Computer-assisted rehabilitation of attention in patients with multiple sclerosis: results of a randomized, double-blind trial.

BACKGROUND: There is controversial information on the efficacy of cognitive rehabilitation in multiple sclerosis (MS). OBJECTIVE: The objective of this paper is to test a home-based computerized program for retraining attention dysfunction in MS. METHODS: Relapsing-remitting patients who failed > 2 tests of attention on an extensive neuropsychological battery were randomized to specific or nonspecific computerized training (ST, n-ST), in one-hour sessions, twice a week for three months. Outcome measures included neuropsychological assessment, depression, fatigue, everyday activities and a visual analogue scale assessing attentive performance (VAS). Assessments were repeated after the interventions and after a further three months. Statistical analysis included the analysis of variance (ANOVA) for repeated measures. RESULTS: Eighty-eight out of 102 randomized patients completed the study (69 women, age 40.9 ± 11.5 years, disease duration 13.0 ± 8.7 years, Expanded Disability Status Scale score 2.7 ± 1.5). Fifty-five patients were randomized to ST, 33 to n-ST. A benefit of the ST was observed on the Paced Auditory Serial Addition Test (p < 0.002). However, patient self-report did not reveal differences between ST and n-ST patient groups. CONCLUSION: Although our program trained different attention components, we could detect some improvements exclusively on tasks of sustained attention. Moreover, patient self-perceived results may be independent of the training program.

The Rao's Brief Repeatable Battery version B: normative values with age, education and gender corrections in an Italian population.

The Brief Repeatable Battery (BRB) of Neuropsychological Tests is one of the most widely used instruments to assess cognitive functioning in multiple sclerosis patients. However, to date, normative data for the Italian population are available only for the version A, which limits the use of the battery in longitudinal evaluations. We administered the BRB version B to 132 healthy subjects to obtain normative values taking into account the influences of demographic factors on the test scores and calculating corrections for these relevant factors (age, gender and education). Higher age and educational level were associated with better performance on all the tests. The World List Generation was also influenced by gender, since women performed better than men. Moreover, some tests of the version B seem to be easier than those of version A. Our data can improve the applicability of the BRB for both clinical and research purposes in longitudinal assessments.

Natalizumab may reduce cognitive changes and brain atrophy rate in relapsing-remitting multiple sclerosis--a prospective, non-randomized pilot study.

BACKGROUND AND PURPOSE: The development of treatment strategies for cognitive impairment in multiple sclerosis (MS) is still in its infancy. The objective of this prospective, non-randomized, pilot study was to assess the possible efficacy of treatment with natalizumab in comparison with interferon beta (IFNB) in a group of relapsing-remitting patients with MS. METHODS: We included 12 patients treated with natalizumab and 14 with IFNB. At baseline and at follow-up, cognitive functioning was assessed through Rao's Brief Repeatable Battery. All the patients underwent brain MR study with the assessment of T2 lesion volumes, neocortical volume, normalized brain volume and percentage brain volume change (PBVC). Evolution of cognitive performance was assessed using available normative data for the Italian population. Treatment comparisons were assessed through the Mann-Whitney U-test, anova for repeated measures and linear multivariate regression analyses. RESULTS: After a mean follow-up of 1.5 years, the mean number of neuropsychological tests with a deteriorating performance was significantly lower in patients treated with natalizumab (0.7 ± 0.7 vs. 1.7 ± 1.4; P = 0.031). Likewise, PBVC was significantly lower in natalizumab-treated subjects than that observed in patients treated with IFNB (-0.51% ± 0.47% vs. -1.18% ± 0.98%; P = 0.050). CONCLUSION: Our results suggest a potential beneficial effect of natalizumab therapy on cognitive functioning in MS, possibly mediated by a reduction of brain atrophy.

Fatigue and its relationships with cognitive functioning and depression in paediatric multiple sclerosis.

