Acceptability, validity and responsiveness of inertial measurement units for assessing motor recovery after gene therapy in infants with early onset spinal muscular atrophy: a prospective cohort study

Abstract

Background: Onasemnogene abeparvovec gene replacement therapy (GT) has changed the prognosis of patients with spinal muscular atrophy (SMA) with variable outcome regarding motor development in symptomatic patients. This pilot study evaluates acceptability, validity and clinical relevance of Inertial Measurement Units (IMU) to monitor spontaneous movement recovery in early onset SMA patients after GT.

Methods: Clinical assessments including CHOPINTEND score (the gold standard motor score for infants with SMA) and IMU measurements were performed before (M0) and repeatedly after GT. Inertial data was recorded during a 25-min spontaneous movement task, the child lying on the back, without (10 min) and with a playset (15 min) wearing IMUs. Two commonly used parameters, norm acceleration 95th centile (||A||_95) and counts per minute (||A||_CPM) were computed for each wrist, elbow and foot sensors.

Results: 23 SMA-patients were included (mean age at diagnosis 8 months [min 2, max 20], 19 SMA type 1, three type 2 and one presymptomatic) and 104 IMU-measurements were performed, all well accepted by families and 84/104 with a good child participation (evaluated with Brazelton scale). ||A||_95 and ||A||_CPM showed high internal consistency (without versus with a playset) with interclass correlation coefficient for the wrist sensors of 0.88 and 0.85 respectively and for the foot sensors of 0.93 and 0.91 respectively. ||A||_95 and ||A||_CPM were strongly correlated with CHOPINTEND (r for wrist sensors 0.74 and 0.67 respectively and for foot sensors 0.61 and 0.68 respectively, p-values < 0.001). ||A||_95 for the foot, the wrist, the elbow sensors and ||A||_CPM for the foot, the wrist, the elbow sensors increased significantly between baseline and the 12 months follow-up visit (respective p-values: 0.004, < 0.001, < 0.001, 0.006, < 0.001, < 0.001).

Conclusion: IMUs were well accepted, consistent, concurrently valid, responsive and associated with unaided sitting acquisition especially for the elbow sensors. This study is the first reporting a large set of inertial sensor derived data after GT in SMA patients and paves the way for IMU-based follow-up of SMA patients after treatment.

Keywords: Gene therapy; Inertial measurement unit; Infants; Neuromuscular disease; Quantitative movement analysis; Spinal muscular atrophy; Wearable sensors.

Fig. 1

Schematic representation of the IMU-measurement protocol. One measurement was made of 3 acquisitions. Acquisition 1: participant lying on the back wearing 4 IMUs on both wrist and both feet without a playset for 10 min (left illustration). Acquisition 2: participant lying on the back wearing 4 IMUs on both wrist and both feet with a playset for 10 min (middle illustration). Acquisition 3: participant lying on the back wearing 4 IMUs on both wrist and both elbows with a playset for 5 min (right illustration). The total measurement duration was 25 min. IMU: Inertial Measurement Unit

Fig. 2

Typical norm acceleration raw data as a function of time for acquisition 1 for one SMA type 1 infant before gene therapy (M0) and 3, 6, 12 and 24 months (M3, M6, M12, M24) after gene therapy for the left wrist sensor (A/) and for the left foot sensor (B/). Sampling frequency is 100 Hz. Corresponding movement counts computed for the norm acceleration with Neishaboury et al. 2022 [35] open Python library with 60 s epochs length for the left wrist sensor (C/) and for the left foot sensor (D/). The horizontal grey dashed lines represent the norm acceleration 95th centile for each measurement (M0, M3, M6…) in graphic A/ and B/ and the mean of movement counts for each measurement (M0, M3, M6…) in graphic C/ and D/. Note the visual increase of the norm of the acceleration and of the computed parameters with time. IMU: Inertial Measurement Unit; SMA: spinal muscular atrophy

Fig. 3

Internal consistency between ||A||_95 computed on the wrist sensors (A/) and on the foot sensors (B/) between acquisition 1 (without playset) and acquisition 2 (with playset) and for the wrist sensor between acquisition 2 and acquisition 3 (with playset and with elbow sensors) (C/). Internal consistency between ||A||_CPM computed on the wrist sensors (D/) and on the foot sensors (E/) between acquisition 1 (without playset) and acquisition 2 (with playset) and for the wrist sensor between acquisition 2 and acquisition 3 (with playset and with elbow sensors) (F/). ICC are given for each plot. All 104 IMU-measurements were included in this analysis. ICC: interclass correlation coefficient. ||A||_95: Norm acceleration 95th centile; ||A||_CPM: Mean counts per minute computed on the norm acceleration

Fig. 4

||A||_95 (6 top plots) and ||A||_CPM (6 bottom plots) as a function of age (left column), CHOP-INTEND score (middle column) and median CMAP (right column) for wrist (first and third lines) and foot sensors (second and fourth lines). Points of the same patient are linked by lines. Dashed lines with empty circles represent SMA type 1 patients with 2 SMN2 copies, continuous lines with filled circles represent SMA type 1 patients with 3 SMN2 copies, squares with continuous lines represent SM1 type 2 patients and stars with continuous lines represent the presymptomatic patient. A hundred and four IMU-measurements were available with the age of the patients (left column). Ninety-eight IMU-measurements were available with CHOPINTEND (middle column). Sixty three IMU-measurements were available with CMAP evaluations (right column). SMA: Spinal Muscular Atrophy; ||A||_95: Norm acceleration 95th centile; ||A||_CPM: Mean counts per minute computed on the norm acceleration; CMAP: compound muscle action potential

Fig. 5

||A||_95 and ||A||_CPM for foot (acquisition 1), wrist (acquisition 1) and elbow (acquisition 3) sensors represented in mean and standard deviation for 15 patients with available data at baseline before gene replacement therapy (M0) and the 12 month follow-up visit (M12). * for p-values < 0.05 (paired student t-test). ||A||_95: Norm acceleration 95th centile. ||A||_CPM: Mean counts per minute computed on the norm acceleration