Successful weaning from mechanical ventilation in a patient with SMA type 1 treated with nusinersen.

SMA type 1 is the most severe type, characterized by early onset at <6 months of age, and rapid progression resulting in permanent assisted ventilation before 2 years of life. Supportive care was the only treatment until the approval of nusinersen, an antisense oligonucleotide drug that increases functional SMN protein levels. We present a case of successful weaning from permanent ventilation via tracheostomy with nusinersen in an infant who had been diagnosed with SMA type 1 at the age of one month and had become ventilator-dependent from the age of 3 months.

Introduction

Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by degeneration of motor neurons of anterior horn cells of the spinal cord, leading to progressive muscle weakness and hypotonia. Homozygous deletion of the survival motor neuron (SMN) 1 gene on chromosome 5q13 resulting in SMN protein deficiency is the cause of 95% cases of SMA. The SMN2 gene, which is homologous to the SMN1 gene, produces approximately 10% of the functional SMN protein through alternative splicing. Fewer copies of SMN2 are associated with more severe phenotypes and earlier onset of disease. , SMA type 1 has the most severe phenotype characterized by onset at an age <6 months, and a rapid progression resulting in respiratory failure. These patients require permanent assisted ventilation within 2 years of life. Nusinersen is an antisense oligonucleotide drug that modifies pre‐mRNA splicing of the SMN2 gene, increasing functional SMN protein levels. , It is known to improve motor function in patients with SMA. However, there have been limited studies that report weaning from permanent mechanical ventilation in patients with SMA type 1 treated with nusinersen. We report the case of a patient with SMA type 1 treated with nusinersen and weaned successfully from permanent mechanical ventilation.

Case Report

A 1‐month‐old male infant was referred to the pediatric neurology outpatient clinic for decreased limb movement and hypotonia. He was born by cesarean section at 40 weeks of gestation, weighing 3670 g and had no perinatal problems. He had no family history of neuromuscular, metabolic, or genetic disorder. On neurologic examination, he showed global hypotonia and inability to move both arms and legs fully against gravity. Tongue fasciculations were observed, and deep tendon reflexes were absent. Although his grasp power was weak, sucking power was sufficient for feeding and gaining weight. His weight, height, and head circumference were 5.1 kg (75th percentile), 54.7 cm (25th percentile), and 37.8 cm (95th percentile), respectively. Homozygous SMN1 deletion and 2 copies of SMN2 were found with multiplex ligation‐dependent probe amplification test. At the age of 2 months, he was admitted with respiratory difficulty and treated with high‐flow nasal cannula therapy. He was transferred to the pediatric intensive care unit on the 2nd day of admission and required a mechanical ventilator on the 6th hospital day due to aggravated respiratory difficulty. After three failed attempts at weaning despite the use of a nasal continuous positive airway pressure device, a tracheostomy was performed at 3 months of age and he was discharged with a home ventilator. He was given the first dose of nusinersen at the age of 4 months after being enrolled in an early access program by Biogen. He completed four loading doses by 6 months of age, and thereafter, maintenance doses were administered at 4‐month intervals. We evaluated his respiratory status by the duration of ventilator support, parameters of home ventilation, and blood gas analysis at each nusinersen therapy session. Motor function was evaluated using the Hammersmith Infant Neurological Examination (HINE‐2) score. The progression of his respiratory status and motor function after administering nusinersen is shown in Table 1. The first trial of weaning off the ventilator was done at 10 months of age, after the 5th dose of nusinersen, and he tolerated 3 h without the aid of the ventilator. At 14 months of age, he could be weaned from the ventilator during the day and needed ventilation only during sleep for about 10–12 h. On each trial of weaning, he was admitted and monitored for more than 24 h of respiratory condition and oxygen saturation. Also, we evaluated the occurrence of respiratory acidosis or difficulty through blood gas analysis and chest X‐ray before and after weaning from a mechanical ventilator. At 30 months of age, there was no respiratory difficulty and his oxygen saturation was maintained above 90% without ventilatory support during the daytime, including daytime naps for 2‐4 h, although the home ventilator was applied during nighttime sleep for the patient’s safety. His HINE‐2 score increased by 10 points from the first treatment, and he was able to move his limbs against gravity. He also performed pincer‐grasp and rolled from a supine to prone position with head control, with some support. Independent sitting posture was not possible.

Table 1

Respiratory and motor function of the patient with spinal muscular atrophy type 1 at each nusinersen therapy.

