitation techniques is warranted. With a 6% coefficient of variation in measuring a baseline lesion load, we calculate the standard error of the mean yearly increase in T2 lesion load (typically 10% in untreated patients) in a treatment arm of 124 patients to be 7.5%. A comparison of several quantitation techniques should be performed in a multicentre longitudinal fashion in order to include variation caused by both scanner and segmentation technique, in addition to biological activity. Received: 29 January 1996 Received in revised form: 15 July 1996 Accepted: 5 August 1996     

Correlation between MRI and short-term clinical activity in multiple sclerosis: comparison between standard- and triple-dose Gd-enhanced MRI

We assessed the relative sensitivities of standard (SD)- and triple-dose (TD) gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) for detecting enhancing lesions in different phases of multiple sclerosis (MS) disease activity. Ten MS patients were studied with monthly brain MRI scans for a 3-month follow-up (i.e., 4 scans were obtained for each patient with both SD and TD). A total of 11 relapses were recorded and treated with short-term high-dose steroid therapy. Enhancing lesion numbers and volumes were significantly higher for TD vs. SD scans (p < 0.0001). For both Gd doses, the numbers and volumes of lesions were higher during clinical relapses; the differences were statistically significant when comparing the results for scans obtained during and after a relapse. The gain in sensitivity of TD vs. SD scans for enhancing lesion detection was lower during relapses, whilst it was maximum after relapses, although these differences did not reach statistical significance. Our data confirm the potential role of TD MRI for monitoring MS activity, since, with its higher sensitivity, it may detect more subtle blood-brain barrier (BBB) damage. They also suggest that the degree of BBB damage in individual lesions changes during different phases of disease activity.     

Comparison of triple dose versus standard dose gadolinium-DTPA for detection of MRI enhancing lesions in patients with primary progressive multiple sclerosis.

This study was performed to evaluate whether a triple dose of gadolinium-DTPA (Gd-DTPA) increases the sensitivity of brain MRI for detecting enhancing lesions in patients with primary progressive multiple sclerosis (PPMS). T1 weighted brain MRI was obtained for 10 patients with PPMS in two sessions. In the first session, one scan was obtained five to seven minutes after the injection of 0.1 mmol/kg Gd-DTPA (standard dose). In the second session, six to 24 hours later, one scan before and two scans five to seven minutes and one hour after the injection of 0.3 mmol/kg Gd-DTPA (triple dose) were obtained. Four enhancing lesions were detected in two patients when the standard dose of Gd-DTPA was used. The numbers of enhancing lesions increased to 13 and the numbers of patients with such lesions to five when the triple dose of Gd-DTPA was used and to 14 and six in the one hour delayed scans. The mean contrast ratio for enhancing lesions detected with the triple dose of Gd-DTPA was higher than those for lesions present in both the standard dose (P < 0.0009) and the one hour delayed scans (P = 0.04). These data indicate that with a triple dose of Gd-DTPA many more enhancing lesions can be detected in patients with PPMS. This is important both for planning clinical trials and for detecting the presence of inflammation in vivo in the lesions of such patients.     

Multiple sclerosis: interobserver agreement in reporting active lesions on serial brain MRI using conventional spin echo, fast spin echo, fast fluid-attenuated inversion recovery and post-contrast T1-weighted images

Previous studies have addressed the question of the precision in assessing multiple sclerosis (MS) activity by counting enhancing lesions on gadolinium enhanced brain magnetic resonance imaging (MRI). However, counting the active lesions on serial unenhanced MRI obtained by various pulse sequences has not been yet considered. We compared the interobserver levels of agreement in reporting active MS lesions on serial enhanced and unenhanced MRI to assess whether the use of various unenhanced techniques may change the degree of interobserver measurement reproducibility. Dual-echo conventional spin echo (CSE), dual-echo fast spin echo (FSE), fast fluid-attenuated inversion recovery (FLAIR) and Gd-enhanced T1-weighted brain MRI were obtained from five MS patients at baseline and monthly for 2 months. Six experienced observers independently identified and counted active MS lesions on the two follow-up MRI scans. Active lesions were considered to be all the enhancing lesions and any new or enlarging lesion on enhanced and unenhanced scans. Interobserver levels of agreement were calculated by weighted κ values. Very good agreement was reached only for counting total and new Gd-enhancing lesions. Good agreement was achieved for counting new lesions on the three unenhanced techniques, whereas the agreement for counting enlarging lesions was poor with all the MRI techniques. The level of agreement was significantly heterogeneous for various MRI techniques but not for various lesion sites. These results confirm that counting enhancing lesions is the most reliable method for assessing MS activity, but the use of any of the available unenhanced MRI techniques did not result in different levels of interobserver agreement when reporting new and enlarging MS lesions on serial scans. Received: 10 December 1998 Received in revised form: 6 April 1999 Accepted: 26 April 1999     

