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.

Efficacy of rituximab in refractory neuromyelitis optica.

BACKGROUND: Despite a growing use of rituximab (RTX) in neuromyelitis optica (NMO), data are lacking in patients with refractory NMO (RNMO), defined as cases with at least one relapse during immunosuppressive therapy. OBJECTIVE: The purpose of this study was to assess RTX as a maintenance therapy in RNMO. METHODS: Out of a total of 305 NMO cases from a population-based cohort, 21 RNMO patients received RTX during a mean follow-up period of 31 months. RESULTS: After RTX, 11 patients (52.3%) were relapse free, meaning that 47.7% were refractory to RTX. The mean annualized relapse rate decreased from 1.3 to 0.4 (p<0.001) and median EDSS from 5 to 3 (p=0.02). Body mass index (BMI) was predictive of EDSS worsening. CONCLUSIONS: RTX is an effective and well-tolerated treatment in RNMO. BMI could be a predictive factor for efficacy.

A 10-year follow-up of the European multicenter trial of interferon ß-1b in secondary-progressive multiple sclerosis.

OBJECTIVES: To explore long-term effects of treatment and prognostic relevance of variables assessed at baseline and during the European secondary progressive multiple sclerosis (SPMS) trial of interferon beta 1b (IFNB-1b). METHODS: We assessed 362 patients (60% female; median age 41 years; Expanded Disability Status Scale (EDSS): 5.5; 51% randomized to IFNB-1b) for their EDSS and treatment history after 10 years. Non-parametric analysis of covariance (ANCOVA) and multivariate linear regression models were applied. RESULTS: Median EDSS was 6.0 at the end of the randomized controlled trial (RCT), in the IFNB-1b and placebo groups, and 7.0 in long-term follow-up patients (those receiving IFNB-1b in the RCT were 6.5 and those receiving placebo in the RCT were 7.0; p = 0.086). 24 patients (6.6%) were deceased. The EDSS at baseline and the EDSS change during the RCT were the most important predictors of the EDSS 10 years later (partial R(2): 0.47). The ability to predict changes in EDSS 10 years after the RCT was limited (R(2): 0.12). Magnetic resonance imaging (MRI) measures remained in the predictive models, but explained < 5% of the variability. CONCLUSIONS: The results from this analysis did not provide convincing evidence to support a favorable long-term outcome in those patients allocated IFNB-1b during the RCT, in our SPMS cohort. The progressive stage of the disease remains largely unpredictable by clinical and conventional MRI measures, so better prognostic markers are needed.

A prospective observational post-marketing study of natalizumab-treated multiple sclerosis patients: clinical, radiological and biological features and adverse events. The BIONAT cohort.

BACKGROUND AND PURPOSE: BIONAT is a French multicentric phase IV study of natalizumab (NTZ)-treated relapsing-remitting multiple sclerosis (MS) patients. The purpose of this study was to collect clinical, radiological and biological data on 1204 patients starting NTZ, and to evaluate the clinical/radiological response to NTZ after 2 years of treatment. METHODS: Patients starting NTZ at 18 French MS centres since June 2007 were included. Good response to NTZ was defined by the absence of clinical and radiological activity. Data analysed in this first report on the BIONAT study focus on patients who started NTZ at least 2 years ago (n = 793; BIONAT2Y ). RESULTS: NTZ was discontinued in 17.78% of BIONAT2Y. The proportion of patients without combined disease activity was 45.59% during the first two successive years of treatment. Systematic dosage of anti-NTZantibodies (Abs) detected only two supplementary patients with anti-NTZ Abs compared with strict application of recommendations. A significant decrease of IgG,M concentrations at 2 years of treatment was found. CONCLUSIONS: The efficacy of NTZ therapy on relapsing-remitting MS in a real life setting is confirmed in the BIONAT cohort. The next step will be the identification of biomarkers predicting response to NTZ therapy and adverse events.

[Is MRI monitoring useful in clinical practice in patients with multiple sclerosis? Yes]. / L'IRM est-elle utile dans le suivi des patients atteints de sclérose en plaques ? Oui.

