Cortical functional reorganization and its relationship with brain structural damage in patients with benign multiple sclerosis.

BACKGROUND: Patients with multiple sclerosis (MS) who have a favourable clinical status several years after disease onset are classified as 'benign'. In many cases brain tissue damage does not differ between benign MS and the 'classical' MS forms. OBJECTIVE: To assess whether the favourable clinical course in benign MS could be explained by the presence of an efficient functional cortical reorganization. METHOD: Twenty-five right-handed patients with benign MS (defined as having Expanded Disability Status Scale ≤ 3 and disease duration >15 years) underwent functional MRI during a simple motor task (right-hand tapping) to assess movement-associated brain activation. This was compared with that of 10 patients with relapsing-remitting MS and 10 normal controls. Benign MS patients also underwent conventional brain MRI and magnetization transfer imaging, which was compared with an identical examination obtained 1 year before. Quantitative structural magnetic resonance measures were baseline and changes over time in T2-lesion volume, magnetization transfer ratio in T2 lesions and normal-appearing brain and total brain volume. RESULTS: Movement-related activation was greater in patients with benign MS than in those with relapsing-remitting MS or normal controls, extensively involving bilateral regions of the sensorimotor network as well as basal ganglia, insula and cerebellum. Greater activation correlated with lower T2-lesion magnetization transfer ratio, and with decreasing brain volume and increasing T2 lesion volume. CONCLUSIONS: The results suggest that bilateral brain networks, beyond those normally engaged in motor tasks, are recruited during a simple hand movement in patients with benign MS. This increased activation is probably the expression of an extensive, compensatory and tissue-damage related functional cortical reorganization. This can explain, at least in part, the favourable clinical expression of patients with benign MS.

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 >or= 2 tests and 88% of patients failing >or= 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.

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 Rao's 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.

APOE-epsilon4 is not associated with cognitive impairment in relapsing-remitting multiple sclerosis.

The objective of this article was to assess the association between apolipoprotein E (APOE)-epsilon4 and cognitive impairment (CI) in relapsing-remitting multiple sclerosis (RRMS). The APOE genotype was assessed in 85 RRMS cases (58 females, mean age 43 +/- 8.4 years, mean disease duration 15.8 +/- 9.6 years, mean Expanded Disability Status Scale (EDSS) 1.7 +/- 1.0). Cognitive functioning was evaluated in the whole sample using Rao's Brief Repeatable Battery (BRB). Performance on each test was assessed by applying the normative values for the Italian population. In a subgroup of 50 patients, a brain magnetic resonance (MR) study was performed including measurement of T2 lesion volumes (T2LV), neocortical volume (NCV) and normalized brain volume (NBV). The relationship between APOE genotype, CI and MR variables was assessed through univariate and multivariate logistic regression models. CI, most commonly involving complex attention and verbal memory tasks, was found in 28 cases (33%). We identified a total of 19 epsilon4carriers (22.4%), who did not differ from non-carriers regarding clinical and demographic characteristics. The presence of the epsilon4 genotype was associated with neither CI (p = 0.28) nor impairment on each neuropsychological test (p > 0.32; corrected for age, gender, disease duration, EDSS, depression and fatigue). The APOE genotype and CI were also not related in the subgroup of younger patients (age < 45 years; p > 0.9). Moreover, CI was related to higher T2LV (p = 0.008) and lower NCV (p = 0.006). In conclusion, in our sample CI was associated with higher subcortical damage and cortical atrophy but not with APOE-epsilon4 genotype. The role of APOE-epsilon4 as a possible biomarker in multiple sclerosis is still questionable.

Prevalence of neuromyelitis optica spectrum disorder and phenotype distribution.

Neuromyelitis optica spectrum disorder (NMOsd) is a group of demyelinating disorders recently redefined and associated with NMO-IgG/anti-aquaporin 4 antibodies. Because NMOsd is of unknown prevalence worldwide, we conducted a retrospective, cross-sectional study of 850 patients with demyelinating disorders hospitalized in North East Tuscany from 1998 to 2006 to examine the prevalence of NMO and related disorders among unselected consecutive neurological patients with inflammatory CNS diseases and to evaluate the clinical phenotype spectrum of identified cases. Clinical data were updated after at least 2 years of follow-up. An immunofluorescence technique was used to detect NMO-IgG on rat brain tissue. Sera from other 828 neurological patients, 65 non-neurological patients and 50 healthy donors served as controls. The prevalence of NMOsd was 1.5%, with a MS:NMOsd ratio of 42.7. Among 13 NMOsd patients, 77% had long spinal cord lesions, 38% had severe optic neuritis and 23% had brain or brainstem lesions. Only 56% had clinically definite NMO at follow-up. The final EDSS score ranged from 1 to 10, mainly depending on brainstem involvement occurrence. Our findings confirm a low prevalence of NMO and related disorders among demyelinating inflammatory diseases in a Caucasian population. Moreover, this study demonstrates an unexpectedly high prevalence of limited and atypical variants of this disease, not previously documented.

