Future Directions


     and SAS
  a.1. Indications
         Oral Appliance
   a.3.1. AHI
   a.3.2. Sleep Quality 
             Variables
   a.3.3. 
Sleepiness
   a.3.4. Snoring
   a.3.5. Blood Pressure
   a.3.6. Upper Airway 
             Resistance Syndrome
   a.3.7. Side Effects
         Effect
   a.4.1. Anatomical Factors
   a.4.2. Functional Factors
   a.4.3. Sleep Position 
     Treatment
     SAS
         Periodontal Disease
         Heart Disease
         Metabolic Syndrome
     Appliances
    Studies
     Potentials
     Variation
a. Periodontal Disease and SAS
Periodontal diseases are very prevalent and affect 50-90% of the global population. Periodontitis is a chronic infection by oral bacteria that affects the supporting structures of the teeth and is a major cause of tooth loss in adults [123]. A mechanism has been proposed whereby the burden of bacterial pathogens, antigens, endotoxins, and inflammatory cytokines in periodontitis contributes to the process of atherogenesis and thromboembolic events. In response to infection and inflammation, susceptible individuals may exhibit greater expression of local and systemic mediators and may thereby be at increased risk for a myocardial infarction or stroke [124].

 a.1. SAS as a Risk Factor for Periodontal Disease
Periodontal diseases are caused by microorganisms such as Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans, and Treponema denticola that colonize the tooth surface at or below the gingival margin. In a patient with 28 teeth with pocket depths of 6-7 mm and bone loss, the subgingival surface area of infection could be roughly similar to the surface area represented by both hands [123]. The subgingival bacteria in deep periodontal pockets exist in a highly organized biofilm. Subgingival biofilms represent a large and continuing bacterial load and are a constant source of lipopolysaccharides, as well as Gram-negative bacteria, to the blood stream. Proinflammatory cytokines can reach high concentrations in the tissues of the periodontium. A mechanism has been proposed whereby the burden of bacterial pathogens, antigens, endotoxins, and inflammatory cytokines in periodontitis contributes to the process of atherogenesis and thromboembolic events. In response to infection and inflammation, susceptible individuals may exhibit greater expression of local and systemic mediators and may thereby be at increased risk for a myocardial infarction or stroke [123].

Table 7. Ratio of periodontal disease and lifestyle-related diseases in 219 SAS patients.

SAS patients

Mean ± SD

Mean age (years)

53.4 ± 13.8

Patients (female:male

219 (156:63)

Mean AHI (No./h)

19.1 ± 16.5

Periodontal status

 

Mean pocket depth less than 3mm (%)

2.7

Mean pocket depth -6mm (%)

58.9

Mean pocket depth over 6mm (%)

38.4

Remaining teeth (No.)

26.2 ± 3.8

Bleeding by probing (No.)

6.5 ± 8.3

Other lifestyle-related diseases

 

Obesity (%)

52.1

Hypertension (%)

39.7

Diabetes mellitus (%)

20.5

Heart disease (%)

20.5

Hyperlipidemia (%)

19.2


The ratio of moderate periodontal disease having pockets 4-6mm was 38.4%, and 58.9% of severe periodontal disease patients presenting pockets deeper than 6mm. Patients having periodontal pockets equal to or less than 3mm were only 2.7%, and all had had periodical periodontal treatment. All patients who had not received periodical periodontal treatment had periodontal disease and morbidity was higher than the rates for lifestyle-related diseases such as hypertension or diabetes mellitus.