The place of magnetic resonance imaging (MRI) in the monitoring of patients with multiple sclerosis (MS) is not codified except during the diagnostic phase. Several studies in the literature have shown that lesion load measured on an MRI done at the beginning of the disease or its increase during the first years had a predictive value, although moderate, on the occurrence of long-term disability as measured by the EDSS. Early worsening of brain atrophy during the early stages of the disease is predictive of worsening cognitive impairment in the following years. Perform an MRI is not required when setting up a first-line disease-modifying therapy (DMT) such as an immunomodulatory treatment but it is useful because it can be used as a reference scan in case of treatment failure. The indications of second-line DMTs, whether prescribed in naive patients with an active disease or after failure of a first-line DMT, are based on combined criteria incorporating MRI data acquired in the previous 3 months compared with a recent MRI. Thus the practical criteria for failure of first-line DMTs are partly based on MRI. During interferon therapy, identification of disease activity on an MRI conducted 1 year after the start of the treatment can predict treatment failure in combination with clinical criteria, such as relapses occurring during the first year. Finally, MRI is essential to the safety monitoring of patients on natalizumab to detect progressive multifocal leukoencephalopathies (PML). In patients at high risk for PML, tested positive for JC virus antibodies and having received natalizumab for more than 2 years, it could be proposed to do a short MRI with FLAIR and diffusion weighted imaging sequences every 3 months to detect preclinical PML.

[Cavitary lesions in multiple sclerosis: multicenter study on twenty patients]. / Formes cavitaires de sclérose en plaques: étude multicentrique sur vingt patients.

INTRODUCTION: Cavitary white matter changes are mainly described in leukodystrophies and especially in vanishing white matter disease. Large cavitary lesions are not typical for multiple sclerosis (MS). METHODS: We studied MS patients with large cavitary brain lesions. Patient characteristics, disease onset/duration/subtype, expanded disability status scale (EDSS), mini mental state (MMS), vanishing white matter disease genetic analysis, and MRI characteristics of the cavitary lesions were analyzed. RESULTS: Twenty patients were analyzed (6 men and 14 women). Mean age at disease onset was 37.6 (range 17-58). Mean disease duration was 10 years (range 2-20). Five patients had initial relapsing-remitting MS and nine patients had primary-progressive MS. Mean EDSS was 5.5 (range 2-8). Mean MMS was 20/30. Vanishing white matter disease genetic analysis was performed and negative in seven patients. Inferior corpus callosum lesions were seen in all patients with available sagittal FLAIR sequences. Cavitary lesions were strictly supratentorial, and located inside the diffuse leukoencephalopathy, with often a posterior predominance. CONCLUSION: MS patients with large cavitary lesions seem to represent a MS subgroup, predominantly women, with relatively late disease onset, predominantly primary-progressive type, relatively high EDSS scores, and severe cognitive dysfunction.

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.

High-risk syndrome for neuromyelitis optica: a descriptive and comparative study.

BACKGROUND: Neuromyelitis optica (NMO) frequently begins with a monofocal episode of optic neuritis or myelitis. A concept named high-risk syndrome (HRS) for NMO has been proposed for patients with monofocal episodes and NMO-IgG antibodies. OBJECTIVE: To describe HRS patients and compare them with NMO patients. METHODS: We identified 30 patients with HRS: 18 with extensive myelitis (HRM) and 12 with optic neuritis (HRON), in a database pooling patients from 25 centres in France. Clinical, laboratory/magnetic resonance imaging (MRI) data and outcome were analysed and compared with a national cohort of 125 NMO patients extracted from the same database. RESULTS: Mean follow-up was 4.8 years. Mean age at onset was 42.8 years (range: 12.4-70) with a female:male ratio of 0.9. Asymptomatic lesions were report on visual evoked potentials in 4/8 tested HRM patients and on spinal cord MRI in 2/7 HRON patients. Three patients died, two owing to a cervical lesion. HRS and NMO patients had similar clinical/paraclinical data, except for a predominance of men in the HRS group and a later mean age at onset in the HRM subgroup. CONCLUSION: The description of HRS patients is compatible with a monofocal form of NMO. Asymptomatic lesions could be included in a new set of NMO diagnostic criteria.

SMILE: a predictive model for Scoring the severity of relapses in MultIple scLErosis.

