Real-world multidisciplinary outcomes of onasemnogene abeparvovec monotherapy in patients with spinal muscular atrophy type 1: experience of the French cohort in the first three years of treatment.

BACKGROUND: Spinal muscular atrophy type 1 (SMA1) is the most severe and early form of SMA, a genetic disease with motor neuron degeneration. Onasemnogene abeparvovec gene transfer therapy (GT) has changed the natural history of SMA1, but real-world data are scarce. METHODS: A French national expert committee identified 95 newly diagnosed treatment-naive SMA1 patients between June 2019 and June 2022. We prospectively report on children treated with GT as the first and only therapy who had more than one-year of follow-up. RESULTS: Forty-six SMA1 patients received GT. Twelve patients received other treatments. Patients with respiratory insufficiency were oriented toward palliative care after discussion with families. Twenty-nine of the treated patients with more than 12 months of follow-up were included in the follow-up analysis. Among them, 17 had 24 months of follow-up. The mean age at treatment was 7.5 (2.1-12.5) months. Twenty-two patients had two SMN2 copies, and seven had three copies. One infant died in the month following GT due to severe thrombotic microangiopathy, and another died due to respiratory distress. Among the 17 patients with 24 months of follow-up, 90% required spinal bracing (15/17), three patients required nocturnal noninvasive ventilation, and two needed gastrostomy. Concerning motor milestones at the 24-month follow-up, all patients held their head, 15/17 sat for 30 s unassisted, and 12/17 stood with aid. Motor scores (CHOPINTEND and HINE-2) and thoracic circumference significantly improved in all patients. CONCLUSIONS: Our study shows favorable motor outcomes and preserved respiratory and feeding functions in treatment-naive SMA1 infants treated by GT as the first and only therapy before respiratory and bulbar dysfunctions occurred. Nevertheless, almost all patients developed spinal deformities.

Polysomnography findings and respiratory muscle function in infants with early onset spinal muscular atrophy after gene replacement as monotherapy: A prospective study.

BACKGROUND: Gene replacement therapy (onasemnogene abeparvovec) is associated with an improvement of the prognosis of children with spinal muscular atrophy, but information on long-term respiratory outcome is scarce. The aim of this study was to report the polysomnography findings and respiratory muscle function of infants with treatment-naive spinal muscular atrophy type 1 and 2 up to 24 months after onasemnogene abeparvovec monotherapy. METHODS: A clinical and motor evaluation, respiratory muscle function testing, and polysomnography were performed repeatedly. RESULTS: Fifteen spinal muscular atrophy patients (1 presymptomatic, 7 type 1b, 6 type 1c, and 1 type 2) were included at a median age of 8.6 months (range 3.8-12.6) and followed for 24 months. The thoracic over head circumference ratio was close to normal at baseline (median 1.00 (range 0.90-1.05)) and increased significantly over time. All polysomnography and nocturnal gas exchange parameters were within normal ranges at baseline (median apnea-hypopnea index 2.5 events/hour (range 0.4-5.3)) and follow-up. The inspiratory muscle strength was normal at baseline but tended to slightly decrease over time and the expiratory muscle strength was low at any time especially for patients with recurrent respiratory infections (median (range) at baseline in cmH2O: crying esophageal pressure 54 (30-110), crying transdiaphragmatic pressure 65 (35-107), gastric pressure during maximal cough 26 (10-130), esophageal pressure during maximal cough 61 (38-150)). Only 3 patients required noninvasive ventilation. CONCLUSION: A continuous respiratory monitoring of spinal muscular atrophy patients during the first years of life following onasemnogene abeparvovec monotherapy seems recommended despite the normality of polysomnography parameters.

Vitamin deficiencies in children: Lessons from clinical and neuroimaging findings.