It has become clear that the majority of SAS patients have periodontal disease (Table 7). In a study by the author [124], the average number of remaining teeth was 26.2. The number of teeth observed to be bleeding by probing showed an average of 5.9. The ratio of moderate periodontal disease having pockets of 4-6mm was 38.4%, and 58.9% showed severe periodontal disease presenting 6mm at the deepest pocket. Patients with periodontal pockets equal to or less than 3mm accounted for only 2.7% of the patients receiving periodical periodontal treatment. The results are based on patients mainly with slight to moderate SAS. Most patients are referred to an expert in sleep medical care who understands that manufacture of an oral appliance is difficult with few teeth. Most patients have periodontal disease with medium or severe grade symptoms, who have not received periodical periodontal treatment. It seems that the ratio of severe periodontal disease increases when we include severe CPAP-managed SAS patients. The reasons why periodontal disease is observed at a high frequency in many SAS patients are the prevalence of both diseases after middle-age, obesity, diabetes mellitus, dryness of the oral cavity due to snoring, diet problems, and excessive occlusal force because of bruxism related to sleep apnea (Figure 23). SAS may be a risk factor for periodontal disease [124]. The relationship among periodontal disease and obesity [125], diabetes mellitus [126] and coronary heart disease has been elucidated. SAS could become an exacerbation factor for a lifestyle-related disease, and obesity is an important risk factor for SAS [124]. If one becomes obese and the internal organs accumulate fat, it increases the risk of developing diabetes mellitus, hyperlipidemia, high blood pressure, and arteriosclerosis. Furthermore, developing coronary heart disease that aggregates these conditions is called metabolic syndrome, and a relationship between SAS and metabolic syndrome has gradually been clarified. Periodontal disease exacerbates lifestyle-related diseases due to slight chronic inflammation, and can aggravate these diseases (Figure 23). In other words, metabolism disorders due to diabetes mellitus and peripheral angiopathy exacerbate periodontal disease. In addition, air is taken in directly via the mouth, and mouth respiration with snoring causes a drying of the gingiva and oral mucosa. This seems to promote progression of periodontal disease so that the self-cleansing and gingival tissue resistance fails. It is thought that "canned coffee syndrome", or drinking large quantities of canned coffee with too much sugar to avoid excessive daytime sleepiness in SAS patients has a bad influence on diabetes mellitus, obesity and periodontal disease. Powerful forces act on teeth in bruxism related to sleep stress and these also accelerate periodontal tissue destruction (Figure 23).



Figure 23. Relationship between periodontal disease and sleep apnea syndrome. SAS acts as an aggravating risk factor of periodontal disease. Periodontal disease or SAS as life-related disease can aggravate a series of life-related diseases.

 a.2. Relationship among Periodontal Disease, Diabetes Mellitus and Heart Disease 
Diabetes mellitus is a common, multifactorial disease process involving genetic, environmental and behavioral risk factors. The chronic condition is marked by defects in glucose metabolism that produce hyperglycemia in patients. The number of Japanese patients with type 2 diabetes (non-insulin-dependent diabetes mellitus) is markedly increasing. This may be due to the rapid Westernization of the lifestyle in Japan. Obesity is the greatest risk factor for diabetes mellitus. Fat cells (adipocytes) in obese patients secrete many cytokines such as tumor necrosis factor (TNF- α), interleukin-6 (IL-6) and leptin. TNF- α is also produced by monocytes or macrophages and plays an important role in inflammation reactions, and it is known to induce insulin resistance [127]. TNF- α is produced by periodontal pockets with chronic periodontal inflammation. It is reported that the serum TNF- α of diabetics is reduced by successful periodontal treatment, and subsequently insulin resistance was improved. It is thought that obesity and diabetes mellitus are important risk factors for periodontal disease. Also, a significant correlation between obesity and periodontal disease is reported [125]. Periodontal disease can induce insulin resistance, and, after initiation, act as promoting factor. It is possible that periodontal disease developing as complication of obesity or diabetes mellitus becomes an aggravating factor for diabetes due to chronic inflammation. The increase in type 2 diabetes mellitus in Asia differs from that reported in other parts of the world: it has developed in a much shorter time, in a younger age group, and in people with much lower body-mass index. There are not so many markedly obese patients with diabetes mellitus in Japan compared with Westerners. This suggests that periodontal disease might exacerbate diabetes mellitus in Japan.

Transient bacteremia can occur due to not only surgical procedures such as extraction of a tooth, but also conservative procedures such as tartar removal. When periodontal bacteria stick to the endocardium and proliferate, it can result in infective endocarditis. The most frequently detected bacteria in infective endocarditis is oral streptococus. Periodontal bacteria are also detected in the tissue of arteriosclerosis.

