Craniofacial dystrophy: A possible syndrome relating malocclusion, sleep-disordered breathing, allergies, depression and a range of other diseases

by Ricardo Meneghin21 min read8th Aug 20203 comments


MedicineDepressionEvolutionWorld Modeling

A 2015 nature piece describes craniofacial dystrophy:

A possible pathological process underlying malocclusion, which relates malocclusion with a range of other diseases and problems.

I've related the article's hypothesis with my knowledge of the other mentioned conditions and have further researched their relationship. Here is what I found.

Allergic Diseases and the Atopic March

The atopic march refers to the natural history of allergic diseases as they develop over the course of infancy and childhood. Classically, the atopic march begins with atopic dermatitis, and progresses to food allergy, asthma, and allergic rhinitis.

In accordance with the atopic march, ashtma and atopic dermatitis are more common in children and decrease in prevalence going into adulthood, when the prevalence of allergic rhinitis dominates over the other two.

Allergic rhinitis and asthma lead to impaired breathing, reduced quality of life and are a major burden associated with increased medical visits and spending.

In "The burden of allergic rhinitis", the author writes:

Although formerly regarded as a nuisance disease, allergic rhinitis (AR) has a considerable effect on quality of life and can have significant consequences if left untreated. The total burden of this disease lies not only in impaired physical and social functioning but also in a financial burden made greater when considering evidence that AR is a possible causal factor in comorbid diseases such as asthma or sinusitis. Compared with matched controls, patients with AR have an approximate twofold increase in medication costs and 1.8-fold the number of visits to health practitioners. Hidden direct costs include the treatment of comorbid asthma, chronic sinusitis, otitis media, upper respiratory infection, and nasal polyposis. Nasal congestion, the most prominent symptom in AR, is associated with sleep-disordered breathing, a condition that can have a profound effect on mental health, including increased psychiatric disorders, depression, anxiety, and alcohol abuse. Furthermore, sleep-disordered breathing in childhood and adolescence is associated with increased disorders of learning performance, behavior, and attention. In the United States, AR results in 3.5 million lost workdays and 2 million lost schooldays annually. Patients struggle to alleviate their misery, frequently self-adjusting their treatment regimen of over-the-counter and prescription medications because of lack of efficacy, deterioration of efficacy, lack of 24-hour relief, and bothersome side effects. Ironically, health care providers overestimate patient satisfaction with therapy. Therefore, improvement in patient–practitioner communication may enhance patient adherence with prescribed regimens.

A relationship between allergic disease and dental malocclusion has been reported in the literature. A study found that children with a history of allergic rhinitis had a threefold increased risk to develop one or more dento‐skeletal alterations. Allergic rhinitis is known to cause breathing alterations such as mouth breathing which lead to abnormal skeletal development.

The prevalence of asthma and/or allergic rhinitis in the general population is estimated to be around 20%.

Depression and Anxiety

The relationship between allergic rhinitis and mood syndromes has also been studied. Allergic patients have an increased probability of presenting comorbid psychiatric disorders such as anxiety, depression and psychosis. A review of the literature found that "the majority of studies [..] indicate associations between allergies and anxiety/mood syndromes, despite a number of methodological variances".

They list a few factors which could mediate the relationship between allergies and mood. I've merged them into what I believe are two possible non-exclusive explanations (more on that later):

1) Some unknown factor, possibly a shared genetic risk, disturbs immune response causing both mood disorders and allergies

The immune system is usually divided into two mutually inhibitory systems, Th1 and Th2. Th1 is responsible for cellular immunity and Th2 for molecular (antibodies) immunity. The Th1/Th2 balance has been shown to be abnormal in allergic patients, with an increased Th2 activity towards innocuous, non-pathological substances. As the body encounters and fights allergens, increased inflammation ensues, something which is known to cause lethargy and depressed mood, and antidepressants have been shown to decrease inflammation in the body. Observational studies have even found a possible positive effect of the non-steroidal anti inflammatory drugs diclofenac and ketoprofen on mood.

From an evolutionary standpoint, it could be the case that the body has evolved to have less activity during periods in which it fights infection, saving energy and increasing fitness. A genetic variant or another factor which causes abnormalities in the immune response could thus increase the chance of developing both allergies and mood disorders.

