Journal of Neuromuscular Diseases 8 (2021) 743–754 743 DOI 10.3233/JND-210655 IOS Press Meeting Report E-Health & Innovation to Overcome Barriers in Neuromuscular Diseases. Report from the 1st eNMD Congress: Nice, France, March 22-23, 2019 Jonathan Pinia , Gabriele Sicilianob , Pauline Lahauta , Serge Braunc , Sandrine Segovia-Kuenyc , Anna Koled , Ines Hérnandoe , Julij Selbf , Erika Schirinzib , Tina Duongg , Jean-Yves Hogrelh , José Javier Serrano Olmedoi,j,k , John Vissingl , Laurent Servaism,n , Dominique Vincent-Genodo , Carole Vuillerotp , Sylvie Bannwarthq,r , Damien Eggenspielers , Savine Vicartt , Jordi Diaz-Manerau,v,w , eNMD group1 , Hanns Lochmüllerx,y,z and Sabrina Sacconia,r,aa,∗ a Université Côte d’Azur (UCA), Centre Hospitalier Universitaire de Nice, Peripheral Nervous System and Muscle Department, Rare Neuromuscular Disease Reference Center, ERN-Euro-NMD, Nice, France b Neurological Clinic, Department of Clinical and Experimental Medicine, Ospedale Santa Chiara, University of Pisa, Pisa, Italy c AFM Telethon, Paris, France d Public Health Policy Director Rare 2030 Lead EURORDIS e Healthcare Director EURORDIS f University Clinic Golnik, Golnik, Slovenia – Medical consultant Parsek, Vienna, Austria g Department of Neurology, Stanford University, Palo Alto, CA, USA h Neuromuscular Physiology and Evaluation Lab, Neuromuscular Investigation Centre, Institute of Myology, Paris, France i Laboratory of Bioinstrumentation and Nanomedicine, Center for Biomedical Technology, Universidad Politécnica de Madrid, Madrid, Spain j Networking Center for Biomedical Research on Bioengineering, Biomaterials and Nanomedicine, Madrid, Spain k Escuela Técnica Superior de Ingenieros de Telecomunicación, Madrid, Spain l Copenhagen Neuromuscular Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark m MDUK Oxford Neuromuscular Center Department of Pediatrics University of Oxford, Oxford, UK n Division of Child Neurology Reference Center for Neuromuscular Disease, Centre Hospitalier Régional de Références des Maladies Neuromusculaires, Department of Paediatrics, University, Oxford, UK o L’Escale, Pediatric Rehabilitation Department, Hospices Civils de Lyon, Lyon, France p Neuron Interaction Team, NeuroMyogène Institute, Lyon University, Lyon, France q Department of Medical Genetics, National Center for Mitochondrial Diseases, Nice University Hospital, Nice, France 1 eNMD group is composed of all the people who have attended this meeting and Michele Cavallia ; Angela Pumaa ; Luisa Villaa ; and Ezaru Andraa ∗ Correspondence to: Sabrina Sacconi, Université Côte d’Azur (UCA), Nice, France. E-mail: sacconi.s@chu-nice.fr. ISSN 2214-3599 © 2021 – The authors. Published by IOS Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (CC BY-NC 4.0). 744 J. Pini et al. / E-Health & Innovation to Overcome Barriers in Neuromuscular Diseases r Institute for Research on Cancer and Aging of Nice (IRCAN), Faculty of Medicine, Université Côte D’Azur (UCA), Nice, France s Healthcare Program Director, Sysnav, Paris, France t Channelopahies Reference Center, Service of Neuro-Myology, University Hospital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France u John Walton Muscular Dystrophy Research Center, Newcastle University, Newcastle, UK v Neurology department. Hospital de la Santa Creu I Sant Pau, Barcelona, Spain w Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Spain x Children s Hospital of Eastern Ontario Research Institute; Division of Neurology, Department of Medicine, The Ottawa Hospital; and Brain and Mind Research Institute, University of Ottawa, Ottawa, Canada y Department of Neuropediatrics and Muscle Disorders, Medical Center – University of Freiburg, Faculty of Medicine, Freiburg, Germany z Centro Nacional de Análisis Genómico (CNAG-CRG), Center for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Barcelona, Catalonia, Spain aa Fédération Hospitalo-Universitaire Oncoage, Centre Hospitalier Universitaire de Nice, Université Côte d’Azur (UCA), Nice, France Pre-press 2 April 2021 Abstract. By definition, neuromuscular diseases are rare and fluctuating in terms of symptoms; patients are often lately diagnosed, do not have enough information to understand their condition and be proactive in their management. Usually, insufficient resources or services are available, leading to patients’ social burden. From a medical perspective, the rarity of such diseases leads to the unfamiliarity of the medical staff and caregiver and an absence of consensus in disease assessment, treatment, and management. Innovations have to be developed in response to patients’ and physicians’ unmet needs. It is vital to improve several aspects of patients’ quality of life with a better comprehension of their disease, simplify their management and follow-up, help their caregiver, and reduce the social and economic burden for living with a rare debilitating disease. Database construction regrouping patients’ data and symptoms according to specific country registration on data privacy will be critical in establishing a clear consensus on neuromuscular disease treatment. Clinicians also need technological innovations to help them recognize neuromuscular diseases, find the best therapeutic approach based on medical consensus, and tools to follow patients’ states regularly. Diagnosis also has to be improved by implementing automated systems to analyze a considerable amount of data, representing a significant step forward to accelerate the diagnosis and the patients’ follow up. Further, the development of new tools able to precisely measure specific outcomes reliably is of the matter of importance in clinical trials to assess the efficacy of a newly developed compound. In this context, creation of an expert community is essential to communicate and