Cumulative effect of a weekly low dose of interferon beta 1a on standard and triple dose contrast-enhanced MRI from multiple sclerosis patients

In patients with multiple sclerosis (MS), we assessed the short- and long-term effects of a weekly low dose of recombinant human interferon beta 1a (rh-IFN beta 1a) on the development of new magnetic resonance imaging (MRI) lesions enhancing at different gadolinium-DTPA (Gd) doses. Every 4 weeks, standard dose (SD) (0.1 mmol/kg of Gd) and triple dose (TD) (0.3 mmol/kg of Gd) Gd-enhanced brain MRI scans were obtained from 18 patients with relapsing-remitting MS for 3 months before treatment, 4 months after treatment initiation (treatment period [TP] I) and 4 months after 1 year of treatment (TP II) with 44 microg of rh-IFN beta 1a subcutaneously, once a week. The mean numbers of new enhancing lesions/patient/month were 1.4 (baseline), 1.1 (TP I) and 0.7 (TP II) on SD scans and 2.4 (baseline), 1.3 (TP I) and 0.8 (TP II) on TD scans. On average, treatment decreased the rate of new enhancing lesion appearance by 24% (SD scans) and 45% (TD scans) during TP I and by 52% (SD scans) and 66% (TD scans) during TP II. This study indicates that the effect of 44 microg of rh-IFN beta 1a given once a week on MRI-monitored MS activity increases over time. It also suggests that TD MRI is useful in detecting early treatment effect, that would otherwise be missed.     

Improved detection of cortical MS lesions with phase-sensitive inversion recovery MRI

Objective Cortical grey matter lesions are common in multiple sclerosis (MS), but usually not seen on MRI. The authors compared the performance of double inversion recovery (DIR, currently considered the best available imaging sequence for detecting cortical lesions) with phase-sensitive inversion recovery (PSIR, a sequence allowing much higher resolution scans to be obtained in a clinically feasible time). Methods Sixty MS patients and 30 healthy controls underwent MRI scanning on a 3 Tesla scanner. The authors compared intracortical (IC) and leucocortical (LC) lesion counts obtained with a standard DIR sequence (1×1×3 mm resolution, obtained in 4 min) and a PSIR sequence (0.5×0.5×2 mm, 11 min). Lesions were marked separately on DIR and PSIR scans. Results In the whole MS cohort, more cortical lesions were seen on the higher-resolution PSIR than the DIR scans (IC mean±SD: 18.1±9.8 vs 5.9±4.5, p<0.001; LC mean±SD: 13.4±12.9 vs 7.3±8.0, p<0.001). On PSIR, ≥1 IC lesion was seen in 60/60 MS patients and 1/30 controls, and ≥1 LC lesion in 60/60 patients and 6/30 controls. On DIR, ≥1 IC lesion was seen in 50/60 patients and 0/30 controls, and ≥1 LC lesion(s) in 60/60 patients and 5/30 controls. Conclusions Compared with DIR, using PSIR the authors are able to detect a significantly greater number of cortical grey matter lesions. The presence of at least one IC lesion in every MS patient, but very few healthy controls, suggests that it may be a useful adjunct to conventional MRI when a diagnosis of MS is suspected but not confirmed.     

Short-term evolution of new multiple sclerosis lesions enhancing on standard and triple dose gadolinium-enhanced brain MRI scans.