2) Airway obstruction disturbs sleep with subsequently negative effects on psychiatric symptoms

Allergy related nasal obstruction impairs breathing and leads to a number of learned compensatory mechanisms, like re-positioning the tongue and mandible, that can only be performed during the day; when the body is asleep, the compensatory mechanisms are not performed and breathing is even more severely impaired. Disturbed breathing leads to microarousals which repeatedly interrupt deep sleep, altering the sleep architecture towards N1 and N2 stages and away from REM and N3 stages. Sleep deprivation is known to cause depressed mood and further exacerbate abnormal immune responses.

This has been widely studied in the context of obstructive sleep apnea syndrome, where the airway is partially or fully blocked for a period greater than 10 seconds leading to oxygen desaturation in the blood, but the effect of less severe (but possibly more frequent) obstruction has been less studied.

The Obstructive Sleep Apnea Syndrome

Obstructive sleep apnea syndrome (OSAS) is a condition in which breathing repeatedly stops during sleep for periods longer than 10 seconds, resulting in lower oxygen saturation in the blood, cerebral arousal, increased cardiac effort and impaired sleep, which leads to fatigue, daytime sleepiness, obesity, cardiovascular disease and generally increased morbidity.

It was first described by Christian Guilleminault, a french doctor who died in 2019.

From Wikipedia:

Guilleminault persuaded cardiologists John Shroeder and Ara Tilkian to spend nights in the hospital's clinical research center monitoring the systemic and pulmonary arterial blood pressure in sleeping patients. The team observed that when patients fell asleep and began snoring, prolonged pauses in their breathing (apneas) were noted that corresponded with dramatic elevations in their resting blood pressure, simulating strenuous exercise as if the patient were lifting weights. Guilleminault then went on to publish several articles illustrating dramatic improvements and reversal of sleep apnea following tracheostomies. Tracheostomy proved curative in these patients, and demonstrated reversal of cardiac arrhythmias and blood pressure abnormalities during sleep; temporarily capping these artificial airways would re-capitulate the changes of sleep apnea, further establishing the causative relationship between sleep apnea and cardiovascular abnormalities.
Guilleminault then went on to describe obstructive sleep apnea in non-obese patients, being the first to coin the term "obstructive sleep apnea syndrome" (OSAS), a term commonly used nowadays. In addition, he described the presence of OSAS in children, demonstrating its association with learning and attention problems along with cardiovascular derangements.

OSAS is highly correlated with an increased neck circumference, older age, high blood pressure and with being male. It is currently diagnosed through a sleep study called a polysomnography, which measures several variables to determine the frequency of breathing interruption during sleep, summarized in the apnea-hypopnea index (AHI). This index measures how many times there is a significant or total reduction of airflow per hour.

Older, obese patients frequently have AHI ranging from 15 to 60, indicating a large number of arousals during the night. A device called CPAP was developed to increase the pressure in the airway during sleep and prevent the airway from collapsing. It proved to be greatly effective in the treatment of OSAS, but patient compliance is poor and many remain untreated. The device involves attaching a mask that the patient breathes through, leading many to find it non tolerable.

Apnea events can also have a neurological cause; if that is the case, they are called central apneas. The cause of central apneas isn't well understood, but it is hypothesized that repeated obstructive apneas could lead to nerve damage of the airway muscles over time, causing the muscles to respond poorly and the airway to become obstructed.

There is a large overlap between the sleepiness and fatigue symptoms of OSAS patients and the symptoms of depression, and children with OSAS have been shown to have a higher incidence of depressive symptoms and attention deficit hyperactivity disorder. OSA is commonly comorbid with depression (17–45 %) and schizophrenia (up to 55 %)[source].

Another study found a very high prevalence of sleep-disordered breathing among adolescents with treatment resistant depression. This study found that the severity of depression had a statistically significant correlation of moderate magnitude with the severity of respiratory disturbances during sleep (the RDI).

A number of antidepressants have been shown to reduce the AHI and lead to improved sleep.

One study on the effects of trazodone on OSAS found that "trazodone resulted in a significant reduction in AHI (38.7 vs. 28.5 events/h, P = 0.041), without worsening oxygen saturation or respiratory event duration". Another found that "trazodone at 100 mg increased the effort-related arousal threshold in response to hypercapnia in obstructive sleep apnoea patients and allowed them to tolerate higher CO2 levels".

Trazodone is, however, a potent alpha adrenergic antagonist, which leads to peripheral vasodilation and increases nasal congestion.

A controlled trial on the effects of mirtazapine on OSAS found:

Daily administration of 4.5 to 15 mg of mirtazapine for 1 week reduces AHI by half in adult patients with OSA. This represents the largest and most consistent drug-treatment effect demonstrated to date in a controlled trial.

