Background

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by degeneration of the anterior horn cells of the spinal cord. Nusinersen has been covered by public healthcare in France since May 2017. The alặng of this article is to report results after 1 year of treatment with intrathecal nusinersen in children with SMA types 1 & 2 in France. Comparisons between treatment onmix (T0) và after 1 year of treatment (Y1) were made in terms of motor function và need for nutritional và ventilatory support. Motor development milestone achievements were evaluated using the modified Hammersmith Infant Neurongắn gọn xúc tích Examination–Part 2 (HINE-2) for patients under 2 years of age & Motor Function Measure (MFM) scores for patients over 2 years of age.

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Results

Data on 204 SMA patients (type 1 or 2) were retrospectively collected from the 23 French centers for neuromuscular diseases. One hundred & twenty three patients had been treated for at least 1 year and were included, 34 of whom were classified as type 1 (10 as type 1a/b & 24 as type 1c) và 89 as type 2. Survival motor Neuron 2 (SMN2) copy numbers were available for all but 6 patients.

Patients under 2 years of age (n = 30), had significantly higher HINE-2 scores at year 1 than at treatment onset but used more nutritional & ventilatory support. The 68 patients over 2 years of age evaluated with the Motor Function Measure test had significantly higher overall scores after 1 year, indicating that their motor function had improved. The scores were higher in the axial và proximal motor function (D2) and distal motor function (D3) parts of the MFM scale, but there was no significant difference for standing and transfer scores (D1). No child in either of the two groups achieved walking.

Conclusion

Nusinersen offers life-changing benefits for children with SMA, particularly those with more severe forms of the disorder. Caregiver assessments are positive. Nevertheless, patients remain severely disabled & still require intensive tư vấn care. This new treatment raises new ethical challenges.


Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by degeneration of the anterior horn cells of the spinal cord resulting in muscle atrophy & proximal muscle weakness without cognitive sầu impairment. It is caused by a homozygous deletion or compound heterozygous alterations (mutation and deletion) in the survival motor neuron 1 ren (SMN1) on chromosome 5q13. The centromeric copy of the ren (SMN2) produces transcripts of the SMN protein lacking exon 7 because of a C-to-T transition that creates an exon-splicing suppressor sequence. SMA phenotype severity depends on the amount of functional SMN protein produced <1> and seems to be related to the number of SMN2 copies present <2, 3>.

The clinical type of SMA is defined by the age of the onphối và the severity of the disease, from type 0, with in utero onmix and reduced or absent movement, muscle contracture and ventilatory support at birth, to type 4, with adult onphối <4, 5>. SMA type 1 begins before 6 months of age, with generalized progressive sầu muscle weakness & atrophy. Infants with SMA type 1 vày not achieve independent sitting. Hypoventilation, poor cough strength and bulbar dysfunction lead to lớn respiratory failure, & death usually occurs before 2 years of age without ventilatory support. Type 1 SMA can be separated inlớn three subtypes: type 1a, in which head control is never achieved & signs appear in the neonatal period; type 1b, in which head control is never achieved but onphối is after the neonatal period; và type 1c, in which head control is achieved và onset is after the neonatal period <6>. SMA type 2 begins after 6 months of age và patients can sit but are unable lớn walk. Multidisciplinary management including respiratory, nutritional and orthopedic care improves survival and long term outcomes in type 1 và 2. Patients with SMA type 3 can walk without tư vấn but scoliosis and loss of ambulation can occur.

A new treatment for SMA patients, nusinersen, has been available in France since May 2017. Nusinersen is an antisense oligonucleotide that acts as a splicing modifier targeting the intronic splicing silencer N1 in the SMN2 intron và is delivered by repeated intrathecal injections. Nusinersen has shown some clinical efficacy in well-controlled clinical trials with prolonged survival after 2 years of age in different populations of SMA patients <7,8,9,10>. However, these motor benefits seem lớn be somewhat offphối by an increased use of invasive sầu treatments such as gastrostomy và ventilatory tư vấn <11, 12>.

The aim of this article is to lớn report the clinical outcomes related khổng lồ the perception of children và caregivers with SMA types 1 và 2 in France after 1 year of treatment with intrathecal nusinersen.