share ideas. To this end, 97 clinicians, healthcare professionals, researchers, and representatives of private companies from 9 different countries met to discuss the new perspective and challenges to develop and implement innovative tools in the field of neuromuscular diseases. Keywords: e-Health, eNMD congress, neuromuscular disease, innovation, unmet needs GOALS OF THE CONGRESS manage, and monitor complex diseases such as NMD. The meeting was attended by 97 participants with 24 Given the complexity of symptoms, management, speakers from 9 different countries: France, Canada, and assessment of neuromuscular diseases (NMD), it Slovenia, Germany, Italy, USA, Spain, Denmark, and is essential to build a community of experts who can Belgium. share resources and knowledge. Further, developing This first eNMD congress aimed to present new new tools to help with patients’ care, follow-up, and tools and innovations developed to overcome barri- disease assessment is important to improve the way ers in NMD and explore the opportunity to use remote patients’ are treated. The eNMD congress is a mile- medicine for patients’ follow-up or connected devices stone in achieving this objective, bringing together to establish new outcomes measures. Overall, this internationally recognized experts on NMD and inno- meeting was divided into five different sessions, each vations able to make tomorrow’s medicine to treat, addressing how new technologies will change the J. Pini et al. / E-Health & Innovation to Overcome Barriers in Neuromuscular Diseases 745 face of NMD assessment, follow-up, and monitoring. medico-economic NMD cohort studies, as well The first session was on the challenges and strategies as patient support program solutions and remote of e-health and innovations. The second session was health monitoring systems (examples including the on e-registries, telemedicine, and m-health apps. The ActiMyo or Feetme and wearable intelligent devices). third one was on robotics and domotics, the fourth on Brain-computer interfaces, communication technolo- connected devices. The last session was on various gies, and speech software were also addressed, which new developments in the field of NMD. are useful for accelerated diagnosis and management. Concluding remarks included the need for electronic patient records, agreed standards for data protec- INTRODUCTORY TALKS tion, funding, and reimbursement models in a highly fragmented market, which should be designed to con- After the introduction by Charles Guepratte, the tribute to the people they are aimed at. Director of Nice University Hospital, Jean-Marc The second introductory talk presented policies. Gambaudo, the President of Côte d’Azur University, Anna Kole and Ines Hernando presented “E-Health and Mathilde Demory-Zory, the city of Nice rep- Strategies and Roadmaps supporting Rare Disease resentative, Serge Braun, the AFM-Téléthon Chief Policies”. Sharing and pooling data between patients Scientific Officer, open the congress with an expla- and health service providers, hospitals, health nation of ten ways in which neuromuscular diseases professionals, and health and research information can benefit from Digital Health. Digital health tech- networks is essential for rare diseases and any area nology (DHT) may help to solve issues such as those requiring a specific concentration of expertise. Only expressed by patients through a barometer published through data aggregation can one attain a critical in 2015 by Maladies rares info service: delay to mass, which generates the knowledge needed to obtain a diagnosis, improper care, stop working for provide the best care quality and drive forward parent careers, insufficient knowledge of health pro- research leading to more innovative treatments: fessionals outside the hospital, and patients’ social electronic health records, telemedicine services, and isolation. portable patient-monitoring devices. Patient data DHT can be used to optimize medical and social sharing is of central importance to the ERN concept resources, ease treatment access, organize multidis- that expertise travels instead of patients and rests ciplinary daily- and social healthcare, speed-up upon data’s ability to travel. For the data to travel, it expertise, improve patient autonomy (visual recog- has to be electronic. The current obstacles in making nition devices, brain-computer interfaces, deep this happen are 1) technical, due to continued lack of learning), and reduce costs (potential 60% in chronic interoperable data platforms; 2) legal due to a lack of diseases), travels, and need of emergency services. clarity and interpretation of data sharing legislation; Conditions are met to implement such tools. Even 3) financial due to inadequate financial support of though 41% of French people have doubts about infrastructures, tools, and expertise needed to meet data security, 75% are ready to communicate through demand; 4) social/political due to a continued need digital channels with their general practitioner, 81% for a paradigm shift in attitudes and the political will of clinicians also accept such technologies, and required for real electronic sharing of patient data. expected reduced costs are close to 100 billion D in Several legislations provide a policy basis to guide the European Union with e-health technologies. activities to overcome these obstacles, including Examples in the NMD field were presented, show- Article 14 of the Directive on Patients’ Rights in ing tools (data mining of online databases, genetic, Cross Border Healthcare (2011), the General Data and omics) to speed-up massive diagnostic delays Protection Regulation (2015), and the Communica- (11 months in ALS, up to 20 years in late-onset acid tion on enabling the digital transformation