BACKGROUND: There is limited information on fatigue and its clinical and psychosocial correlates in children and adolescents with multiple sclerosis (MS). OBJECTIVE: To assess the relationships between fatigue, cognitive functioning and depression in paediatric MS. METHODS: The study cohort consisted of patients with MS recruited for an Italian collaborative study on cognitive and psychosocial functioning in paediatric MS. The present assessment included evaluation of fatigue on the Pediatric Quality of Life Inventory-Multidimensional Fatigue Scale, cognitive functioning on an extensive neuropsychological battery and depression on the Children's Depression Inventory (CDI). A psychiatric interview through the Kiddie-SADS-Present and Lifetime Version was also administered. RESULTS: In total, 57 patients with relapsing-remitting MS were compared with 70 healthy controls. Percentages of fatigued patients ranged from 9% to 14% according to self-reports, and from 23% to 39% according to parent reports. Fatigue was significantly related with higher scores on the CDI (p < 0.03). Higher levels of self-reported cognitive fatigue were associated with impaired performance on a problem-solving test, whereas higher levels of parent-reported cognitive fatigue were associated with impairment on tests of verbal learning, processing speed, complex attention and verbal comprehension. CONCLUSIONS: Our data show that fatigue can affect a sizeable proportion of paediatric MS patients, and confirm the association between fatigue and depressive symptoms in MS. They also highlight the difficulties of fatigue assessment in the paediatric population and provide a few clues to further research in the field.

Cognitive impairment and event-related potentials in paediatric multiple sclerosis: 2-year study.

Approximately, 3-10% of patients with multiple sclerosis (MS) present a disease onset before the age of 18 years. Although growing attention is dedicated to cognitive impairment and its functional consequences in paediatric MS, so far no study has explored possible neurophysiologic correlates. The study's aim was to describe event-related potentials in relationship with cognitive performance in children and adolescents with MS compared with demographically matched healthy controls (HC), providing two-year follow-up data. Six MS subjects aged between 9 and 17 years were assessed through an extensive neuropsychological battery at two time points. Event-related potentials with an odd-ball acoustic paradigm were also recorded in the patients and in nine HC. At baseline, four out of six patients failed three or more cognitive tasks and were classified as cognitively impaired. In all the cognitively impaired patients, we found abnormal latencies and amplitudes of the P300. After 2 years, five patients exhibited a deteriorating cognitive performance and a corresponding deterioration of the P300 parameters. In our group of children and adolescents with MS, changes in P300 parameters proceeded in parallel with deteriorating cognitive performance. P300 might represent an objective parameter to monitor cognitive changes in paediatric MS.

Effects of immunomodulatory treatment with subcutaneous interferon beta-1a on cognitive decline in mildly disabled patients with relapsing-remitting multiple sclerosis.

The objective of this study was to assess the effects of subcutaneous (sc) interferon beta-1a (IFNbeta-1a) on cognition in mildly disabled patients with relapsing-remitting multiple sclerosis (RRMS). Patients aged 18-50 years with RRMS (McDonald criteria; Expanded Disability Status Scale score

Cognitive impairment in pediatric multiple sclerosis.

Cognitive impairment has been recently recognized in patients with pediatric multiple sclerosis in more than 30% of cases. Altered functions with variable frequency are: attention, language (receptive, verbal fluency, naming), visual-spatial and motor functions, spatial memory, executive functions and abstract reasoning. Fatigue and affective disorders are associated, but not correlated with cognitive impairment. The frequency and severity of cognitive impairment increase with time. Cognitive impairment has a negative impact on patient's life limiting social, academic and recreational activities.

Cognitive impairment in early stages of multiple sclerosis.

Cognitive dysfunction involves 40-65% of multiple sclerosis patients and can have a great functional impact. It can be detected in all the disease phenotypes since the early stages of the disease, and tends to progress over time. Memory, complex attention, information-processing speed and executive functions are most commonly involved. The relationship between cognitive changes and magnetic resonance imaging (MRI) findings may involve changes in different areas, including white matter lesions, cortical and deep grey matter and normal appearing brain tissue on conventional MRI. The search for effective therapeutic strategies is a major undertaking, involving the use of both pharmacologic and rehabilitative approaches. Early treatment with disease-modifying drugs that can contain the disease burden in the brain seems to be highly advisable in order to prevent or delay the development of cognitive impairment.

Psychosocial issue in children and adolescents with multiple sclerosis.

