Spinal Muscular Atrophy Type I Research Articles

Electrical impedance tomography detects changes in ventilation after airway clearance in spinal muscular atrophy type I

The effect of mechanical insufflation-exsufflation (MIE) for airway clearance in patients with spinal muscular atrophy type I (SMA‐I) on the distribution of ventilation in the lung is unknown, as is the duration of its beneficial effects. A pilot study to investigate the feasibility of using three dimensional (3-D) electrical impedance tomography (EIT) images to estimate lung volumes pre- and post-MIE for assessing the effectiveness of mechanical insufflation-exsufflation (MIE) was conducted in 6 pediatric patients with SMA‐I in the neuromuscular clinic at Children's Hospital Colorado. EIT data were collected before, during, and after the MIE procedure on two rows of 16 electrodes placed around the chest. Lung volumes were computed from the images and compared before, during, and after the MIE procedure to assess the ability of EIT to estimate changes in lung volume during insufflation and exsufflation. Images of pulsatile pulmonary perfusion were computed in subjects able to perform breath-holding. In four of the six subjects, lung volumes during tidal breathing increased after MIE (average change from pre to post MIE was 58.8±55.1 mL). The time-dependent plots of lung volume computed from the EIT data clearly show when the MIE device insufflates and exsufflates air and the rest periods between mechanical coughs. Images of pulmonary pulsatile perfusion were computed from data collected during breathing pauses. The results suggest that EIT holds promise for estimating lung volumes and ventilation/perfusion mismatch, both of which are useful for assessing the effectiveness of MIE in clearing mucus plugs.

PRO67 The Use of Vignettes to Derive Health Utilities for Spinal Muscular Atrophy Type I (SMA-I)

Spinal muscular atrophy type I (SMA-I) is a rare genetic condition usually diagnosed before 6 months of age. Health utilities are required to evaluate the economic impact of treatments for SMA-I. However, it is impossible for these to be derived directly from affected children. The aim of this study was to derive SMA-I health utilities via vignettes. Participants were presented with 4 vignettes describing SMA-I health states that differed in levels of severity: 1. Permanent Assisted Ventilation (PAV); 2. Non-sitting; 3. Sitting; and 4. Walking. Participants were asked to imagine themselves as parents to a child with SMA. For each vignette participants first determined whether the state was worse than death (WTD) using a visual analogue scale (VAS) (range: -100 to 100). Health state utilities were then captured using time trade-off (TTO) and standard gamble (SG). Task wording was varied depending on whether the state was rated WTD. The study was completed online with a representative sample of the UK adult population. 321 participants completed the study (age: 18-65; 49.7% females). Mean health state utilities for TTO were: -0.0243 [PAV, 95% confidence interval: -0.0914, 0.0428]; -0.0264 [Non-sitting, -0.0966, 0.0438]; 0.0977 [Sitting, 0.0291, 0.1664]; 0.3844 [Walking, 0.3225, 0.4463]. For the SG: 0.0028 [-0.0611, 0.0677], 0.0139 [-0.0505, 0.0783], 0.0946 [0.0302, 0.1591] and 0.3782 [0.3176, 0.4388]. The least severe health state (“Walking”) differed significantly from the other three states (p<0.0001). Mean utilities were not statistically significant for the worst 2 health states. Mean health state utilities differed in line with severity of SMA-I. Although participants were not able to discriminate between the two worst health states, this, and the relatively low spread between mean utilities reflect the severity of SMA. These results contribute to a growing body of utility data for use in economic models of SMA treatments.

Predictive energy equations for spinal muscular atrophy type I children

Knowledge on resting energy expenditure (REE) in spinal muscular atrophy type I (SMAI) is still limited. The lack of a population-specific REE equation has led to poor nutritional support and impairment of nutritional status. To identify the best predictors of measuredREE (mREE) among simple bedside parameters, to include these predictors in population-specific equations, and to compare such models with the commonpredictive equations. Demographic, clinical, anthropometric, and treatment variables were examined as potential predictors of mREE by indirect calorimetry (IC) in 122 SMAI children consecutively enrolled in an ongoing longitudinal observational study. Parameters predicting REE were identified, and prespecified linear regression models adjusted for nusinersen treatment (discrete: 0=no; 1=yes) were used to develop predictive equations, separately in spontaneously breathing and mechanically ventilated patients. In naïve patients, the median (25th, 75th percentile) mREE was 480 (412, 575) compared with 394 (281, 554) kcal/d in spontaneously breathing and mechanically ventilated patients, respectively (P=0.009).In nusinersen-treated patients, the median (25th, 75th percentile) mREE was 609 (592, 702) compared with 639 (479, 723) kcal/d in spontaneously breathing and mechanically ventilated patients, respectively (P=0.949).Both in spontaneously breathing and mechanically ventilated patients, the best prediction of REE was obtained from 3 models, all using as predictors: 1 body size related measurement and nusinersen treatment status. Nusinersen treatment was correlated with higher REE both in spontaneously breathing and mechanically ventilated patients. The population-specific equations showed a lower interindividual variability of the bias than the other equation tested, however, they showed a high root mean squared error. We demonstrated that ventilatory status, nusinersen treatment, demographic, and anthropometric characteristics determine energy requirements in SMAI. Our SMAI-specific equations include variables available in clinical practice and were generally more accurate than previously published equations. At the individual level, however, IC is strongly recommended for assessing energy requirements. Further research is needed to externally validate these predictive equations.

