Pr Carole VUILLEROT

My main research theme concerns evaluation and biometrics, in the sense of measuring life, applied to improving care, more particularly for children with disabilities. The modeling of my research axes in pediatric MPR can be considered transversal in several areas between clinical research in MPR and neurology and fundamental research. The double integrative scale (from the singular to the holistic) makes it possible to structure the framework of our research into two axes which we would call, on the one hand, Tool or Instrument-oriented type research and, on the other hand, research Patient-oriented. The clinical position is from this point of view privileged because it is in constitutive tension between these two axes.

Axis 1 :Our previous work allowed us to confirm the intrinsic and extrinsic properties of MFM through the use of mathematical models and the study of its applicability in different pathological groups. Thanks to this, MFM is now commonly used in clinical trials which are currently being deployed thanks to advances in genetic and drug research.

Having, thanks to the MFM database, more than 10,000 MFMs in more than 5,000 different patients, we wish to develop curves of evolution of the motor function of patients according to their age, their treatment or their pathology which can be used to better clarify the prognosis of each patient and to constitute homogeneous groups of patients for clinical trials. This work is carried out in collaboration with Professor Fischer, Basel (Switzerland) (Hafner P, 2021)

Widely underlined by the EMA and the FDA, the insufficiency of the small p to demonstrate the effectiveness of therapies on the primary endpoint led us to develop measures to specify the quantity of clinically relevant change for the patient ( MCID) by pathology (ASI, DMC). (Le Goff L, 2021)(Duong T, 2021)

We now wish, using digital technologies, to propose an evolution of our MFM tool towards a serious game type tool: MFM-play. The objective is to have a more precise measurement due to the automation of the rating thanks to software analyzing the motion capture data and more fun due to the creation of a serious game allowing the child to be immersed during your assessment in a video game atmosphere. Funding for the pilot study on 5 items was obtained (GIRCI 2020). Full funding for the complete development of the application was obtained by Roche laboratories as well as the start of funding for the validation study by the AFM. A PHRIP 2021 file has been submitted. (3rd cycle thesis supervision of Mrs. Dominique Vincent Genod, Physiotherapist, first article under review Pediatric Physical Therapy)

Axis 2: Beyond motor function, fatigue appears as a disabling symptom in certain MNMs, particularly in Infantile Spinal Muscular Atrophy (ASI). The current target of treatments in this pathology remains the motor neuron (gene therapy, ASO, small molecules) allowing stabilization or even some motor progress in these patients without allowing recovery. Significant disability associated with disabling muscle atrophy persists, particularly in treated patients. The description of new patient phenotypes now widely treated by these innovative molecules appears important for preparing new therapeutic approaches. As part of a RHU 2021 call for projects, in tandem with Professor Schaeffer, we obtained funding for the SMART project (SMA muscle atrophy remediative therapy) with a consortium of industrial partners (Roche, Sysnav, Cytoo, Enyo pharma ) and clinicians (Pr. Guillaume Millet, St Etienne, Pr. Laurent Servais, Oxford, UK). The objectives of this project are to better understand the molecular mechanisms underlying muscle atrophy in order to develop specific therapeutic approaches. The clinical part of the project will allow the description of the first “natural” history of new phenotypes of patients with ASI treated with a focus on the development of valid outcomes to measure persistent symptoms (fatigue, osteopenia, cognitive profile, orthopedic profile).

Axis 3: The SAS classification (SOFMER activity score) should allow a better assessment of the real activity level of patients in SSR, for better quantification of the care burden as closely as possible to the patient’s needs. with ultimately a better adaptation of the resources of SSR services to the patients received. This project benefited from PREPS 2016 funding which is still ongoing. The inter-observer validation study has just been completed with the inclusion of 109 patients (Charvolin L, Arch Phys Med Rehab 2021). The studies of validity against criterion (comparison with reference scales MIF, MIF-Mômes, ADL, BREF, MMSE, BREV, items from the Weschler scales) and sensitivity to change began in September 2020 and will allow the inclusion of 200 additional patients.

The objective of axis 4: My research is to conduct therapeutic trials in order to offer the best care to patients to enable them to achieve or maintain optimal functioning in interaction with the environment. Due to the international recognition of our MFM tool and the numerous links with the industry around the design of research protocols, it is quite naturally that we were identified as a service likely to host therapeutic trials from 2008 ( 8 trials in total), mainly in the field of MNM. Our objective is to be able to develop our research team in order to host other therapeutic trials in neuromuscular diseases in collaboration with the adult neurology sector within a platform for evaluation and access to innovative therapies in MNM from child to adult. The links developed with the INMG with common research themes allow a translational approach as a bridge between fundamental research and applied research, from the understanding of molecular mechanisms to therapeutic trials in patients.

Several international collaborations around the training and dissemination of the MFM tool (Motor Function Measurement) in particular with the USA (Mina Jain; Leslie Nelson; Tina Duong), Brazil (Juliana Gianetti; Gabriela Palhares) and China (Huang Mei Huan).

