Long-term follow-up of peripheral lymphocyte subsets in a cohort of multiple sclerosis patients treated with natalizumab.

Natalizumab, an anti-alpha4 integrin monoclonal antibody inhibiting the adhesion of lymphocytes to the endothelium, is a widely accepted drug treatment for relapsing-remitting multiple sclerosis (RRMS). A peripheral increase of T and B lymphocytes has already been observed as an early treatment effect. This retrospective observational study was aimed to evaluate the peripheral lymphocyte subsets during a long-term treatment follow-up. We included 23 RRMS patients treated with natalizumab for at least 24-48 months who had pretreatment lymphocyte evaluation. Baseline values of lymphocyte subsets and CD4/CD8 ratio did not differ significantly from the 23 matched healthy subjects. The periodic (every 3-6 months) assessment of immune cell subsets was performed by flow cytometry on peripheral blood collected before drug injection. Therapy with natalizumab was confirmed to be effective during the observational period. For all patients, the increase in lymphocytes during natalizumab therapy compared to baseline at every assessment was significantly higher compared to that of overall white blood cells (2·1- and 1·3-fold, respectively, P < 0·0001). Both T cell subsets were proportionally modified and the CD4/CD8 ratio did not change significantly, while B cells increased significantly compared to T and NK cells (3·2-, 1·88- and 1·92-fold, respectively, P < 0·0001). These changes remained constant throughout the 25-48-month period of therapy. In conclusion, effective natalizumab treatment of RRMS patients was associated with the persistence of its biological effects through a stable increase of peripheral lymphocytes, mainly B cells, and an unchanged proportion of T cell subsets in long-term follow-up.

Devic's neuromyelitis optica and mitochondrial DNA mutation: a case report.

Cases are described with Leber's optic atrophy and neurological symptoms and/or MRI lesions suggestive of multiple sclerosis. We describe a case of a young woman with Devic's neuromyelitis optica and 3460 homoplasmic mitochondrial DNA mutation.

Interferon-beta-1a in relapsing-remitting multiple sclerosis: effect on hypointense lesion volume on T1 weighted images.

OBJECTIVE: Recently, a strong correlation between the increase in hypointense lesion load on T1 weighted spin echo images, and the increase in disability was reported. Although the effect of interferon-beta has been demonstrated both in reducing exacerbation rate, frequency of enhancing lesions, and accumulation of disease burden on T2 weighted images, the impact on the accumulation of hypointense lesions has not yet been evaluated. The aims of the present study were: (a) to assess for the first time the effect of interferon-beta-1a on T1 weighted MRI hypointense lesion volume; and (b) to evaluate the relation between changes on hypointense, hyperintense, and enhancing lesion volume before and during interferon-beta-1a treatment in relapsing-remitting multiple sclerosis. METHODS: After a baseline scan and 6 month pretreatment period, 67 patients with relapsing-remitting multiple sclerosis were treated with interferon-beta-1a by subcutaneous injection three times a week during a 12 month treatment period. All patients had MRI every month during the 6 month pretreatment period and for the first 9 months of the treatment period. A final MRI was also performed at the end of the 12 month treatment period. RESULTS: There was a significant increase in the mean hyperintense lesion volume during the pretreatment phase (6 months) and a slight decrease during the treatment period (12 months), whereas the hypointense lesion volume increased significantly before treatment and remained substantially stable during treatment. There was a significant correlation between changes in hypointense and hyperintense lesion volume during the observation period, but not during treatment. The monthly mean volume of Gadolinium-DTPA enhancing lesions was significantly higher during the pretreatment than the treatment period, and the enhancing lesion volume correlated with changes of hyperintense and hypointense lesion volumes only during the observation period. CONCLUSION: These data suggest that interferon-beta-1a has a stabilising effect on T1 weighted hypointense lesion volume.

Determinants of Gd-enhanced MRI response to IFN-beta-1a treatment in relapsing-remitting multiple sclerosis.

