4 DISCUSSION
SMA of type 1 is more severe, and both the age at death and the number
of people using ventilators are respectively earlier and more than those
in other SMA types.1,10 Most children with SMA type 1
over two years of age need tracheotomy or all-day noninvasive
ventilation for survival.11 Children with type 2 have
a progressive decline in overall function and need noninvasive
ventilation from five to thirteen years old.12Similarly, our study showed that the risk for RRTIs and/or ARF in type 1
is approximately four times higher than that in types 2 and 3. The
average age of type 1 patients in our study was over two years, but none
of them had received disease-modifying medications or long-term
mechanical ventilation therapies. Among the 14 cases of type 1 with SMN2
copy number detected, five cases had 2 copies, and nine cases had 3
copies, which indicated the milder SMA types 1b and
1c.1 This was because most of the patients who could
come to Beijing for treatment from other areas of China would have had
mild symptoms, and the type 1 population in China might carry more
copies of SMN2.13 Therefore, if all patients were
considered, the risk of type 1 RRTIs and/or ARF should be higher.
Malnutrition is common in children with SMA. Our study showed that
age-specific BMIz decreased in all three types and was lowest in type 1,
which was consistent with other studies.14Malnutrition in SMA is always related to the severity of pulmonary
complications. For example, children with dysphagia often have
aspiration pneumonia and respiratory distress and rely on mechanical
ventilation earlier.15 The age at gastrostomy is
related to the first appearance of ARF and initiation of continuous
mechanical ventilation.11 Similarly, our study showed
that BMIz is an independent risk factor for RRTIs and/or ARF in children
with SMA, and the risk increases by approximately one and a half times
for every one unit decrease in BMIz. In terms of mechanism, masticatory
muscle weakness, dysphagia and respiratory problems will reduce the
intake of calories, while the work of breathing will increase energy
consumption. As a result, the more severe the children are, the higher
their risk of malnutrition.1 Therefore, it is crucial
to pay attention to the BMIz level to prevent the occurrence of RRTIs
and/or ARF. The appropriate intervention includes adequate nutritional
supplementation, treatment with disease-modifying medications and
treatment with hypopnea.
PSG is the gold standard for the diagnosis of sleep-disordered
breathing, which can be used to monitor the problem of nocturnal
hypopnea in children with SMA. Although expert opinion supports using
PSG for diagnosing and noninvasive ventilation to prevent recurrent
RRTIs and ARF, there is still no specific standard.2The diagnostic criteria for obstructive sleep apnea are only suitable
for patients with obstructive problems in the airway, not for patients
with neuromuscular disorders mainly caused by
hypopnea.16 The Duchenne muscular dystrophy
guidelines17 have proposed the following indication
for nocturnal noninvasive ventilation: PCO2> 6.7 kPa (50 mmHg) or > 1.3 kPa (10 mmHg) of
the awake baseline at least 2% of the total sleep time, oxygen
saturation < 88% for at least five minutes, or AHI
> 5 events/h. This standard may be used as a reference for
SMA, but the data were not obtained from SMA patients themselves. The
questionnaires could be used to assess sleep disorders in
SMA.18 but have limitations of subjectivity because
nocturnal hypopnea can also be found in pediatric SMA patients without
clinical symptoms.19,20 Sleep-disordered breathing is
associated with RRTIs in children with SMA, and long-term noninvasive
ventilation can improve PSG scores and reduce the incidence of
respiratory tract infection.21 Our study used SMA
children as samples and analyzed the association between PSG scores and
the occurrence of RRTIs and ARF, which ensured the objectivity of the
results and applicability to SMA disease. Our study showed that AHI
> 10.2 events/h and MSpO2 <
95.5% suggested a high risk for RRTIs and/or ARF in children with SMA.
Lung function declines with age, and the severity is also related to the
type of SMA.22,23 Our study also showed that the FVC
and PEF % predicted in type 2 were lower than those in type 3 and were
lower in the disease group than in the control group. The raw scores of
FVC and PEF in type 2 were approximately 60% of the predicted scores,
which were approximately 90% in type 3, approximately 40% - 50% in
the disease group, and approximately 60% - 70% in the control group.
Spirometry can only be performed with the cooperation of children over
five years old, so the lung function test could only be used for the
evaluation of older children with types 2 and 3. However, for SMA
patients, type 1 with younger age is more severe and requires closer
observation and proactive intervention. Therefore, for children under
five years old, especially those with type 1, it is more important to
pay attention to BMIz and PSG scores.
Our study showed that age, MI-E usage and EtCO2 were not
associated with RRTIs and/or ARF. The reasons for these inconsistencies
with conventional thinking may be as follows. First, the patient’s
condition should degenerate with age and progression of the disease. The
factor of age should be based on the type and severity of individual
cases. Therefore, there was no correlation in our study because the
subjects included all three types of SMA. The cutoff points of age to
assess the risk for RRTIs and/or ARF for each SMA type might be obtained
if the sample size was sufficient. Second, MI-E usage had a positive
effect on the intervention against respiratory problems in SMA patients
with types 1 and 2.2 However, our study did not show a
correlation, indicating that the effect of MI-E usage should be shown
only in patients who have a weak cough and need airway clearance
techniques. Finally, the diagnostic criterion for sleep-related
hypoventilation diseases is PCO2 > 6.7 kPa
(50 mmHg), which accounts for more than 25% of the total sleep time
according to the international classification of sleep
diseases.24 However, our study showed that in 27
cases, only one child of type 2 with severe adenoidal hypertrophy
complied with the criteria mentioned above. The OAI of this patient was
29.3 events/h, which was much higher than the HI representing hypopnea
of 5.0 events/h. Our study also did not show a correlation between
PCO2 and hypoventilation in children with SMA. This
might be because the tested value of EtCO2 in patients
with neuromuscular disorders was lower than the realistic
value.25 On the other hand, this might be consistent
with the finding from another study that higher values of
PCO2 were not measured in type 1 than in types 2 and 3,
and PCO2 levels during sleep might not be used to
accurately evaluate hypopnea in children with SMA.3,26
Over the last decade, the approach to treating the respiratory
manifestations of SMA has shifted from a reactive approach only when
there is a clear indication to a proactive approach of applying
therapies earlier in the disease process.2 The use of
disease-modifying medications such as nusinersen may delay the decline
in lung function, but the effect on long-term improvement is
unknown.27-29 Proactive respiratory management and
nutrition support still play important roles in the improvement of
living conditions in SMA.30,31 Therefore, the
assessment of BMIz and PSG should be performed. Furthermore,
malnutrition and hypoventilation should be treated to prevent RRTIs and
ARF. Our study showed that the accuracy, sensitivity and specificity of
the standard of MSpO2 < 96% and AHI
> 10 events/h or BMIz < -1 with the occurrence of
RRTIs and/or ARF in SMA were 0.798, 0.513 and 0.957, respectively. The
high specificity meant that children with SMA who reached this standard
would almost certainly develop RRTIs or ARF and should receive
intervention.