Reply to Chacko et al.: Limited Assessment of Respiratory Muscle Response to Nusinersen Treatment in Infants with Spinal Muscular Atrophy

From the Authors:

We thank Chacko and colleagues for their interest in our study (1). We agree that multiple factors must be considered when discussing access and reimbursement criteria, and that a combination of tests is advisable to assess the therapeutic effects of drugs. In fact, we also reported Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (2, 3) scores and daily hours of mechanical ventilation (1).

In our study, motor function, ventilatory support, respiratory rate, and Vt improved in patients with spinal muscular atrophy (SMA) treated with nusinersen compared with untreated patients irrespective of disease severity, with those with type 1C showing the highest values. Inspiratory paradox of the rib cage (IPRC) was present in treated patients with SMA1 A and B but not in those with type 1C.

Optoelectronic plethysmography (OEP) allows one to gather additional information about the pathophysiology of SMA in a noninvasive manner by providing nonvolitional global and specific indexes of respiratory function. We think that the alternative tools proposed by Chacko and colleagues—respiratory impedance plethysmography (RIP) (4) and forced oscillation technique (FOT) (5)—may have some limitations and may not provide additional information about the effect of nusinersen on respiratory function.

RIP provides qualitative information regarding thoracoabdominal asynchronies by measuring changes in only two cross-sectional areas. Its limited calibration methods to estimate chest wall/lung volume require subject-specific calibration during a long period of regular breathing, which can be problematic in infants and children because they frequently may cry, babble, or speak.

Conversely, OEP provides accurate chest wall volumes and anatomical thoracoabdominal subdivision, and its calibration does not depend on the subject. We agree, however, that studies comparing the two techniques would be of interest, because RIP is more widely available.

FOT has great clinical potential, but it provides data on passive properties (resistance and reactance) of the respiratory system rather than on the force/action of respiratory muscles. FOT does not discriminate between obstructive and restrictive lung disorders (5) and was shown by Gauld and colleagues to not differentiate between SMA2 and SMA3 (6), while OEP data were sensitive to disease severity (7). FOT still needs to be extensively investigated in SMA1 (8), and no reliable reference values are available for young children (6).

Our data provide further insights into the mechanisms underlying different individual responses to treatment, but they cannot be interpreted as supporting access to or exclusion from treatment or as parameters for starting or stopping treatment, as several other factors must be considered. We showed that IPRC was still present in our treated children with SMA1 A and B (1), but IPRC per se is not a problem, as it is present in healthy infants (9). When IPRC is accompanied by breathing difficulties, it becomes a medical emergency. In SMA, it is the consequence of progressive ribcage muscle weakness/atrophy that triggers a cascade of events: inefficient cough (coughing relies principally on ribcage muscles [10]), bell-shaped chest (11), hypoventilation, atelectasis (associated with recurrent aspiration due to bulbar impairment), excessive work of breathing, and ventilatory failure.

Future larger studies are needed to identify drug responders and nonresponders, with age of symptoms onset, clinical presentation (including IPRC), and SMN2 copy numbers as independent factors.

Of note, SMN2 copy numbers did not affect our results, as they were equally distributed (50% with two copies and 50% with three copies) with no difference between the two groups.

We do not think that age may have played a role in our results, because 1) clinical evidence suggests that IPRC gets worse with age in natural-history SMA1 owing to the progression of weakness/atrophy of the ribcage muscles (12, 13), 2) the two treated groups were similar in age (21 mo [1A and 1B] and 29.7 mo [1C]) (1), and 3) physiological IPRC should not be present in the awake state at those ages.

In conclusion, we believe that our study provides important data for future studies seeking to better understand the effects of nusinersen and other emerging drugs on respiratory function in patients with SMA.