Differential diagnosis, discerning depression from cognition.

Cognitive impairment is common in multiple sclerosis (MS), affecting up to 70% of patients. One of the most important possible confounders to cognitive assessment is the occurrence of depression, a common consequence of MS. Cognition and depression have been linked in recent neuropsychiatric research that proposed a number of neurocognitive models of mood disorders. According to these models, primary failure of key brain regions of emotional processing and regulation or abnormal connectivity between them contributes to the adoption of maladaptive cognitive strategies and the development of mood disorders. In MS, a similar interplay between cognitive function and depression has been reported. In particular, depression seems to alter attentional capacity in terms of deficits in working memory and, more specifically, deficits in the executive control. However, cognitive impairment in MS does exist also in the absence of depression and it is more likely that depression exacerbates existing cognitive difficulties rather than cause them per se. On the other hand, it is possible that a dysexecutive syndrome secondary to MS might in turn precipitate depression.

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.

Anxiety state affects information processing speed in patients with multiple sclerosis.

The aim of this study was to investigate the impact of anxiety on the cognitive performance of a clinical sample of relapsing-remitting (RR) MS patients. One hundred ninety patients (140 females) were included in the study and assessed through the beck depression inventory, the state-trait anxiety inventory and the Rao's brief repeatable battery which assesses cognitive domains most frequently impaired in MS. As for neuropsychological performance, a total of 76 (40%) subjects fulfilled our criterion for cognitive impairment. Tests most frequently failed by cognitive impairment (CI) patients were those assessing complex attention and information processing speed [Simbol Digit Modalities Test (SDMT), Paced Auditory Serial Auditory Test (PASAT) 3 and 2] and verbal memory. In the univariate analysis, state anxiety was related to failure on the SDMT (p = 0.042), and marginally, to failure on the PASAT-3 (p = 0.068), and to the presence of CI (p = 0.082). Moderate/severe depression was detected in 38 (20%) patients and fatigue in 109 (57%). Higher depression scores were related to impairment on the ST (OR = 1.05; 95% CI 1.01-1.10; p = 0.029).

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.

No association between chronic cerebrospinal venous insufficiency and pediatric-onset multiple sclerosis.

OBJECTIVE: Chronic cerebrospinal venous insufficiency (CCSVI) was hypothesized to play a causative role in multiple sclerosis (MS). The assessment of pediatric-onset MS (POMS) may provide a unique window of opportunity to study hypothesized risk factors in close temporal association with the onset of the disease. METHODS: Internal jugular veins, vertebral veins and intracranial veins were evaluated with extracranial and intracranial ultrasound in 15 POMS and 16 healthy controls. Assessor's blinding was maintained during the study. We considered subjects positive to CCSVI when at least two criteria were fulfilled. RESULTS: CCSVI frequency was comparable between POMS and controls (p > 0.05). Clinical features were not significantly different between CCSVI-positive and CCSVI-negative patients. CONCLUSIONS: Our findings add to previous data pointing against a causative role of CCSVI in MS.

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.

Multiple sclerosis in Italy: cost-of-illness study.

This study estimates the direct costs of multiple sclerosis (MS) in Italy from the perspective of the National Health System. Patients diagnosed with MS for ≥1 year prior to study entry were included in the analysis; neurological disability was assessed using the Expanded Disability Status Scale (EDSS). Cost variables were analyzed according to: MS phenotype, disease course over the previous year and EDSS rating. A total of 510 patients were included in the analysis. Overall costs were significantly higher for relapsing-remitting MS and secondary progressive MS than for primary progressive MS (P < 0.05). Costs were higher for EDSS scores 0.0-3.5 and 4.0-6.0 than for scores > 6.0 (P < 0.05). The extrapolated data gave an estimated annual direct cost of MS per patient of 18,030. In conclusion, relapsing-remitting MS or secondary progressive MS phenotypes and lower estimated EDSS scores appear to be associated with higher costs.

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.

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

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system typically affecting young adults. Psychological coping has proved to be crucially important for adjusting to the adaptive demands of chronic diseases, and in the last few years it has received growing interest in MS. A common finding in the literature is that MS patients tend to adopt dysfunctional avoiding strategies and to rely less on task-oriented and positive attitude strategies, which represent a better adjustment to disease-related challenges. Moreover, the studies show higher psychoticism in MS subjects compared with the general population, and higher levels of depression and anxiety that can contribute to lower QoL perception. In our study including 63 MS patients cognitive functioning did not seem to influence the type of coping. However, subjects with impairment on tasks that assess sustained attention and some aspects of executive function were less prone to adopt positive coping strategies. Cognitive and emotional problems should be carefully monitored, providing prompt diagnosis and treatment as appropriate.