We compared the short-term magnetic resonance imaging (MRI) evolution of new multiple sclerosis (MS) lesions enhancing after single dose (SD) (0.1 mmol/kg) or triple dose (TD) (0.3 mmol/kg) gadolinium-DTPA (Gd) to explore possible differences in the pathological substrates of acute MS lesions. Brain MRI scans were obtained at baseline and every 4 weeks for a 3-month period in 18 relapsing-remitting MS patients. At each time point, using two separate sessions, we obtained dual echo and T1-weighted scans before and after SD and TD of Gd. New enhancing lesions detected at month 1 and 2 were entered into the analysis. The presence of corresponding hypointense lesions on unenhanced T1-weighted scans and hyperintense lesions on T2/proton density (PD)-weighted images was assessed on the same scan and on the scans performed 1 month before and 1 month after the new lesion development. Persistence of enhancement was evaluated on the SD and TD scans obtained 1 month after new lesion appearance. One-hundred and sixty lesions were studied. Of these, 97 lesions were enhancing after both SD and TD (group A) and 63 lesions only after TD (group B). Thirty (31%) of the lesions enhancing after both SD and TD and ten (16%) of the lesions enhancing only after TD had corresponding T1-weighted lesions (P = 0.03). Of these lesions, 87% in group A and 40% in group B (P = 0.003) were not hypointense on the previous scans. No differences were found in the frequencies of corresponding T2/PD-weighted abnormalities (92% in Group A vs. 87% in Group B lesions). Of these hyperintense areas, 62% in group A and 56% in group B were not present on the previous scans. On follow-up scans, 52% of the lesions enhancing after SD and TD and 70% of the lesions enhancing only after TD did not show enhancement after the injection of both the doses of Gd (P = 0.02). The frequencies of corresponding T2/PD and T1-weighted abnormalities were higher in Group A than in Group B lesions, but the differences were not statistically significant. Our findings suggest that the pathological process is less severe in MS lesions enhancing only after TD injection than in those enhancing after the SD.     

Asymmetries in the spatial distributions of enhancing lesions and black holes in relapsing-remitting MS

Magnetic resonance imaging (MRI) is the most important paraclinical test in the diagnosis of multiple sclerosis (MS) and for delineating its natural history. We investigate MRIs from a longitudinal study of 24 relapsing-remitting MS patients who had monthly MRI examinations for one year, and were not receiving active MS therapy during this period. We hypothesized that lesions occur randomly throughout the brain, and that patients are homogeneous with regard to spatial patterns of lesion presentation. We recorded the numbers and locations of enhancing lesions and hypointense lesions (black holes) in all scans, and found asymmetrical patterns of lesions about the mid-transaxial, mid-coronal, and mid-sagittal planes. Furthermore, in distinct subsets of patients, enhancing lesions and black holes tend to occur in the same locations. Clustering in lesion locations may be of functional significance, with consequent therapeutic implications.     

The predictive value of gadolinium enhancement for long term disability in relapsing-remitting multiple sclerosis--preliminary results

As short-term MRI studies are increasingly being used to monitor disease activity in multiple sclerosis (MS) it is vital to establish if short-term MRI activity is predictive of long term clinical outcome. We followed up after 5 years a group of 10 benign (relapsing-remitting MS with a disease duration > 10 years and EDSS < or = 3) and 10 early relapsing-remitting patients who previously had monthly serial MRI scans for 6 months. In the early relapsing-remitting group median EDSS at entry to the initial serial study was three and in the benign group 2.5. At 5-year follow up, five of these 20 patients had developed a definite deterioration in EDSS. The median number of new enhancing lesions detected originally in the group that had deteriorated was 11 (7-17) compared to 0 (0-5) new enhancing lesions, for those who had not deteriorated (P < 0.05). There was a trend towards a higher baseline T2 lesion load in the group with a definite change in EDSS but this was not significant This study suggests that short-term measurement of the number of gadolinium enhancing lesions may predict long term outcome in relapsing-remitting MS.     

