French validation of the Brief International Cognitive Assessment for Multiple Sclerosis.

BACKGROUND: Cognitive impairment is important to consider in the assessment of multiple sclerosis (MS) patients. A short battery of cognitive assessment, the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS), has been developed to address the need for rapid assessment by combining 3 tests assessing the main cognitive spheres reached in MS. OBJECTIVES: To establish regression-based norms of the BICAMS in French speaking healthy subjects (HS) and validate its use in persons with multiple sclerosis (PwMS). METHODS: In all, 123 PwMS including 40 with relapsing-remitting MS, 41 patients with secondary progressive MS and 42 with primary progressive MS and 276 HS were evaluated by the BICAMS including 3 tests, the Symbol Digit Modalities Test (SDMT), the French Verbal learning test (FVLT) a French-adapted memory test, (or the California Verbal Learning Test (CVLT) at retesting) and the Brief Visuo-Spatial Memory Test (BVMT-R). The standards for these tests were established in the healthy population using a multiple regression technique. Validity in MS was measured. RESULTS: Regression-based norms of BICAMS tests have been established in the HS population. 50.4% of PwMS have impairment for at least one BICAMS test (-1.5SD on the Z-score). The most common pathological test was the FVLT altered in 36.6% of patients, followed by the SDMT and the BVMT-R. The re-test reliability was good for the various BICAMS tests, 0.891 for SDMT, 0.781 for FVLT/CVLT and 0.669 for BVMT-R. CONCLUSION: This study establishes the validity of the BICAMS as a short and easy to apply battery for a brief assessment of the speed of information processing and episodic memory in MS.

MR imaging of relapsing multiple sclerosis patients using ultra-small-particle iron oxide and compared with gadolinium.

BACKGROUND AND PURPOSE: Inflammatory multiple sclerosis (MS) lesions are characterized by microglia activation and infiltration of T cells, B cells, and macrophages across the blood-brain barrier (BBB). In the experimental autoimmune encephalomyelitis (EAE) rat model of MS, previous MR imaging investigations with a new contrast agent ultra-small-particle iron oxide (USPIO) that accumulates in phagocytic cells revealed in vivo the presence of macrophage brain infiltration. The goal of this study was to characterize MS lesions with the use of this contrast agent. METHODS: A prospective MR imaging study of 10 patients with MS in acute relapses was achieved by using USPIO and gadolinium. RESULTS: Twenty-four hours after USPIO injection, 33 acute MS lesions in 9 patients showed USPIO uptake. Lesions were seen as high signal intensities on T1-weighted images and low signal intensities on T2-weighted images. Gadolinium enhancement was seen in 31 of these lesions in 7 patients. These 7 patients presented 24 gadolinium-enhanced lesions that did not enhance with USPIO. Two patients showed USPIO-enhanced lesions but no gadolinium-enhanced lesions. CONCLUSION: Taken together with earlier findings obtained in experimental models or in human stroke, the visualization of macrophage activity in vivo with USPIO characterize a distinct cellular and inflammatory event of the dynamic process of MS lesion formation. The macrophage activity information obtained with USPIO is distinct and complementary to the increased BBB permeability seen with gadolinium.

MRI predictors of cognitive outcome in early multiple sclerosis.

OBJECTIVE: To determine MRI predictors for cognitive outcome in patients with early relapsing-remitting multiple sclerosis (MS). METHODS: Forty-four patients recently diagnosed with clinically definite MS were followed up with clinical and cognitive evaluations at 1, 2, 5, and 7 years and underwent brain MRI including magnetization transfer (MT) imaging at baseline and 2 years. Cognitive evaluation was also performed in 56 matched healthy subjects at baseline. Cognitive testing included the Brief Repeatable Battery. Imaging parameters included lesion load, brain parenchymal fraction (BPF), ventricular fraction (VF), and mean MT ratio (MTR) of lesion and normal-appearing brain tissue (NABT) masks. RESULTS: At baseline, patients presented deficits of memory, attention, and information processing speed (IPS). Over 2 years, all magnetic resonance parameters deteriorated significantly. Over 7 years, Expanded Disability Status Scale score deteriorated significantly. Fifty percent of patients deteriorated on memory cognitive domain and 22.7%of patients on IPS domain. Seven-year change of memory scores was significantly associated with baseline diffuse brain damage (NABT MTR). IPS z score change over 7 years was correlated with baseline global atrophy (BPF), baseline diffuse brain damage, and central brain atrophy (VF) change over 2 years. CONCLUSION: The main predictors of cognitive changes over 7 years are baseline diffuse brain damage and progressive central brain atrophy over the 2 years after MS diagnosis.

Should SDMT substitute for PASAT in MSFC? A 5-year longitudinal study.