SMA patient files were provided by 23 French centers for rare pediatric diseases in the French FILNEMUS network for rare neuromuscular diseases. This multicenter study was commissioned by the neuromuscular commission of the French Society of Pediatric Neurology (Sociéngã Française de Neuropédiatrie), which holds monthly discussion group meetings. The data for this study were collected from May 2017 (when nusinersen became available in France) until February 2019. The inclusion criteria were:

1.

A genetically proven SMN1 mutation: homozygous deletion or compound heterozygous alterations (mutation & deletion) of exon 7 on chromosome 5q13

2.

SMA type 1 or 2, as defined by the HAS (Haute Autoribổ de Sanvấp ngã, French National Authority for Health)

3.

A complete clinical description at treatment onset (T0)

4.

Treatment with intrathecal nusinersen injections for at least 1 year ±2 months (Y1). (Patients were evaluated after 10, 12 or 14 months’ treatment depending on the study center).

The data collected retrospectively were: date of birth, gender, age at diagnosis, SMA type, number of copies of the SMN2 ren, age at treatment onphối, motor development milestone achievement, nutritional and ventilatory support information before & after 12 ± 2 months of year of treatment.

In order khổng lồ standardize care throughout the country, a standard khung was made available for all centers. These forms were therefore filled at each visit by the local investigator. Forms were then anonymized.

Intrathecal nusinersen injections, adverse events, & evaluation by caregivers after one SMA type was defined using the Mercuri classification as 1a/b, 1c, or 2 <4>.

Motor development milestone achievement was evaluated using different scales depending on the patient’s age at treatment onset.

The modified Hammersmith Infant Neurongắn gọn xúc tích Examination–Part 2 (HINE-2) <13> and the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOPhường INTEND) <14> were used to assess the motor development of children less than 2 years old and the Motor Function Measure (MFM) was used for children older than 2 years (MFMđôi mươi for children between 2 và 5 years old & MFM32 for children above sầu 6 years of age) <15>. The MFM scale assesses motor function in three domains: D1, standing và transfer; D2, axial và proximal motor function; & D3, distal motor function <16>. All MFM evaluations were carried out by an MFM trained & certified physiotherapist.

Nutritional tư vấn was defined as use of a nasogastric tube or gastrostomy and ventilatory tư vấn was defined as non-invasive or tracheostomy-assisted ventilation for more than 12 h per day.

Caregivers’ evaluations were graded using the Clinical Global Impressions-Improvement (CGI-I) scale <17> with 7 ratings scored from very much improved (rating 1) to very much worse (rating 7). The caregivers were the parents, và it was asked khổng lồ one of them to lớn fill the CGI-I scale.

Statistical analysis

Paired comparisons were performed to assess the evolution of the patients’ parameters after 1 year (± 2 months; initial visit versus after 1 year of treatment). Qualitative variables (such as the use of nutritional or ventilatory support) were compared using McNemar’s demo và quantitative sầu variables (such as the HINE-2 and CHOPhường INTEND scores) were compared using Wilcoxon signed rank tests for paired data. Results are presented as mean, median & range. Differences were considered statistically significant at p SMN2 copy number was evaluated using a chi-squared test & the intensity of the association was evaluated using Cramér’s V.

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The data were analyzed by age subgroup, under 2 years & above 2 years of age, with the second group subsequently split into two additional subgroups (2–5 years & 6–17 years).

Statistical analyses were carried out by a statistician using SPSS (IBM SPSS Statistics) version 20.0.


Of the 204 SMA patients treated with nusinersen in the 23 French centers, 123 with at least 1 year of treatment were finally included in the study (Fig. 1). Five sầu patients with SMA type 1a/b died before completing a full year of treatment và one patient with SMA type 1c died after 1 year of treatment.


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Population description

The patients’ characteristics are shown in Table 1. There were 68 girls (55.3%) & 55 boys (44.7%). Thirty-four patients were classified as type 1 (10 as type 1a/b và 24 as type 1c) and 89 as type 2. SMN2 copy numbers were available for all but six patients: 18 patients had two SMN2 copies, 96 had three SMN2 copies, and 3 patients had four SMN2 copies. There was a medium lớn strong association between SMA type and SMN2 copy number (Cramér’s V = 0.33; 95% CI, 0.16–0.43, chisq test: p 18>. The patients’ age at treatment onmix ranged from 3 months khổng lồ 16 years (Fig. 2). Thirty children (24.4%) were under 2 years of age at treatment onset. Of the remaining 93 (75.6%) aged 2 years or older at treatment onset, 47 were 2–5 years of age and 46 were 6–17 years old.