of health maltase deficiency). Similar approaches can be used and care in the Digital Single Market (2018). Several to identify new treatment opportunities (ex: combi- multi-stakeholder initiatives are addressing current natorial pharmacology). Examples of tele-expertise challenges as well. Out of necessity, people living application in the multidisciplinary management of with rare diseases may be the most motivated to NMD were presented, which improve care manage- ensure that their health data are used as effectively ment and break the isolation of patients affected as possible to improve their own health outcomes by NMD. Useful E-learning tools were presented, and well-being and those of future generations, as together with clinical and monitoring tool-based evidenced by a EURORDIS Rare Barometer Survey 746 J. Pini et al. / E-Health & Innovation to Overcome Barriers in Neuromuscular Diseases on data sharing. Several patient-centered policy or telemedicine development eased monitoring and initiatives in eHealth and data sharing aim to maxi- follow-up by making them remote. mize the implementation of comprehensive e-health Despite all this significant progress, these appro- in Europe, most recently EURORDIS’ paper on a aches present some limitations that have to be over- Mature ERN System (http://download2.eurordis.org/ come. First, the level of details and the amount of documents/pdf/EURORDIS vision on mature ERN data generated by automated analysis require spe- s FINAL.pdf) and the multi-stakeholder Rare 2030 cific analysis and interpretation tools. Data storage, Foresight Study on rare disease policy collection, and sharing can be a problem due to ethi- cal issues as each country has its registration on data TOPIC 1: CHALLENGES AND STRATEGIES privacy. These concerns have to be addressed before OF E-HEALTH AND INNOVATION large-scale deployment of such approaches. Hanns Lochmüller talked about the RD-Connect’s New technologies have transformed the way we approach to identify genetic causes in rare neuro- communicate and live our lives. A few years ago, a muscular diseases. Indeed, 6-8% of the European meeting could only be done in person. Still, one can population – between 27 and 36 million people – are now attend a virtual meeting worldwide without mov- affected by one of the 5000-8000 distinct rare dis- ing from our location, allowing communication and eases. RD-Connect (www.rd-connect.eu) is a unique exchange internationally. Digital tools are part of our global infrastructure project that links up databases, daily practice and have evolved alongside progress registries, biobanks, and clinical bioinformatics data in robotics, artificial intelligence, and others. This used in rare disease research into a central resource technology integrates into our daily lives through the for researchers worldwide. It has developed an inte- ability to control our home with a smartphone, unlock grated research platform in which complete clinical our car without keys and phone applications, and profiles are combined with -omics data and sam- change our social behavior. New technologies can ple availability for rare disease research, particularly change the way patients are diagnosed, care is man- research funded under the International Rare Dis- aged, and disease progression is understood. Some eases Research Consortium (IRDiRC; www.irdirc. incurable illnesses are now manageable, and treat- org). ments exist to help patients. RD-Connect’s mechanism for sharing and analyz- Sabrina Sacconi started the meeting with an over- ing rare disease genomic data begins with submitting view of the recent technological progress and the raw.bam or fastq files, which is essential to their application in NMD in terms of diagnosis allow data from multiple sequencing providers to and care. Genetic tools’ evolution revolutionized be processed through a standard pipeline to ensure genetic disease diagnosis, allowing identifying many comparability. The raw data are stored for long-term genes involved in neuromuscular or other dis- access at the European Genome-phenome Archive eases’ pathophysiology, leading to the elaboration (EGA), a secure, controlled-access repository. In con- of new treatments and improving patients’ quality trast, the processed data are made accessible online of life. Routine analysis has also evolved through for real-time analysis in the RD-Connect genomics the implementation of new or already existing tools analysis interface. Thanks to the initial collaboration amelioration. The level of details and the imaging with the two partner projects, NeurOmics and EURe- machine’s resolution are now so refined that it is pos- nOmics, the platform is a rich resource containing sible to classify disease severity or detect tiny muscle whole exomes and genomes of a large number of changes based on MRI analysis [1]. An electromyo- individuals with rare neuromuscular and rare renal gram can be performed using bracelet-type sensors disease. It is still growing rapidly for other RD areas to stimulate and detect muscle contraction. Muscle such as mitochondrial, neurogenetic, and immuno- pathology also benefited from technological progress logical disorders. Several thousand more datasets are to identify reliable biomarkers for disease evolution planned for submission in the coming year through and severity, with machine learning and automated submissions by Solve-RD and the European Refer- tissue pattern recognition approaches to quantify the ence Networks (ERNs), now that the platform is open muscular dystrophies, inflammation, and fat infil- for submission of data from all rare disease projects tration. The emergence of new devices to precisely [3–5]. measure and record specific outcomes such as dis- These talks presented exciting