The authors, however, advised against the use of mirtazapine in the treatment of OSAS, since weight gain and sedation are well known side effects and both very undesirable in that context.

What is the proposed mechanism behind the supposed effect of mirtazapine on SDB? The authors of the first human study provide a possible explanation:

[..] it is now established that during wakefulness serotonin, most probably acting through 5-HT2A receptors, provides a tonic excitatory input to hypoglossal motor neurons innervating the genioglossus and other upper airway dilating muscles. It follows that withdrawal of this serotonergic input during sleep might predispose to airway obstruction in the form of apnea or hypopnea. Accordingly, systemic administration of 5-HT2 receptor antagonists to English bulldogs—an animal model of obstructive sleep apnea/hypopnea—reduced upper airway caliber and muscle tone.5 Conversely, serotonin promotion by a combination of trazadone and l-tryptophan reduced the apnea-hypopnea index (AHI) in this model system.6 This therapeutic rationale has been tested in both openlabel and blinded placebo-controlled clinical studies designed to promote serotonergic activity in the brain. Collectively, studies using either serotonin precursors7 or reuptake inhibitors8,9 have demonstrated limited promise for reducing SRBD severity during non-rapid eye movement (NREM) sleep, but no benefit has been observed during rapid eye movement (REM) sleep.

Mirtazapine's happens to be a potent 5-HT2A antagonist.

This result failed to replicate in two subsequent studies. The authors list possible reasons for their result, which was inconsistent with the previous human study and studies performed in an animal model of OSAS, that also showed a beneficial effect, but with no clear explanation. One possibility is that the response at week 1, which was the duration of the first study, is different than that at week 2, the minimum duration of the other studies. As a direct antagonist of 5-HT2A, chronic mirtazapine administration could lead to up-regulation of the receptors and thus decreased efficacy.

Trazodone also happens to be a potent 5-HT2A antagonist, as are the atypical antipsychotic drugs clozapine, olanzapine, quetiapine, risperidone and asenapine.

The chronic administration of the most popularly used antidepressants, the selective serotonin reuptake inhibitors, is also known to desensitize 5-HT2A receptors.

Several studies have also found relationships between 5-HT2A gene polymorphisms and sleep disordered breathing or psychiatric disorders. A study found the 1438G-A polymorphism was associated with OSAS, as did another. The same polymorphism has been linked to bipolar disorder, major depressive disorder, anorexia nervosa and panic disorder.

In the famous 2018 systematic review and network meta-analysis of 21 antidepressant drugs, mirtazapine was found to be the second most effective antidepressant, lagging behind only amitriptyline, and to be as tolerable as placebo.

I haven't found any studies investigating the effect of amitriptyline on sleep disordered breathing, but a study on the similar dibenzocycloheptadiene Protriptyline found:

Apnea, as a percent of disordered breathing time, fell from 60.4 ± 27.2% to 35.5 ± 26.7% (p < 0.01) and was accompanied by a reduction in the peak fall in oxygen saturation from 16.2 ± 6.2% to 9.2 ± 4.7% (p < 0.01). During REM sleep there was no change in the pattern, duration, or frequency of SDB, or reduction in the peak fall in oxygen saturation. However, there was a reduction in the amount of Stage REM sleep, thereby reducing the more severe SDB events (p < 0.01) and further improving nocturnal oxygenation. In 10 of 12 patients, there was subjective improvement in daytime hypersomnolence, which was associated with an increase in median sleep onset time from 3.3 ± 2.2 to 5.1 ± 2.1 min (p < 0.01).

Many antidepressants and antipsychotics are also potent antitistamines. Mirtazapine is the most potent antihistamine ever discoreved, the mechanism responsible for it's sedation and weight gain side effects, as H1 receptor activation leads to wakefulness and suppresses appetite. Antihistamines are particularly known in the context of treating allergies, since peripherally histamine is involved in the inflammatory response and has a central role as a mediator of itching.

After studying OSAS, Guilleminault studied a different group of patients presenting with clinical symptoms similar to those of OSAS, such as fatigue and complaints of poor sleep and mood, but without any accompanying obesity or old age, and which presented a low to mild AHI index. This profile made them unfit to the usual diagnostic criteria for moderate/severe OSAS. Guilleminault went on to describe a second sleep syndrome that could explain the observations in this group: the upper airway resistance syndrome.

