Gianfranco Siracusa

Neocortical volume decrease in relapsing-remitting MS patients with mild cognitive impairment.

Objective: To assess neocortical changes and their relevance to cognitive impairment in early relapsing–remitting (RR) multiple sclerosis (MS). Methods: Conventional MR was acquired in 41 patients with RR MS and 16 demographically matched normal control subjects (NCs). An automated analysis tool was used with conventional T1-weighted MRI to obtain measures of cortical brain volumes normalized for head size. Neuropsychological performance of MS patients was assessed using the Rao Brief Repeatable Battery. Relationship between volumetric MR measures and neuropsychological scores was assessed. Results: Neuropsychological assessment allowed for the identification of 18 cognitively preserved (MS-cp) and 23 cognitively impaired (MS-ci) MS patients. The whole MS sample showed lower values of normalized cortical volumes (NCVs) than did the NC group (p = 0.01). Upon grouping of MS patients according to cognitive performance, NCV values were lower (p = 0.02) in MS-ci patients than in both MS-cp patients and NCs. Moreover, there were positive correlations between NCV values and measures of verbal memory (r = 0.51, p = 0.02), verbal fluency (r = 0.51, p = 0.01), and attention/concentration (r = 0.65, p < 0.001) in MS-ci patients. Furthermore, NCV values were decreased in patients who scored lower on a greater number of tests (r = −0.58, p < 0.01) in the MS-ci group. None of the neuropsychological measures correlated to NCV values in the MS-cp patient group. Conclusions: Cortical atrophy was found only in cognitively impaired patients and was significantly correlated with a poorer performance on tests of verbal memory, attention/concentration, and verbal fluency. Gray matter pathology may contribute to the development of cognitive impairment in MS from the earliest stages of the disease.

Cognitive impairment predicts conversion to multiple sclerosis in clinically isolated syndromes

Significant cognitive impairment has been found in 20—30% of patients with clinically isolated syndromes suggestive of multiple sclerosis. In this study we aimed to assess the prognostic value of the presence of cognitive impairment for the conversion to multiple sclerosis in patients with clinically isolated syndromes. All patients with clinically isolated syndromes consecutively referred to our centre since 2002 and who had been followed-up for at least one year underwent cognitive assessment through the Rao’s Battery and the Stroop test. Possible predictors of conversion to clinically definite multiple sclerosis were evaluated through the Kaplan Meier curves and Cox regression analysis. A total of 56 patients (41 women; age 33.2 ± 8.5 years; expanded disability scale score 1.2 ± 0.7) were recruited. At baseline, 32 patients (57%) fulfilled McDonald’s criteria for dissemination in space. During the follow-up (3.5 ± 2.3 years), 26 patients (46%) converted to a diagnosis of multiple sclerosis. In particular, 64% of patients failing ≥ 2 tests and 88% of patients failing ≥ 3 tests converted to multiple sclerosis. In the Cox regression model, the failure of at least three tests (HR 3.3; 95% CI 1.4—8.1; p = 0.003) and the presence of McDonald’s dissemination in space at baseline (HR 3.8; 95% CI 1.5—9.7; p = 0.005), were found to be predictors for conversion to multiple sclerosis. We conclude that cognitive impairment is detectable in a sizable proportion of patients with clinically isolated syndromes. In these subjects cognitive impairment has a prognostic value in predicting conversion to multiple sclerosis and may therefore play a role in therapeutic decision making.

Cognitive assessment and quantitative magnetic resonance metrics can help to identify benign multiple sclerosis.