The decision to use interferon beta (IFN-beta) as a treatment for relapsing-remitting multiple sclerosis (RRMS) is based on both clinical characteristics and course of the disease. To better identify the profile of responders, the relationships between baseline clinical/MRI characteristics and therapeutical response was analyzed in 49 patients with RRMS randomly assigned to receive subcutaneously 3 or 9 MIU of IFN-beta-1a. The therapeutical response was evaluated as a per cent change in the mean number and volume of monthly Gd-enhancing lesions in both first (early response) and second (late response) 6-month period of treatment, compared to the 6-month pre-treatment period. A better early response was seen in patients with a lower number of relapses during the pre-treatment period, while the late response was favourably influenced by a lower baseline EDSS and the high dose. Our findings suggest that the effect of IFN-beta-1 a on disease MRI activity is dose-related and dependent on the relapse rate and the level of disability before treatment.

Effect of steroids on Gd-enhancing lesions before and during recombinant beta interferon 1a treatment in relapsing remitting multiple sclerosis.

The aim of this study was to investigate whether a concomitant treatment with recombinant interferon beta 1a (rIFN beta-1a) modifies the effect of steroids on the blood-brain barrier (BBB) in relapsing remitting MS patients, as evaluated by enhanced MRI of the brain. We evaluated 19 patients with a clinical relapse treated only with intravenous methylprednisolone (IVMP; 1 g daily for 6 days), and 10 patients who experienced a clinical relapse and were treated with IVMP (1 g daily for 6 days) during an rIFN beta-1a treatment period. The number and volume of enhancing lesions were analyzed on four serial MR images obtained at monthly intervals (one scan before and three scans after IVMP treatment). A significant reduction in the mean number and volume of enhancing lesions was seen in the first scan after IVMP treatment in all patients. However, while persistently low enhancement was seen in the follow-up scans of patients treated with rIFN beta-1a, a rebound effect (i.e., increase in the number and volume of gadolinium-enhancing lesions) was observed in the other patients during the follow-up. These data suggest that rIFN beta-1a prolongs the beneficial effect of steroids on the BBB.

MRI measures and their relations with clinical disability in relapsing-remitting and secondary progressive multiple sclerosis.

To further evaluate the relationship between clinical disability and Magnetic Resonance Imaging (MRI) lesion burden, we examined 85 patients with clinically definite multiple sclerosis (54 relapsing-remitting and 31 secondary progressive). This cross-sectional study reports on the correlations between total and infratentorial lesion volume on both T1 and T2 weighted images, and overall physical disability measured by Expanded Disability Status Scale, ambulation index and individual functional systems. Assessment of the hypointense lesion load on T1 weighted images rather than the hyperintense lesion load on T2 weighted images at brain MRI was shown to be useful for differentiating relapsing-remitting from secondary progressive Multiple Sclerosis. A weak relationship between disability and total lesion volume on both T1 and T2 weighted images was found in relapsing-remitting Multiple Sclerosis. In secondary progressive Multiple Sclerosis, infratentorial lesion volume on T2 weighted images represents the only marker of disability. Finally, the presence of cerebellar, brainstem and mental impairment was significantly associated to a greater total lesion volume on MRI, while no relationship was found with other functional systems.

Fast spin-echo and fast fluid-attenuated inversion-recovery versus conventional spin-echo sequences for MR quantification of multiple sclerosis lesions.