BACKGROUND: In relapsing-remitting multiple sclerosis (RRMS), relapse severity and residual disability are difficult to predict. Nevertheless, this information is crucial both for guiding relapse treatment strategies and for informing patients. OBJECTIVE: We, therefore, developed and validated a clinical-based model for predicting the risk of residual disability at 6 months post-relapse in MS. METHODS: We used the data of 186 patients with RRMS collected during the COPOUSEP multicentre trial. The outcome was an increase of ≥ 1 EDSS point 6 months post-relapse treatment. We used logistic regression with LASSO penalization to construct the model, and bootstrap cross-validation to internally validate it. The model was externally validated with an independent retrospective French single-centre cohort of 175 patients. RESULTS: The predictive factors contained in the model were age > 40 years, shorter disease duration, EDSS increase ≥ 1.5 points at time of relapse, EDSS = 0 before relapse, proprioceptive ataxia, and absence of subjective sensory disorders. Discriminative accuracy was acceptable in both the internal (AUC 0.82, 95% CI [0.73, 0.91]) and external (AUC 0.71, 95% CI [0.62, 0.80]) validations. CONCLUSION: The predictive model we developed should prove useful for adapting therapeutic strategy of relapse and follow-up to individual patients.

Effect of cognitive rehabilitation on neuropsychological and semiecological testing and on daily cognitive functioning in multiple sclerosis: The REACTIV randomized controlled study.

BACKGROUND: Specific cognitive rehabilitation (SCR) has been suggested for multiple sclerosis (MS). A randomized controlled trial (RCT) evaluating the therapeutic effects of SCR is necessary. OBJECTIVE: To demonstrate the superiority of a SCR program (REACTIV) over nonspecific intervention (NSI) for neuropsychological (NP) assessment, virtual reality (VR) cognitive testing and daily cognitive functioning. METHODS: A single-blind RCT compared SCR and NSI in patients with MS with cognitive complaint. Both programs included 50 individual sessions, 3 times a week for 17 weeks in a real-world setting. The primary end-point was NP assessment. Secondary end-points included semiecological VR tasks (Urban Daily Cog®) and daily cognitive functioning assessment. Maintenance of the effects at 8 months was studied. RESULTS: Of the 35 patients, 18 completed the SCR, and 17 completed the NSI. Several NP and semiecological scores improved significantly more after SCR than after NSI. More NP scores improved significantly after SCR than after NSI. SCR improved daily cognitive functioning. Most improvements were maintained at 8 months. CONCLUSION: SCR performed in a real-world setting is superior to NSI for improving performance in specific cognitive domains and information processing speed, and for improving cognitive functioning, as evaluated by ecological tools close to daily life and a daily cognitive functioning questionnaire.

Shorter infusion time of ocrelizumab: Results from the randomized, double-blind ENSEMBLE PLUS substudy in patients with relapsing-remitting multiple sclerosis.

BACKGROUND: Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). Shortening the 600 mg infusion to 2 hours reduces the total site stay from 5.5-6 hours (approved infusion duration including mandatory pre-medication and post-infusion observation) to 4 hours. The safety profile of shorter-duration ocrelizumab infusions was investigated using results from ENSEMBLE PLUS. METHODS: ENSEMBLE PLUS is a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810). In ENSEMBLE, patients with early-stage relapsing-remitting MS received ocrelizumab 600 mg infusions every 24 weeks for 192 weeks. In ENSEMBLE PLUS, ocrelizumab 600 mg administered over the approved 3.5-hour infusion time (conventional duration) is compared with a 2-hour infusion (shorter duration); the durations of the initial infusions (2×300 mg, 14 days apart) were unaffected. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first Randomized Dose. RESULTS: From November 1, 2018, to December 13, 2019, 745 patients were randomized 1:1 to the conventional or shorter infusion group. At the first Randomized Dose, 99/373 patients (26.5%) in the conventional and 107/372 patients (28.8%) in the shorter infusion group experienced IRRs. The majority of IRRs were mild or moderate; >99% of all IRRs resolved without sequelae in both groups (conventional infusion group, 99/99; shorter infusion group, 106/107). No IRRs were serious, life-threatening, or fatal. No IRR-related discontinuations occurred. During the first Randomized Dose, 22/373 (5.9%) and 39/372 (10.5%) patients in the conventional and shorter infusion groups, respectively, had IRRs leading to infusion slowing/interruption. Adverse events were consistent with the known safety profile of ocrelizumab. CONCLUSION: The rates and severity of IRRs were similar between conventional and shorter infusions. No new safety signals were detected. Shortening the infusion time to 2 hours reduces the total site stay time (including mandatory pre-medication/infusion/observation) from 5.5-6 hours to 4 hours, and may reduce patient and site staff burden. A short video summarizing the key results is provided in supplemental material.