CONGENITAL MYOPATHIES (CNM): P.138The CHOP INTEND scale (Children's Hospital of Philadelphia infant test of neuromuscular disorders) in X-linked myotubular myopathy: content validity and psychometric performance

XLMTM is a rare, congenital neuromuscular disorder characterized by extreme hypotonia, respiratory failure, and premature death. The CHOP INTEND is a measurement tool developed to assess motor function in patients with spinal muscular atrophy type I (SMAI), and successfully used in clinical trials to assess treatment response. As SMA I patients have a similar phenotype to infants with XLMTM, this study evaluated the CHOP INTEND as a measure of motor function in children with XLMTM. A literature review and qualitative interviews were completed (11 clinical experts, 5 caregivers); findings were used to determine content validity and develop a conceptual model of XLMTM, which were also assessed in a Delphi panel (7 clinical experts). Inter-rater reliability was evaluated among 15 physical therapists, with agreement between the ratings assessed based on independent review of videotaped assessments. The conceptual model of XLMTM includes body function and structural impairments (neuromuscular, pulmonary, musculoskeletal, gastrointestinal), as well as disease impacts (development skills, activities of daily living, caregiver burden). Concepts related to motor function map to most CHOP INTEND items. Caregiver descriptions of their child's function also align with items evaluated in the CHOP INTEND. The Delphi panel achieved consensus on the conceptual model of XLMTM and the appropriateness of the CHOP INTEND to assess motor function in XLMTM. Finally, the inter-rater reliability was supported with an intraclass correlation coefficient of 0.938 (95% CI: .902-.965). Results from this study suggest that the CHOP INTEND is a valid and reliable assessment tool for children with XLMTM, and support the appropriateness of its use in the ASPIRO gene therapy clinical trial as a co-primary endpoint. Next steps include evaluation of the psychometric performance of the CHOP INTEND in this population.

Matching pairs difficulty in children with spinal muscular atrophy type I

This study aimed to investigate the performance on pair-matching tasks in children with Spinal Muscular Atrophy type I (SMA-I) and the relationship between this performance and motor function, functional independence and quality of life. SMA-I (n = 12; 6.0 ± 2.3 yrs; 9 boys, 3 girls) and control sex-, age-matched children (n = 12; 6.2 ± 2.6 yrs) performed four pair-matching figure, number and letter tasks. The eye tracker detected eye movements. SMA-I children were assessed with CHOP INTEND, Pediatric Evaluation of Disability Inventory, and Pediatric Quality of Life Inventory. Analysis of variance showed that SMA-I children had a lower percentage of correct answers and longer timed performance compared to controls (p < 0.05). Pediatric Evaluation of Disability Inventory score (social function domain) was correlated to the percentage of correct answers on the pair-matching tasks on task 1 (r = 0.81; p = 0.001) and task 2 (r = 0.66; p = 0.020). Pair-matching performance of SMA-I children was poorer than the performance of control children. There was a relationship between pair-matching performance and social function. The restricted interaction with the environment, due to severe paralysis and poor verbal communication, is associated with cognitive difficulties in SMA-I children. The eye tracker was helpful in cognitive assessment of SMA-I children, who responded to the cognitive tests with eye movements.