perspectives in the tance, speed, movement, and mobile application [2] NMD diagnosis, care, and management, bringing J. Pini et al. / E-Health & Innovation to Overcome Barriers in Neuromuscular Diseases 747 hope to improve patients’ quality of life, monitor- social systems (Directive 2011/24/EU : DIRECTIVE ing, and treatment. Further, all this technological 2011/24/UE DU PARLEMENT EUROPÉEN ET DU progress paved the way to new medical approaches CONSEIL du 9 mars 2011 relative à l’application in which medical care will be personalized to inte- des droits des patients en matière de soins de grate differences among people (genetic, proteomic, santé transfrontaliers, 4.4.2011 Journal officiel de metabolomics [6]), predictive to treat people the ear- l’Union européenne L 88/45). The PITEM-PROSOL liest possible, proactive, to empower patients and program triggers vulnerable populations, such as preventive to keep people informed. elderly, women (family responsibilities and a longer life prevent a proper care of themselves, and increase age-related issues), and pediatric population (adapted TOPIC 2: E-REGISTRIES – schooling to enable proper care is not always pos- TELEMEDICINE – M-HEALTH APPS sible). This project, led by Prof. Sacconi’s team in France (https://www.systeme-nerveux-peripherique- Neuromuscular diseases are rare disorders, i.e., muscle.chu-nice.fr/la-telemedecine/), aims to set with a prevalence lower than 1:2000. Usually, doc- up a telemedicine platform, and provide education tors are unfamiliar with these diseases because of the through digital tools. Patients living in the remote rarity and are unaware of such disorder’s signs and Alpine area will thus be able to consult their spe- symptoms, leading to a delayed diagnosis and med- cialized practitioner either from home or from the ical care. Further, access to care can be challenging nearest healthcare facility. Through this platform, for people with a severely debilitating disease or liv- patients, caregivers, and healthcare professionals ing far from the hospital. To counter these problems, (HCP) will also have access to educational content telemedicine appears to be a good alternative. such as e-learning and MOOCS. First, Julij Šelb discussed the results of stud- An ongoing clinical study on the French bor- ies examining the acceptance, safety, and efficiency der side ensures patients’ follow-up’s feasibility via of telemedical solutions in different NMD (i.e., teleconsultation by assessing the users’ satisfaction FSHD, ALS). Due to their physical disabilities, NMD (patients, caregivers, HCP) based on technical and patients preferred telemedicine to in-person visits, medical criteria. The platform will then be tested especially when living far from the doctor’s office for cross-border teleconsultations. The study results [7–10]. Telemedicine is also useful in 1) patients are not known yet, but this project’s success relies with advanced cancer where telemedical monitor- on technical standards to ensure interoperability and ing improved the overall patients’ survival [11]; 2) good network coverage, patient engagement, care- hypertension where the use of telemedicine was asso- givers, HCP, and continuous telemedicine services’ ciated with reductions in systolic and diastolic blood quality monitoring. To summarize, telemedicine is pressure [12]; 3) diabetes where telemedicine sig- not a regular medical practice replacement and must nificantly improves the levels of HbA1c [13] and 4) comply with the same safety and quality requirements heart failure where the use of telemedicine was asso- as in routine practice. ciated with improvements in overall mortality and Erika Schirinzi illustrated mobile applications’ heart failure-related hospitalizations [14]. Overall, growing implications in healthcare and disease man- telemedicine proves to be adequate to help to assess agement. In recent years digital technologies have diagnosis and improve patients’ medical care. generated a new relationship paradigm between clin- Pauline Lahaut presented the PITEM-PROSOL icians and patients, in different clinical settings, project to develop and experiment innovative solu- particularly in the continuity of care for patients suf- tions in the healthcare and social welfare sectors fering from chronic diseases. A mobile app, called (https://www.interreg-alcotra.eu/fr/decouvrir-alcotra AIGkit, specifically designed for adult patients with /presentation-generale-du-programme, https://www. Pompe disease, was developed as a prototype of a interreg-alcotra.eu/fr/decouvrir-alcotra/les-projets-fi high-risk frailty population, in which the phenotypic nances/pro-sol). This project is funded by the complexity requires to refine monitoring and clini- ALCOTRA Program (Alpes Latines COopération cal data collection. The aim is to provide clinicians a TRAnsfrontalière), a European program dedicated continuous tracking of each patient in real-time and to the French-Italian Cooperation to improve the real-ambient of everyday life. The app is structured as quality of life of the population, sustaining the a sort of diary, in which the patient data entered, such development of the territory, the economy, and the as respiratory parameters or motor training programs, 748 J. Pini et al. / E-Health & Innovation to Overcome Barriers in Neuromuscular Diseases are shared by synchronization with a web platform combination of specialized engineering and neuro- monitored by physicians. The app could represent physiological knowledge to set up devices able to an innovative tool for disease management, clinical apply a mere copy strategy in compensating the data collection, and the definition and evaluation of deficit and understand, translate, and model the physi- outcome measures towards trial readiness. The