Lesser Studied Nonrespiratory Complications in Nusinersen-Treated SMA1 May Affect Outcomes

The respiratory complications of spinal muscular atrophy are well-researched, but a new study provides insight into nonrespiratory complications that may be just as crucial.

The growing treatment landscape for spinal muscular atrophy (SMA) has increased survival expectations in a typically devastating disease. But a recent study accepted for publication in Pediatric Pulmonology reported 3 nonrespiratory complications—facial deformities, feeding problems, and spinal deformities—in nusinersen-treated patients that may directly or indirectly affect respiratory function.

SMA is an inherited neurodegenerative disorder that causes progressive muscle weakness, respiratory complications, and death in severe phenotypes. Infants affected by type 1 SMA (SMA1), the most common, typically show symptoms before 6 months of age. Untreated, the life expectancy of these infants is generally less than 2 years of age and they are typically incapable of sitting independently.

New treatments, including nusinersen, zolgensma, and risdiplam, can significantly improve therapeutic outcomes in SMA1, but not much is known regarding the long-term respiratory outcomes and complications. Previous studies have shown that patients treated with nusinersen still required ventilator support and have reported patients having complications in other organ systems that could impact respiratory function.

Researchers at Tel Aviv Sourasky Medical Center used their existing patient database on these complications in real-world SMA1 patients treated with nusinersen to glean insight on their effects on respiratory outcomes. The data were pulled from interviews with patients' legal guardians and patients’ medical files throughout a 3-year period. The data focused on pre- and post-treatment assessments of facial hypoplasia or deformity, feeding-related information (method of feeding, weight, length, BMI, and aspirations), and spinal deformities.

A total of 20 SMA1 patients (12 female, 8 male) treated with nusinersen were included in the study. Median age was 13.5 months, and all but one patient were diagnosed with SMA postnatally at the onset of clinical symptoms. Nusinersen treatment was started at median 13.5 months of age. Of the 20 patients, 2 died from acute respiratory failure during the first year of treatment and 1 patient stopped treatment during the second year after sustaining an anoxic brain injury due to massive aspiration. The remaining 17 patients finished 3 years of treatment with 100% adherence to the regimen.

At the start of treatment, 16 of 20 patients needed respiratory support. All 17 patients at the end of the 3-year period were ventilated, and all 17 routinely used daily mechanical insufflation-exsufflation at the 3-year mark versus 11 total patients at treatment initiation.

Prior to starting treatment, 4 patients had facial deformities. Fifteen of the 17 surviving patients showed facial changes at 3 years of follow-up.

The authors note that long-term noninvasive ventilation (NIV) has long been a standby for treating respiratory disorders and insufficiency in children with muscle weakness, but new treatments have changed the approach. Attempts to start respiratory support as early as possible in anticipation of future waning may be contributing to facial deformity, as younger infants have more flexible skulls and are more prone to deformity.

“It should also be noted that once a facial deformity has occurred, the fitting of an appropriate mask or interface becomes more challenging,” the authors wrote. “This is of considerable concern for treated patients since most of them still require assisted ventilation in the first years of life.” Masks with adjustable interfaces or custom-made masks with varying pressure points may help alleviate the issue.

Before treatment, 7 patients received oral feeding, 12 patients were fed by a percutaneous gastrostomy (PG), and 1 patient was fed by a nasogastric tube (NGT). At follow-up, all but 1 patient were fed invasively (15 via PG, 1 via NGT). Four patients maintained oral feeding in addition to PG, but all showed clinical and radiologic evidence of aspirations regardless of the food consistency or swallowing techniques.

Feeding issues also persisted in the study, suggesting that improvements in motor function associated with treatment do not necessarily parallel improvements in feeding ability.

At the start of treatment, 5 patients had been diagnosed with scoliosis. At the 3-year follow-up, 13 of 17 patients were diagnosed with scoliosis and 4 of those patients had already undergone corrective surgery. Three were planned for surgery at follow-up. In total, 15 patients showed scoliosis over the course of study.

Severe scoliosis in patients undergoing treatment is significant, as it can inhibit the chest wall from fully expanding and further reduce respiratory capacity. Scoliosis is also a concern because nusinersen is administered intrathecally, so surgeries must preserve the ability to continue the course of treatment as live expectancy increases.

Overall, the study was small and limited to a single center but suggests the non-respiratory complications of SMA in nusinersen-treated patients are just as crucial to study and understand as the continuously studied respiratory outcomes.

"Pulmonologists such as ourselves often focus upon the respiratory system when assessing SMA1 patients,” the authors wrote. “This study aims to raise the level of awareness of the impact of problems in other organs or systems which are often no less significant and should be sought after and treated. “


Lavie M, Rochman M, Sagi L, et al. Non-respiratory complications of nusinersen-treated spinal muscular atrophy type 1. Pediatr Pulmonol. Published online December 18, 2021. doi:10.1002/ppul.25795