Primary progressive multiple sclerosis diagnostic criteria: a reappraisal.

The diagnostic criteria used in primary progressive (PP) and relapsing-remitting (RR) multiple sclerosis (MS) show substantial differences. This introduces complexity in the diagnosis of MS which could be resolved if these criteria could be unified in terms of the requirements for dissemination in space (DIS). The aim of this study was to assess whether a single algorithm may be used to demonstrate DIS in all forms of MS. Five sets of RRMS criteria for DIS were applied to a cohort of 145 patients with established PPMS (mean disease duration: 11 years - PPMS-1): C1: Barkhof-Tintoré (as in 2005 McDonald's criteria); C2: Swanton et al. (as in JNNP 2006); C3: presence of oligoclonal bands plus two lesions (as in McDonald's criteria); C4 and C5: a two-step approach was also followed (patients not fulfilling C1 or C2 were then assessed for C3). Two sets of PPMS criteria for DIS were applied: C6: Thompson et al. (as in 2001 McDonald's criteria); C7: 2005 McDonald criteria. A second sample of 55 patients with less than 5 years of disease duration (PPMS-2) was also analysed using an identical approach. For PPMS-1/PPMS-2, fulfilment was: C1:73.8%/66.7%; C2:72.1%/59.3%; C3:89%/79.2%; C4:96%/92.3%; C5:96%/85.7%; C6:85.8%/78.7%; C7:91%/80.4%. Levels of fulfilment suggest that the use of a single set of criteria for DIS in RRMS and PPMS might be feasible, and reinforce the added value of cerebrospinal fluid (CSF) findings to increase fulfilment in PPMS. Unification of the DIS criteria for both RRMS and PPMS could be considered in further revisions of the MS diagnostic criteria.

[Assessing incapacity at early stages of Multiple sclerosis using the EDSS]. / Place de l'EDSS dans l'évaluation précoce du handicap.

The Expanded Disability Status Score (EDSS) is the most commonly used scale to assess disability in multiple sclerosis (MS). A major criticism concerns its low interobserver reproducibility. To improve this reproducibility, we propose scoring guidelines for French-speaking neurologists (NEUROSCORE).

[Magnetic resonance imaging of central nervous system inflammation]. / Imagerie par résonance magnétique de l'inflammation du système nerveux central.

Magnetic resonance imaging (MRI) is widely used to explore central nervous system inflammatory disorders, especially multiple sclerosis (MS). Advanced MRI methods are bringing more sensitive and specific tools for each step of the inflammatory process. In this review, we discuss the different MRI approaches for inflammatory disorders exploration, especially MS. We give particular emphasize on sensibility and specificity of each MRI approach and we also discuss the current knowledge concerning biological and histopathological substratum that could explain MRI signal with each modality.

Effectiveness of delayed-release dimethyl fumarate on patient-reported outcomes and clinical measures in patients with relapsing-remitting multiple sclerosis in a real-world clinical setting: PROTEC.