In adult-onset multiple sclerosis (MS) cases, major depression, fatigue and psychological distress are common, whereas there is little information on these issues in children with the disease. The aim of this study was to assess psychosocial disorders in an Italian cohort of children and adolescent with MS. We evaluated 56 patients through self-assessment scales of depression (Children Depression Inventory) and fatigue (Fatigue Severity Scale), a psychiatric interview [Kiddie-SADS-Present and Lifetime Version (K-SADS-PL)] and an interview on school and everyday activities. Significant fatigue was found in 11 patients (20%). Twelve of the 39 patients who underwent the K-SADS-PL received a formal diagnosis of an affective disorder. Moreover, MS affected school activities in 28% of cases, daily living activities in 41% and social relationships in 28%. Our study confirms the critical role of psychosocial difficulties in children and adolescents with MS and provides a few cues to clinical management.

ApolipoproteinE epsilon 4 allele is not associated with disease course and severity in multiple sclerosis.

BACKGROUND: No study has assessed the association between apolipoproteinE (APOE) and multiple sclerosis (MS) forms grouped by also taking into account cognitive performance. AIMS OF THE STUDY: To assess the relationship between APOE and disease course, particularly focusing on benign MS (BMS), defined as also including cognitive preservation. METHODS: In 173 consecutive patients, we assessed the association between APOE and MS course and severity. RESULTS: Twenty-nine APOE-epsilon4 carriers were identified. The epsilon4 allele was not associated with BMS. Moreover, it was associated neither with other disease courses nor with the time to reach disability milestones and secondary progression. CONCLUSION: Although plausible, the association between APOE and MS course (particularly with BMS defined by including cognitive preservation) and disease severity remains controversial.

'Subclinical MS': follow-up of four cases.

BACKGROUND AND PURPOSE: Subclinical multiple sclerosis (S-MS) can be defined as the discovery of characteristic lesions at magnetic resonance (MR) or at autopsy, in the absence of clinical evidence consistent with MS. To describe four cases of S-MS cases followed-up with clinical and MR examinations. METHODS: The four patients were initially evaluated because of accidental MRI findings suggestive of MS that fulfilled the Barkhof criteria. At the moment of MR examination, patients were asymptomatic or complained of unspecific symptoms. The objective examinations as well as the clinical history were negative. An extensive diagnostic work-up excluded alternative diagnoses. RESULTS: Case 1: 40-year woman undergoing MR examination due to trivial cervical trauma. The cerebrospinal fluid (CSF) analysis showed an IgG Index of 3.32 and presence of oligoclonal bands (OCB). New MR enhancing lesions were detected in the brain and cervical cord after 2 and 5 years. The patient remained clinically asymptomatic. Neuropsychological assessment (NPS) performed after 5 years revealed moderate deficits of attention/concentration and executive functions. Case 2: 35- year man, undergoing MR due to recent-onset headache. CSF analysis showed an IgG Index of 1.54 and presence of OCB. At baseline, NPS assessment revealed moderate deficit on complex attention tasks. New MR enhancing lesions were detected in the brain after 1 and 3 years. Four years after the first MR, the patient presented double vision with internuclear ophthalmoplegia. He fulfilled Polman's criteria for MS and he started interferon beta therapy. He remained stable at a 8-year follow-up. Case 3: 32-year man, undergoing MR due to brief loss of consciousness following neck hyperextension. CSF analysis showed absence of OCB and normal IgG Index. At baseline, NPS assessment revealed mild deficits of attention and executive functions. Over a 5-year follow-up the subject remained asymptomatic and MR was unchanged. Case 4: 40-year woman, sister of an MS patient. MR was required during a period of marked tiredness taking into account the family history. The patient did not present any relevant symptoms and MRI remained unchanged over a 6-year follow-up. NPS evaluation performed after 7 years showed moderate impairment of memory, attention and executive functions. CONCLUSION: With the increased use of MR, S-MS cases can be identified more often. In our series, despite the absence of any typical symptoms, an NPS assessment detected cognitive impairments consistent with those reported in MS.

Association of MRI metrics and cognitive impairment in radiologically isolated syndromes.