The Upper Airway Resistance Syndrome

This syndrome was first identified in a group of children in 1982 and later fully described in adults in the 1993 article which coined the Upper Airway Resistance Syndrome (UARS) term.

Guilleminault found that, despite having a low AHI and none of the usual risk factors for OSAS, these patients had a different type of respiratory arousal at night in which there was increased respiratory effort without an accompanying total blockade of the airway, but still resulting in EEG abnormalities and causing sleep fragmentation. All studied subjects had upper airway anatomy that was mildly abnormal, and treatment with CPAP showed to be effective in reducing the arousals and improving clinical symptoms. Later, the RERA polysomnography measure was developed to register this new kind of arousal.

It was further found that people with UARS more frequently have hypotension instead of hypertesion, with accompanying dizziness, and a narrow, high arched palate. Teeth extractions and malocclusion were found to be predisposing factors.

This disease has generated controversy in the medical community as to whether it should really be considered a separate disorder to OSAS, be considered a milder point in the spectrum of OSAS, or as to whether it even exists. I find this controversy highly absurd given the disease was described by the very person who *invented* sleep medicine. As a result of this debacle though, the disease has been understudied and undertreated.

Separate disorder or not, treatment to UARS is similar to the treatment of OSAS, notably the use of CPAP or corrective surgical or orthodontical procedures to improve breathing (more on that later). However, even after almost 30 years of it's description, recognition has lacked and many patients with these complaints go on without treatment because they don't match the diagnose criteria for moderate/severe OSAS.

Together with OSAS, UARS encompasses a group of disorders called sleep disordered breathing.

Estimates of the prevalence of sleep disordered breathing

Several studies have estimated the prevalence of sleep disordered breathing in the general population. Most only studied the prevalence of OSAS.

A study published in The Lancet recorded polysomnography data from 2121 people in Lausanne, Switzerland. The results were alarming:

The median apnoea-hypopnoea index was 6·9 events per h (IQR 2·7–14·1) in women and 14·9 per h (7·2–27·1) in men. The prevalence of moderate-to-severe sleep-disordered breathing (≥15 events per h) was 23·4% (95% CI 20·9–26·0) in women and 49·7% (46·6–52·8) in men. After multivariable adjustment, the upper quartile for the apnoea-hypopnoea index (>20·6 events per h) was associated independently with the presence of hypertension (odds ratio 1·60, 95% CI 1·14–2·26; p=0·0292 for trend across severity quartiles), diabetes (2·00, 1·05–3·99; p=0·0467), metabolic syndrome (2·80, 1·86–4·29; p<0·0001), and depression (1·92, 1·01–3·64; p=0·0292).

It should be noted that it's very likely that this is an overestimation due to selection bias. However, other studies have also found a large incidence of SDB; usual numbers vary from 5% to 20%.

Research on the prevalence of UARS is extremely scarce, with a single Brazilian study estimating the prevalence of UARS, excluding patients with an AHI of more than 15, at 16%.

Functional somatic syndromes

The term functional somatic syndrome refers to a group of chronic diagnoses with no identifiable organic cause. It encompass disorders such as chronic fatigue syndrome, fibromyalgia, chronic widespread pain, temporomandibular disorder, irritable bowel syndrome, lower back pain and others.

Researchers have for long struggled to find an explanation for these conditions, and treatment is done on a symptomatic basis or with therapy, with generally unsatisfactory results. Their very name implies that those are purely psychological diseases, without a real underlying, treatable cause.

A study was done to elucidate the relationship between the functional somatic syndromes and the upper airway resistance syndrome. The researchers found that "the symptoms/signs of UARS closely resemble those of the functional somatic syndromes".

Cancer, cardiovascular disease, and others

Cardiovascular disease is the leading global cause of death, closely followed by cancer. It is widely known that obesity leads to cardiovascular disease, but the relationship between sleep and cardiovascular disease and cancer is much less publicized.

A study on the association between cardiovascular disease and SDB found:

Sleep-disordered breathing was associated more strongly with self-reported heart failure and stroke than with self-reported coronary heart disease: the relative odds (95% CI) of heart failure, stroke, and coronary heart disease (upper versus lower AHI quartile) were 2.38 (1.22–4.62), 1.58 (1.02– 2.46), and 1.27 (0.99–1.62), respectively.

Another study of chronic heart failure found that SDB was present in 76% of patients (40% central (CSA), 36% obstructive sleep apnoea (OSA)).