BACKGROUND: Patient-reported outcomes (PRO) and clinical outcomes give a broad assessment of relapsing-remitting multiple sclerosis (RRMS) disease. OBJECTIVE: The aim is to evaluate the effectiveness of delayed-release dimethyl fumarate (DMF) on disease activity and PROs in patients with RRMS in the clinic. METHODS: PROTEC, a phase 4, open-label, 12-month observational study, assessed annualized relapse rate (ARR), proportion of patients relapsed, and changes in PROs. Newly diagnosed and early MS (≤3.5 EDSS and ≤1 relapse in the prior year) patient subgroups were evaluated. RESULTS: Unadjusted ARR at 12 months post-DMF versus 12 months before DMF initiation was 75% lower (0.161 vs. 0.643, p < 0.0001) overall (n = 1105) and 84%, 77%, and 71% lower in newly diagnosed, ≤3.5 EDSS, and ≤1 relapse subgroups, respectively. Overall, 88% of patients were relapse-free 12 months after DMF initiation (84%, newly diagnosed; 88%, ≤3.5 EDSS; 88%, ≤1 relapse). PRO measures for fatigue, treatment satisfaction, daily living, and work improved significantly over 12 months of DMF versus baseline. CONCLUSION: At 12 months after versus 12 months before DMF initiation, ARR was significantly lower, the majority of patients were relapse-free, and multiple PRO measures showed improvement (overall and for subgroups), suggesting that DMF is effective based on clinical outcomes and from a patient perspective.Clinical trial: A Study Evaluating the Effectiveness of Tecfidera (Dimethyl Fumarate) on Multiple Sclerosis (MS) Disease Activity and Patient-Reported Outcomes (PROTEC), NCT01930708, https://clinicaltrials.gov/ct2/show/NCT01930708.

Unexpected multiple sclerosis: follow-up of 30 patients with magnetic resonance imaging and clinical conversion profile.

The concept of preclinical multiple sclerosis is now well recognised, and a diagnosis of silent brain T2 lesions is frequent because of the ease of performing MRI. Nevertheless, patients with incidental brain MRI fulfilling Barkhof- Tintoré criteria are more rare. We report a descriptive retrospective study of clinical and 5 year MRI follow-up in patients with subclinical demyelinating lesions fulfilling MRI Barkhof-Tintoré criteria with a normal neurological examination. 30 patients were identified and the first brain MRI was performed for various medical events: headaches (n = 14), migraine with (n = 2) or without (n = 4) aura, craniocerebral trauma (n = 3), depression (n = 3), dysmenorrhoea (n = 2), epilepsy (n = 1) and cognitive changes (n = 1). Mean time for the second brain MRI was 6 months (range 3-30). 23 patients had temporospatial dissemination (eight with gadolinium enhancement). 11 patients had clinical conversion: optic neuritis (n = 5), brainstem (n = 3), sensitive symptoms (n = 2) and cognitive deterioration (n = 1). Eight (72%) already had criteria of dissemination to space and time before the clinical event. Mean time between the first brain MRI and clinically isolated syndrome (CIS) was 2.3 years. To our knowledge, this is the first cohort of CIS with preclinical follow-up. Early treatment should be discussed in view of the predictive value on conversion of the MRI burden of the disease.

[Long-term effects of glatiramer acetate in multiple sclerosis]. / Activité à long terme de l'acétate de glatiramère dans le traitement de la sclérose en plaques : état des connaissances.

INTRODUCTION: Multiple sclerosis is a chronic progressive neurological disorder. For this reason, the clinician needs to have access to treatments that are effective and well-tolerated over decades. However, in the absence of long-term controlled clinical trials, it is difficult to assess the long-term benefit provided by currently available immunomodulatory treatments. The objective of this report is to review the strengths and limitations of available long-term data obtained in different phases of the randomized phase III clinical trial with glatiramer acetate collected over a 10-year period in particular. METHODS: Data were obtained from six published analyses of data from the phase III randomized clinical trial of glatiramer acetate performed at different times over a 10-year period. Initially patients were randomized to receive glatiramer acetate (n=125) or placebo (n=126) for 24 months under a double blind scheme, which was subsequently extended to up to 35 months. All patients were then proposed to continue glatiramer acetate treatment in an open-label prospective extension. Analyses of this extension study were performed at six and eight years after initial randomization. Finally, a pooled analysis was performed after a mean treatment duration of 10 years of all patients who had ever received glatiramer acetate during the study. Data were available for 68% of the original cohort at 10 years. At this stage, 108 patients (46.6%) had been continually treated with glatiramer acetate for a mean duration of 10 years. RESULTS: After one year of treatment, the annualized relapse rate decreased by around 50% from 1.18 relapses/year before inclusion to 0.60 relapses/year. Thereafter, relapse rates continued to decline progressively, reaching less than 0.2 relapses/year from the ninth year of treatment onward. For 65% of patients, EDSS disability scores remained stable or improved over the entire treatment period, and 8% had reached a score of 6 on the EDSS scale (inability to walk unaided) after a mean continuous treatment duration of 10 years. With respect to safety, 23 patients (< 10%) needed to stop treatment due to an adverse event over the 10-year follow-up period. The most frequently encountered adverse events were local injection site reactions and systemic immediate postinjection reactions. No specific safety issue associated with long-term treatment was identified. CONCLUSIONS: The information collected from prospective long-term follow-up of patients treated with glatiramer acetate extending out to 10 years provide clear evidence for the long-term efficacy and adequate safety of this immunomodulatory treatment in the treatment of relapsing-remitting multiple sclerosis over a period of at least 10 years.