app ological sensorimotor synergies. When appropriately creation was supported by the Italian patients Associ- used, technological tools can integrate the con- ation of Glycogenoses (AIG) and the Italian scientific ventional therapeutic approach providing adjustable Society of Myology (SIM) and technically designed replacement supports and, when possible, targeted by Vidiemme Consulting. training systems. During this session, the talks were articulated The next topic, presented by Tina Duong, high- around telemedicine’s use and benefits to moni- lighted the application of powered clothing to tor patients’ quality of life and disease evolution improve functional mobility for Duchenne Muscu- remotely. Telemedicine seems to be a good com- lar Dystrophy (DMD) utilizing wearable technology promise between classical medical care, where the from Seismic Company that integrates robotics with patient has to come to the hospital and see different clothing to augment and support the movement. The specialists, and home care, where the medical staff design approach is based on the human kinetics’ has to go to the patient’s home. Telemedicine com- mechanics with a base garment for support, power, bines the advantages of both approaches: patients and strength through conformal textile springs, flex can receive classical medical care without going to grips to distribute the load, inertial measurement units the hospital, and medical staff can take care of the (IMU) to measure body orientation, flex anchors, patients without going to their homes. However, as and actuators for power. The Solid suit has 3 proto- telemedicine development is very recent, there are type developments: 1) Ankle stretch system for active currently some issues. For example, telemedicine set- and passive range of motion, 2) Mobility for the ting up requires technical training and equipment and trunk and hip support to improve standing stabil- reduces in-person interaction. Further, there is no ity and assisted sit to stand 3) Reach for chest and long-term hindsight on the telemedicine benefits in arm support for upper limb function. The presenta- patients’ care. To conclude, telemedicine is a promis- tion focused on the sit-to-stand prototype for DMD. ing approach to renew classical medical care, but such The suit design integrates human movement knowl- practices have not yet found their final place in the edge based on muscle imbalances from DMD disease landscape of health care. progression with a multidisciplinary team of soft- ware and mechanical engineers, industrial designer, and physical therapist. With a user-centric design TOPIC 3: ROBOTICS, DOMOTICS approach, all team members were introduced to indi- viduals with DMD, understood the disease’s clinical Recent years have seen the emergence of robotics progression, and reviewed videos for movement anal- and domotics fields, aiming to automate and facilitate ysis. All stages of early prototype testing involved daily life. When applied to medicine, these technolo- individuals with DMD as users. DMD movement pat- gies contribute to the apparition of robotic prostheses, terns were based on compensations seen in middle to exoskeleton, assistive tools, or automated solutions to late ambulatory stages of the disease. Understanding help patients with disabilities. disease progression was essential in this modular con- Gabriele Siciliano pointed out that technology- cept to address changing needs for don/doff, comfort driven assistive solutions to support patients with and mobility with disease progression. Sit-to-stand neuromuscular diseases have seen rapid development movement analysis was broken down into 7 stages in the last years. However, integrating sensors to mon- based on DMD muscle compensations with focal itor and adapt the patients’ existing motor schemes areas of assist and stabilization defined for each continuously recognizes some limits. One critical stage driving lines of action and degree of assistance point is that a fundamental background of neuro- required to reduce weight and bulk of the suit. The physiological insights is necessary to distinguish the suit objective was to augment functional movement normal and the pathological aspects of the senso- by working with compensations seen in a typical rimotor functions to help the adaptive mechanisms DMD sit-to-stand, including trunk momentum to ini- adopted by the impaired neuromuscular system. tiate movement, use of upper limbs to compensate Consequently, the assistive tool’s design requires a for hip extension weakness, and abduction of lower J. Pini et al. / E-Health & Innovation to Overcome Barriers in Neuromuscular Diseases 749 limbs. Stability was provided with significant consid- José Javier Serrano Olmedo presented the eGla- eration to not inhibit or make more difficult sitting and nce methodology, a procedure to help blind people trunk movements more difficult. Functional move- to obtain information about the physical context “at ment requires repeated movement from initiation, a glance.” With eGlance, blind users can choose the sustain of range of motion and return to baseline. physical direction to acquire data on which physi- The DMD functional apparel is an adjustable mod- cal objects are located. This augmented reality tool ular suit that allows for refinement of elements with informs in real-time blind people on the surround- motor declines based on disease progression. ing context, providing information on physical events Jean-Yves Hogrel discussed the potential exoske- or the presence of objects not accessible by hand or leton use to compensate for disability in NMD. with the white cane help. This tool has two main Since the beginning of the century, the number features: remotely visiting and real-time accompany- of