Regarding cancer, a systematic review and meta-analysis found:

In the unadjusted analysis, patients with SDB/OSA were at an increased risk of incident cancer (relative risk [RR]: 1.53, 95% confidence interval [CI]: 1.31–1.79, P <0.001, I2: 0, five included studies). When adjusted for traditional cancer risk factors, the association between SDB/OSA and cancer incidence, although attenuated (RR: 1.40, 95% CI: 1.01–1.95, P = 0.04, I2: 60%, five included studies), remains significant.

A meta-analysis of 4 million people found that SDB is associated with a 26% increase in the risk of developing dementia.

A meta-analysis of 2,343 stroke sufferers found that the frequency of SDB with AHI > 5 was 72% and with AHI > 20 was 38%.

A meta-analysis on polycistic ovary syndrome found that "risk of OSA was significantly increased in adult patients with PCOS (odds ratio (OR) 9.74, 95% CI: 2.76–34.41)".

A review found that "published studies, as well as our own pilot data support the hypothesis that SDB, secondary to adenotonsillar hypertrophy increases the risk of growth failure in children".

A study on the chest wall deformity pectus excavatum found that "the prevalence of OSA in patients with PE seemed to be higher than that previously reported in the general population, implying that OSA might be a potential etiology or, at least, an aggravating factor for the development or progression of PE", a claim later substantiated by another study.

Whether these associations are causative or not remains to be further elucidated. Improvement of these conditions/outcomes following SDB treatment could point to a causal relation existing.

The most popular surgical treatment for nasal obstruction is ineffective at treating sleep disordered breathing

If you have ever been to an ENT doctor with complaints of nasal obstruction, you were probably told you had a deviated septum and enlarged turbinates, and that you needed to surgically correct the deviation and reduce the turbinate tissue. Many patients find relief after the procedure. Some may develop empty nose syndrome, a condition in which the patient feels obstruction symptoms despite an open airway, or atrophic rhinitis, a condition in which the soft tissues of the nasal cavity atrophy. Turbinectomy involves the reduction or complete removal of a functional organ, which is something that doesn't sound good from a first-principles, evolutionary standpoint, and which has led to absurd practice in the past, like widespread tonsillectomy.

In accordance to that, a meta-analysis has shown that turbinectomy and septoplasty are ineffective in treating OSAS. There was a small reduction in the AHI from 35.2 to 33.5 and also a reduction in the sleepiness scale scores, but the post-treatment AHI remained very high (remember an AHI of 33 means you wake up during sleep every 2 minutes, for a period too short to remember).

Once you analyse the full anatomy of the skull and the upper airway, this is no surprise at all. Septoplasty and lower turbinectomy cannot touch the pharynx or even the upper and medium turbinates, so they can only achieve partial improvement in the airflow. Since the airway is a pipe, it is subject to bottlenecks: if a single portion of it is constricted, you will have reduced airflow. It is also limited to working on the skeletal space of the nasal cavity: what if the whole nasal cavity and airway are too small and that is what is causing obstruction?

If that is the case, a procedure intended to improve breathing during the night needs to increase the volume of the whole upper airway, all the way from the nostrils to the trachea. If the airway is smaller than ideal for airflow, you shouldn't simply cut the turbinates, which moisturize and filter air and exist for an evolutionary reason. You should increase the volume of the airway.

Craniofacial dystrophy: reduced airway volume and malocclusion are both caused by skeletal abnormalities

In the Nature piece, craniofacial dystrophy is described as a abnormal change in the shape of the modern human skull in relation to that of earlier humans. The signs are described as such:

The maxilla and the surrounding bones are the most affected, both in position and shape, although their overall volume remains relatively constant. [..] the maxilla drops down and back [..]. This reduces the eye support; flattens the cheekbones; narrows the nasal airway; lengthens the mid facial third; and lowers the palate, which narrows.

This puts forward the hypothesis that nasal/airway obstruction is caused by a change in the skull format that has been happening since the agricultural revolution. The author lists a few possible causes for this change, which will be discussed later below.

If the skull is deformed, fixing the deformity could prove to have beneficial effects on nasal obstruction and sleep disordered breathing.

And it has.