[Cognitive disorders in multiple sclerosis]. / Les troubles cognitifs au cours de la sclérose en plaques.

Forty to sixty percent of patients with multiple sclerosis (MS) have cognitive dysfunction. The frequency of cognitive disturbances according to the clinical form is not completely understood and the natural history of these disorders has not been extensively studied. Cognitive deficits can be detected in early stages of the disease. Their frequency increases from clinically isolated syndromes, to relapsing-remitting and secondary progressive MS. Cognitive abnormalities are frequently observed also in primary progressive MS. The most frequently impaired functions are information processing speed, attention and memory. Dementia is uncommon but may disclose the disease. Diffuse cerebral injury, assessed by magnetic resonance imaging, contributes to cognitive dysfunction in MS, probably by interrupting connecting fibers between neuronal networks involved in these cognitive functions. Compensatory mechanisms may occur at early stages but they are limited by extension of brain injury.

[Validation of EHD self questionnaire in multiple sclerosis]. / Validation de l'Echelle d'Humeur Dépressive (EHD), version autoquestionnaire, dans la sclérose en plaques.

Depressive Mood Scale (EHD) aims at assessing the various depressive mood dimensions as "blunted affect" and "lack of emotional control". It is an 18 items hetero-evaluation scale. The aim of this study was the validation of an EHD self questionnaire version. Self questionnaire items were generated from genuine scale items. As in the former version, response format was a Lickert 5 point scale. This validation study was carried out on 77 Multiple Sclerosis (MS) patients. Mood disorders are frequent during the course of MS and might be triggered or worsened by immuno-modulation therapies. Principal Component Analysis (ACP) with Varimax rotation revealed a two factors structure. The first one, corresponding to a "blunted affect" dimension, explained 33.5% of the scale variance and was composed of 7 items. The second one, corresponding to a "lack of emotional control" dimension, explained 20% of total scale variance and was composed of 4 items. The questionnaire internal coherence coefficient (Cronbach alpha) was excellent (=0.87) and the two sub-scales ones were satisfactory [0.89 for "blunted affect" dimension and 0.71 for "lack of emotional control" dimension. The questionnaire's external validity was confirmed by a positive correlation between "lack of control" sub-score and state sub-score of the Stait-Trait Anger eXpression Inventory (STAXI)] (r=0.55, p<0.01). Moreover we found a positive correlation between the total EHD autoquestionnaire score and both sub-scores on the one hand, and the Beck Depression Inventory score on the second hand (EHD/BDI: r=0.76, p<0.01; "lack of emotional control"/BDI: r=0.68, p<0.01; "blunted affect"/BDI: r=0.63, p<0.01). Test-retest reliability was good with a positive correlation between all the initial scores and their retests, a week later. Secondarily, a structural equation modeling analysis confirmed the two-factors structure model suggested by ACP. Various indicators showed a good fit between theoretical variance-covariance matrix and the observed one (chi(2)=41.55, p=0.49, ddl=42, Goodness Fit Index GFI=0.91, Root Mean Square Residual RMSEA=0.00). Thus, we proposed a well validated self questionnaire that allows the assessment of "blunted affect" and "lack of emotional control". It should be challenging to correlate those dimensions with neuro-psycho-logical testing and neuro-imagery, in patients affected by CNS diseases. Moreover, the assessment of those dimensions during interferon treatment in MS could allow a more precise evaluation of the emotional changes potentially induced by immuno-modulatory treatments.

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.