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.

Switching to second-line therapies in interferon-beta-treated relapsing-remitting multiple sclerosis patients.

BACKGROUND: Interferon-beta (IFNB) therapies are the most widely used as first-line intervention in the treatment of relapsing-remitting (RR) multiple sclerosis (MS). Despite long-term experience, however, the definition and prediction of response remain controversial. AIM: The objective of this study was to assess the long-term validity of the main clinical definitions of response applied after 1 and 2 years of IFNB therapy in a cohort of RRMS patients followed up for at least 5 years. METHODS: We tested these different definitions against a 'hard' parameter of treatment failure, represented by the need to suspend IFNB and switch to an intravenous immunosuppressive (IVIS) treatment, using Kaplan-Meier and Cox survival analyses. RESULTS: Out of 147 RRMS patients treated with IFNB therapy and followed up for 7.8 +/- 2.1 years, 26 (18%) were switched to an IVIS therapy. On the whole, disability progression as indicated using the Expanded Disability Status Scale (EDSS) and a higher number of relapses in the first 2 years of therapy were related to long-term treatment failure. CONCLUSION: Our study highlights the role of disability and high relapse rate in the first 2 years of treatment in predicting long-term response and the switching to second-line therapies.

'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.

Long-term adherence to interferon beta 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-beta (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.

Prevalence of patient-reported dysphagia in multiple sclerosis patients: an Italian multicenter study (using the DYMUS questionnaire).

OBJECTIVE: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) with a chronic course. Dysphagia represents one of the current challenges in clinical practice for the management of MS patients. Dysphagia starts to appear in mildly impaired MS subjects (EDSS 2-3) and becomes increasingly common in the most severely disabled subjects (EDSS 8-9). The aim of the present study was to evaluate the frequency and characteristics of patient-reported dysphagia in MS patients with a multicenter study using the recently developed DYMUS (DYsphagia in MUltiple Sclerosis) questionnaire. DESIGN: Data were collected in a multi-centre, cross-sectional study using a face-to-face structured questionnaire for clinical characteristics and the DYMUS questionnaire. RESULTS: 1875 patients were interviewed. The current study has shown a correlation between patient-reported dysphagia and EDSS and disease course but not with age, gender and disease duration. Questionnaires were divided into "patient-reported dysphagia-yes" (587, 31.3%) and "patient-reported dysphagia-no" (1288, 68.7%). Compared with the patient-reported dysphagia-no group, patients in patient-reported dysphagia-yes group had higher EDSS score (mean EDSS 4.6 vs. 2.8; p<0.001) and had a longer disease duration (mean duration 13 years vs. 11 years; p<0.001), while there was no significant difference in gender (32.7% vs. 30.5% male and 67.3% vs. 69.5% female) and in age composition (46.18 vs. 42.05). CONCLUSIONS: This study represents the largest, multi-centre sample of MS patients evaluated for patient-reported dysphagia utilizing an ad-hoc questionnaire for this condition.

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.

Cortical lesions in radiologically isolated syndrome.

OBJECTIVE: To assess the presence of cortical lesions (CLs) as detected by MRI in subjects with radiologically isolated syndrome (RIS). METHODS: Fifteen subjects with RIS underwent an MRI examination, including a double inversion recovery sequence for CL assessment. T2-hyperintense white matter (WM) lesion volume (LV) and normalized volumes of brain and cortex were also obtained. RESULTS: Thirty-four CLs were identified in 6 of 15 (40%) subjects with RIS and predominantly distributed in frontotemporal lobes. CLs were frequent in subjects with RIS with immunoglobulin G oligoclonal bands on CSF, cervical cord lesions, and dissemination in time on brain MRI. WM LV was higher in subjects with CLs than in those without CLs (11.5 ± 10.1 vs 3.9 ± 2.8 cm(3), p = 0.04). Indeed, CL number and volume correlated with WM LV (r = 0.57, p = 0.03 and r = 0.61, p = 0.01). All subjects with CLs were classified in a previous study as having a very high probability of having relapsing-remitting multiple sclerosis (MS) on a logistic regression analysis of quantitative MRI indices. CONCLUSIONS: We found CLs in subjects with RIS, a condition characterized by the unanticipated MRI finding of WM lesions highly suggestive of MS in the absence of a clinical scenario. CLs were mainly localized to the frontotemporal lobes and were associated with important markers of evolution to MS.