Since my Post Doctoral stay at the National Institute of Health (Bethesda, MD, USA), we have continued our collaborations with Professor Carsten Bönnemann and his team Neuromuscular and Neurogenetic disorders of childhood within the NINDS (National Institute of Neurological Diseases and Stroke) essentially on the development and validation of tools for measuring motor function in congenital muscular dystrophies and the description of natural histories, an essential preamble to the development of therapeutic trials in the pathology.

Professor Dirk Fisher, Basel Children’s University Hospital, particularly around the use of MFM in Duchenne muscular dystrophy with the description of the curve of evolution of the motor function of patients according to their age which can be used as a prognostic tool .

Finally, joint work was set up with Professor Laurent Servais, department of pediatrics, Children’s hospital, Oxford University as part of a collaboration around the development of judgment criteria in neuromuscular diseases in children with a focus particularly on the measurement of fatigue. This collaboration is developing as part of the RHU SMART Spinal muscular atrophy remediative therapy obtained in 2021 which involves Oxford and numerous French and European investigators.

1. Psychometric Characteristics of the Motor Function Measure in Neuromuscular Diseases: A Systematic Review1. J Neuromuscul Dis 2023;10:301–314.

Ribault S, Rippert P, Jain M, Le Goff L, Vincet-Genod D, Barriere A, Berruyer A, Garde C, Tinat M, Pons C, Vuillerot C

2. Does accelerometry reflect hand function in infants at risk of unilateral cerebral palsy? A secondary analysis of BB-Bim results. Res Dev Disabil 2023;139:104549.

Bard-Pondarré R, Al-Abiad N, Verdun S, Naaïm A, Agopyan H, Chaléat-Valayer E, Vuillerot C

3. CDM MFM Study Group. Rasch analysis of the motor function measure in patients with congenital muscle dystrophy and congenital myopathy. Arch Phys Med Rehabil 2014;95:2086–2095.

Vuillerot C, Rippert P, Kinet V, Renders A, Jain M, Waite M, Glanzman AM, Girardot F, Hamroun D, Iwaz J, Ecochard R, Quijano-Roy S, Bérard C, Poirot I, Bönnemann CG

4. SUNFISH Working Group. Risdiplam in types 2 and 3 spinal muscular atrophy: A randomised, placebo-controlled, dose-finding trial followed by 24 months of treatment. Eur J Neurol 2022.

Mercuri E, Baranello G, Boespflug-Tanguy O, De Waele L, Goemans N, Kirschner J, Masson R, Mazzone ES, Pechmann A, Pera MC, Vuillerot C, Bader-Weder S, Gerber M, Gorni K, Hoffart J, Kletzl H, Martin C, McIver T, Scalco RS, Yeung WY, Servais L

5. Determining the Interrater Reliability of the SOFMER Activity Score (version 2) for Individuals in Rehabilitation Centers. Arch Phys Med Rehabil 2022;103:1122–1130.

Charvolin L, Rippert P, Roche S, Rabilloud M, Morard M-D, Marco JD, Dinomais M, Pouyfaucon M, Gimat R, Perennou D, Houx L, Iwaz J, Rode G, Vuillerot C,

6. MFM registry Study Group. Implementation of Motor Function Measure score percentile curves – Predicting motor function loss in Duchenne muscular dystrophy. Eur J Paediatr Neurol 2022;36:78–83.

Hafner P, Schmidt S, Schädelin S, Rippert P, Hamroun D, Fabien S, Henzi B, Putananickal N, Rubino-Nacht D, Vuillerot C, Fischer D

7. AVCnn Study Group. Additional validation study and French cross-cultural adaptation of the Pediatric Stroke Outcome Measure-Summary of Impressions (PSOM-SOI). Ann Phys Rehabil Med 2021;64:101341.

Morard M-D, Dinomais M, Bull K, Rippert P, Chevignard M, deVeber G, Chabrier S, Vuillerot C

8. Responsiveness and Minimal Clinically Important Difference of the Motor Function Measure in Collagen VI-Related Dystrophies and Laminin Alpha2-Related Muscular Dystrophy. Arch Phys Med Rehabil 2021;102:604–610.

Le Goff L, Meilleur KG, Norato G, Rippert P, Jain M, Fink M, Foley AR, Waite M, Donkervoort S, Bönnemann CG, Vuillerot C

9. Understanding the relationship between the 32-item motor function measure and daily activities from an individual with spinal muscular atrophy and their caregivers’ perspective: a two-part study. BMC Neurol 2021;21:143.

Duong T, Braid J, Staunton H, Barriere A, Petridis F, Reithinger J, Cruz R, Jarecki J, De Lemus M, Gusset N, Broekgaarden R, Randhawa S, Flynn J, Arbuckle R, Reif S, Yang L, De Martini A, Vuillerot C

10. Adolescebat autem obstinatum propositum erga haec et similia multa scrutanda, stimulos admovente regina, quae abrupte

Muntoni F, Bertini E, Comi G, Kirschner J, Lusakowska A, Mercuri E, Scoto M, van der Pol WL, Vuillerot C, Burdeska A, El-Khairi M, Fontoura P, Ives J, Gorni K, Reid C, Fuerst-Recktenwald S