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Aurélie RUET

Senior Teacher/Researcher

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43 publication(s) since Mars 2010:

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15/08/2020 | J Neurol Sci   IF 3.1
Effect of cognitive rehabilitation on neuropsychological and semiecological testing and on daily cognitive functioning in multiple sclerosis: The REACTIV randomized controlled study.
Lamargue D, Koubiyr I, Deloire M, Saubusse A, Charre-Morin J, Moroso A, Coupe P, Brochet B, Ruet A

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(R)) 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.

23/07/2020 | Rev Neurol (Paris)   IF 1.9
French validation of the Brief International Cognitive Assessment for Multiple Sclerosis.
Maubeuge N, Deloire MSA, Brochet B, Erhle N, Charre-Morin J, Saubusse A, Ruet A

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.

05/05/2020 | j clin apher   IF 1.6
Double-blind, randomized controlled trial of therapeutic plasma exchanges vs sham exchanges in moderate-to-severe relapses of multiple sclerosis.
Brochet B, Deloire M, Germain C, Ouallet JC, Wittkop L, Dulau C, Perez P, Thevenot F, De Seze J, Zephir H, Vermersch P, Pittion S, Debouverie M, Laplaud DA, Clavelou P, Ruet A

INTRODUCTION: No randomized controlled clinical trial of therapeutic plasma exchanges (TPE) has yet been performed for moderate-to-severe relapses of multiple sclerosis (MS). OBJECTIVE: To compare TPE to sham-TPE in patients with a recent steroid-resistant moderate-to-severe MS relapse. METHODS: Patients presenting with an MS relapse of less than 2 months without improvement and 15 days after a course of steroids were randomized. Specific criteria were used for each relapse type to define moderate-to-severe disability. The primary endpoint was the proportion of patients with at least a moderate improvement based on objective and functional evaluation after 1 month. RESULTS: Thirty-eight patients were randomized. The intention-to-treat analysis included 14 patients in the TPE group and 17 in the Sham-TPE group. The proportion of patients with at least moderate improvement at 1 month did not differ between the groups (P = .72), although 57.1% of the TPE group had full recovery compared with 17.6% of the sham group. Considering optic neuritis (ON), a significant difference in the proportion of different levels of improvement was observed in favor of the TPE group (P = .04). The combined Kurtzke's functional systems scores were significantly more improved in the TPE group than in the sham-TPE group at months 1 (P < .01), 3 (P < .05), and 6 (P < .05). No major side effects were observed. CONCLUSIONS: A significant difference between TPE and Sham-TPE at the primary endpoint was only observed in patients with ON. Neurological function improved significantly more often in the TPE group than in the sham-TPE group.

05/09/2019 | Brain   IF 11.8
Dynamic modular-level alterations of structural-functional coupling in clinically isolated syndrome.
Koubiyr I, Besson P, Deloire M, Charre-Morin J, Saubusse A, Tourdias T, Brochet B, Ruet A

Structural and functional connectivity abnormalities have been reported previously in multiple sclerosis. However, little is known about how each modality evolution relates to the other. Recent studies in other neurological disorders have suggested that structural-functional coupling may be more sensitive in detecting brain alterations than any single modality. Accordingly, this study aimed to investigate the longitudinal evolution of structural-functional coupling, both at the global and modular levels, in the first year following clinically isolated syndrome. We hypothesized that during the course of multiple sclerosis, patients exhibit a decoupling between functional and structural connectivity due to the disruptive nature of the disease. Forty-one consecutive patients with clinically isolated syndrome were prospectively enrolled in this study, along with 19 age-, sex- and educational level-matched healthy control subjects. These participants were followed for 1 year and underwent resting-state functional MRI and diffusion tensor imaging at each time point, along with an extensive neuropsychological assessment. Graph theory analysis revealed structural reorganization at baseline that appeared as an increase in the clustering coefficient in patients compared to controls (P < 0.05), as well as modular-specific alterations. After 1 year of follow-up, both structural and functional reorganization was depicted with abnormal modular-specific connectivity and an increase of the functional betweenness centrality in patients compared to controls (P < 0.01). More importantly, structural-functional decoupling was observed in the salience, visual and somatomotor networks. These alterations were present along with preserved cognitive performance at this stage. These results depict structural damage preceding functional reorganization at a global and modular level during the first year following clinically isolated syndrome along with normal cognitive performance, suggesting a compensation mechanism at this stage of the disease. Principally, structural-functional decoupling observed for the first time in multiple sclerosis suggests that functional reorganization occurs along indirect anatomical pathways.

