Down syndrome: Tongue stimulation device reduces sleep apnea in adolescents


A surgically implanted device that moves the tongue forward during sleep was found to safely and effectively reduce sleep apnea in adolescents with Down syndrome, according to a new study published April 21 in JAMA Otolaryngology – Head & Neck Surgery.

Children with Down syndrome are significantly more likely to have obstructive sleep apnea and current treatment options are often ineffective.

The implantable pacemaker-like device, called a hypoglossal nerve stimulator, may offer a new treatment option for this medically underserved population, according to the study’s authors.

They plan to build upon the findings and test the treatment in additional clinical trials looking at outcomes including improvements in neurocognition and language ability.

“This study was born out of the frustration of not having an effective treatment option for children with Down Syndrome who struggle with sleep apnea,” said lead study author Christopher Hartnick, MD, MS, director of the Division of Pediatric Otolaryngology and the Pediatric Airway, Voice and Swallowing Center at Mass Eye and Ear, and professor of Otolaryngology–Head and Neck Surgery at Harvard Medical School.

“Sleep apnea significantly impacts these children, often affecting their language, behavior and ability to do well in school. Any diminishment in these areas is critical for families, and our study suggests we may finally have an option to help.”

Sleep apnea’s disproportionate impact on Down syndrome community

Pediatric obstructive sleep apnea occurs when a child’s airway is blocked during sleep, causing snoring, difficulty breathing and restless sleep. For any child, it can result in daytime sleepiness, behavioral issues and learning challenges.

However, the condition is particularly prevalent in children with Down syndrome: About 80 percent of children with Down syndrome have obstructive sleep apnea, compared to 5 percent of the general pediatric population.

Children with Down syndrome and sleep apnea are more likely to experience aggressive behavior, brain fogging and a loss of nearly 10 points in IQ compared to those without.

Surgery to remove the adenoids and tonsils is the traditional first-line treatment option for opening the airway, but studies have shown less than 30 percent of children with Down syndrome benefit from the procedure.

Experts believe this may be because children with Down syndrome are more likely to have a larger tongue. Another procedure, a tongue base surgery, can be painful with limited evidence of effectiveness. What’s more, children with Down syndrome often have difficulty adhering to continuous positive airway pressure (CPAP) therapy due to sensory difficulties.

Upper airway stimulation using a hypoglossal nerve stimulator is a well-studied sleep apnea treatment in adults who can’t tolerate CPAP therapy.

The hypoglossal nerve stimulator is a Food and Drug Administration-approved device that is surgically implanted in an outpatient setting. When the device senses someone trying to take a breath, it sends an electrical pulse to the hypoglossal nerve that controls the tongue, causing it to move forward in the mouth, thereby opening the airway.

Testing device for safety and efficacy

This phase I clinical trial was the first to test the device in a pediatric population with Down syndrome.

In the study, 42 adolescents with Down syndrome and severe obstructive sleep apnea between the ages of 10 and 22 were recruited across five U.S. medical centers. They all underwent surgery to implant the hypoglossal nerve stimulator and were tracked for one year.

The researchers measured participants’ apnea-hypopnea index (AHI), which is a measurement used to indicate severity of sleep apnea by counting the number of apnea events per hour during a sleep study. In children, an AHI of 0-to-1 is normal, 1-to-5 is mild sleep apnea, 6-to-10 is moderate and anything more than 10 events per hour is considered severe.

At one year follow-up, 27 patients (66 percent) responded well to treatment; the AHI of these patients decreased by at least 50 percent. On average, the patients reduced their AHI by 12.9 events per hour following treatment, a drop of more than 51 percent.

Following treatment, 30 patients (73.2 percent) had an AHI under 10 events per hour, 14 patients (34.1 percent) had an AHI under 5 events per hour, and three patients (7.3 percent) had an AHI under 2 events per hour.

Quality-of-life surveys filled out by parents reported significant improvements in daily functioning, behavior and language.

The procedure was also found to be safe overall. The most common adverse event was tongue discomfort in five patients, which typically resolved in weeks.

According to the researchers, the findings move them closer towards their goal of providing enough data to the FDA to approve the indication of this device for children younger than age 18 with Down syndrome.

“Sleep apnea remains one of the most common conditions that I grapple with working with patients with Down syndrome and their families,” said study co-author Brian Skotko, MD, MPP, the Emma Campbell Endowed Chair on Down Syndrome at Massachusetts General Hospital.