Age (mo)	Number of nusinersen	Respiratory state					Motor function (score)
		Duration of ventilator support (hr)	Ventilator mode	PIP (cmH2O)	pH	pCO2 (mmHg)	Total HINE‐2	Voluntary grasp	Ability to kick	Head control	Rolling	Sitting, crawling, standing, walking
4	1	24	P‐SIMV	17	7.38	31.4	0	(0)	(0)	(0)	(0)	(0)
5	2	24	P‐SIMV	16	7.46	24.6	1	Grasp with whole hand (1)	(0)	(0)	(0)	(0)
5.5	3	24	P‐SIMV	14	7.47	23.8	1	Grasp with whole hand (1)	(0)	(0)	(0)	(0)
6	4	24	P‐SIMV	14	7.44	25.8	2	Grasp with whole hand (1)	Kick horizontally (1)	(0)	(0)	(0)
10	5	16	P(A)CV	20	7.46	25.0	2	Grasp with whole hand (1)	Kick horizontally (1)	(0)	(0)	(0)
14	6	10–12	P(A)CV	15	7.50	21.2	2	Grasp with whole hand (1)	Kick horizontally (1)	(0)	(0)	(0)
18	7	10–12	P(A)CV	11	7.47	22.8	4	Grasp with whole hand (1)	Kick upward (2)	(0)	Rolling to side (1)	(0)
22	8	10–12	P(A)CV	14	7.42	23.6	8	Index finger and thumb but immature grasp (2)	Touch leg (3)	(0)	Supine to prone (3)	(0)
26	9	10–12	P(A)CV	12	7.44	31.4	10	Pincer grasp (3)	Touch leg (3)	Wobble (1)	Supine to prone (3)	(0)
30	10	8–10	P(A)CV	10	7.46	32.0	10	Pincer grasp (3)	Touch leg (3)	Wobble (1)	Supine to prone (3)	(0)

Abbreviations: HINE, Hammersmith Infant Neurologic Examination; hr, hours; mo, month; P(A)CV, Pressure control ventilation; PIP, peak inspiratory pressure; P‐SIMV, Pressure‐synchronized intermittent mandatory ventilation.

This study was approved by the Institutional Review Board (IRB) of Samsung Seoul Hospital (IRB No. 2020‐04‐154‐001) and written informed consent was obtained from the patient’s parents.

Discussion

The indication for nusinersen covered by national or public insurance, including that of South Korea, is patients who are not fully dependent on a mechanical ventilator. This is based on the initial clinical trial. This case report shows that even if the patient is completely dependent on mechanical ventilation, they can be partially weaned off the ventilator with nusinersen treatment. This report supports the evidence expanding the indication of nusinersen to patients dependent on a permanent ventilator in the early stage of the disease. Several studies have shown the effects of nusinersen on motor function or survival rate in SMA type 1 patients, however, they did not focus on respiratory function or weaning from the ventilator in patients with a tracheostomy before treatment , , , , , , Other studies on SMA type 1 patients with ventilatory support via a tracheostomy reported an improvement in respiratory function with nusinersen treatment , , (Table 2). Among them, there was no patient with ventilatory support via tracheostomy who was weaned from permanent assisted ventilation, even though they showed a decreased duration and termination of noninvasive ventilatory support. A case report of a male infant with SMA type 1 who had undergone a tracheostomy at 75 days of age and treated with nusinersen at 99 days of age demonstrated that he could be weaned from the ventilator for 1.5 h/day after 6 months of nusinersen treatment. In our case, the duration of self‐breathing without ventilatory support was over 12 h/day. Although we applied the ventilator during nighttime for patient safety, under close observation, he can maintain stable respiration during sleep. Because, there are few reports proving the effectiveness of the treatment on respiration, it is difficult to perform parallel comparison taking into account various factors that may affect treatment response. However, the patient in this study showed remarkable improvement in respiratory capacity that he could spend more than half of the day without respiratory assistance after early treatment.

Table 2

Literature review: progression of respiratory and motor function in patients with spinal muscular atrophy type 1 treated with nusinersen.

		Pechmann et al.	Pane et al.	Sansone et al.
Total patients, n		61	85	118
Duration of follow‐up, months		6	12	10
At 1st nusinersen	Mean age (range)	21.08 months (1–93 months)	4.7 years (2 months–15 years)	42.8 months (11.0–102.8 months)
	NIV > 16 h/d (A.pechmann et al.) or > 10 h/d (Pane et al. and Sansone et al.), n	6	19	24
	Tracheostomy, n	12	8	46
Assessment of respiratory function	Decreased duration or termination of NIV support, n	4 (6.6%)	2 (2.4%)	3 (2.5%)
	Removal of tracheostomy tube, n	0	0	0
Assessment of motor function	Mean improvement of HINE‐2 score	1.4	1.34	N/A
	Mean improvement of CHOP INTEND score	9	5.46	N/A

Abbreviation: NIV, noninvasive ventilation; HINE, Hammersmith Infant Neurologic Examination; CHOP INTEND, Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders; N/A, not available.

We report a case of successful weaning from a mechanical ventilator for more than 12 h/day after early nusinersen treatment for SMA type 1. Further clinical evidence is necessary to prove the possibility of weaning off the ventilator by starting nusinersen treatment at an early stage of disease, even in SMA type 1 patients on ventilatory support via tracheostomy.

Conflict of Interest

The authors have no potential conflicts of interest to disclose.

Authors’ Contributions

Se Eun Park reviewed the case and prepared the manuscript. Dajeong Lee and Joo Young Song clinically managed and evaluated the patient with functional assessment. Jiwon Lee managed the patient and prepared and reviewed the manuscript. Jeehun Lee leaded the clinical team, and designed and reviewed the manuscript.