OBJECTIVE: To evaluate cognitive changes in a cohort of radiologically isolated syndromes (RIS) suggestive of multiple sclerosis (MS) and to assess their relationship with quantitative magnetic resonance (MR) measures such as white matter (WM), lesion loads, and cerebral atrophy. METHODS: We assessed the cognitive performance in a group of 29 subjects with RIS recruited from 5 Italian MS centers and in a group of 26 patients with relapsing-remitting MS (RRMS). A subgroup of 19 subjects with RIS, 26 patients with RRMS, and 21 healthy control (HC) subjects also underwent quantitative MR assessments, which included WM T1 and T2 lesion volumes and global and cortical brain volumes. RESULTS: Cognitive impairment of the same profile as that of RRMS was found in 27.6% of our subjects with RIS. On MR scans, we found comparable levels of lesion loads and brain atrophy in subjects with RIS and well-established RRMS. In subjects with RIS, high T1 lesion volume (ρ = 0.526, p = 0.025) and low cortical volume (ρ = -0.481, p = 0.043) were associated with worse cognitive performance. CONCLUSIONS: These findings emphasize the importance of including accurate neuropsychological testing and quantitative MR metrics in subjects with RIS suggestive of MS. They can provide a better characterization of these asymptomatic subjects, potentially useful for diagnostic and therapeutic decisions.

Cognitive and psychosocial features in childhood and juvenile MS: two-year follow-up.

OBJECTIVE: To assess the evolution of cognitive and psychosocial functioning in a cohort of childhood and juvenile multiple sclerosis (MS) cases after a mean period of 2 years had elapsed since baseline evaluation. METHODS: In this cohort study, we used the same extensive neuropsychological battery with alternative versions of the tests assessing memory, attention/concentration, executive functions, and language. Fatigue and depression were also measured. An interview on school and daily living activities was obtained from the parents. The cognitive performance of the patients was compared with that of demographically matched healthy controls (HC). RESULTS: Fifty-six patients and 50 HC were assessed. At follow-up, criteria for cognitive impairment (failure on at least 3 tests) were fulfilled in 39 patients (70%) and 75% of the cases were classified as having a deteriorating cognitive performance. Changes were prominent in tests of verbal memory, complex attention, verbal fluency, and receptive language. In the regression analysis, the only significant predictor of cognitive deterioration was older age of the subject (odds ratio 1.9, 95% confidence interval 1.2-2.9, p = 0.003). Psychiatric disorders, most frequently depression, were diagnosed in 12 patients (30.5%). Fatigue was reported by 21% of the patients. MS negatively affected school and everyday activities in 30% to 40% of the subjects. CONCLUSIONS: Our findings confirm the importance of systematic assessment of cognitive and psychosocial issues in children and teens with MS. The progressive nature of the cognitive difficulties emphasizes the need for developing effective treatment strategies.

A short version of Rao's Brief Repeatable Battery as a screening tool for cognitive impairment in multiple sclerosis.

Rao's Brief Repeatable Battery (BRB) is the most widely used instrument for cognitive evaluation in multiple sclerosis (MS). We assessed a short version of the BRB in 116 relapsing-remitting participants. We found that the administration of three tests, the Selective Reminding Test, the Paced Auditory Serial Addition Test-3 seconds and the Symbol Digit Modalities Test, was able to detect cognitive impairment with a sensitivity of 94%, a specificity of 84%, and an accuracy of 89%. On the basis of these results we developed a screening algorithm requiring 5 to 15 minutes, which may represent a highly sensitive and rapid tool to detect MS-associated cognitive impairment.

The brief neuropsychological battery for children: a screening tool for cognitive impairment in childhood and juvenile multiple sclerosis.

BACKGROUND: A critical problem with neuropsychological assessment in children and adolescents with multiple sclerosis (MS) is the absence of a standardized, well-validated neuropsychological battery specifically tailored for detecting disease-related cognitive problems in this age range. OBJECTIVE: To develop a Brief Neuropsychological Battery for Children (BNBC) with MS. METHODS: We assessed cognitive functions in 61 patients with childhood and juvenile MS and 58 demographically matched healthy controls through an extensive neuropsychological battery. RESULTS: In MS patients, we found a proportion of cognitive impairment of 41%. In the BNBC, we included the tests with higher discriminating ability (the Selective Reminding Test, the Symbol Digit Modalities Test, the Trail Making Test, and the Vocabulary test from the Wechsler Intelligence Scale for children). The BNBC yielded a sensitivity of 96% and a specificity of 76%. CONCLUSION: Our findings provide preliminary evidence of the usefulness of the BNBC as a screening tool for detecting cognitive impairment in childhood and juvenile MS cases.

Cognitive impairment and its relation with disease measures in mildly disabled patients with relapsing-remitting multiple sclerosis: baseline results from the Cognitive Impairment in Multiple Sclerosis (COGIMUS) study.