Background: The definition of benign multiple sclerosis (B-MS) is still controversial. This mainly takes into account the subject’s motor ability, with little or no relevance to other important features such as cognition. Moreover, no paraclinical markers are currently available to reliably identify patients who will remain benign in the long term. Objectives: To assess, by using quantitative magnetic resonance (MR) metrics, differences in tissue damage between B-MS patients after dividing them into two groups on the basis of their cognitive performance. Methods: Forty-seven B-MS patients (Expanded Disability Status Scale score ≤3.0 and disease duration ≥15 years) underwent neuropsychological assessment through the Rao Brief Repeatable Battery and the Stroop Test. At that time, B-MS patients underwent conventional brain MR and magnetization transfer (MT) imaging. White matter lesion load, global and regional brain volumes, and MT ratio (MTr) in lesions and normal-appearing brain were measured. Quantitative MR measures were compared in cognitively impaired (CI-MS) and cognitively preserved (CP-MS) patients and in 24 demographically matched healthy controls. Test performance was correlated with MR changes in specific cortical regions. Results: Eleven patients were classified as CI-MS, and 36 were classified as CP-MS. Both T2-weighted and T1-weighted lesion loads were higher (p = 0.05 and 0.001) in CI-MS than in CP-MS patients. Furthermore, CI-MS patients were characterized by more pronounced decrease in neocortical volume (p = 0.005) and cortical MTr (p = 0.02) values than CP-MS patients. Finally, test performance correlated significantly with MR changes in relevant cortical regions. Conclusions: Cognitive assessment and quantitative magnetic resonance can help to reliably identify benign multiple sclerosis patients.

Long-Term Adherence to Interferon β Therapy in Relapsing-Remitting Multiple Sclerosis

Background/Aims: To assess the proportion and the reasons of drop-outs in relapsing-remitting multiple sclerosis patients treated with interferon-β (IFNB) and the outcome of switching subjects. Methods: Patients stopping IFNB were classified according to the reason of drop-out: perceived lack of efficacy (PLE) side effects (SE) and other reasons. Long-term adherence was described using the Kaplan-Meier curves. Results: We evaluated 225 subjects (158 women; age = 36.6 ± 9.2 years, disease duration = 8.0 ± 6.1 years, Expanded Disability Status Scale score = 1.9 ± 1.2) who received Betaferon (46), Avonex (88) and Rebif (91) therapy. The mean follow-up duration was 4.2 ± 2.7 years. Forty-six percent of patients suspended therapy, 29% because of PLE, 15% because of SE and the remaining 2% due to other reasons. Twenty-five out of 33 subjects who suspended IFNB because of SE and 62 out of 65 patients who suspended the therapy due to PLE were switched to another disease-modifying drug. At the end of the follow-up, the majority of these patients could continue the treatment. Conclusions: When starting IFNB therapy in relapsing-remitting multiple sclerosis, a relatively high proportion of discontinuation is to be expected over time. Switching from a treatment to another taking into account the reasons of drop-out and the disease activity is a suitable option.

Neuropsychological and MRI measures predict short-term evolution in benign multiple sclerosis

Objective: To assess whether neuropsychological tests and MRI measures could be used as predictors of short-term disease evolution in a population of patients with benign multiple sclerosis (B-MS). Background: The definition of B-MS is controversial. Recent data suggest that neuropsychological tests and MRI measures can provide valuable information for a more correct definition and interpretation of B-MS. Methods: Sixty-three patients with B-MS (Expanded Disability Status Scale [EDSS] ≤3.0 and disease duration ≥15 years) underwent neuropsychological assessment using the Raos Brief Repeatable Neuropsychological Battery and the Stroop Test. At that time, conventional brain MRI and magnetization transfer (MT) imaging was performed. White matter lesion load, global and regional brain volumes, and MT ratio in lesions and normal-appearing brain were measured. After a mean follow-up of 5 years, patients still having an EDSS score ≤3.5 were classified as still benign, whereas patients who had developed a secondary progressive course or who had an EDSS score ≥4.0 were defined as no longer benign (NLB). Results: At end of follow-up, 29% of patients were classified as NLB. Male gender (hazard ratio [HR] = 2.9; 95% confidence interval [CI] 1.2–7.5; p = 0.02), number of neuropsychological tests failed (HR = 1.4; 95% CI 1.1–1.7; p = 0.003), and T1-weighted lesions (HR = 1.3; 95% CI 1.1–1.5; p = 0.002) were related to NLB status. In a model including these 3 variables, the NLB status was predicted with an accuracy of 82%. Conclusions: Cognitive assessment and MRI metrics can predict short-term disease evolution in benign multiple sclerosis (B-MS). This information can be useful to correctly identify patients with B-MS.

Differences in mesenchymal stem cell cytokine profiles between MS patients and healthy donors: implication for assessment of disease activity and treatment.