Spinal Muscular Atrophy Type I

The natural history of spinal muscular atrophy type I (SMA-I) has changed as improved medical support has become available. With investigational drugs for spinal muscular atrophy now in clinical trials, efficient trial design focuses on enrolling recently diagnosed infants, providing best available supportive care, and minimizing subject variation. The quandary has arisen whether it is ethically appropriate to specify a predefined level of nutritional and/or ventilation support for spinal muscular atrophy type I subjects while participating in these studies. We conducted a survey at 2 spinal muscular atrophy investigator meetings involving physician investigators, clinical evaluators, and study coordinators from North America, Europe, and Asia-Pacific. Each group endorsed the concept that having a predefined degree of nutritional and ventilation support was warranted in this context. We discuss how autonomy, beneficence/non-maleficence, noncoercion, social benefit, and equipoise can be maintained when a predefined level of supportive care is proposed, for participation in a clinical trial.

Early disruption of neurovascular units and microcirculatory dysfunction in the spinal cord in spinal muscular atrophy type I

Spinal muscular atrophy type I (SMA-I) is characterized by progressive muscle weakness with onset in early infancy, usually resulting in mortality before two years of age. However, the processes underlying the pathophysiological progression of the disease remain unclear. Prior to the onset of muscle weakness, a regression of local capillaries is observed along with motor neuron loss. Local populations of neurons, astrocytes, and vascular endothelial cells constitute a neurovascular unit (NVU), in which neuronal and synaptic metabolism is tightly coupled to capillary blood flow by astrocyte-mediated vasodilatory control. We hypothesize that survival motor neuron protein deficiency and initial neuronal dysfunction leads to the regression of vascular beds and the disruption of NVU function. As a result, local capillary blood flow becomes insufficient, leading to metabolic stress in neurons, endothelial cells, pericytes, and astrocytes, ultimately disrupting the astrocytic regulation of capillaries. This pathogenic process may accelerate the loss of anterior horn motor neurons, leading to the further regression of capillaries and astroglial dysfunction. Hypocapnia, resulting from dehydration and hyperventilation during therapeutic manual ventilation, might further damage the NVU. Moreover, disruption of the microcirculation may affect sympathetic and sensory neurons in the spinal cord, contributing to sympathetic hyperactivity and sensory nerve degeneration, respectively. These mutually reinforcing processes may underlie the progression of muscle weakness during infancy in SMA-I. Therefore, disruption of the NVU and a stressful neurovascular environment in the anterior horn may play important roles in disease initiation and/or progression in SMA-I. The NVU is therefore a critical therapeutic target for treating SMA-I. Our hypothetical model may provide insight into why most neuroprotective strategies that do not address astroglial and vascular cell dysfunction have limited efficacy.

Spectrum of neuropathophysiology in spinal muscular atrophy type I.

Neuropathologic findings within the central and peripheral nervous systems in patients with spinal muscular atrophy type I (SMA-I) were examined in relation to genetic, clinical, and electrophysiologic features. Five infants representing the full clinical spectrum of SMA-I were examined clinically for compound motor action potential amplitude and SMN2 gene copy number; morphologic analyses of postmortem central nervous system, neuromuscular junction, and muscle tissue samples were performed and SMN protein was assessed in muscle samples. The 2 clinically most severely affected patients had a single copy of the SMN2 gene; in addition to anterior horn cells, dorsal root ganglia, and thalamus, neuronal degeneration in them was widespread in the cerebral cortex, basal ganglia, pigmented nuclei, brainstem, and cerebellum. Two typical SMA-I patients and a milder case each had 2 copies of the SMN2 gene and more restricted neuropathologic abnormalities. Maturation of acetylcholine receptor subunits was delayed and the neuromuscular junctions were abnormally formed in the SMA-I patients. Thus, the neuropathologic findings in human SMA-I are similar to many findings in animal models; factors other than SMN2 copy number modify disease severity. We present a pathophysiologic model for SMA-I as a protein deficiency disease affecting a neuronal network with variable clinical thresholds. Because new treatment strategies improve survival of infants with SMA-I, a better understanding of these factors will guide future treatments.

Observational study of spinal muscular atrophy type I and implications for clinical trials.

Prospective cohort study to characterize the clinical features and course of spinal muscular atrophy type I (SMA-I). Patients were enrolled at 3 study sites and followed for up to 36 months with serial clinical, motor function, laboratory, and electrophysiologic outcome assessments. Intervention was determined by published standard of care guidelines. Palliative care options were offered. Thirty-four of 54 eligible subjects with SMA-I (63%) enrolled and 50% of these completed at least 12 months of follow-up. The median age at reaching the combined endpoint of death or requiring at least 16 hours/day of ventilation support was 13.5 months (interquartile range 8.1-22.0 months). Requirement for nutritional support preceded that for ventilation support. The distribution of age at reaching the combined endpoint was similar for subjects with SMA-I who had symptom onset before 3 months and after 3 months of age (p=0.58). Having 2 SMN2 copies was associated with greater morbidity and mortality than having 3 copies. Baseline electrophysiologic measures indicated substantial motor neuron loss. By comparison, subjects with SMA-II who lost sitting ability (n=10) had higher motor function, motor unit number estimate and compound motor action potential, longer survival, and later age when feeding or ventilation support was required. The mean rate of decline in The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders motor function scale was 1.27 points/year (95% confidence interval 0.21-2.33, p=0.02). Infants with SMA-I can be effectively enrolled and retained in a 12-month natural history study until a majority reach the combined endpoint. These outcome data can be used for clinical trial design.