03/09/2019 | JAMA Neurol   IF 12.3
Progressive Multifocal Leukoencephalopathy Incidence and Risk Stratification Among Natalizumab Users in France.
Vukusic S, Rollot F, Casey R, Pique J, Marignier R, Mathey G, Edan G, Brassat D, Ruet A, De Seze J, Maillart E, Zephir H, Labauge P, Derache N, Lebrun-Frenay C, Moreau T, Wiertlewski S, Berger E, Moisset X, Rico-Lamy A, Stankoff B, Bensa C, Thouvenot E, Heinzlef O, Al-Khedr A, Bourre B, Vaillant M, Cabre P, Montcuquet A, Wahab A, Camdessanche JP, Tourbah A, Guennoc AM, Hankiewicz K, Patry I, Nifle C, Maubeuge N, Labeyrie C, Vermersch P, Laplaud DA

Importance: Risk of developing progressive multifocal leukoencephalopathy (PML) is the major barrier to using natalizumab for patients with multiple sclerosis (MS). To date, the association of risk stratification with PML incidence has not been evaluated. Objective: To describe the temporal evolution of PML incidence in France before and after introduction of risk minimization recommendations in 2013. Design, Setting, and Participants: This observational study used data in the MS registry OFSEP (Observatoire Francais de la Sclerose en Plaques) collected between April 15, 2007, and December 31, 2016, by participating MS expert centers and MS-dedicated networks of neurologists in France. Patients with an MS diagnosis according to current criteria, regardless of age, were eligible, and those exposed to at least 1 natalizumab infusion (n = 6318) were included in the at-risk population. A questionnaire was sent to all centers, asking for a description of their practice regarding PML risk stratification. Data were analyzed in July 2018. Exposures: Time from the first natalizumab infusion to the occurrence of PML, natalizumab discontinuation plus 6 months, or the last clinical evaluation. Main Outcomes and Measures: Incidence was the number of PML cases reported relative to the person-years exposed to natalizumab. A Poisson regression model for the 2007 to 2016 period estimated the annual variation in incidence and incidence rate ratio (IRR), adjusted for sex and age at treatment initiation and stratified by period (2007-2013 and 2013-2016). Results: In total, 6318 patients were exposed to natalizumab during the study period, of whom 4682 (74.1%) were female, with a mean (SD [range]) age at MS onset of 28.5 (9.1 [1.1-72.4]) years; 45 confirmed incident cases of PML were diagnosed in 22 414 person-years of exposure. The crude incidence rate for the whole 2007 to 2016 period was 2.00 (95% CI, 1.46-2.69) per 1000 patient-years. Incidence significantly increased by 45.3% (IRR, 1.45; 95% CI, 1.15-1.83; P = .001) each year before 2013 and decreased by 23.0% (IRR, 0.77; 95% CI, 0.61-0.97; P = .03) each year from 2013 to 2016. Conclusions and Relevance: The results of this study suggest, for the first time, a decrease in natalizumab-associated PML incidence since 2013 in France that may be associated with a generalized use of John Cunningham virus serologic test results; this finding appears to support the continuation and reinforcement of educational activities and risk-minimization strategies in the management of disease-modifying therapies for multiple sclerosis.