Reducing craniofacial dystrophy effectively treats sleep-disordered breathing

A 2016 systematic review and meta-analysis found that maxillary and maxillomandibular expansion are effective treatments for obstructive sleep apnea syndrome in adults. In the maxillary expansion studies, the mean AHI decreased from 24.3 to 9.9, and from a mean of 47.53 to 10.7 in the double maxillary and mandibular expansion studies. Some patients were completely cured of their apnea, and this is without the use of a CPAP device, the usual treatment for moderate to severe sleep apnea.

Maxillary or palatal expansion is the expansion of the upper jaw bone, frequently done in children to fix crossed bite, a type of malocclusion. It involves the use of a device (haas or hyrax) placed on the roof of the mouth and attached to teeth at both sides, which slowly expands in width, pushing your top teeth further apart and fixing their bad occlusion with lower teeth. This also causes an expansion of the bony roof of your mouth, the hard palate, making it wider and lower.

The thing is: the hard palate is literally the same bone that makes the bottom of the nasal cavity, the nasal floor. By widening and lowering the palate, you are effectively increasing the nasal cavity in width and height, greatly increasing the nasal airflow and improving breathing, leading to the large AHI reductions observed in these studies. See these images to better understand the anatomy of the nasal cavity: nasal cavity cross section, nasal ct scan post and pre maxillary expansion. It was found in a 2019 study that a mean increase of 3.47mm of the nasal cavity width led to an increase of 30.28% in the inspiratory peak flow.

How exactly does the bone expand? The skull bones have things called sutures, which are fibrous joints around which growth occurs. In children, because of growth, the sutures are not yet closed, so simply applying force will cause them to separate and new bone to grow in the resulting gap. In children, tooth-borne rapid palatal expansion (RPE) will result in an expansion of the jaw at the dental (changing teeth inclination), alveolar (widening and deforming the spongious bone that the tooth root attaches to) and skeletal (widening the dense bony part that divides the nasal cavity and the mouth, where the suture is located) levels. However, in adolescent and adults, the palatal suture has already fused, such that RPE has no effect on the skeletal level, only on the dentoalveolar level.

To circumvent this, orthodontists developed a technique called Surgically Assisted Rapid Palatal Expansion (SARPE). This is a procedure in which the palatal suture is separated surgically, allowing a device to generate expansion on the suture like it does on children. This comes with the disadvantage and side effects of having a surgery performed.

Enter the scene mini-implant assisted rapid palatal expansion (MARPE). Doctors discovered that the palatal suture isn't really that strongly fused in adults, and, if you apply enough force to it, it will eventually split. So they developed a technique in which you insert mini screws into the bone and then expand a device attached to these screws, resulting in an almost pure skeletal expansion. MARPE causes changes in the whole maxillary-zygomatic complex by weakening sutures and moving bones all over to accommodate the new palate width, effectively causing your bony nasal walls to rotate outwards, leading to a triangular shaped expansion in the nasal cavity from top to bottom. Small changes in the width of the nasal cavity in this manner lead to dramatic increases in the airflow, as the previously mentioned 2019 study found.

MARPE could also result in an improvement of nasal septum deviations. By increasing the height of the nasal cavity, you are effectively stretching the septum, which is attached to the top and bottom of the cavity, thus straightening it. Research on this possibility is still scarce, with a single study finding a beneficial effect of traditional RPE in children and another finding no effect (of traditional RPE) on adolescents (but remember, the suture is closed after age 12, so this is expected). This is merely speculation on my part, but the very reason the septum becomes deviated could be that, as a cartilaginous tissue, it overgrows the abnormal bony nasal cavity that contains it, being forced to bend.

While the expansion of the maxilla/nasal cavity alone had a large effect on the AHI index, the nasal cavity isn't the only space air has to grow trough to get to your lungs. After the nasal cavity, we have three other distinct segments through which air flows: the nasopharyx, the oropharynx and the hypopharynx (see this image). They are the segments that come behind the soft palate, behind the tongue and behind your mandible.

Maxillary expansion has unclear effect on the naso/oropharynx and no effect on the hypopharyx, because limited space in in these areas comes from having a receded maxilla and mandible, and maxillary expansion isn't very good at bringing the maxilla forward (in this direction, there are studies on the association of a regular MARPE expander with a face mask which pulls the maxilla forward) and does not affect the mandible at all. Unlike the nasal cavity, these structures can also have their size reduced by surrounding fat, which further complicates the situation and contributes to apnea, as research has found.

