A. Paolillo

Sex hormones modulate brain damage in multiple sclerosis: MRI evidence

Background: Sex related differences in the course and severity of multiple sclerosis (MS) could be mediated by the sex hormones. Objective: To investigate the relation between serum sex hormone concentrations and characteristics of tissue damage on conventional magnetic resonance imaging (MRI) in men and women suffering from relapsing-remitting MS. Results: Serum testosterone was significantly lower in women with MS than in controls. The lowest levels were found in women with a greater number of gadolinium enhancing lesions. A positive correlation was observed between testosterone concentrations and both tissue damage on MRI and clinical disability. In men, there was a positive correlation between oestradiol concentrations and brain damage. Conclusions: The hormone related modulation of pathological changes supports the hypothesis that sex hormones play a role in the inflammation, damage, and repair mechanisms typical of MS.

'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.

Correlation between fatigue and brain atrophy and lesion load in multiple sclerosis patients independent of disability.

BACKGROUND Fatigue is a major problem in multiple sclerosis (MS), and its association with MRI features is debated. OBJECTIVE To study the correlation between fatigue and lesion load, white matter (WM), and grey matter (GM), in MS patients independent of disability. METHODS We studied 222 relapsing remitting MS patients with low disability (scores <or=2 at the Kurtzke Expanded Disability Status Scale). Lesion load, WM and GM were measured by fully automated, operator-independent, multi-parametric segmentation method. T1 and T2 lesion volume were also measured by a semi-automated method. Fatigue was assessed by the Fatigue Severity Scale (FSS), and patients divided in high-fatigue (FSS>or=5; n=197) and low-fatigue groups (FSS<or=4; n=25). RESULTS High-fatigue patients showed significantly higher abnormal white matter fraction (AWM-f), T1 and T2 lesion loads, and significant lower WM-f, and GM-f. Multivariate analysis showed that high FSS was significantly associated with lower WM-f, and GM-f. Females and highly educated patients were significantly less fatigued. CONCLUSION These results suggest that among MS patients with low disability those with high-fatigue show higher WM and GM atrophy and higher lesion load, and that female sex and higher levels of education may play a protective role towards fatigue. Furthermore, they suggest that in MS, independent of disability, WM and GM atrophy is a risk factor to have fatigue.

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.

A 6-year clinical and MRI follow-up study of patients with relapsing-remitting multiple sclerosis treated with interferon-beta

There are few long‐term clinical and magnetic resonance imaging (MRI) data on patients treated with interferon‐beta (IFN‐β) for relapsing–remitting multiple sclerosis (RRMS). The aim of this study was to provide clinical and MRI data on 68 patients with RRMS treated over a 6‐year period and to investigate whether a baseline MRI predicts their long‐term clinical and MRI outcome. Six MRI scans were performed monthly before treatment and a further 13 scans were performed during treatment with IFN‐β, the last of which 6 years after commencement of treatment. The relapse rate, disability as measured by the Expanded Disability Status Scale (EDSS), and MRI parameters, including Gd‐enhancing lesion load (Gd‐LL), T2 hyperintense lesion load (T2‐LL) T1 hypointense lesion load (T1‐LL) and supratentorial brain volume (SBV) were measured throughout the study. The mean annual relapse rate over the 6 years was 0.52 (SD 0.67), which is significantly lower (68.6%) than the mean annual relapse rate of 1.6 observed during the 2‐year period before the commencement of treatment (P < 0.01). The median EDSS score increased from 2 to 2.5, remaining stable in 60% of the patients. From the baseline scan to the final scan, there was a median increase of 7% in the T2‐LL and 23.9% in the T1‐LL, whilst SBV decreased by 2.7%. The increase in the EDSS over the course of the study was significantly correlated with a reduction in brain volume (r = 0.46, P = 0.001). Greater brain damage at baseline, as measured by both T2‐LL and T1‐LL, was significantly associated with an increase in disability over the 6 years (r = 0.44, P = 0.0009; r = 0.50, P = 0.0007, respectively). This study shows a sustained effect of IFN‐β on the relapse rate, which is lower than during the 2 years before treatment commencement. More than half the patients showed an improvement or stabilization in the EDSS score. The increment in disability was correlated with the development of brain atrophy but not with increases in lesion burden. Finally, the finding that the extent of lesion burden at the baseline was a strong predictor of increasing disability suggests that IFN‐β treatment might have a moderate effect in modifying the multiple sclerosis (MS) disease course over 6 years unless preventive treatment is started early.