Respiratory muscle function in infants with spinal muscular atrophy type I.

To determine the feasibility and safety of respiratory muscle function testing in weak infants with a progressive neuromuscular disorder. Respiratory insufficiency is the major cause of morbidity and mortality in infants with spinal muscular atrophy type I (SMA-I). Tests of respiratory muscle strength, endurance, and breathing patterns can be performed safely in SMA-I infants. Useful data can be collected which parallels the clinical course of pulmonary function in SMA-I. An exploratory study of respiratory muscle function testing and breathing patterns in seven infants with SMA-I seen in our neuromuscular clinic. Measurements were made at initial study visit and, where possible, longitudinally over time. We measured maximal inspiratory (MIP) and transdiaphragmatic pressures, mean transdiaphragmatic pressure, airway occlusion pressure at 100 msec of inspiration, inspiratory and total respiratory cycle time, and aspects of relative thoracoabdominal motion using respiratory inductive plethysmography (RIP). The tension time index of the diaphragm and of the respiratory muscles, phase angle (Φ), phase relation during the total breath, and labored breathing index were calculated. Age at baseline study was 54-237 (median 131) days. Reliable data were obtained safely for MIP, phase angle, labored breathing index, and the invasive and non-invasive tension time indices, even in very weak infants. Data obtained corresponded to the clinical estimate of severity and predicted the need for respiratory support. The testing employed was both safe and feasible. Measurements of MIP and RIP are easily performed tests that are well tolerated and provide clinically useful information for infants with SMA-I.

The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND): Test development and reliability

The motor skills of patients with spinal muscular atrophy, type I (SMA-I) are very limited. It is difficult to quantify the motor abilities of these patients and as a result there is currently no validated measure of motor function that can be utilized as an outcome measure in clinical trials of SMA-I. We have developed the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (“CHOP INTEND”) to evaluate the motor skills of patients with SMA-I. The test was developed following the evaluation of 26 infants with SMA-I mean age 11.5 months (1.4–37.9 months) with the Test of Infant Motor Performance and The Children’s Hospital of Philadelphia Test of Strength in SMA, a newly devised motor assessment for SMA. Items for the CHOP INTEND were selected by an expert panel based on item mean and standard deviation, item frequency distribution, and Chronbach’s alpha. Intra-rater reliability of the resulting test was established by test–retest of 9 infants with SMA-I over a 2 month period; Intraclass correlation coefficient (ICC) (3,1) = 0.96. Interrater reliability was by video analysis of a mixed group of infants with neuromuscular disease by 4 evaluators; ICC (3,4) = 0.98 and in a group of 8 typically developing infants by 5 evaluators ICC (3,5) = 0.93. The face validity of the CHOP INTEND is supported by the use of an expert panel in item selection; however, further validation is needed. The CHOP INTEND is a reliable measure of motor skills in patients with SMA-I and neuromuscular disorders presenting in infancy.

The Test of Infant Motor Performance: Reliability in Spinal Muscular Atrophy Type I

The aim of this article was to determine reliability of the Test of Infant Motor Performance (TIMP) in infants with spinal muscular atrophy, type I (SMA-I). Interrater reliability training was undertaken by 17 physical therapist evaluators using 6 infants with hypotonia and weakness (5 videotaped, 1 live). Eight trained evaluators then conducted a test-retest reliability study at their own center, performing 2 tests approximately 1 month apart on each of 11 infants with genetically confirmed SMA-I (5 boys, 6 girls; age range 37-501 days; 3 on pulmonary support). The interrater reliability training session had an overall weighted Kappa of 0.61 (95% confidence interval 0.59-0.63). For the test-retest reliability study, the intraclass correlation coefficient for the TIMP Total Score was 0.85 (95% confidence interval: 0.54-0.96). The test scores were not significantly different between the 2 sessions (Bradley-Blackwood test was nonsignificant). TIMP scores can be reliably obtained in infants with SMA-I.