BACKGROUND AND AIMS: Water-soluble vitamins play an essential coenzyme role in the nervous system. Acquired vitamin deficiencies are easily treatable, however, without treatment, they can lead to irreversible complications. This study aimed to provide clinical, laboratory parameters and neuroimaging data on vitamin deficiencies in an attempt to facilitate early diagnosis and prompt supplementation. METHODS: From July 1998 to July 2023, patients at Necker-Enfants-Malades Hospital presenting with acute neurological symptoms attributed to acquired vitamin deficiency were included. Clinical data were extracted from Dr Warehouse database. Neuroimaging, biochemical and electrophysiological data were reviewed. RESULTS: Patients with vitamin B1 deficiency exhibited abnormal eye movements (n = 4/4), fluctuations in consciousness (n = 3/4), and ataxia (n = 3/4). Brain MRI showed alterations of fourth ventricle region (n = 4/4), periaqueductal region (n = 4/4), tectum (n = 3/4), and median thalami (n = 3/4). Patients with vitamin B2 deficiency presented with early onset hypotonia (n = 3/4), hyperlactatemia (n = 4/4), and hyperammonemia (n = 4/4). Plasma acylcarnitines revealed a multiple acyl-coA dehydrogenase deficiency-like profile (n = 4/4). In vitamin B12 deficiency, young children presented with developmental delay (n = 7/7) and older children with proprioceptive ataxia (n = 3/3). Brain MRI revealed atrophy (n = 7/7) and spinal MRI hyperintensity in posterior cervical columns (n = 3/3). Metabolic findings showed elevated methylmalonic acid (n = 6/7) and hyperhomocysteinemia (n = 6/7). Patients with vitamin C deficiency exhibited gait disturbances and muscle weakness (n = 2/2). CONCLUSIONS: Acquired vitamin deficiencies may display reversible clinical symptoms mimicking inherited metabolic disorders. Some situations raise suspicion for diagnosis: concordant clinical presentation, suggestive neuroimaging findings, and/or biochemical evidence. Any acute neurological condition should be treated without waiting for definitive biochemical confirmation.

JAK Inhibition in Aicardi-Goutières Syndrome: a Monocentric Multidisciplinary Real-World Approach Study.

The paradigm type I interferonopathy Aicardi-Goutières syndrome (AGS) is most typically characterized by severe neurological involvement. AGS is considered an immune-mediated disease, poorly responsive to conventional immunosuppression. Premised on a chronic enhancement of type I interferon signaling, JAK1/2 inhibition has been trialed in AGS, with clear improvements in cutaneous and systemic disease manifestations. Contrastingly, treatment efficacy at the level of the neurological system has been less conclusive. Here, we report our real-word approach study of JAK1/2 inhibition in 11 patients with AGS, providing extensive assessments of clinical and radiological status; interferon signaling, including in cerebrospinal fluid (CSF); and drug concentrations in blood and CSF. Over a median follow-up of 17 months, we observed a clear benefit of JAK1/2 inhibition on certain systemic features of AGS, and reproduced results reported using the AGS neurologic severity scale. In contrast, there was no change in other scales assessing neurological status; using the caregiver scale, only patient comfort, but no other domain of everyday-life care, was improved. Serious bacterial infections occurred in 4 out of the 11 patients. Overall, our data lead us to conclude that other approaches to treatment are urgently required for the neurologic features of AGS. We suggest that earlier diagnosis and adequate central nervous system penetration likely remain the major factors determining the efficacy of therapy in preventing irreversible brain damage, implying the importance of early and rapid genetic testing and the consideration of intrathecal drug delivery.

Limitations of the apnea-hypopnea index in children and young adults with neuromuscular disorders.

There are no validated criteria to initiate noninvasive ventilation (NIV) in children and young adults with neuromuscular disease (NMD). In order to analyze NIV initiation criteria, we reviewed the polysomnography (PSG) criteria that led to the initiation of NIV in 61 consecutive patients with NMD, median age 4.1 (0.8-21) years, who had a PSG during their routine care. NIV was initiated on abnormal PSG data (apnea-hypopnea index (AHI) > 10 events/h and/or a transcutaneous carbon dioxide pressure > 50 mmHg and/or a pulse oximetry 〈 90%, both during at least 2% sleep time or 〉 5 consecutive minutes) in 11 (18%) patients. Six of these 11 patients had an AHI ≤ 10 events/h and would not have been ventilated if only AHI was retained. However, one of these 6 patients had isolated nocturnal hypoxemia, 3 isolated nocturnal hypercapnia and 2 abnormal respiratory events. Six (10%) patients with a normal PSG were started on NIV on clinical criteria. Our results show the limitation of the AHI when taken as the unique PSG criterion for NIV initiation in young patients with NMD and underline the need to include also abnormalities of overnight gas exchange into the NIV decision-making process.