BACKGROUND: The multiple sclerosis functional composite (MSFC) includes the Paced Auditory Serial Addition test (PASAT) as a measure of cognition. OBJECTIVES AND METHODS: We compared the MSFC incorporating the Symbol Digit Modalities test (SDMT) (MSFC [sdmt]) to the usually applied MSFC (MSFC [pasat]) in a sample of 46 ptients with relapsing-remitting MS who were followed over a five-year period. Magnetic resonance imaging was performed at baseline. RESULTS: The Expanded Disability Status scale (EDSS) deteriorated significantly over 5 years (P < 0.01), but MSFC scores remained stable. MSFC [sdmt] correlated with EDSS at all time points of evaluation, but MSFC [pasat] correlated with EDSS only at baseline, 1, and 5 years. The 5-year EDSS correlated significantly with baseline MSFC [sdmt] and MSFC [pasat] but did not correlate after adjustment for baseline EDSS. No significant correlation was found at baseline between MSFC and imaging parameters (lesion load, brain parenchymal fraction [BPF], ventricular fraction, mean magnetization transfer ratio of lesions and normal-appearing brain tissue), but baseline BPF correlated significantly with changes of SDMT z score (P = 0.0003), MSFC [pasat] (P = 0.006), and MSFC [sdmt] (P = 0.0002) over 5 years. CONCLUSION: We propose not to substitute PASAT by SDMT in the MSFC but to consider SDMT as a complementary useful approach to evaluate overall MS disease.

How to detect cognitive dysfunction at early stages of multiple sclerosis?

Detecting cognitive dysfunction may be clinically important during the early stages of multiple sclerosis (MS). We assessed a self-report questionnaire on cognitive complaints and individual neuropsychological tests to select patients with early relapsing-remitting MS (RRMS) who needed comprehensive cognitive testing. Fifty-seven patients underwent neurological and neuropsychological assessment, including Rao's Brief Repeatable Battery (BRB) and the complete SEP-59 Questionnaire, a French adaptation of the MSQOL-54, which contains four specific questions about self-perception of cognitive functions. Predictive values, specificity, sensitivity and accuracy of five individual neuropsychological tests--Selective Reminding Test, Symbol Digit Modalities Test (SDMT), Similarities Subtest, PASAT and Stroop Test--were calculated to predict cognitive impairment. Only 10.5% of patients did not report any cognitive complaint, while most reported complaints. On the basis of cognitive performances, 59.7% of patients were classified as cognitively impaired, although only one cognitive score was correlated with cognitive complaints. Depressive symptoms and fatigue were associated with more cognitive complaints. Sensitivity of the SDMT to predict cognitive impairment was 74.2%, specificity was 76.9% and accuracy was 75.4%. Since, at this stage, patients' cognitive complaints are already influenced by depression and fatigue and do not accurately reflect cognitive performances, the SDMT may help to select patients for testing with a more complete cognitive battery.

Early macrophage MRI of inflammatory lesions predicts lesion severity and disease development in relapsing EAE.

Magnetic resonance imaging (MRI) is of great utility in diagnosis and monitoring of multiple sclerosis (MS). Axonal loss is considered the main cause of accumulating irreversible disability. MRI using ultrasmall-super-paramagnetic-iron-oxide (USPIO) nanoparticles is a new technique to disclose in vivo central nervous system (CNS) inflammatory lesions infiltrated by macrophages in experimental autoimmune encephalomyelitis (EAE). Here, we raised the question of whether USPIO-enhanced MRI could serve as a tool to predict disease severity. We investigated, in a relapsing EAE model with various degrees of disease severity, the interindividual differences at the beginning of CNS inflammation as revealed in vivo by MRI with USPIO in correlation to the severity of both acute and chronic tissue damage including axonal loss. At the onset of the disease, observation of MRI alterations with USPIO allowed assignment of animals into USPIO+ and USPIO- groups. In 54.5% of diseased rats, MRI with USPIO+ at first attack revealed signal abnormalities mainly localized in the brainstem and cerebellum. Although animals did not present any clinically significant differences during the first attack, USPIO+ rats presented significantly more important tissue alterations at the first attack (onset and initiated recovery phase) and, at the second attack, more severe clinical disease with axonal loss compared to USPIO- rats. MRI lesion load and volume at the first attack correlate significantly with inflammation, macrophage recruitment, demyelination, acute axonal damage and, at the second attack, extent of axonal loss. This new MRI application of in vivo monitoring of macrophage infiltration provides a new platform to investigate the severity of inflammatory demyelinating CNS diseases.

Cognitive impairment as marker of diffuse brain abnormalities in early relapsing remitting multiple sclerosis.

OBJECTIVES: To establish the frequency of cognitive impairment in a population based sample of patients with recently diagnosed relapsing-remitting multiple sclerosis (RRMS), and to determine the relation between cognitive abnormalities and the extent of macroscopic and microscopic tissue damage revealed by magnetic resonance imaging (MRI) and magnetisation transfer (MT) imaging. METHODS: 58 patients with RRMS consecutively diagnosed in the previous six months in Aquitaine and 70 healthy controls underwent a battery of neuropsychological tests. Lesion load and atrophy indices (brain parenchymal fraction and ventricular fraction) were measured on brain MRI. MT ratio (MTR) histograms were obtained from lesions, normal appearing white matter (NAWM), and normal appearing grey matter (NAGM). Gadolinium enhanced lesions were counted. RESULTS: 44 RRMS patients could be individually matched with healthy controls for age, sex, and education. Patients performed worse in tests of verbal and spatial memory, attention, information processing speed, inhibition, and conceptualisation. Measures of attention and information processing speed were correlated with lesion load, mean NAWM MTR, and the peak location of the NAGM MTR histogram in the patients. Multivariate regression analysis showed that lesion load and mean NAWM MTR were among the MR indices that were most significantly associated with impairment of attention and information processing speed in these early RRMS cases. CONCLUSIONS: Cognitive impairment appears to be common in the early stages of RRMS, mainly affecting attention, information processing speed, memory, inhibition, and conceptualisation. The severity of these deficits reflects the extent of the lesions and the severity of tissue disorganisation outside lesions.