Enter the scene the second part of the meta-analysis: mandibular expansion. Unlike the palate, there is no suture in the mandible that can be expanded. The mandibular symphysis, the suture in the middle of your chin, is closed at age two and cannot be expanded even in children. To overcome this, doctors use a procedure called distraction osteogenesis, which involves making a surgical cut, generating an artificial gap, that can then be expanded exactly in the same way as the maxilla. This takes advantage of the natural healing process of bone fractures. The chin is expanded, causing a slight rotation outwards of each of the mandible sides. This makes the mandible slightly longer, and the chin significantly wider, depending on the magnitude of the expansion, and leaves more space for your tongue to move forward, lowering the soft palate and liberating space in the oro and hypopharynx in a way that maxillary expansion can't.

Is maxillomandibular expansion (not to be confused with maxillomandibular advancement, an extremely invasive surgery which is also very effective) a complete cure for SDB then? Not quite. First, there were only 2 studies analysed, so the data is very scarce. It's hard to see how mandibular expansion could worsen the outcomes of maxillary expansion alone, so we should expect maxillomandibular expansion to be, at the very least, as effective as maxillary expansion. However, even in the studies analysed, there was still residual AHI after the procedures, so there are unknown factors remaining to be fixed.

I hypothesized that one remaining problem in these patients could be fat limiting the space in the pharynx, which isn't fixable by maxillomandibular expansion. I looked further into the studies data to check for this possibility.

The first study was simply a case report of a patient with an extremely high AHI of 80, which reduced to 9 after treatment, but the patient's BMI wasn't reported.

The second study was performed by Guilleminault (the previously mentioned discoverer of both OSAS and UARS) and Kasey Li, another authority in the subject. It was a small study of only 6 patients, but they recorded BMI data. The 4 patients that were in the normal BMI range all had a post-treatment of AHI <2, but they had mild AHI to begin with. The other 2 patients were in the overweight range (BMI 26), had moderate/severe pre-treatment AHI, and ended up with mild post-treatment AHI. I think it's hard to take conclusions from this little data but, since excess weight is already known to contribute to OSAS and a range of other diseases, losing weight if you're overweight is a great recommendation anyway.

I haven't looked at the data in the maxillary-only expansion studies, but I suspect a similar relationship may be found.

What else does maxillary and/or mandibular expansion treat? If research on the effect of RPE on sleep disordered breathing on adults is scarce, research on its other effects is nearly non-existent. A case report of an adolescent with treatment resistant depression found that after performing RPE despite no orthodontic recommendation, the patient experienced "a marked improvement of his sleep quality, anxiety, fatigue and sleepiness", and that "his improvement has been maintained off all psychotropic medication and his depression has remained in remission for approximately two years". The researchers go as far as speculating that "the symptoms of upper airway resistance syndrome are non-specific enough that every adolescent with depression, even those responding to medication, may have underlying sleep disordered breathing".

Even given the scarcity of research in this area, it's not hard to extrapolate the positive benefits maxillary expansion could have on psychiatric, immune and cardiovascular symptoms of patients with sleep disordered breathing, given the widely studied relationship between these conditions.

Research shows fixing the skull can greatly improve nasal obstruction. But why has the skull become deformed in the first place?

Changes in dietary habits in the last centuries are causing craniofacial dysthropy: the masticatory effort hypothesis

The author of the nature article puts forward the hypothesis that changes towards softer food, early stop of breast-feeding and swallowing pattern could be etiological factors involved in craniofacial dystrophy.

From the article:

Masticatory effort: Between the Neolithic and Medieval periods it was common to completely wear away the clinical crown by the age of 45. This was due to a tougher, more fibrous, less calorific diet and non-nutritive uses, such as leather processing and tool making. Compared to modern attrition this suggests a massive reduction in muscle usage over this time period. The effect of changes in the action of the masticatory muscle due to strokes, nerve damage, muscular dystrophy or animal experiments on the anterior craniofacial structure (ACS) are well established and well-marked.
Posture: [..] If the nasal airway is blocked then the tongue and mandible are lowered, the lips separated and the head postured forwards. [..] The effects of a change in the mode of breathing and tongue posture in isolation on the AFC are unequivocal.
Swallowing pattern: In an ideal adult swallow, the tongue should push upwards, outwards and forward on the palate and the perioral muscles should be passive. This now seems rare, with most individuals displaying some perioral activity, with a 'suckling like' swallow, that pulls backwards and inwards on the dentition and does not support the maxilla. The teeth and alveolus are pulled inward and backwards, reducing the tongue space. The suggested cause has been a lack of breast-feeding, however, the author also proposes the early introduction of semi-solid foods before the adult swallowing reflex is fully developed as a factor.