Preventing falls: the use of machine learning for the prediction of future falls in individuals without history of fall.

Nowadays, it becomes of paramount societal importance to support many frail-prone groups in our society (elderly, patients with neurodegenerative diseases, etc.) to remain socially and physically active, maintain their quality of life, and avoid their loss of autonomy. Once older people enter the prefrail stage, they are already likely to experience falls whose consequences may accelerate the deterioration of their quality of life (injuries, fear of falling, reduction of physical activity). In that context, detecting frailty and high risk of fall at an early stage is the first line of defense against the detrimental consequences of fall. The second line of defense would be to develop original protocols to detect future fallers before any fall occur. This paper briefly summarizes the current advancements and perspectives that may arise from the combination of affordable and easy-to-use non-wearable systems (force platforms, 3D tracking motion systems), wearable systems (accelerometers, gyroscopes, inertial measurement units-IMUs) with appropriate machine learning analytics, as well as the efforts to address these challenges.

An opinion paper on the maintenance of robustness: Towards a multimodal and intergenerational approach using digital twins.

The increasing number of frail elderly people in our aging society is becoming problematic: about 11% of community-dwelling older persons are frail and another 42% are pre-frail. Consequently, a major challenge in the coming years will be to test people over the age of 60 years to detect pre-frailty at the earliest stage and to return them to robustness using the targeted interventions that are becoming increasingly available. This challenge requires individual longitudinal monitoring (ILM) or follow-up of community-dwelling older persons using quantitative approaches. This paper briefly describes an effort to tackle this challenge. Extending the detection of the pre-frail stages to other population groups is also suggested. Appropriate algorithms have been used to begin the tracing of faint physiological signals in order to detect transitions from robustness to pre-frailty states and from pre-frailty to frailty states. It is hoped that these studies will allow older adults to receive preventive treatment at the correct institutions and by the appropriate professionals as early as possible, which will prevent loss of autonomy. Altogether, ILM is conceived as an emerging property of databases ("digital twins") and not the reverse. Furthermore, ILM should facilitate a coordinated set of actions by the caregivers, which is a complex challenge in itself. This approach should be gradually extended to all ages, because frailty has no age, as is testified by overwork, burnout, and post-traumatic syndrome.

Template-DTW based on inertial signals: Preliminary results for step characterization.

In this paper, we present a method for the creation of a library of inertial signals based on Dynamic Time Warping (DTW) for step characterization, with preliminary results in control subjects and patients with neurological diseases. Subjects performed a protocol including a 10 m straight walking, then turn back and walking for additional 10 m. The library is constructed with inertial signals (acceleration and angular velocities recorded in three directions) aligned with the DTW. Templates in the library are obtained for a specific cohort and for the different walking phases of the protocol. They are compared to the signal of a single subject by calculating a Pearson correlation coefficient. The method has been tested on a database of 864 exercises, obtained from 71 healthy controls, 24 patients with Parkinson disease and 48 patients with Radiation Induced Leukoencephalopathy (RIL). Pearson correlation classification reports a precision of about 85% for step detection. For exercise characterization the sensitivity is about 57%, 56% and 82% for Parkinson, RIL and control subjects respectively.

Inertial Sensors to Assess Gait Quality in Patients with Neurological Disorders: A Systematic Review of Technical and Analytical Challenges.

