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Comparison of Two Novel Treatment Options Upon Clinical Experience for Spinal Muscular Atrophy Type 1: Risdiplam Vs

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Comparison of Two Novel Treatment Options Upon Clinical Experience for Spinal Muscular Atrophy Type 1: Risdiplam Vs Research Article Journal of Volume 5:4, 2020 DOI: 10.37421/jpnm.2020.05.150 Pediatric Neurology and Medicine ISSN: 2472-100X Open Access Comparison of Two Novel Treatment Options upon Clinical Experience for Spinal Muscular Atrophy Type 1: Risdiplam vs. Nusinersen Mehmet Çeleğen*, Selman Kesici, Benan Bayrakci Department of Pediatric Intensive Care Unit, Hacettepe University İhsan Doğramacı Children’s Hospital, Ankara, Turkey Abstract Nusinersen and risdiplam are emerging molecules started to be used in Spinal muscular atrophy (SMA) treatment. In this observational study, we aimed to compare the effects of these two molecules on SMA type 1 patients. In the two patients we presented in this report, both were diagnosed as SMA type 1 in the neonatal period, and their genetic defects were similar and their treatments were initiated at the same age and this exceptional similarity served us the opportunity for comparison. Two patients were intubated because of respiratory failure secondary to pneumonia. Case 2 receiving risdiplam was successfully extubated after pneumonia treatment but Case 1 receiving nusinersen could not be extubated and needed permanent assisted ventilation. Case 2 received a drug with an ease of use, showed better muscle strength, preserved native swallowing capability, revealed normal growth pattern, did not need further respiratory support as a result of better respiratory status. Keywords: Spinal muscular atrophy • Nusinersen • Risdiplam Outcome Introduction hypoxia and development of respiratory acidosis, the patient was intubated. After mechanical ventilatory support, antibiotic treatment and regular postural drainage atelectasis resolved. Consecutive extubation attempts with Spinal muscular atrophy (SMA) is a neuromuscular disease characterized noninvasive respiratory support under ideal hemodynamic conditions were by degeneration of the α-motor neurons in the brain stem and in the anterior horn unsuccessful. Maximum inspiratory pressure (MIP) via endotracheal tube that of the spinal cord [1]. SMA disease occurs as a result of mutations in survival was measured during sedative free period ranged between -8 and -10 cmH2O. motor neuron (SMN1) in chromosome 5q13 [2]. These mutations cause a lack MIP is the negative deflection measured by a manometer through closed of functional SMN protein and this situation leads to muscle atrophy, muscle respiratory circuit during inspiration resembling the maximum inspiratory effort weakness, and life-threatening complications [3]. The SMN protein produced that the patient can generate. Due to prolonged intubation and inadequate by the SMN2 gene cannot compensate for the lack of SMN1 gen [2, 4]. SMA respiratory effort, tracheostomy was performed on the 14th ventilator day. MIP disease is classified according to the age of onset of the disease symptoms value measured thru tracheostomy was -20 cmH2O and patient required only and the clinical severity of the disease. Most common and severe type is type nocturnal MV support then. Because of swallowing dysfunction a nasogastric 1 in which symptoms begin in infancy period. The baby is hypotonic, cannot tube was placed for enteral feeding. The patient was discharged from the hold his head, cannot sit, encounters respiratory distress and usually needs hospital after the completion of the family education for home ventilation. Since mechanical respiratory support. In these patients, respiratory failure develops he was dependent on the mechanical ventilator, his treatment with nusinersen within the first year of life and they cannot survive without respiratory support. was discontinued and the effect of the treatment on the muscle strength, Recently, there have been promising advances in the treatment of SMA especially the respiratory muscles could not be evaluated. (Table 1) disease. Nusinersen and risdiplam are two new molecules that are being used in SMA treatment. In this case study, we aimed to compare the effects of these Case 2 two emerging molecules on SMA type 1 patients with similar clinical features and have 2 SMN2 copy numbers. SMA type 1 patient who has been receiving oral risdiplam treatment since 2 months of age admitted to pediatric intensive care unit in an outer center because of respiratory failure at the age of 6 months. No viral or bacterial agent Case Report was detected in respiratory tract examinations. The patient was intubated and mechanical ventilatory support was started. Patient was referred to our Case 1 hospital on the 14th mechanical ventilator day because of extubation failure. On physical examination the