“Until now, so many of our patients had run out of treatment options, and their health and well-being were declining. Now, with the hypoglossal nerve stimulator treatment, we may have an effective and safe way to treat apnea and maximize brain health for people with Down syndrome.”

Findings fuel further study

The new research lays the groundwork to conduct further studies. According to Dr. Hartnick, the findings raise a need for looking at additional outcome measures besides AHI. Even children who had an AHI reflecting moderate to severe sleep apnea after surgery still reported quality-of-life improvements, which suggests neurocognition might be a more appropriate outcome to study, he said.

“Although our results were compelling, it revealed that we need to carefully look at what other outcome measures we’re using,” said Dr. Hartnick. “That’s what our next study is looking for.”

Dr. Hartnick and Dr. Skotko received a $4 million, five-year grant from the National Institutes of Health (NIH) in January 2021 to study if upper airway stimulation might improve neurocognition and language in young patients with Down syndrome.

“When parents reported anecdotally that the implant seemed to improve speech in their loved ones, we knew that we needed to investigate this further,” added Dr. Skotko. “The NIH grant will enable us to formally analyze improvements that the implant may or may not have on speech and cognition.”

The number of patients referred to sleep units has risen recently; however, the global need is not sufficiently met. As the results of our study revealed, patients had to wait for PSG, which renders the prediction of patients with severe OSA quite significant. Accordingly, studies conducted to this end have been limited in number, and their conclusions have been contradictory. The results of our study revealed, contrary to our initial hypothesis, that we were not able to predict severe OSA in children with DS through age, sex, exposure to second-hand smoke, clinical findings, anthropometric features, and the presence of comorbidities.

Although the correlation between obesity and the significance of sleep apnea in adult patients with DS has been proven, such a correlation in children with DS is not clear. Although some studies have not been able to demonstrate a relationship between BMI and SBD [19, 31, 32], others, such as that by Basil et al., found that moderate and severe OSA was more frequent in patients with obesity [27]. In a study by Chamseddin et al., children with obesity were found to have severe OSA more frequently [25]. Despite that the AHI scores of the obese/overweight group were higher than the others, interestingly, no significant relationship between BMI percentiles, BMI-z-scores, and overweight/obesity, and moderate or severe OSA was detected in the present study.

There may be various reasons why such a relationship is seen among adults, but it varies among children; it is important to clarify this point through further studies. We believe that this situation stems from the facts that OSA is not affected only by obesity and DS has multiple predisposing factors for OSA, apart from obesity. As a result, determining the contribution of obesity in DS requires studies with larger groups of participants.

As is the case with obesity, the relationship between predisposing comorbid conditions and OSA in children with DS remains obscure in limited studies. In their study conducted with infants with DS, Goffinski et al. argued that there was a relationship between OSA and certain comorbid conditions such as CHD, prematurity, and GERD. However, very few patients in the study received full-night PSG [23]. On the other hand, Diez et al. found no relationship between CHD and SBD in their study [31]. Even though comorbidity presence was questioned on a large scale in the present study, we failed to identify a relationship between comorbid conditions and severe OSA. It was notable that the increasing number of comorbid conditions was not associated with severe OSA. There was only a relationship between congenital heart disease and the number of comorbidities detected for AHI ≥ 5. However, there was no significant relation in regression analysis. The relation between age group and AHI ≥ 5 was explained by the fact that young children with severe OSA findings were referred for PSG.

Diez et al. found that male sex, being younger than 8 years, and tonsillar hypertrophy predicted OSA [31], and Dyken et al. reported that older age and elevated BMI could be associated with more severe OSA in their study conducted with 19 patients [10]. Yet, in a study conducted to ascertain predictors for OSA by Hills et al., the authors found no correlations between OSA and age, BMI, and tonsil size [33]. Only a few of the studies in the literature specifically aimed to predict severe OSA, as was the case in our study. It was, however, quite challenging to predict OSA, especially severe OSA in patients with DS, as was shown by the examples and the results of our study. There may be many reasons why the prediction of severe OSA is challenging because DS manifests many of the predisposing conditions to OSA. However, our results indicate that congenital heart diseases and the number of comorbidities may be important in predicting moderate to severe OSA, and more studies are needed on this subject.