Gait disorders are major causes of falls in patients with neurological diseases. Understanding these disorders allows prevention and better insights into underlying diseases. InertiaLocoGraphy (ILG) -the quantification of gait by using inertial measurement units (IMUs) -shows great potential to address this public health challenge, but protocols vary widely and normative values of gait parameters are still unavailable. This systematic review critically compares ILG protocols, questions features extracted from inertial signals and proposes a semeiological analysis of clinimetric characteristics for use in neurological clinical routine. For this systematic review, PubMed, Cochrane and EMBASE were searched for articles assessing gait quality by using IMUs that were published from January 1, 2014 to August 31, 2016. ILG was used to assess gait in a wide range of neurological disorders - including Parkinson disease, mild cognitive impairment, Alzheimer disease, cerebral palsy, and cerebellar atrophy - as well as in the faller or frail older population and in people presenting rheumatological pathologies. However, results have not yet been driving changes in clinical practice. One reason could be that studies mainly aimed at comparing pathological gait to healthy gait, but there is stronger need for semiological descriptions of gait perturbation, severity or prognostic assessment. Furthermore, protocols used to assess gait using IMUs are too many. Likely, outcomes are highly heterogeneous and difficult to compare across large panels of studies. Therefore, homogenization is needed to foster the use of ILG to assess gait quality in neurological routine practice. The pros and cons of each protocol are emphasized so that a compromise can be reached. As well, analysis of seven complementary clinical criteria (springiness, sturdiness, smoothness, steadiness, stability, symmetry, synchronization) is advocated.

Observational Study of 180° Turning Strategies Using Inertial Measurement Units and Fall Risk in Poststroke Hemiparetic Patients.

OBJECTIVE: We analyzed spontaneous 180° turning strategies in poststroke hemiparetic patients by using inertial measurement units (IMUs) and the association of turning strategies with risk of falls. METHODS: We included right paretic (RP) and left paretic (LP) post-stroke patients, and healthy controls (HCs) from a physical and rehabilitation department in France between July 2015 and October 2015. All subjects were right-handed and right-footed for mobilization tasks. Participants were instructed to turn 180° in a self-selected direction after a 10-m walk while wearing three IMUs on their trunk and both feet. We defined three turning patterns based on the number of external steps (pattern I = 1; II = 2-4 steps; and III ≥ 5) and four turning strategies based on the side chosen to turn (healthy or paretic) and the stance limb used during the first step of the turn (healthy or paretic). Falls in the 6 months after measurement were investigated. RESULTS: We included 17 RP [mean (SD) age 57.5 (9.5) years (range 43-73)], 20 LP patients [mean age 60.7 (8.8) years (range 43-63)], and 15 HCs [mean age 56.7 (16.1) years (range 36-83)]. The LP and RP groups behaved similarly in turning patterns, but 90% of LP patients turned spontaneously to the paretic side versus 59% of RP patients. This difference increased with turning strategies: 85% of LP versus 29% of RP patients used strategy 4 (paretic turn side with paretic limb). Patients using strategy 4 had the highest rate of falls. CONCLUSION: We propose to consider spontaneous turning strategies as new indicators to evaluate the risk of fall after stroke. IMU could be routinely used to identify this risk and guide balance rehabilitation programs.

Kinetics of gravity-driven water channels under steady rainfall.

We investigate the formation of fingered flow in dry granular media under simulated rainfall using a quasi-two-dimensional experimental setup composed of a random close packing of monodisperse glass beads. Using controlled experiments, we analyze the finger instabilities that develop from the wetting front as a function of fundamental granular (particle size) and fluid properties (rainfall, viscosity). These finger instabilities act as precursors for water channels, which serve as outlets for water drainage. We look into the characteristics of the homogeneous wetting front and channel size as well as estimate relevant time scales involved in the instability formation and the velocity of the channel fingertip. We compare our experimental results with that of the well-known prediction developed by Parlange and Hill [D. E. Hill and J. Y. Parlange, Soil Sci. Soc. Am. Proc. 36, 697 (1972)]. This model is based on linear stability analysis of the growth of perturbations arising at the interface between two immiscible fluids. Results show that, in terms of morphology, experiments agree with the proposed model. However, in terms of kinetics we nevertheless account for another term that describes the homogenization of the wetting front. This result shows that the manner we introduce the fluid to a porous medium can also influence the formation of finger instabilities. The results also help us to calculate the ideal flow rate needed for homogeneous distribution of water in the soil and minimization of runoff, given the grain size, fluid density, and fluid viscosity. This could have applications in optimizing use of irrigation water.