Magnetization transfer changes in the normal appering white matter precede the appearance of enhancing lesions in patients with multiple sclerosis

Serial monthly magenetization transfer (MT) imaging was performed to evaluate whether a change of the normal appearing white matter (NAWM), which precedes the appearance of enhancing lesions, is seen in patients with multiple sclerosis (MS). Every 4 weeks for 3 months, 10 patients with relapsing-remitting MS were scanned with a T1-weighted sequence, 20 minutes after injection with 0.3 mmol/kg gadolinium-DTPA (Gd-DTPA). During each of the monthy sessions, MT and dual dual echo scans were also performed before Gd-DTPA injection. On coregistered images, the same slices but outside any present or future MR abnormality, and in enhancing lesions at the time of their apperance. Forty-eight new enhancing lesions with no corressponding abnormalities, the mean MTR in NAWM, measured from areas corresponding to future enhancing lesions, was significantly lower than the mean MTR in NAWM outside enhancing areas; the MTR decreased steadily as the time when the enhanced lesion approached. These results suggest that changes in the NAWM of patients with MS occur before lesions becomes evident on conventional MRI scans.     

Age-related gadolinium-enhancement of MRI brain lesions in multiple sclerosis

There is evidence that inflammatory processes in multiple sclerosis (MS) are age-dependent. In this study we evaluated the impact of aging on gadolinium (Gd) enhancement of brain magnetic resonance imaging (MRI) lesions in MS patients. Pre- and post-contrast MRI scans, acquired using a standardized procedure by the same MRI scanner, at least 1 month far from clinical relapse or steroid treatment, were examined in 200 disease-modifying treatment free MS patients. Seventy-three patients (36.5%) showed at least one enhancing lesion. Age at MRI examination (p=0.0001), disease duration (p=0.002) and EDSS score were significantly (p=0.02) lower, whereas relapse rate in the preceding 2 years was higher (p=0.003) in patients with enhancing lesions than in patients with unenhancing scans. Multivariate logistic analysis showed that current age was the variable better predicting Gd enhancement (p=0.004). The odds ratios were 0.95 (CI: 0.92-0.98) for each year of patient's age and 0.64 (CI: 0.48-0.87) for each age decade. The main changes in enhancement risk occurred after 35 years of age. Multivariate Poisson regression model showed that relapse rate in the preceding 2 years (p<0.0001) and current age (p=0.0003) were the best predictors of the number of enhancing lesions. This information can be used to increase the statistical power of clinical trials using Gd-enhancing lesions as an outcome measure.     

Interpreting therapeutic effect in multiple sclerosis via MRI contrast enhancing lesions: now you see them,now you don’t

Gadolinium (Gd) enhancement of multiple sclerosis (MS) lesions on MRI scans is a commonly used outcome measure in therapeutic trials. However, enhancement depends on MRI acquisition parameters that might significantly alter detectability. We investigated how the difference in blood–brain barrier (BBB) permeability threshold between MRI protocols affects lesion detection and apparent enhancement time using dynamic-contrast-enhanced (DCE) MRI. We examined fourty-four relapsing-remitting MS patients with two MRI protocols: ‘standard sensitivity’ (SS) (1.5 T, single-dose Gd) and ‘high sensitivity’ (HS) (3 T, triple-dose Gd, delayed acquisition). Eleven patients had at least one enhancing lesion and completed the 1-month follow-up. We acquired DCE-MRI during the HS protocol and calculated BBB permeability. Sixty-five lesions were enhanced with the SS vs. 135 with the HS protocol. The detection threshold of the HS was significantly lower than that of the SS protocol (K _trans = 2.64 vs. 4.00E?3 min^?1, p < 0.01). Most lesions (74 %) were in the recovery phase; none were in the onset phase and 26 % were at the peak of enhancement. The estimated duration of detectability with the HS protocol was significantly longer than for the SS protocol (6–12 weeks vs. 3 weeks). Our observations on the protocol-dependent threshold for detection and time-course help explain discrepancies in the observed effects of anti-inflammatory therapies on MS lesions.     