Coping strategies, psychological variables and their relationship with quality of life in multiple sclerosis.

The aim of this study was to assess the impact of psychological features in the choice of coping strategies in multiple sclerosis (MS) patients, and their influence on quality of life (QoL). One hundred four patients (72 women, age 45.3 +/- 10.9 years, disease duration 17.9 +/- 13.2 years, Expanded Disability Status Scale 2.8 +/- 2.0) were assessed through the Beck Depression Inventory, the State-Trait Anxiety Inventory, the Eysenck Personality Questionnaire, the Coping Orientation for Problem Experiences-New Italian version and the MSQoL-54. MS patients were less likely to use problem-focused strategies, whereas avoiding strategies were adopted more frequently. The use of positive strategies positively influenced both mental and overall QoL. Depression had a negative impact on all QoL domains and anxiety on mental domains. These data point out the importance of a comprehensive assessment of MS patients. Orienting therapeutic interventions, to oppose depression and anxiety and to favour more appropriate coping strategies can improve the patients' QoL.

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.

Intravenous mitoxantrone and cyclophosphamide as second-line therapy in multiple sclerosis: an open-label comparative study of efficacy and safety.

The study's aim was to compare the efficacy and safety of intravenous cyclophosphamide (CTX) and mitoxantrone (MITO) as second-line therapy in a clinical sample of active relapsing-remitting (RR) or secondary-progressive (SP) multiple sclerosis subjects. MITO was administered at a dosage of 8 mg/m(2) monthly for 3 months, then every 3 months, until a dosage of 120 mg/m(2) was reached. CTX was administered at a dosage of 700 mg/m(2) monthly for 12 months, then bimonthly for another 24 months. We used the Kaplan-Meier curves to assess time to the first relapse in RR and SP patients with relapses, and time to progression on the Expanded Disability Status Scale (EDSS) in all the patients. MRI was assessed at baseline and after 12 months. Moreover, side effects were recorded. Seventy-five patients received MITO (31 RR, 44 SP) and 78 CTX (15 RR, 63 SP). The two groups differ only in terms of a significantly higher proportion of RR patients in the MITO group. After a mean follow-up of 3.6 years there was no significant difference in terms of time to the first relapse (MITO 2.6 years, CTX 2.5 years; p=0.50), whereas time to disease progression was slightly shorter in MITO than in CTX group (MITO 3.8 years, CTX 3.6 years; p=0.04). After 12 months of treatment, active MRI scans were reduced by 69% in MITO and 63% in CTX patients (p=0.10). Discontinuation due to side effects was more frequent in CTX patients. However, the overall tolerability profile was acceptable in both groups.

Association of neocortical volume changes with cognitive deterioration in relapsing-remitting multiple sclerosis.

BACKGROUND: We previously reported selective decreases of neocortical volumes in patients with early relapsing-remitting (RR) multiple sclerosis (MS) with mild cognitive impairment, with a good correlation between cortical volumes and cognitive measures. OBJECTIVE: To assess the relevance of gray matter changes over time to changes in cognition in RRMS. DESIGN: A longitudinal survey after 2.5 years. Each patient underwent a magnetic resonance imaging (MRI) protocol identical to that performed at baseline; cognitive performance was reassessed with the Rao Brief Repeatable Battery of Neuropsychological Tests in Multiple Sclerosis. SETTING: Two university MS clinics. PATIENTS: Of 41 patients with RRMS who participated in the original cross-sectional study, 28 were available for the follow-up evaluation (18 women; mean +/- SD age, 37.1 +/- 8.9 years; mean +/- SD MS duration, 7.3 +/- 2.9 years; mean +/- SD Expanded Disability Status Scale score, 1.8 +/- 1.5). MAIN OUTCOME MEASURES: We measured the percentage of brain volume changes, normalized cortical volume (NCV) changes, and normalized deep gray matter volume changes on conventional T1-weighted MRIs and changes in lesion load on T2-weighted MRIs. The number of tests failed on the Rao Brief Repeatable Battery were used to classify the patients as cognitively deteriorating or stable or improving. RESULTS: We identified 12 of 28 cognitively deteriorating and 16 of 28 stable or improving patients. These subgroups did not differ in the mean +/- SD percentage of brain volume changes (-2.1% +/- 1.2% vs -1.3% +/- 1.3%; P = .11), normalized deep gray matter volume changes (-2.1 +/- 2.8 mL vs -0.6 +/- 3.1 mL; P = .60), and changes in lesion load on T2-weighted MRIs (1.9 +/- 2.6 mL vs 1.6 +/- 2.3 mL; P = .73). However, NCV changes were significantly higher in deteriorating than in stable or improving patients (-43.0 +/- 18.9 mL vs -17.8 +/- 26.6 mL; P = .007). In deteriorating patients, NCV changes were correlated with performance in a verbal fluency test (r = 0.73; P < .001). In a regression model, only NCV changes were significantly associated with deteriorating cognitive performance (odds ratio, 0.8; 95% confidence interval, 0.7-0.9). CONCLUSION: Progressive neocortical gray matter loss is relevant to MS-associated cognitive impairment and may represent a sensitive marker of deteriorating cognitive performance in RRMS.