The relationship between inflammation and atrophy in clinically isolated syndromes suggestive of multiple sclerosis: A monthly MRI study after triple-dose gadolinium-dtpa

Abstract.Objective:To examine the relationship between inflammation and brain atrophy in patients with a clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS).Methods:Monthly triple-dose gadolinium (Gd/DTPA)-enhanced MRI scans over 6 months were obtained in 62 consecutive CIS patients with an abnormal baseline MRI scan. Subsequently MRI was performed at months 12 and 18. Patients who developed a clinically definite MS (i. e., a second clinical episode) ended the study at the time of the relapse. For each scan, the number and volume of newly active lesions (Gd-enhancement/new or newly enlarging T2 lesion that did not enhance), and the number and volume of T2 hyperintense lesions (T2-LL) and T1-black holes (T1- LL) were calculated. The percentage of brain volume changes (PBVC) was assessed using a fully automated technique (SIENA; Structural Image Evaluation using Normalization of Atrophy).Results:Twenty-four (39%) developed clinically definite MS by month 18. Thirty-eight (61%) were relapsefree and completed the MRI follow-up. Relapse-free patients showed a progressive median increase between baseline and month 18 in T1-LL (25%, p < 0.001), but not in T2-LL (8.5%, p = ns). PBVC decreased by 1.1% (p < 0.001) in a time-dependent pattern (Kendall coefficient of concordance = 0.85). Exploratory subgroup analyses showed a trend towards progressive decreases in brain volume in active patients (i. e., those with at least one newly active lesion during monthly MRI scanning; Spearman’s R = –0.61; p < 0.001), but not among inactive patients (Spearman’s R = –0.10; p = 0.53). Significant differences in median brain volume changes between the active and inactive patient groups were found at months 12 and 18; the difference detected at month 6 was not significant. The cumulative number and volume of new Gd-enhancing lesions developed during the 6 months of frequent MRI scanning were highly correlated with PBVC over the 18-month period (Spearman R values were 0.73 and 0.85, respectively). The strongest predictor of PBVC at 18 months was the cumulative volume of newly active lesions during frequent MRI scanning [ß = –0. 83, standard error (SE) = 0.07, p < 0.001].Conclusions:This study shows that visible inflammation as detected by monthly, triple-dose Gd-enhanced MRI is an important factor in the pathogenesis of brain tissue loss in CIS patients. However, inflammation and brain atrophy do not proceed in parallel: atrophy appeared only after a delay of months following acute inflammation. Frequent MRI scanning allows for the detection of CIS patients who will develop brain atrophy in the short-term.

Fate of neutralizing and binding antibodies to IFN beta in MS patients treated with IFN beta for 6 years

An increasing number of evidence is showing that during prolonged treatment of relapsing-remitting multiple sclerosis (RRMS) with interferon (IFN) beta 1a or IFN beta 1b, the patients may develop serum anti-IFN antibody. It has been argued that some of the RRMS patients receiving IFN beta, who developed antibodies to IFN, lose them over time even though the treatment continues. To gain further insights into this issue, we performed a study to establish what happened to binding antibodies (BAB) and neutralizing antibodies (NAB) in 42 RRMS patients treated for 6 years with IFN beta 1a and/or IFN beta 1b. While the data of BAB analysis did not allow to reach definite conclusions, the results on NAB development confirm that the presence of this type of antibodies is transitory; in fact, most of the positive patients reverted to seronegative, although the IFN treatment is still ongoing; the only patients who were positive for NAB at 6 years of treatment are those whose serum contains high concentration of them. The paper also shows that patients lose antibodies to IFN independently on the type of IFN used for the treatment. In conclusion, the data indicate that the disappearance of the anti-IFN antibodies from the serum while the patients are still undergoing IFN treatment depends on the titer of antibodies but not on the type of IFN administered.