BACKGROUND: Cognitive impairment is a common symptom of multiple sclerosis (MS), but the association between cognitive impairment and magnetic resonance imaging (MRI) disease measures in patients with relapsing-remitting (RR) MS is unclear. OBJECTIVES: To study the prevalence of cognitive impairment and its relation with MRI disease measures in mildly disabled patients with RRMS. METHODS: Patients aged 18-50 years with RRMS (McDonald criteria) and an Expanded Disability Status Scale (EDSS) score or=3 cognitive tests) was present in approximately 20% of all patients and in the subgroup who underwent MRI. T2 hyperintense and T1 hypointense lesion volumes were significantly higher in patients with cognitive impairment (defined as impaired performance on at least three tests of the Rao's battery) than those without. EDSS score was also significantly higher in cognitively impaired than in cognitively preserved patients. Disease duration, depression, and years in formal education did not differ significantly between cognitively impaired and cognitively preserved patients. T2 lesion volume, performance intelligence quotient, and age were significant predictors of cognitive impairment in this population. Weak correlations were found between performance on individual cognitive tests and specific MRI measures, with T1 and T2 lesion volumes correlating with performance on most cognitive tests. CONCLUSIONS: Cognitive impairment occurs in approximately one-fifth of mildly disabled patients with MS and is associated with specific MRI disease measures. Assessment of cognitive function at diagnosis could facilitate the identification of patients who may benefit from therapeutic intervention with disease-modifying therapies to prevent further lesion development.

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] < or =3.0 and disease duration > or =15 years) underwent neuropsychological assessment using the Rao's 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 < or =3.5 were classified as still benign, whereas patients who had developed a secondary progressive course or who had an EDSS score > or =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.

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 /=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.

Cognitive and psychosocial features of childhood and juvenile MS.

OBJECTIVE: To assess the impact of multiple sclerosis (MS) on cognitive and psychosocial functioning in childhood and juvenile cases. METHODS: We used an extensive neuropsychological battery assessing IQ, memory, attention/concentration, executive functions, and language. Fatigue and depression were also measured. An interview on school and daily living activities was obtained from the parents. Performance of cases was compared with that of demographically matched healthy controls. RESULTS: Sixty-three patients and 57 healthy controls were assessed. Five patients (8%) exhibited a particularly low IQ (<70). Criteria for cognitive impairment (failure on at least three tests) were fulfilled in 19 patients (31%), whereas 32 patients (53%) failed at least two tests. Beyond deficits in memory, complex attention, and executive functions, the profile of deficits was characterized by involvement of linguistic abilities. In the regression analysis, the only significant predictor of cognitive impairment was an IQ score lower than 90 (odds ratio [OR] 18.2, 95% CI 4.6-71.7, p < 0.001). Considering the IQ score as a dependent variable, the only significant predictor was represented by younger age at onset (OR 0.7, 95% CI 0.5-0.9, p = 0.009). Depressive symptoms were reported by 6% of the cases, and fatigue was reported by 73% of the cases. MS negatively affected school and everyday activities in 56% of the subjects. CONCLUSIONS: In childhood and juvenile cases, multiple sclerosis (MS) is associated with cognitive impairment and low IQ scores, the latter related to younger age at onset. These aspects are of critical importance in helping children and adolescents with MS to manage their difficulties and psychosocial challenges.

The Rao's Brief Repeatable Battery and Stroop Test: normative values with age, education and gender corrections in an Italian population.

The Brief Repeatable Battery of Neuropsychological Tests (BRB) is by far the most widely used instrument to estimate cognitive dysfunction in multiple sclerosis (MS) patients. However, the paucity of normative data currently limits its applicability. We administered the BRB to 200 healthy subjects to obtain normative values. Moreover, we assessed the influence of demographic factors on the test scores and calculated corrections for these relevant factors. To test executive functions not explored by the BRB, we also included the Stroop word-color task (ST). Higher educational level was associated with better performance on all the tests, except for the world list generation (WLG) and the ST, considering version A, and on Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT) and Selective Reminding Test-Delayed (SRT-D), considering version B. Females performed better than males on the WLG considering version A, and on the SRT-Long-Term Storage (SRT-LTS) and SRT-Consistent Long-Term Retrieval (SRT-CLTR) considering version B. Increasing age was associated with worse performance on the ST in version A, and on the SRT-LTS, SRT-CLTR and WLG in version B. Our data can improve the applicability of the BRB for both clinical and research purposes.