studies involving exoskeletons has grown expo- ing. The interior spaces, previously virtualized as 3D nentially. Technologies evolution for compensating scenarios, can be seen and memorized from home, motor disabilities caused by varying conditions can helping people move when physically present. Fur- explain this. Exoskeletons are defined as wearable ther, if electromagnetic beacons were placed in the machines. They can be either active (implying electric room(s), blind people can visit new, unfamiliar indoor motors, pneumatics, levers, hydraulics, mechanics, areas. In a non-intrusive way, eGlance can describe or a combination of technologies) or passive (using on-demand or proactively, especially in case of risk, elastics, straps, or springs), which allow movement which objects are around, closer or further away, with increased strength or endurance. Initially, they while the user walks. It can also guide the user, if were primarily developed for military applications, requested, to specific locations [17–19]. but now they are used for industrial and medi- This session presented complex applications of cal purposes. As technical aids for neuromuscular robotics and domotics to improve patients’ quality of disorders, they can be classified into different cate- life. These applications rely on too sophisticated sen- gories, i.e., rehabilitation, substitution, and assistive sors to precisely measure body position, limb angle, devices. For rehabilitation, robot-assisted therapy or recorded physical objects location to help blind enables effective and intensive training and ensures people move. However, it is crucial to fully charac- optimal neuroplasticity and recovery potential. For terize the sensors system catching all the physical substitution, such devices replace a completely lost variables used to help patients. Indeed, such a sys- function (for example, paralysis) and act instead of tem’s reliability has to be assessed to ensure that the the person. Assistive devices partly compensate for sensors measure what it is supposed to measure. In impairments and help individuals perform compli- other terms, the system has to be accurate and reliable. cated movements. Several exoskeletons have been This can be tested, for example, by correlating move- approved to be on the market, but only in the field ment recorded by the sensors with motion analysis to of rehabilitation [15, 16]. ensure the correctness of the system Exoskeletons are required to interact with an indi- vidual. A very precise cohabitation is necessary for the device to adapt to its symptoms, morphology, TOPIC 4: CONNECTED DEVICES and abilities. In the beginning, using an exoskeleton may be costly (from a metabolic point of view) and Connected devices are tools that can help to mon- exhausting. Particularly in NMD, an individual often itor patients’ condition. While some devices are has a modified motor schema, which becomes very developed for clinical trials to precisely measure established over the years, progressively encoded in some outcomes, reduce variability or harmonize the the motor cortex to adapt to his/her impairments results, others are developed to benefit the patients (particularly muscle weakness). The interference of and assessed specific functions such as motor neu- another decision loop may add difficulties. Since the ron, ability to walk a certain distance in a defined aim is to regain mobility and independence, the bal- amount of time. Data are then wirelessly transmitted ance between benefits and risks must be carefully to a mobile application, and results can be analyzed studied. The clinical trials’ design is thus mandatory remotely by the clinician. and must assess the short, mid, and long-term safety, To illustrate the benefits of connected devices in feasibility, usability, and efficacy of such technolo- monitoring patients’ conditions, John Vissing pre- gies. sented his experience with the 6-Minute Walking 750 J. Pini et al. / E-Health & Innovation to Overcome Barriers in Neuromuscular Diseases Test (6MWT). This test is a common outcome in digital tablet, the objectives are to improve the MFM follow-up and clinical trials in patients with NMD. acceptability and reliability and improve children’s However, this test’s reliability is weakened by first participation by adding the digital assessment into a learning effect (patients push themselves further a serious game. The feasibility study assessed the once they know the test) and second a day-to-day system’s relevance to capture postures and motions variation caused by unstable motivation. Correction during an MFM test. Among the 32 items of the of performed walking distance by heart pulse rate can MFM, 14 were recognized by the Kinect, and 3 items eliminate the learning effect and weed out the day- were performed using a tablet. MFM scoring pro- to-day variation that does not reflect a real change vided by a therapist looking directly at the patients in a patient’s clinical condition [20]. Based on these was compared to MFM scoring based on the Kinect observations, the 6MWT+ project is under develop- sensor’s digital data. On 21 MFM records, a high con- ment and aimed to improve the monitoring system cordance was found between the two independent of chronic neuromuscular diseases through a mobile scorings (76%). To compare the scoring of 3 items application and the integration of biomechanical sen- using paper versus a digital tablet, a study enrolling sors into the test while providing clinicians more 100 patients was performed to report on a high or information on the disease progression. The pilot good concordance for items 18, 19, and 22 of the project integrates several sensors to evaluate walk- MFM. An ongoing step is to include the assessment ing function in