Serial study of gadolinium-DTPA MRI enhancement in multiple sclerosis

We performed serial baseline and gadolinium (Gd)-DTPA-enhanced MRI in 4 patients with definite multiple sclerosis. Studies were performed every month for a total of 4 scans. We obtained short TR/short TE sequences at 10 and 60 minutes after Gd-DTPA injection. All patients had multiple hyperintense lesions seen on baseline MRI with long TR/short and long TE. There was Gd-DTPA enhancement in new, enlarging, and preexisting lesions that were unchanged in size. The enhancing lesions were always seen on T2-weighted images. There was no difference in enhancement between the 10- and 60-minute studies. Six of 85 preexisting lesions enhanced whereas all new or enlarging lesions enhanced. Enhancement persisted in only 1/3 of the new or enlarging lesions, suggesting that MR enhancement is a transient phenomenon due to local temporary blood-brain barrier breakdown. Our data indicate that Gd-DTPA enhancement monitoring is more sensitive than unenhanced MRI for detecting disease activity in MS.     

Multisequence MRI in clinically isolated syndromes and the early development of MS.

OBJECTIVE: To apply multisequence MRI techniques to patients with clinically isolated syndromes, to document the pattern and frequency of abnormalities at baseline and early follow-up, and to determine their predictive values for the early development of clinical MS. BACKGROUND: Disseminated lesions on T2-weighted brain MRI confer an increased risk of progression to clinically definite MS. Newer MRI techniques increase detection of lesions in both brain and spinal cord, and clarify further their pathology. The predictive value of such techniques for the development of clinical MS needs to be defined. METHODS: Brain and spinal MRI were performed on 60 patients after their first demyelinating event. A total of 50 patients were followed for 1 year, and 49 underwent repeat brain MRI 3 months after the initial scan. RESULTS: At baseline, 73% of patients had lesions on T2-weighted fast spin-echo (FSE) brain images and 42% had asymptomatic spinal cord lesions. Fast fluid-attenuated inversion-recovery brain did not improve detection of brain lesions. Repeat brain MRI demonstrated new FSE lesions in 43% of patients. After 1 year, 26% of patients developed MS. The MRI features that provided the best combination of sensitivity and specificity for the development of MS were the presence of new FSE lesions at follow-up and enhancing lesions at baseline. The frequency of developing clinical MS was higher for those with both brain and spinal cord lesions at baseline (48%) than brain lesions alone (18%). CONCLUSIONS: The combination of baseline MRI abnormalities and new lesions at follow-up, indicating dissemination in space and time, was associated with a high sensitivity and specificity for the early development of clinical MS. These data suggest a potential role for new diagnostic criteria for MS based on early MRI activity. Such criteria may be useful in selecting patients for therapeutic trials at this early clinical stage.     

Serial Gadolinium-enhanced MRI in untreated patients with acute optic neuritis: implications for natural history

Introduction - Serial brain MRIs with and without Gadolinium (Gd)-DTPA were performed in acute optic neuritis (ON). Material and methods - Fifty-nine untreated patients (44 female) aged 20–57 years with ON underwent MRI median 16 d from onset of symptoms of ON and at 1 and 12 months follow-up. Results - At onset of monosymptomatic ON (AMON), 13 of 40 (33%) patients had lesions on MRI without Gd-DTPA compared with 15 of 19 (79%) patients with ON as part of clinically definite multiple sclerosis (CDMS). An initially abnormal MRI never normalized, whereas 3 patients with AMON with initially normal MRI had lesions at follow-up. In AMON enhancing lesions were seen in 5% of patients at onset, in 12% after 1 month, and in 11% after 12 months. The corresponding figures in CDMS were 21 %. 38%, and 33%. All enhancing lesions were also seen on MRI without Gd-DTPA. The number of lesions on MRI without Gd-DTPA increased significantly with time in the 8 patients with AMON with enhancing lesions at one or more MRIs. New enhancing lesions appeared in 11 patients (6 AMON), of whom 3 (2 AMON) had an exacerbation. In contrast. 12 (5 AMON) patients had an exacerbation, being accompanied by new enhancing lesions in only 3 (2 AMON) patients. Conclusion - Gd-DTPA did not increase the sensitivity of MRI, which was significantly higher in CDMS than in AMON, but improved the understanding of the natural history of AMON and CDMS. The dynamics of enhancing lesions did not correlate well with exacerbations. Serial MRI and clinical assessment are supplementary in monitoring disease activity.     