patient's muscle strength was not bad despite SMA type 1 patient who has been receiving intrathecal nusinersen sedation. MIP measurement revealed -30 cmH2O. She was extubated after (Spinraza®) treatment since 2 months of age admitted to pediatric intensive a successful spontaneous breathing test with t-tube and switched to non- care unit because of respiratory failure at the age of 6 months. No microbial invasive mechanical ventilation thru nasal cannula. On the first day after agent was found in viral and bacterial examinations of the respiratory tract. extubation, a total atelectasis developed in the left lung which then easily Chest X-ray revealed right sided total atelectasis and non-invasive mechanical resolved with postural drainage and deep tracheal aspiration. The patient ventilation support was started initially. Because of no improvement in weaned successfully from the noninvasive mechanical ventilation on the third day after extubation. The patient was discharged without any respiratory support. Risdiplam treatment continued. (Table 1) *Address for Correspondence: Mehmet C, Pediatric Intensive Care Unit, Hacettepe University İhsan Doğramacı Children’s Hospital, Ankara, Turkey, Tel: 905076335194; E-mail: [email protected] Discussion Copyright: © 2020 Mehmet C. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted SMA type 1 is the most common and most severe type of SMA disease. The use, distribution, and reproduction in any medium, provided the original author weakness of respiratory muscles in SMA type 1 patients leads to progressive and source are credited. respiratory failure. Intercostal muscles are more affected than the diaphragm, Received 19 October 2020; Accepted 26 October 2020; Published 03 November resulting in a paradoxical breathing pattern and a classical bell-shaped chest 2020 deformity. Other conditions contributing to the development of respiratory failure Çeleğen C, et al. J Pediatr Neurol Med, Volume 5:4, 2020 Table 1: Clinical characteristics of 2 cases. Case 1 Case 2 Age at the diagnosis of SMA 2 months 1 month Genetic result SMN1 DelE7-8 SMN1 DelE7-8 Copy number of SMN2 gene 2 2 Treatment Nusinersen Risdiplam Administration route of drug Intrathecal Oral Age at first dose of drug 2 months 2 months Age at the time of intubation 6 months 6 months Cause of respiratory failure Pneumonia Pneumonia Weight (At admission) 5.5 kg (<3p) 8 kg (50-75p) Height (At admission) 65.5 cm (10-25p) 70 cm (90-97p) Weight: -3.4 Weight: 1.5 Z score Height: -0.9 Height: 0.6 Maximum inspiratory pressure (MIP) -8 and -10 cmH2O -30 cmH2O Extubation success No Yes Hammersmıth Infant Neurologıcal Examınatıon (HINE 2) score 2 7 Respiratory support at discharge Home ventilation via tracheostomy None Feeding route at discharge Nasogastric tube Oral in patients with SMA are cough insufficiency and impaired airway cleaning extubation at the 17th day of mechanical ventilation. Extubation of an SMA- which are additional consequences of muscle weakness. SMA type 1 patients 1 patient after prolonged ventilation is astounding because these patients easily who develop respiratory insufficiency and need ventilator support usually get addicted to mechanic ventilator in less than 2 days of application [9]. A sub become mechanical ventilator dependent swiftly. Until recently, we have been sequential left lung atelectasis resolved easily with postural drainage and patient's seeing SMA type 1 patients prognosticatively die due to respiratory failure or native cough. The patient was discharged without any respiratory support. survive with lifelong respiratory support. Pathophysiology of SMA disease is When two patients were evaluated in terms of anthropometric the deficiency of SMN protein resulting from homozygous deletion or mutation measurements, it is seen that the growth of the second case is much better. in the SMN1 gene. Deficiency of SMN protein results in degeneration of motor We confirmed the swallowing dysfunction in Case 1 due to his muscle fatigue. neurons in brain stem and spinal cord [5]. SMN protein is also encoded by Swallowing function test was not performed in both patients, evaluation SMN2 gene but large portion of the protein encoded by the SMN2 gene is done according to clinical observation. Malnutrition was not only related with truncated and it is nonfunctional because of aberrant splicing [6]. It is known swallowing dysfunction but, increased respiratory effort consuming lots of that higher copy number of SMN2 gene is related with milder phenotype. SMN energy also contributed to its development. (Table 1) protein plays a critical role in some basic cellular functions of some parts of the body such as skeleton, heart muscle, bone, autonomic and central nervous These two patients were also comparable in terms of motor development. systems, and its deficiency causes disease clinic. Nusinersen is an antisense
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