Brain damage as detected by magnetization transfer imaging is less pronounced in benign than in early relapsing multiple sclerosis.

The trend to start disease-modifying therapy early in the course of multiple sclerosis makes it important to establish whether the benign form is a real entity. In previous studies, measures of magnetization transfer (MT) ratio (MTr) have been shown to provide good estimates of the amount of tissue damage occurring in multiple sclerosis brains. Thus, with the hypothesis that if benign multiple sclerosis patients were really benign, sensitive measures of subtle tissue damage would be less pronounced in these patients than in very early relapsing-remitting (RR) multiple sclerosis patients. We carried out conventional MRI and MT imaging in 50 patients with benign multiple sclerosis [defined as having Kurtzke Expanded Disability Status Score (EDSS) <3 and disease duration >15 years] and in 50 early RR patients selected to have similar disability (EDSS <3) and short disease duration (<3 years). Data were compared with those of 32 demographically-matched normal controls. We used a fully automated procedure to measure lesional-MTr, perilesional-MTr, normal-appearing white matter (NAWM) MTr and cortical-MTr. We found that, after correction for common effects of age, lesional-MTr and perilesional-MTr of benign patients were significantly (P < 0.0001) lower than WM of normal controls, but significantly (P < 0.0001) higher than corresponding tissues of RR patients. In NAWM and cortex, MTr values of benign patients were similar to those of normal controls (P > 0.5) and significantly higher than those of the RR patients (P < 0.0001 and P < 0.01, respectively). Similar differences in MTr measures between benign and RR patients were found when patient groups were selected to have no disability (EDSS < or = 2) and, for benign multiple sclerosis, very long disease duration (>20 years) or when both groups were matched for high lesion load (T2-weighted lesion volume >10 cm3). We conclude that lesional and non-lesional MTr values can be significantly less pronounced in benign multiple sclerosis than in a cohort of RR patients at their earliest disease stages, suggesting that brain tissue damage is milder in benign multiple sclerosis than in early RR disease. This can be due to an extraordinary beneficial response to demyelination of benign patients and may represent the evidence that benign multiple sclerosis truly exists and might be differentiated from other forms of this illness.

Benign multiple sclerosis: cognitive, psychological and social aspects in a clinical cohort.

OBJECTIVES: A study of cognitive, psychological and social aspects in benign multiple sclerosis (MS). Methods One hundred and sixty three patients with benign MS (defined as disease duration > or = 15 years and Expanded Disability Status Scale (EDSS) score < or = 3.0 ) underwent neuropsychological testing on the Rao's Brief Repeatable Battery (BRB) and the Stroop test, evaluation of depression on the Montgomery and Asberg Depression Rating Scale (MADRS), of fatigue on the Fatigue Severity Scale (FSS) and of handicap on the Environmental Status Scale (ESS). Patients' cognitive performance was compared with that of 111 demographically matched healthy controls. Cognitive impairment was defined as the failure in at least 3 tests, using the fifth percentile of controls' performance as the cut-off point. Clinical correlates of cognitive impairment were determined by multiple logistic regression analysis. RESULTS: Cognitive assessment led to the identification of 74 subjects (45%) with cognitive impairment. Significant fatigue was found in 80 subjects (49%) and depression in 88 patients (54%). In comparison with cognitively preserved subjects, cognitively impaired patients exhibited higher handicap scores on the ESS (p = 0.005). In the regression analysis, only EDSS scores were significantly associated with cognitive impairment (OR 1.8, 95%CI 1.2-2.6). CONCLUSION: Current definitions of benign MS may overestimate this entity, since they are mainly weighted for the patients' motor abilities and fail to capture relevant disease-related cognitive, psychological and social problems.

Neocortical volume decrease in relapsing-remitting multiple sclerosis with mild cognitive impairment.