MRI brain volume changes in relapsing-remitting multiple sclerosis patients treated with interferon beta-1a

The aim of this study was to investigate changes of brain volume as measured by magnetic resonance imaging (MRI) in relapsing-remitting multiple sclerosis (MS) patients under treatment with interferon beta-1a. Moreover, the relationship between brain volume changes and standard MR or clinical outcome variables was determined. After a 6-month pretreatment period, 52 patients with relapsing-remitting MS were assigned to receive interferon beta-1a (Rebif-Serono) during a 24-month treatment period. MRI scans were performed monthly during the 6-month pretreatment period and for the first 9 months of the treatment period. A final MRI scan was also performed at the end of the 12- and 24-month treatment period. Over 24 months of IFNβ-1a treatment, a significant decrease of hyperintense lesion volume was found (−18.0%; p<0.0001) compared to the last pretreatment scan, while T1 hypointense volume showed a slight nonsignificant increase (+2.2%), and brain volume showed a significant decrease (−2.2%; p<0.0001). The mean volume of enhancing lesions over the 6-month pretreatment period was significantly related to absolute (p=0.02; r=−0.32) and per cent change (p=0.03; r=−0.30) of brain volume during 24-month treatment period. No correlations between changes in brain volume and changes in T2 hyperintense volume or T1 hypointense volume were observed. Neither was there a relationship between brain volume and changes of Expanded Disability Status Scale (EDSS) or frequency in clinical relapses. Of the group in whom was detected a significant decrease of brain volume, 13 out of 26 (50%) had a sustained change in EDSS while in the group that did not have a significant decrease of brain volume, only 3 out of 26 (11.5%) had a sustained EDSS change (p=0.02). In this study a decrease of brain volume was found in relapsing-remitting MS patients treated with IFNβ-1a over 2 years. The only parameter that predicted brain volume decrease by 2 years of IFNβ-1a treatment was the mean volume of enhancing lesions over the 6-month pretreatment period.

Excessive daytime sleepiness in myotonic dystrophy

The aim of the present study was to assess whether or not there is any correlation between magnetic resonance imaging (MRI) abnormalities and excessive daytime sleepiness (EDS) in a consecutive series of patients with myotonic dystrophy (MD). The influences of nocturnal breathing abnormalities and sleep morphology on EDS were also evaluated. Ten MD patients were studied by means of an all-night polysomnographic recording, the multiple sleep latency test (MSLT) and MRI. Diagnosis of MD was established on the basis of the clinical and electrophysiological evidence of myotonia as well as of the characteristic genetic pattern. No patient had respiratory failure. Polysomnography and MSLT were also evaluated in ten healthy age-matched controls under the same environmental conditions. The mean MSLT value was significantly lower in patients than in controls. Five of the ten patients were found to have pathological EDS. The quantitative sleep variables and the nocturnal apnoeas in these five patients were not significantly different from those of the patients without EDS. As two patients did not undergo MRI because of claustrophobia, the MRI data were considered in eight patients. Corpus callosum (CC) atrophy was detected in four patients, whereas three patients showed hyperintense areas in the white matter. No correlation was found between EDS and MRI indexes of subcortical atrophy as well as volume of the hyperintense areas. By contrast, a correlation was found between the MSLT value and the reduction in the anterior area of the CC. Our data suggest that CC atrophy might occur in MD patients, and that the size of the CC anterior area might be associated with EDS.

Longitudinal evaluation of depression and anxiety in patients with clinically isolated syndrome at high risk of developing early multiple sclerosis

We investigated the relationship between emotional changes, brain lesion burden and development of multiple sclerosis (MS). Thirty-seven consecutive patients with clinically isolated syndrome (C IS) were prospectively assessed with the Expanded Disability Status Scale (EDSS), the 21-item Beck Depression Inventory (BDI), the State-Trait A nxiety Inventory (STAI) and gadolinium enhanced (Gd+) MRI scans. BDI and STAI were also administered to 36 age-matched controls. C onversion to MS was defined as the occurrence of a clinical relapse. C IS patients were more likely to endorse symptoms of anxiety and depression than controls. Baseline scores for depression and anxiety did not correlate with the total lesion load (i.e., volume of Gd+, T2 and T1 lesions) and the number of Gd+ lesions during the first six months of follow-up. A positive correlation was found between severity of depressive scores and the lesion load in the right temporal region (P =0.005). After 339-6 months of the study entry, patients who had a clinical relapse were more frequently depressed (P =0.001) than those relapse free. Emotional disturbances are frequently observed in C IS patients and show a tendency towards a normalization in relapse-free patients. The increased rate of depressive symptoms observed in patients who developed MS seems to result from a combination of psychological and organic features. The lesion load in the right temporal region is confirmed as a key area for developing depressive symptoms, even in the early phase of the disease.