*

One patient died after 14 months of treatment, of a viral cardiomyopathy.

Need for nutritional & ventilatory support

There was no significant change in the number of patients requiring ventilatory or nutritional tư vấn between T0 & Y1 overall (Fig. 3a and b). Among the youngest patients however (under 2 years old, SMA type 1), there was a non-significant increase in the number requiring nutritional tư vấn (three patients at T0 and five sầu at Y1) & in the number requiring ventilatory tư vấn (five sầu patients at T0 & eight at Y1).


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Motor function evaluation in children under 2 years of age (n = 30)

The patients’ motor function skills at T0 and Y1 were compared using the HINE-2 (20 patients with total scores only, 17 with detailed subscores) and/or CHOP-INTEND (n = 14) scales. Twelve sầu patients were assessed using both methods, two patients were evaluated using MFM đôi mươi only, & six patients were evaluated using different methods at T0 & Y1.

There was a statistically significant increase in the total HINE-2 scores between T0 và Y1 (p 2 compares the patients’ HINE-2 motor function scores before & after 1 year of treatment. Figure 4 highlights the improvement in the total HINE scores after 1 year of treatment. The 14 patients who were assessed with the CHOP-INTEND scale also showed overall improvement, with the mean total score increasing from 35.1 to lớn 50.3.


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Motor function evaluation in children older than 2 years (n = 93)

For these patients, motor function assessments at T0 and Y1 were mainly performed using the MFM scale (n = 68) (73% of the age subgroup; 5 with SMA type 1c & 63 with type 2 SMA) và only these data were analyzed. The 25 remaining patients were evaluated with either the HINE-2 or CHOP-INTEND methods.

Table 3 compares the motor milestone achievements of the patients at T0 & Y1. Motor function improved slightly overall after 1 year of treatment (the median total MFM score increased by 6). In the different domains, there were significant improvements in the median scores in D2 (+ 9 percentage points, p p n = 33, + 8 points overall, + 12 points in D2 and + 9 points in D3; p ≤ 0.001 in each case) than in those older than 6 years at treatment onset (+ 4 points overall, p = 0.099; + 6 points in D2, p = 0.457; and + 5 points in D3, p = 0.04). Figure 5 shows the distribution of MFM scores at T0 và Y1 for the D1, D2 & D3 domains.


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General considerations

Caregiver evaluations of the benefits of treatment after 1 year were available for 105 patients. No caregiver rated their patient’s condition as minimally, much or very much worse (ratings 5, 6 và 7, respectively), 13% observed no change (rating 4), 35% a minimal improvement (rating 3), 46% considered that the patient’s condition was much improved (rating 2) & 6% very much improved (rating 1).

We counted 95 adverse events in 25 patients. They consisted in technical difficulties for lumbar puncture (n = 55) with fluoroscopic guidance required in 17 cases, headađậy (n = 23), post lumbar puncture syndrome (n = 6), nausea và vomiting (n = 4), asthenia (n = 4), back pain (n = 2), fever (n = 1).

Standard treatments such as motor và respiratory physiotherapy, orthoses (corphối, brace) were maintained in keeping with recommended practice in France. Respiratory function was evaluated if possible but these data were not analyzed for this report.


In France, 204 children treated in referral centers for rare neuromuscular diseases received nusinersen between May 2017 (when the treatment became available) & February 2019, of whom more than 90% were patients with SMA type 1 or 2. This group of 204 patients represents about half of the children with SMA type 1 và type 2 in France. Based on ethical considerations và in accordance with parental wishes, some patients with SMA type 1 received palliative care without nusinersen <19>. In addition, some children and/or their parents refused the treatment because of the intrathecal delivery while in some older patients, intrathecal injections were impossible because of arthrodesis.