As humans move towards ever softer food, masticatory effort reduces and craniofacial dystrophy increases. I'll not expand too much on this hypothesis since it's already covered in the article and in it's supporting references.

The hygiene hyphotesis

From Wikipedia:

In medicine, the hygiene hypothesis states that early childhood exposure to particular microorganisms (such as the gut flora and helminth parasites) protects against allergic diseases by contributing to the development of the immune system.

I put forward the hypothesis that craniofacial dystrophy could also be exacerbated by increased hygiene, mediated by the resulting respiratory allergies.

The link between allergies and microbe exposition during early childhood is well reported. Studies have found an association of cesarean delivery with the incidence of asthma. This relationship could be confounded by and increased rate of cesareans in wealthier mothers; however, a study found that the effect was more pronounced in cesareans in which there was no membrane rupture, pointing towards something in cesarean delivery having a causative effect in the increased incidence of asthma. This is not a small effect either: the ratio of asthma from cesarean to vaginal birth was found to be 2.18.

Birth is the first time the immune system has contact with the external world, and could be an important point of first calibration of the immune response. By reducing early contact with microbes which generate Th1 responses, there could be a resulting increase in the Th2 activity, leading the immune system to become less tolerant and to attack innocuous substances, also known as allergy.

Children that grow with larger numbers of siblings and pets are also known to have reduced incidence of allergic diseases and asthma. The development of allergy follows a U shaped curve in relation to the early childhood exposure to the allergen: both no exposure or high exposure leads to reduced allergy, and moderate exposure leads to increased allergy. With no exposure, the immune system does not generate a antibody response and thus no allergy develops. High exposure will lead to tolerance.

Children that grow in cities have a higher rate of allergic diseases than children who grow in the rural area, as do wealthier children compared to their poorer counterparts.

After the body has developed allergies, the ensuing airway obstruction could lead to the compensatory mechanisms listed above, exacerbating craniofacial dysthrophy. The airway obstruction would further increase during development due to the ensuing skeletal abnormalities, exacerbating allergy through lack of sleep. In Primate experiments on oral respiration, researchers blocked the airway of rhesus monkeys with silicon plugs and observed them for 3 years, with the following findings:

In general, the experimental animals maintained an open mouth. Some increased the oral airway rhythmically, while others maintained the mandible in a lower position with or without protruding the tongue. All experimental animals gradually acquired a facial appearance and dental occlusion different from those of the control animals.

What exact kinds of changes were observed?

The common finding was a narrowing of the mandibular dental arch and a decrease in maxillary arch length, causing an incisor cross-bite. Animal 7042 developed the most severe dental malocclusion of this type, a full Class III according to Angle’s classification [..]
Some animals developed other types of malocclusion. The permanent maxillary canines erupted into cross-bite in Animal 6992 but showed a strong tendency to upright themselves after the nasal respiration had been restored and the animal could again keep its mouth closed (Fig. 2). Animal 8108 developed a severe open-bite, but a neutral molar relationship was maintained (Fig. 4), while animal 16440 developed a maxillary overjet and overbite with a tendency toward a Class II molar relationship

The first line treatments for allergic rhinitis and asthma are nasal and inhaled corticosteroids. Corticosteroids have been shown to impair bone growth, leading to reduced stature in asthmatic children that receive this treatment modality. Nasal corticosteroids have little known systemic effects, but could still potentially impair bone growth in the nasal cavity, given the proximity to the nasal mucosa to which they are delivered. This could cause the palate to become narrow and elevated as the rest of the skull bones grow around it, leading to an under-developed nasal cavity and long term nasal obstruction. I have found no research investigating this possibility.

In conclusion, I have found this hypothesis to be remarkably elegant and have powerful explanatory power for most of the above observations. We are observing ascending trends in the rates of several diseases in the general population, yet our genetics is nearly identical to that of early humans. Dietary changes, hygiene and sedentary lifestyle are arguably the most striking environmental changes modern humans have faced, so it could be the case that they are main factors driving the observed increase in the incidence of those diseases. Other changes worth investigating are increased loneliness and air pollution, both of which are related to immune impairment and/or respiratory diseases.

I believe this is a criminally understudied area which looks to be the crux of the problem regarding sleep-disordered breathing, with possible ramifications to many other non-communicable diseases, which have seen a steady rise in the past century and which impact the quality of life of millions of people across the world.