To the best of our knowledge, our study is the first to show the relationship between smoke exposure and an increase in sleep-related symptoms. Our results revealed no significant differences in other parameters such as sex, anthropometric measures, comorbidities, and PSG features between symptomatic and asymptomatic patients. Similarly, Howard et al. reported no association between reported symptoms and the degree of AHI [11]. We found that 37% of children with OSA had no symptoms related to sleep abnormalities. Also, high rates of severe OSA were prevalent, even in children without a history of SBD (40%), in line with the results of Maris et al. (53.8%) [34]. The fact that severe OSA was seen in patients with DS, including the asymptomatic patients, reveals the importance of PSG screening in such patients.

The results of our study and others indicate that OSA is common in children with DS, and more than half (53.1%) have severe disease, as was the case in the study conducted by Maris et al. (52%) (34). Studies in the literature reported varying results regarding the prevalence of OSA (33). There may be many reasons for such differences; the characteristics of the patient population, the type of PSG performed, the definition of sleep apnea, and the methodological differences in the studies. Our study included patients with a wide age range, the majority of whom had been referred because of sleep-related symptoms, and the sleep unit in the study was based at a large referral center. Moreover, full-night PSG was performed on all children. The prevalence of OSA might have been found higher than those of some other studies in the literature due to these reasons.

To the best of our knowledge, our study is the first to show that the caregivers of patients with DS had very little knowledge of sleep disorders. A great majority of parents (89%) did not know about sleep disorders until they were referred to the sleep unit. Previous studies demonstrated the underestimation of sleep-related symptoms by parents of children with DS [19, 35]. Some of the parents interviewed within the scope of our study indicated that they were not aware of their children experiencing sleep-related symptoms or believed that such symptoms were normal for their children. Such underestimation might be based on their lack of information. Offering information to parents at the onset of diagnosis can lead to better observations of OSA symptoms. It is, therefore, important for physicians performing routine follow-ups of children with DS to be adequately sensitive about this matter.

The prevalence of CSA ranges between 1 and 5% in the pediatric age group; it is seen rarely after the age of 2 years due to maturation of the central nervous system [36]. The association of CSA and certain diseases such as the Prader-Willi syndrome, Arnold-Chiari malformations, and achondroplasia was reported previously [36, 37]. However, only a few reported increases in the frequency of CSA in DS [30, 38]. Our results demonstrated that CSA in children with DS was twice as common than in other children. Moreover, we also documented a high frequency of predominant central apneas. However, even though the central apnea index is higher at younger ages, that there was no significant difference in patients younger and older than 2 years proves to be one of the interesting results of our study. In a study by Fan et al., the central apnea ratio was higher in children younger than 3 years of age. The authors argued that central apneas could be related to immature respiratory central control and hypotonia seen in early childhood based on this finding [39]. In another study, in which 10 patients with DS were compared with patients with fragile X syndrome, it was reported that central apneas were predominant in patients with DS and that it increased by age. The authors suggested that the underlying cause of this might be brainstem dysfunction [38]. Similarly, the results of our study emphasize the importance of central apneas, but the relationship between central apnea and age in DS still needs to be clarified by a larger cohort in prospective studies.

In our study, it was also observed that adenotonsillectomy procedures were not often performed, despite about half of our patients having severe OSA. Some studies reported that upper respiratory system procedures had limited benefits for the treatment of OSA in patients with DS [40]. Hill et al. stated that physicians might be reserved about the issue due to the limited information about OSA-related morbidities in children with DS, along with the limited number of studies on DS and tonsillectomy [33]. Further prospective studies are needed to clarify this issue.

Our study had several limitations. First, the study population age group represented a wide range. We included all children with DS regardless of the reason for referral, which might have caused bias. Also, our study was conducted at a large referral hospital in Turkey; therefore, the disease severity could have been different from the general population of children with DS. Also, children with and without upper airway surgery were included. We did not include overnight carbon dioxide measurements because they were absent in more than half of the patients; thus, we could not evaluate hypoventilation. A standardized sleep questionnaire could not be performed because of the long duration of the study period and the COVID-19 pandemic, which is one of the most significant limitations of our investigation. Although demographic and PSG data were retrospectively collected in our study, all retrospective data were confirmed through phone interviews with the families. The strength of our study was the questioning of important points such as the families’ levels of information, retrospective awareness by phone interview.

reference link :

More information: Evaluation of Upper Airway Stimulation for Adolescents With Down Syndrome and Obstructive Sleep Apnea, JAMA Otolaryngology–Head & Neck Surgery (2022). DOI: 10.1001/jamaoto.2022.0455


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