As already reported, the number of SMN2 copies was found to lớn be correlated with the patients’ phenotype. However, this correlation was only medium khổng lồ strong and the phenotype could not be predicted based on the SMN2 copy number alone, notably in patients with three copies of SMN2, in contrast with previous reports <3, 20>. Despite progress in understanding phenotype–genotype correlations in SMA, this issue remains to lớn be clarified.

The benefits of nusinersen treatment were evaluated in the 123 patients who had received nusinersen for at least 1 year in the study period. No severe adverse events were observed, in agreement with previous studies <11, 12, 21, 22>. The results for this large cohort of patients with SMA type 1 (n = 34) and type 2 (n = 89) confirms that nusinersen improves motor function, in agreement with previous observational studies <11, 12, 21, 22>. Similar improvements have already been reported for children with type 1 SMA by Pechman et al. <11> in 61 patients followed for 6 months, by Aragon-Gawinska et al. in 33 patients followed for 6 months <12>, and by Pane et al. in 85 patients followed for 1 year <21>. Darras et al.’s <22> is the only existing study to lớn have reported on the effects of nusinersen treatment in patients with type 2 (n = 11) & type 3 (n = 17) SMA, who were followed for between 6 and 12 months. All but three of the children under 2 years of age in this study (27/30) had significantly improved HINE-2 scores after 1 year of treatment. However, our results confirm the importance of analyzing all the components of this score to lớn properly evaluate the benefits of the treatment. Indeed, despite real improvements in motor function, none of the children were able to walk và the maximum motor màn chơi achieved seems khổng lồ match that of a patient with type 2 SMA. Furthermore, our results confirm the previously observed <11, 12, 21> increased use of nutritional và ventilatory tư vấn. These treatments were in some case preventive sầu to improve respiratory function & nutritional status.

The group of children older than 2 years (93 patients, 13 with SMA type 1c, 80 with SMA type 2), were evaluated using the French MFM demo, which has never been used before in this context. The MFM assessments available for 68 patients indicated significant improvements in motor function, in keeping with those reported by Darras et al. <22> and Mercuri et al. <10>. Darras et al. <22> observed average gains for patients with SMA type 2 of 10 points on the Expanded Hammersmith Functional Motor Scale (HFMSE) & of 4 points on the Revised Upper Limb Module (RULM).) For our patients, there was no difference in the D1 domain (standing and transfer) scores, but an improvement in those for the D2 tên miền (axial and proximal motor functions, corresponding lớn the items of the HFMSE) và in those for the D3 domain name (distal motor functions, corresponding to lớn the RULM). The nutritional and ventilatory tư vấn requirements of this group of patients remained stable.

Interestingly, the improvements in motor function were greater in the subgroup of children younger than 6 years of age, who gained 12 points on average including 8 points in D3, whereas those aged 6–17 years only gained 6 points on average including 5 points in D3. In particular, 85% of the younger children had scores above 70% in D2, indicating that they could perform most normal daily activities (eating alone, combing their hair, rolling over during sleep...). However, no child in either of these two subgroups achieved walking. The motor benefit seems clearly related to lớn early treatment as reported by other teams <12>.

This is the first time that a clinical evaluation of a large cohort of SMA patients in a real life setting has been combined with an assessment of caregiver opinions (CGI-I scale). The positive sầu responses of the caregivers despite generally mild motor benefits may reflect the considerable hopes invested in this new therapy, or on the h&, reflect limitations in the scales used to evaluate the benefits of the treatment. We did not use a generic tool for estimating the health-related unique of life of patients and/or caregivers. This should certainly be considered as a limitation of our study as this information is worth for the decision-making process, & it can offer the health benefits from a broader point of view not only for the patient also for the caregivers.


Nusinersen changes the natural history & standard care of children with SMA <23, 24>, particularly for severe forms and in younger children. It is a well-tolerated treatment. In spite of these improvements, patients with SMA types 1 & 2 treated with nusinersen still require intensive support care and remain severely disabled. There is nonetheless real optimism among mỏi caregivers after 1 year of treatment. This treatment raises new ethical challenges. We agree with King và Bisiêu thị <25> that families need khổng lồ know more about what it means khổng lồ live sầu with SMA & what the benefits and burdens of the available treatments are. Parents of affected children and the patients themselves as they grow up face high stakes decisions about chronic treatment và potentially aggressive life prolonging therapies.