PURPOSE: To compare fast spin-echo (FSE) and fast fluid-attenuated inversion recovery (FLAIR) sequences with conventional spin-echo (CSE) MR imaging in the quantification of the number and volume of multiple sclerosis lesions. METHODS: In 30 patients with relapsing-remitting multiple sclerosis, we calculated the total number and volume of lesions detected with each of the three sequences using a semiautomated program. RESULTS: On CSE sequences, we calculated a total of 2,583 lesions with a global volume of 836.3 cm3. With FSE sequences, we observed a 16% relative reduction in the number of lesions detected and a 25% relative reduction in global volume as compared with CSE. With fast FLAIR sequences, we detected a significantly lower number and volume of infratentorial lesions, whereas at the cortical/subcortical level the lesions were both more numerous and bulkier than on CSE sequences. Finally, we observed a higher lesion/white matter contrast, a significant reduction in time required for the quantification of lesion load, and a very low interobserver variability in favor of fast FLAIR sequences. CONCLUSION: Despite its limitations in the detection of infratentorial lesions, the fast FLAIR sequence in conjunction with a semiautomated quantification program provides a reliable means to evaluate the total lesion burden in patients with MS.

The influence of clinical relapses and steroid therapy on the development of Gd-enhancing lesions: a longitudinal MRI study in relapsing-remitting multiple sclerosis patients.

Fifty-three patients with relapsing-remitting multiple sclerosis who had monthly Gd (gadolinium) enhanced MRI (Magnetic Resonance Imaging) and clinical evaluation, were divided into two subgroups: 1) patients with a clinical relapse, treated with IVMP (intravenous methylprednisolone) and at least one enhancing lesion on MRI. 2) patients who did not have a clinical relapse but with at least one enhancing lesion on MRI. In group 1, we evaluated the number and volume of enhancing lesions on the scan before and three scans after IVMP therapy; in group 2, we considered the first scan with enhancing lesions and the subsequent three scans. The mean number and volume of enhancing lesions on the first scan was significantly higher in patients with clinical relapse compared to patients without clinical relapse. In group 1, we found a consistent reduction in the first scan following steroid treatment which returned to initial levels at the following scan. Both volumetric and numerical evaluation are appropriate MRI outcome measures in monitoring therapeutic trials.

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.

Interferon beta 1a.

An improved understanding of the immunopathogenesis of multiple sclerosis (MS) has led to therapeutic attempts using immunoregulatory agents in patients with MS, including interferon beta. IFN-beta 1a has been tested in relapsing-remitting MS and its effectiveness in reducing exacerbation rate and in slowing sustained worsening of disability after 2 years has been shown. Magnetic resonance imaging results supported the clinical findings, showing a significant reduction in Gd-enhancing lesion frequency and new lesion formation on T2-weighted images. This type of interferon is well tolerated and most adverse events are mild and transient. Further trials are in progress to amplify and clarify the observed benefits of IFN-beta 1a.

No increase of serum autoantibodies during therapy with recombinant human interferon-beta1a in relapsing-remitting multiple sclerosis.

OBJECTIVES: The present investigation was aimed at establishing whether interferon (IFN)-beta would induce the synthesis of autoantibodies in patients affected by multiple sclerosis (MS). MATERIALS AND METHODS: The titres of different autoantibodies were measured in a group of 68 relapsing-remitting MS patients before and during treatment with human recombinant IFN-beta1a (3 MIU or 9 MIU subcutaneously 3x a week). ANA, anti-thyroid, anticardiolipin serum autoantibodies were assayed in all cases: when patients were found positive to ANA > 1 : 40, they were also tested for anti-DNA and anti-ENA antibodies. RESULTS: No increase was found in autoantibodies synthesis during 6 months of r-hIFNbeta1a therapy, either at low or high dosages. The percentage of patients positive to different types of autoantibodies varied between 0 and 29%, which are values similar to those already reported in untreated MS patients. CONCLUSION: Our data indicate that the short-term use of IFN-beta1a in MS is safe in terms of the induction of humoral autoimmune responses: however, further follow-up is needed to confirm these findings during long-term treatments.

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.

Involvement of the limbic system in multiple sclerosis patients with depressive disorders.