The aim of the study was to assess neocortical changes and their relevance to cognitive impairment in early relapsing-remitting multiple sclerosis (RRMS). Conventional magnetic resonance was acquired in 41 RRMS patients and 16 demographically matched normal controls (NC). An automated analysis tool was used to obtain measures of cortical brain volumes normalized for head size. Neuropsychological performance of MS patients was assessed through the Rao's Brief Repeatable Battery. We identified 18 cognitively preserved (MS-cp) and 23 cognitively impaired (MS-ci) MS patients. Values of normalized cortical volumes (NCV) in the whole MS sample were lower than those in the NC group (p=0.01). MS-ci patients showed NCV values lower (p=0.02) than did both MS-cp patients and NC. Moreover, we found a positive correlation 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 significantly decreased in patients who scored lower on a greater number of tests (r=-0.58, p<0.01) in the MS-ci group. Only MS-ci patients had cortical atrophy significantly correlated with a poorer neuropsychological performance. Grey matter pathology may contribute to the development of cognitive impairment in MS from the earliest stages of the disease.

Efficacy of azathioprine on multiple sclerosis new brain lesions evaluated using magnetic resonance imaging.

BACKGROUND: Azathioprine is an immunosuppressive agent that reduces relapse rates in patients with multiple sclerosis (MS), but its efficacy in suppressing new brain lesions has never been evaluated. OBJECTIVE: To evaluate the efficacy of azathioprine therapy on new brain lesion suppression in MS. DESIGN: Open-label treatment vs baseline study. SETTING: Outpatient MS clinical center at a university hospital. PATIENTS: Fourteen patients with relapsing-remitting MS of short duration and at least 3 gadolinium-enhancing (Gd+) brain lesions observed within 6 months before treatment. INTERVENTION: Azathioprine, up to 3 mg/kg daily, individually adjusted according to blood lymphocyte number and the occurrence of adverse events. MAIN OUTCOME MEASURES: Brain Gd+ lesions evaluated by monthly magnetic resonance imaging for 6 months before and 6 months during treatment and new T2 lesions evaluated during the same periods and after an additional 6 months. RESULTS: The treatment reduced to 0 the median Gd+ lesion number and volume per magnetic resonance image (P<.001 for both), resulting in a Gd+ lesion number reduction of 50% or more in 12 of 14 patients (P<.01). An equivalent reduction in the new T2 lesion number was observed (P<.02); this activity also persisted during the additional treatment period evaluated using this outcome measure (P<.01). The median azathioprine dose administered (2.6-2.8 mg/kg daily) reduced the mean blood lymphocyte count to 57% of the baseline value. Adverse events were transient or reversible with dose adjustment. CONCLUSIONS: This study indicates for the first time that azathioprine, administered at lymphocyte-suppressing doses, is effective in reducing MS new brain inflammatory lesions and is well tolerated.

Influence of apolipoprotein E epsilon4 genotype on brain tissue integrity in relapsing-remitting multiple sclerosis.

BACKGROUND: Recent clinical and imaging studies have raised the hypothesis that patients with multiple sclerosis (MS) and the apolipoprotein E (ApoE) epsilon4 allele may have a more severe disease course than those without the ApoE epsilon4 allele. This seems to be related to more extensive tissue destruction and less efficient neuronal maintenance and repair in ApoE epsilon4 carriers. OBJECTIVE: To evaluate the influence of different ApoE genotypes on brain tissue integrity in patients with relapsing-remitting MS (RRMS). DESIGN: We determined the ApoE genotype in 76 RRMS patients. Conventional T1-, T2-, and proton density-weighted magnetic resonance (MR) images were obtained for each patient and in a group of demographically matched healthy control subjects. On conventional T1-weighted MR images, an automated analysis tool was used to obtain total brain volumes normalized for head size (NBVs). Total brain lesion load was estimated on proton density- and T2-weighted MR images. RESULTS: From the whole group of RRMS patients, we identified 18 with and 58 without the epsilon4 allele. Both patient groups were not significantly different in age, age of disease onset, clinical disability, and disease duration. Carriers of the epsilon4 allele showed significantly (P =.01) lower NBVs than controls and non-epsilon4 allele carriers. When a similar analysis was performed on only those patients with both very short disease duration and absence of clinical disability, NBV values were still significantly lower in RRMS patients with the epsilon4 allele than in those without it (P =.02) and in controls (P =.007). In contrast, RRMS patients with different ApoE genotypes did not show significant differences in values of total brain T2-weighted lesion volumes. CONCLUSIONS: The presence of significant NBV decreases only in the group of RRMS patients with the ApoE epsilon4 genotype provides new evidence that links ApoE epsilon4-related impaired mechanisms of cell repair and severe tissue destruction in MS. Results of the present study suggest that this negative influence of the ApoE epsilon4 genotype might be active from the earliest disease stages.

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.