Maria Pia Amato

International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions.

Background: There has been tremendous growth in research in pediatric multiple sclerosis (MS) and immune mediated central nervous system demyelinating disorders since operational definitions for these conditions were first proposed in 2007. Further, the International Pediatric Multiple Sclerosis Study Group (IPMSSG), which proposed the criteria, has expanded substantially in membership and in its international scope. Objective: The purpose of this review is to revise the 2007 definitions in order to incorporate advances in delineating the clinical and neuroradiologic features of these disorders. Methods: Through a consensus process, in which input was sought from the 150 members of the Study Group, criteria were drafted, revised and finalized. Final approval was sought through a web survey. Results: Revised criteria are proposed for pediatric acute disseminated encephalomyelitis, pediatric clinically isolated syndrome, pediatric neuromyelitis optica and pediatric MS. These criteria were approved by 93% or more of the 56 Study Group members who responded to the final survey. Conclusions: These definitions are proposed for clinical and research purposes. Their utility will depend on the outcomes of their application in prospective research.

Multiple sclerosis-related cognitive changes: A review of cross-sectional and longitudinal studies

Prevalence estimates of cognitive impairment in multiple sclerosis (MS) range from 40% to 65%, depending on the research setting. Cognitive dysfunction virtually encompasses all the disease stages and types of clinical course, although it is generally less frequent in relapsing-remitting (RR) patients compared with secondary progressive (SP) patients, and tends to be less frequent in primary progressive (PP) patients. Moreover, it causes role limitations in work and social life, independently of the degree of physical disability. Relatively little is known about the evolution of cognitive impairment in MS, particularly starting from the early stages of the disease. Controlled studies, however, have clearly shown that cognitive deterioration tends to progress over time. Among clinical predictors, incipient cognitive decline seems to be the major risk factor for further deterioration in the short-term. In the long-term, the likelihood increases that also patients with initial cognitive preservation may deteriorate. As for magnetic resonance imaging (MRI), there are consistent, albeit moderate, correlations between the progression of cognitive impairment and increasing brain lesion load and brain atrophy. The aim of this paper is to provide a review of existing cross-sectional and longitudinal studies on cognitive deterioration in MS.

Quality of life in multiple sclerosis: the impact of depression, fatigue and disability:

This study deals with the assessment of quality of life and its main clinical and demographical determinants in a clinical series of 103 patients with multiple sclerosis (MS) (37 men; 66 women; mean age 44.89 years; mean disease duration 12.40 years; mean EDSS score 4.07). We used the MSQOL-54 inventory, a disease-specific instrument recently validated in an Italian population. Each patient underwent a complete clinical assessment, including that of disability status (Expanded Disability Status Scale), cognitive function (Mini Mental State Examination), depression (Hamilton Rating Scale for Depression) and fatigue (Fatigue Severity Scale). In terms of Pearsons correlations, there was a moderate inverse relationship between disability level and the MSQOL-54 physical composite score, and a moderate to strong inverse correlation between depression or fatigue severity and both the physical and mental composite scores. In a stepwise linear regression analysis, depression, fatigue and disability level were confirmed to be significant and independent predictors of quality of life. Quality of life instruments can help to provide a broader measure of the disease impact and to develop a care program tailored to the patients needs.

Recommendations for a Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS)

Background: Cognitive impairment in MS impacts negatively on many patients at all disease stages and in all subtypes. Full clinical cognitive assessment is expensive, requiring expert staff and special equipment. Test versions and normative data are not available for all languages and cultures. Objective: To recommend a brief cognitive assessment for multiple sclerosis (MS) that is optimized for small centers, with one or few staff members, who may not have neuropsychological training and constructed to maximize international use. Methods: An expert committee of twelve members representing the main cultural groups that have so far contributed considerable data about MS cognitive dysfunction was convened. Following exhaustive literature review, peer-reviewed articles were selected to cover a broad spectrum of cultures and scales that targeted cognitive domains vulnerable to MS. Each was rated by two committee members and candidates scales were rated on psychometric qualities (reliability, validity, and sensitivity), international application, ease of administration, feasibility in the specified context, and acceptability to patients. Results: The committee recommended the Symbol Digit Modalities Test, if only 5 minutes was available, with the addition of the California Verbal Learning Test – Second Edition and the Brief Visuospatial Memory Test – Revised learning trials if a further 10 minutes could be allocated for testing. Conclusions: A brief cognitive assessment for MS has been recommended. A validation protocol has been prepared for language groups and validation studies have commenced.

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.

New natural history of interferon‐β–treated relapsing multiple sclerosis

To investigate the impact of interferon‐beta (IFNβ) on disease progression in relapsing‐remitting multiple sclerosis patients.

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.

The prevalence of pain in multiple sclerosis A multicenter cross-sectional study

In a multicenter cross-sectional study, the authors assessed pain in patients with multiple sclerosis (MS) using a symptom-oriented approach. Out of 2,077 questionnaires, we used 1,672 for data analysis. Pain and frequencies included trigeminal neuralgia 2%, Lhermitte’s sign 9%, dysesthetic pain 18.1%, back pain 16.4%, and painful tonic spasms 11%. Comparison between different groups showed significant differences for age, Expanded Disability Status Scale, disease duration, and disease course, but not for sex. This study underlines the relevance of pain in the clinical history of MS.

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.

Treatment of cognitive impairment in multiple sclerosis: position paper

Cognitive impairment in multiple sclerosis (MS) is common, debilitating and burdensome. Key evidence from trials was reviewed to enable recommendations to be made to guide clinical practice and research. Behavioural and pharmacological interventions on cognition reported in published studies were reviewed. Most studies evaluating behavioural treatment for impairment in learning and memory, deficits of attention and executive function have demonstrated some improvement. Controlled studies in relapsing remitting MS indicate interferon (IFN) β-1b and IFN β-1a were associated with modest cognitive improvement. The effects of symptomatic therapies such as modafinil and donepezil are inconsistent. Most studies yielding positive findings have significant methodological difficulties limiting the confidence in making any broad treatment recommendations. There are no published reports of glatiramer acetate, natalizumab and fingolimod being effective in improving cognition in controlled trials. The effects of disease modifying therapies in other forms of MS and clinically isolated syndrome have not yielded positive results. Data linking behavioural therapy, symptomatic treatment or disease modifying treatment, to either reducing cognitive decline or improving impaired cognition are limited and inconsistent. The treatment and prevention of cognitive impairment needs to remain a key research focus, identifying new interventions and improving clinical trial methodology.