This study investigates the relationship between depression and both anatomic and cerebral blood flow abnormalities in multiple sclerosis (MS) patients. Ten nondepressed MS patients were compared with 10 depressed MS patients matched for age, sex, and functional disability. Both groups were evaluated by means of neuropsychological tests, magnetic resonance imaging, and single-photon emission tomography imaging. There was no difference between the two groups with regard to the global cognitive score. Magnetic resonance imaging data showed no significant differences in the number, side, location, and area of the demyelinating lesions between the two groups; however, regional cerebral blood flow asymmetries in the limbic cortex did distinguish the two groups. Analysis of variance showed a significant effect of depression on the perfusion asymmetries in the limbic cortex. Finally, perfusion asymmetries in limbic cortex significantly correlated with depression test scores. Our findings suggest that depression in MS patients could be induced by a disconnection between subcortical and cortical areas involved in the function of the limbic system.

High-dose contrast-enhanced MRI in multiple sclerosis.

Contrast-enhanced MRI is effective for assessing disease activity in multiple sclerosis (MS) and may provide an outcome measure for testing the efficacy of treatment in clinical trials. To compare the sensitivity of high-dose gadolinium-HP-DO3A with that of a standard dose of gadolinium-DTPA, we studied 16 patients with relapsing-remitting MS in the acute phase of the disease. Each underwent two MRI examinations within at most 48 h. The initial MRI study was with a standard dose of gadolinium-DTPA (0.1 mmol/kg), and the second one an experimental dose of gadolinium-HP-DO3A (0.3 mmol/kg). No adverse effects were attributed to the contrast media. The high-dose study revealed more enhancing lesions than the standard-dose study (56 vs 38). This difference was found to be more relevant for infratentorial and small lesions. Furthermore, with the higher dose, there was a marked qualitative improvement in the visibility and delineation of the lesions.

Fatigue in MS is associated with specific clinical features.

INTRODUCTION: fatigue is a common and disabling symptom in multiple sclerosis (MS). In this study we evaluated if fatigue is associated with different demographic and clinical features of MS. MATERIAL: A survey was performed on 507 consecutive patients affected by clinically definite MS referred to our centre between January 1 and December 31, 1993. During the examination patients were asked to answer a brief fatigue questionnaire. To evaluate the probability of the occurrence of fatigue in association with several covariant factors (age, sex, duration, disease form, disease severity, month of examination, functional sub-systems on the expanded disability status scale (EDSS), a logistic regression analysis was performed. RESULTS: we confirmed that fatigue is common in MS, recorded in 53% of patients. Patients affected by a more severe disability, by progressive MS, both primary and secondary, with an older age at examination, and assessed during spring, had a significantly higher risk of fatigue. Sex was not associated with the occurrence of fatigue. When the single items of EDSS were considered, we found that fatigue is also associated with the occurrence of cerebellar, sphincteric, pyramidal and sensitive signs, but not with brain stem, visual and cognitive impairment. CONCLUSION: fatigue in MS is more frequent in association with specific clinical features.

Human recombinant interferon beta in the treatment of relapsing-remitting multiple sclerosis: preliminary observations.

An open comparative, randomized trial with recombinant human interferon beta (r-hIFN-beta) involving 72 patients with clinically definite and/or laboratory-supported relapsing-remitting MS is in progress at the University 'La Sapienza' and at the S. Camillo Hospital of Rome. After a 6 month period of clinical and magnetic resonance imaging (MRI) observation (baseline findings), patients are randomly assigned to one of two treatment groups receiving 3 or 9 MIU of recombinant human IFN-beta (r-hIFN-beta) self-administered by subcutaneous injection three times a week for 6 months. All patients are examined by MRI with and without gadolinium (Gd-DTPA) every 4 weeks for the entire duration of the study (12 months). The main aim of the study is to test the hypothesis that r-hIFN-beta may halt or slow the progression of the disease by showing a significant reduction in MRI activity. This will be achieved by comparing pre and post-treatment periods. As an additional clinical end point, the exacerbation rate during these two periods will be compared. This study began in June 1993 and the final analysis of MRI data is planned for the spring of 1995.