MSCs have been proposed as possible treatment in MS: In this study MSCs obtained from 10 MS patients and 6 healthy donors (HD) were compared in terms of phenotypical and functional characteristics. We show that MSCs isolated from MS and HD differ significantly for IP10 production. Therefore, although MSCs isolated from MS patients exhibit the same properties of HD MSCs in terms of proliferation, phenotype, in vitro differentiation, TLR expression, immunosuppressive ability, inhibition of DC differentiation and activation, the use of autologous MSCs in cell therapy of autoimmune diseases should be submitted to attentive evaluation and treatment.

Changes in Neuropsychological Test Performance Over the Workday in Multiple Sclerosis

Fatigue, a common symptom of multiple sclerosis (MS), is associated with impairment in performing daily activities, poor quality of life and premature retirement from the workforce. There is little doubt that patients with MS can exhibit marked weakness and other objective signs of physical fatigue, but whether cognitive performance by patients declines more rapidly than that by controls as a function of time engaged in mental activity remains controversial. Krupp and Elkins (2000) reported more rapid deterioration of performance by MS patients on two of five cognitive measures when subjects performed 3 hr of continuously effortful tasks between baseline and posttest. Others, using shorter and less taxing interpolated tasks found similar changes in performance over time for patients and controls. In the present study participants completed a timed walk, fatigue ratings and four cognitive tests that emphasized processing novel information before they went to work and again after completing a normal workday. Patients with MS walked somewhat more slowly and performed more poorly on two of the cognitive tests, but they did not show more decline from baseline to posttest on any of these objective measures of cognitive fatigue. By contrast, subjective ratings of fatigue showed a greater increase over the day for patients than for controls. These results confirm other reports that patients’ subjective ratings of their fatigue are not valid indicators of their actual performance on cognitive tests. Furthermore, laboratory studies that report “objective” cognitive fatigue in MS may utilize conditions that model the cognitive fatigue associated with the jobs patients actually perform rather poorly.

Association of apolipoprotein E polymorphism to clinical heterogeneity of multiple sclerosis.

In this study we investigated the distribution of apolipoprotein E (APO E) genotypes in sporadic multiple sclerosis (MS) cases and in normal controls. Later onset of chronic progressive MS was observed in patients carrying the epsilon2 allele, whereas APO E alleles were found at similar frequency in MS and in the control population. These findings indicate that clinical heterogeneity, but probably not susceptibility to the disease, is associated to APO E genotypes.

Long‐term safety of azathioprine therapy in multiple sclerosis

We compared the frequency of malignancies in 207 multiple sclerosis patients (mean age 35.75 years, SD 10.60) who took 2.0 mg/kg azathioprine daily (mean duration 4.16 years; SD 2.38) and in 247 nontreat-ed patients (mean age 35.44 years; SD 11.94). Five malignancies were diagnosed in the azathioprine group compared with seven in the control group. The age-adjusted occurrence rate was 3.62/1,000 person-years (95% CI, 1.17 to 8.43) in the treated and 4.24/1,000 person-years (95% CI, 1.70 to 8.73) in the nontreated group; the age-adjusted relative risk of developing a tumor was 0.85.

Impact of cognitive impairment on coping strategies in multiple sclerosis

OBJECTIVES To assess the impact of cognitive impairment (CI) on coping strategies in multiple sclerosis (MS). MATERIALS AND METHODS Sixty-three patients (40 women, 55 relapsing-remitting and 8 secondary progressive, age 42.6+/-10.1 years, Expanded Disability Status Scale 2.2+/-1.7) were assessed using the Coping Orientation for Problem Experiences-New Italian version Inventory, the Beck Depression Inventory and the Raos Brief Repeatable Battery. RESULTS MS patients were less likely to use positive and problem-focused strategies, whereas avoiding strategies were adopted more frequently. Twenty-three (36.5%) cases were CI. We found no differences in the type of coping between CI and cognitively preserved patients. Scores on the Stroop test (beta=-0.91, p=0.04) and on the Word List Generation (beta=1.15, p=0.04) were associated with poorer coping strategies. CONCLUSIONS Our study suggests that cognitive functioning (in particular on sustained attention and aspects of executive function) must be considered in a comprehensive account of the factors contributing to successful coping in MS patients.