05/2019 | Mult Scler   IF 5.6
Efficacy of rituximab in refractory RRMS.
Durozard P, Maarouf A, Boutiere C, Ruet A, Brochet B, Vukusic S, Carra-Dalliere C, Labauge P, Mathey G, Debouverie M, Papeix C, Maillart E, Lubetzki C, Bensa C, Gout O, Giannesini C, Stankoff B, Ciron J, Brassat D, Pelletier J, Rico Lamy A, Audoin B

OBJECTIVE: To investigate the efficacy of rituximab as rescue therapy in patients with relapsing-remitting multiple sclerosis (RRMS) and persistent disease activity confirmed by magnetic resonance imaging (MRI) despite immunosuppressive disease-modifying therapy (DMT). METHODS: In this observational nationwide retrospective multicenter study, we first identified 351 off-label rituximab-treated patients through a cohort of 15,984 RRMS patients. In this group, we identified patients with disease activity prior to rituximab confirmed by MRI (one or more new T2 lesion and/or gadolinium-enhancing lesion) despite immunosuppressive DMT (fingolimod, natalizumab, or mitoxantrone) with a follow-up after rituximab initiation longer than 6 months. Outcome data were collected from the French Observatory of Multiple Sclerosis (OFSEP) register and medical charts. RESULTS: A total of 50 patients were identified. Median rituximab treatment duration was 1.1 (0.5-6.4) year. Mean annualized relapse rate significantly decreased from 0.8 during last immunosuppressive DMT to 0.18 after rituximab ( p < 0.0001). While 72% of patients showed gadolinium-enhancing lesions on the last MRI performed during last immunosuppressive DMT, 8% of them showed gadolinium-enhancing lesions on the first MRI performed 6.1 (range 1.4-18.4) months after rituximab ( p < 0.0001). CONCLUSION: This study provides level IV evidence that rituximab reduces clinical and MRI disease activity in patients with active RRMS despite immunosuppressive DMT.

23/04/2019 | J Neurol   IF 4.2
Pathologic and MRI analysis in acute atypical inflammatory demyelinating lesions.
Ayrignac X, Rigau V, Lhermitte B, Vincent T, de Champfleur NM, Carra-Dalliere C, Charif M, Collongues N, de Seze J, Hebbadj S, Ahle G, Oesterle H, Cotton F, Durand-Dubief F, Marignier R, Vukusic S, Taithe F, Cohen M, Guennoc AM, Kerbrat A, Edan G, Carsin-Nicol B, Allou T, Sablot D, Thouvenot E, Ruet A, Magy L, Boncoeur-Martel MP, Labauge P, Kremer S

BACKGROUND: The diagnosis of atypical inflammatory demyelinating lesions can be difficult. Brain biopsy is often required to exclude neoplasms. Moreover, the relationship between these lesions and multiple sclerosis and NMOSD is not clear. OBJECTIVES: Our objectives were to describe radiological and pathological characteristics of patients with acute inflammatory demyelinating lesions. METHODS: We retrospectively identified patients with brain biopsy performed for diagnostic uncertainty revealing a demyelinating lesion. A complete clinical, biological, radiological and pathological analysis was performed. RESULTS: Twenty patients (15 with a single lesion) were included. MRI disclosed a wide range of lesions including infiltrative lesions (40%), ring-like lesion (15%) Balo-like lesion (15%) and acute haemorrhagic leukoencephalitis (20%). In spite of a marked heterogeneity, some findings were common: a peripheral B1000 hyperintense rim (70%), a slight oedema with mild mass effect (75%) and an open-rim peripheral enhancement (75%). Histopathology revealed that all cases featured macrophages distributed throughout, extensive demyelination, axonal preservation and absence of haemorrhagic changes. In the majority of cases, macrophages were the predominant inflammatory infiltrate and astrocytes were reactive and dystrophic. Aquaporin-4 staining was systematically preserved. After a mean follow-up of 5 years (1-12), 16/20 patients had a diagnosis of monophasic acute atypical inflammatory demyelinating lesion. One patient was diagnosed with MS and 3 with AQP4 negative NMOSD. DISCUSSION: Although imaging findings in patients with atypical inflammatory demyelinating lesions are heterogeneous, some common features such as peripheral DWI hyperintense rim with open-rim enhancement and absence of oedema argue in favour of a demyelinating lesion and should preclude a brain biopsy. In this context, AQP4 staining is systematically preserved and argues against an AQP4-positive NMOSD. Moreover, long-term follow-up is characterized by low recurrence rate.