patients affected by DMD, Becker into a playful scenario to improve children’s partici- muscular dystrophy, and Myotonic Dystrophy. pation [27–29]. Laurent Servais presented the story behind the This session’s talks highlighted the auspicious and European Medical Agency (EMA) approval of the powerful use of connected devices in patients’ health- 95th centile of the stride speeds, which is a digi- care, whether it be to monitor patients or the reliability tal outcomes measure. Magneto inertial technology of clinical trial results. However, two main questions offers researchers the opportunity to continuously arise from this session. First, what are the primary assess patients’ movement quantity and quality in a outcomes of connected devices? Are they made to controlled [21] and non-controlled environment [22, measure changes in patients’ condition with treat- 23]. Several challenges are associated with such mea- ment or be used as a self-rehabilitating tool? This sures: the first one is related to the quality of the sensor depends on the type and role of the devices. For and the required level of precision in the calibration example, 6MWT+ has a role in clinical trials to have to ensure reliable measures, the second is to deal with reliable and standardize results, while digital MFM real-life hazard and events, the third is to reduce the with Kinect aimed to monitor and assess patients’ amount of data provided into a single outcome that disease progression. is clinically meaningful. In DMD, the 95th centile Second, is it possible to monitor several diseases/ of the stride speeds recorded during 180 hours has functions with the same devices? Even if a device is been proven reliable, clinically meaningful, sensitive designed for a specific disease, it should be possible to change, and poorly sensitive to real-life events such to use it for another disease, provided that they are as weather or timing in the day. It has been qualified as similar and without modification. If the diseases are a valid secondary outcome by the EMA [24]. Similar too different, it should still be possible to use the same work is ongoing in non-ambulant patients and other device, but the algorithm must be adapted to the new diseases, such as Spinal Muscular Atrophy [21, 25, disease. 26], FSHD, ALS, and MS. Dominique Vincent-Genod presented on the role PITCH SESSION: WHAT IS NEW ON of connected devices to measure motor function NEUROMUSCULAR DISEASES? in patients with Spinal Muscular Atrophy (SMA). Indeed, given the progress of research and man- The last session was concentrated on the advance agement in SMA and the parallel development of on NMD knowledge. As these diseases are rare, a bet- technology in motion capture and virtual reality, ter understanding of their pathophysiology is crucial interactive and child friendly validated tools are to improve patients’ healthcare and quality of life. needed to assess patients’ motor function. The Motor Sylvie Bannwarth presented MitoDIAG, the Function Measure assessment (MFM) is a validated French network for mitochondrial diseases. Mito- and sensitive tool designed for patients with neuro- chondrial diseases are amongst the most genetically muscular disorders. Using a Microsoft Kinect and a and phenotypically diverse groups of inherited J. Pini et al. / E-Health & Innovation to Overcome Barriers in Neuromuscular Diseases 751 diseases. This heterogeneity, the vast phenotypic economic and social impact. These collected data overlap with other disease entities, and the absence will allow a characterization of the periodic paralysis of reliable biomarkers make molecular diagnosis population [38]. difficult. Mitodiag, the French network of 11 labo- Jordi Diaz-Manera presented a study in which ratories for diagnosing mitochondrial diseases, has the authors have developed a new way to guide been created to improve the diagnosis. MitoDIAG the diagnosis of muscular dystrophies, called has developed (i) a new bioinformatic tool, eKLIPse, “MYO-GUIDE.” They have developed an artificial to detect and quantify mtDNA deletions from NGS intelligence tool to analyze fat replacement patterns data [30] and (ii) a specific database, Mitomatcher, in muscle MRIs of 10 different genetically confirmed to combine phenotypic and genomic information of muscular dystrophies. In detail, they have applied French mitochondrial disease patients. a machine learning strategy using Random Forest Damien Eggenspieler talked about ActiMyo, a dig- to analyze the results of fat replacement quantifi- ital biomarker platform developed for NMD. While cation in patients’ muscles. The authors developed a very active space, drug development in rare neuro- 2000 different models and got the one with the high- muscular diseases has led to very few drug approvals est accuracy. The final model has an accuracy of in the past three decades [31]. The lack of a reliable 95% with very high specificity and sensibility val- and meaningful motor outcome, which is objective ues. When compared with human experts on the field, (limiting traditional bias like motivation & fatigue) the tool had higher accuracy than humans. In sum- and sensitive (enough to change to pick up early mary, this study demonstrates that machine learning signs of efficacy), is one factor hindering drug is useful in analyzing muscle MRIs to help guide the development. genetic diagnosis of patients with muscular dystro- The advance of digital outcome has proven its phies [39]. potential to fill this gap by providing devices to Overall, this pitch session brought exciting insight capture objective Real World motor evidence from into the next era in diagnosing and managing neuro- patients. Sysnav took the challenge to develop a holter muscular disease from patients’ and clinicians’ sides. of movement, with the appropriate level of preci- Establishing new ways to investigate neuromuscular sion & accuracy, and disease optimized outcomes. disease pathophysiology and management will allow The first outcome, Stride Velocity 95th centile, has better patient care and a faster diagnosis establish- been approved by EMA and reviewed by the FDA ment. It is critical to use the latest progress in artificial for ambulant patients living with DMD. New partner- intelligence and machine learning to design new tools ships & collaborations with leading institution & drug to improve patients’ quality of life. developers are starting to qualify outcomes beyond DMD and expand the benefits to other diseases and CONCLUSIONS with both ambulant & non-ambulant patients. Savine Vicart showed the design of a clinical and By their rarity, many patients with NMD experi- medico-economic national study involving an m- ence a long diagnostic odyssey or are misdiagnosed, health monitoring tool on a rare disease cohort on leading to inadequate care or treatment. No cure periodic paralysis (RaDiCo-PP). Periodic paralysis is exists for these diseases, although significant progress a rare disease characterized by episodic muscle weak- was made in recent years. NMD management is also ness attacks. The collection of information necessary complicated by multi-system involvement of disease for patient follow-up and therapeutic adaptations and inconsistent standards of care with annual or is complicated because of the symptoms’ episodic bi-annual basis patient visits. These visits do not nec- and variable expression [32–35]. Patients struggle to essarily reflect the patient’s health state in between report the characteristics of their crisis accurately. clinic visits. With evolving technology, there is still Presently, there is no validated tool to assess para- a gap in the technological resources to decrease care lytic attacks in a standardized way. Physical disability management burdens, leading to the need for family during attacks directly impacts the social and profes- or caregiver assistance to perform daily living activi- sional life of patients and caregivers [36, 37]. ties. There is a real need to improve and introduce They proposed a clinical trial to study the fea- new technologies and innovations to complement sibility, acceptability, and utility of a smartphone patients’ classical medical care (Fig. 1). application to collect, in real-time, precise and During this meeting, many promising approaches comparable data and evaluated the disease’s medico- were shown to improve patients’ management and 752 J. Pini et al. / E-Health & Innovation to Overcome Barriers in Neuromuscular Diseases Fig. 1. Patients’ unmet needs and potential solutions using innovative technologies. quality of life, ranging from telemedicine to mobile CONFLICTS OF INTERESTS applications to avoid unnecessary patient travel for clinic visits that do not require physical examinations. T. Duong received consultancy and advisory Technological advances may decrease caregiver boards from Solid Bio, Biogen, Sarepta, Roche, and burden, increase patient autonomy with robotic Novartis. prostheses or powered clothing. However, these J.Y. Hogrel received consultancy fees from Biogen, applications will only reach their full potential when Minoryx, and Sarepta. we will provide access to these innovations to all L. Servais received consultancy from Biogen, Nov- patients. Indeed, patients’ do not have to search for artis, Roche, Santhera, Sarepta, RegenexBio, Pfizzer, innovations, but innovations have to reach them. Affinia, Dynacure. He chairs the DSMB of Lupin and Discussions at the meeting attempted to address Fibrogen translation of innovation to patients by increasing J. Vissing has received consultancy fees from clinicians’ awareness of the disease, its symptoms, Argenx, Roche, Viela Bio, Biogen, Amicus Thera- how to manage it, and up to date on the recent peutics, Genethon, PTC Therapeutics, Sanofi/Gen- technological advancements. This can be done with zyme, Ultragenyx Pharmaceutical, Fulcrum Thera- innovative tools such as mobile applications and peutics, ML Bio Solutions, Sarepta Therapeutics, congresses such as this one. Sharing information is Novartis Pharma AG, Stealth Biotherapeutics, crucial to improve patients’ wellness and transform Zogenix, Regeneron, UCB Pharma, Viela Bio, Lund- the way medical practices are done today: shifting beck Pharma, and Lupin Limited. from the classical medical care to an anticipator per- S. Sacconi served as a consultant for Sanofi-Ge- sonalized medicine care paradigm to avoid delay in nzyme. diagnosis and long term preventative healthcare. All other authors declare no conflict of interests. With this meeting, NMD specialists and inno- vations experts convened to build a community to contribute to the world-wide effort to improve ACKNOWLEDGMENTS patients care outcomes, quality of life, disease assess- ment, and monitoring, with a particular effort on the We would like to thank the University Hospi- development of new tools to help to diagnose; assess tal of Nice for hosting the congress, the Centre and monitor NMD. d’Innovation et d’Usages en Santé for their precious J. Pini et al. / E-Health & Innovation to Overcome Barriers in Neuromuscular Diseases 753 help in the organization of the whole event, the Euro- Patient-Reported Outcomes for Symptom Monitoring Dur- pean Reference Network for Neuromuscular Disease ing Routine Cancer Treatment. JAMA. 2017;318:197-8. https://doi.org/10.1001/jama.2017.7156. (ERN Euro-NMD), and the City of Nice for their [12] Tucker KL, Sheppard JP, Stevens R, Bosworth HB, help in the achievement of this event. We would Bove A, Bray EP, et al. 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