A preliminary study into the sensitivity of disease activity detection by serial weekly magnetic resonance imaging in multiple sclerosis.

Long TR and gadolinium enhanced spin echo brain MRI was performed weekly for three months in three patients with relapsing-remitting or secondary progressive multiple sclerosis. During the study, 38 new enhancing lesions were seen; 11 showed enhancement for less than four weeks, and two enhanced on only one scan. All 16 new lesions seen on long TR scans showed initial enhancement. When only every fourth (monthly) scan was analysed, a total of 33 new enhancing lesions were seen. Subject to confirmation in a larger cohort, the results suggest: (a) that blood brain barrier leakage is an invariable event in new lesion development in relapsing-remitting and secondary progressive multiple sclerosis; (b) the small increase in sensitivity of weekly scanning does not justify its use in preference to monthly scanning when monitoring treatments.     

A pilot trial of combination therapy with mitoxantrone and interferon beta-1b using monthly gadolinium-enhanced magnetic resonance imaging

OBJECTIVE: To examine the safety of combination therapy with mitoxantrone (MITX) and interferon beta-1b (IFNbeta-1b) in patients with multiple sclerosis (MS) and a high on-therapy relapse rate and enhancing lesions on baseline magnetic resonance imaging (MRI) scan. METHODS: Ten patients with worsening relapsing remitting or secondary progressive MS were studied using monthly MRI with triple-dose gadolinium contrast. All patients must have been on IFNbeta-1b for at least six months, have at least one enhancing lesion on a screening MRI, at least one relapse on IFNbeta-1b in the six months prior to study entry and be neutralizing antibody negative. Monthly MRI scans using triple dose contrast and a 30-minute delay between contrast administration and scanning were carried out three times over two months to obtain baseline numbers of enhancing lesions each month. At the end of the baseline phase, MITX was administered at 12 mg/m2 (month 3), and 5 mg/m2 at months 4 and 5. Dosing was continued at 5 mg/m2 every third month. Monthly MRI scanning was continued throughout the duration of MITX dosing. The primary outcome measure was the frequency of new enhancing lesions. Secondary outcome measures included relapse rate, and T1 hypointense and T2 lesion burden. RESULTS: Following the addition of MITX to IFNbeta-1b mean enhancing lesion frequency decreased 90% at month 7 (P = 0.008) and enhancing lesion volume decreased by 96% (P = 0.01). Relapse rates decreased 64% (P = 0.004). T2 lesion burden and T1 hypointense lesion burden increased slightly during the baseline phase and decreased following MITX but the difference did not reach statistical significance. There were no serious adverse events on combination therapy and no drop-outs due to toxicity. Total white blood cell count was reduced at 14 days post-MITX infusion but returned to normal levels by day 21. There were no neutropenic fevers and there was no clinically significant elevation of liver function tests. CONCLUSIONS: While the number of patients in this study was small, the results suggest that the combination is safe and well tolerated. Disease activity was substantially reduced following the addition of MITX to IFNbeta-1b.     

Modelling new enhancing MRI lesion counts in multiple sclerosis.

Magnetic resonance imaging (MRI) has been established as the most relevant paraclinical tool for diagnosing and monitoring multiple sclerosis (MS). In this context, counting the number of new enhancing lesions on monthly MRI scans is widely used as a surrogate marker of MS activity when evaluating the effect of treatments. In this study, we investigated whether parametric models based on mixed Poisson distributions (the Negative Binomial (NB) and the Poisson-Inverse Gaussian (P-IG) distributions) were able to provide adequate fitting of new enhancing lesion counts in MS. We found that the NB model gave good approximations in relapsing-remitting and secondary progressive MS patients not selected for baseline MRI activity, whereas the P-IG distribution modelled better new enhancing lesion counts in relapsing-remitting MS patients selected for baseline activity. This study shows that parametric modelling for MS new enhancing lesion counts is feasible. This approach should provide more targeted tools for the design and the analysis of MRI monitored clinical trials in MS.