The relationships between cognitive impairment that exist during the clinical course of multiple sclerosis (MS) remain poorly described. The effect of disease duration has been studied in a few longitudinal cohorts and some cross-sectional studies that suggest that cognitive deficits tend to extend with disease duration. However, the effect of disease duration seems to be confounded by the effect of age. At the pre-clinical stage, cognitive deficits have been observed in patients with radiologically isolated syndromes, and their profile is similar than in clinically isolated syndromes (CIS) and relapsing-remitting MS (RRMS). The frequency of cognitive impairment tends to be higher in RRMS than in CIS. In these phenotypes, slowness of information processing speed (IPS) and episodic verbal and visuo-spatial memory deficits are frequently observed, but executive functions, and in particular verbal fluency, could also be impaired. More frequent and severe deficits are reported in SPMS than in RRMS with more severe deficits for memory tests, working memory and IPS. Similarly to what is observed in SPMS, patients with primary progressive MS (PPMS) present with a wide range of cognitive deficits in IPS, attention, working memory, executive functions, and verbal episodic memory with more tests and domains impaired than RRMS patients. Altogether these data suggested that not only the duration of the disease and age play an important role in the cognitive profile of patients, but also the phenotype itself, probably because of its specific pathological mechanism.

27/11/2018 | Mult Scler   IF 5.3
Longitudinal study of functional brain network reorganization in clinically isolated syndrome.
Koubiyr I, Deloire M, Besson P, Coupe P, Dulau C, Pelletier J, Tourdias T, Audoin B, Brochet B, Ranjeva JP, Ruet A

BACKGROUND:: There is a lack of longitudinal studies exploring the topological organization of functional brain networks at the early stages of multiple sclerosis (MS). OBJECTIVE:: This study aims to assess potential brain functional reorganization at rest in patients with CIS (PwCIS) after 1 year of evolution and to characterize the dynamics of functional brain networks at the early stage of the disease. METHODS:: We prospectively included 41 PwCIS and 19 matched healthy controls (HCs). They were scanned at baseline and after 1 year. Using graph theory, topological metrics were calculated for each region. Hub disruption index was computed for each metric. RESULTS:: Hub disruption indexes of degree and betweenness centrality were negative at baseline in patients ( p < 0.05), suggesting brain reorganization. After 1 year, hub disruption indexes for degree and betweenness centrality were still negative ( p < 0.00001), but such reorganization appeared more pronounced than at baseline. Different brain regions were driving these alterations. No global efficiency differences were observed between PwCIS and HCs either at baseline or at 1 year. CONCLUSION:: Dynamic changes in functional brain networks appear at the early stages of MS and are associated with the maintenance of normal global efficiency in the brain, suggesting a compensatory effect.

06/2018 | Rev Neurol (Paris)   IF 1.8
Update on pediatric-onset multiple sclerosis.
Ruet A

Pediatric-onset multiple sclerosis (POMS) has distinctive features compared with adult-onset multiple sclerosis (AOMS), and warrants caution despite being a rare form of MS. POMS diagnostic criteria are somewhat different from those used in AOMS, with acute disseminated encephalomyelitis being a key differential diagnosis of MS in children. Other differential diagnoses that have to be ruled out before diagnosing MS include demyelinating syndromes, autoimmune and systemic pathologies, and infectious, genetic, metabolic and neoplastic diseases. Compared with AOMS, POMS has several different clinical, biological and imaging findings. At onset, high-level inflammatory activity is mainly reported, and patients with POMS are also at high risk of developing early physical disabilities and early cognitive impairment. Yet, treating patients with POMS is challenging due to a lack of randomized controlled trials. Some of the disease-modifying drugs currently prescribed are analogous to therapies used in adults, and are associated with good tolerability in pediatric patients. However, a few clinical trials dedicated to POMS are now in progress, and the future outlook is to improve the long-term prognosis of POMS patients with early effective and safe treatments.