Coronary heart disease is the most frequent cause of death in diabetics. It has become clear that chronic inflammation participates in the initiation of arteriosclerosis and coronary heart disease, and that C- reactive protein (CRP) promotes aggravation of vascular lesions [128]. CRP acts on the vascular endothelium, and is a promotion factor in arteriosclerosis. The CRP level increases when people are infected by periodontal bacteria. In addition, interleukin-6 of adipose tissue origin induces CRP production from hepatocytes. Severe periodontal disease may thus have an influence on the development of arteriosclerosis (Figure 23).

 a.3. Relationship between Periodontal Disease and Metabolic Syndrome
Lifestyle-related diseases are defined as diseases that appear to increase in frequency as countries become more industrialized and people live longer. They include Alzheimer's disease, atherosclerosis, cancer, chronic liver disease or cirrhosis, chronic obstructive pulmonary disease, type 2 diabetes, heart disease, nephritis or chronic renal failure, osteoporosis, stroke, and obesity. "Healthy Japan 21" targeted the primary prevention of lifestyle-related disease, and it was devised in 2000 by the Minister of Health, Labour and Welfare of Japan. Nine fields including nourishment and eating habits, physical activity and exercise, rest and mental health, smoking, alcohol, dental health, diabetes mellitus, cardiovascular disease, and cancer were chosen. Periodontal disease was chosen along with obesity, hypertension and diabetes mellitus and came to be recognized as a lifestyle-related disease. Most SAS patients suffer from diabetes mellitus, obesity, hypertension, hyperlipidemia, and cardiovascular disease. SAS can become an exacerbating factor for other lifestyle-related diseases. Japanese suffer from SAS more easily compared with Westerners due to their craniofacial morphology characteristics, even if they are not so obese, but about 70% of Japanese SAS patients are also obese. Obesity is an important risk factor for SAS. In addition, SAS is considered to be one of the factors for hypertension. Metabolic syndrome is a combination of medical disorders that increases the risk of cardiovascular disease and diabetes [129]. It affects a large number of people in a clustered fashion. In some studies, the prevalence in the USA is calculated as being up to 25% of the population. The relationship between SAS and metabolic syndrome has gradually been clarified. Periodontal disease is observed in almost all patients as a complication of an SAS lifestyle-related disease, and it occurs at the highest frequency (Table 7). Periodontal disease promotes lifestyle-related disease via slight chronic inflammation, and can augment disease progression even if the degree of obesity is low (Figure 23) [124].

 a.4. Oral Appliance Therapy of SAS and Oral Hygiene
When a patient is referred for oral appliance therapy for SAS, dentists should be aware that periodontal disease is a lifestyle-related disease and that it promotes other diseases. It is necessary to treat periodontal disease [124]. It is important not to disturb self-purification of saliva when we make an oral appliance and not to cover the gingival margin with any device. In addition, it is important to design oral appliances that reduce discomfort and minimize bruxism. It is also important to restrain mouth breathing, and not to dry the oral cavity. We should follow-up periodontal disease along with a periodical follow-up of oral appliances. A patient unaware of SAS and lifestyle-related disease can have a checkup at a dentist for dental treatment (Figure 24). It is necessary for dentists to refer SAS patients with other lifestyle-related diseases for diagnosis and treatment. In addition, dentists should recognize that the majority of SAS patients have periodontal disease and that it can worsen a series of lifestyle-related diseases. It seems meaningful to recommend appropriate dental treatment for patients using CPAP in departments of respiratory medicine or otolaryngology. Recently, the influence of periodontal disease on these diseases and the role of periodontal treatment have been clarified [123]. It is now clear that blood pressure falls significantly after oral appliance treatment [66]. However, the influence on lifestyle-related diseases of periodontal disease in SAS patients, and the changes in condition of patients after oral appliance treatment have not been clarified. This will become a significant clinical issue in the future and medical departments and dentistry departments must cooperate to elucidate the relevance of these diseases [124].



Figure 24. A seventy-year old man (a) was referred to our hospital with chief complaint of discomfort in the oral cavity at the time of getting up. His oral hygiene was extremely bad, absorption of alveolar bone was observed, and he was diagnosed as a severe periodontal disease (b). There were obesity, snoring, daytime sleepiness, too, and SAS was suspected. As a result of sleep study, he was diagnosed as moderate SAS. As a result of blood examination, diabetes mellitus, hyperlipemia became clear, too. It is important for us to cooperate and perform dental treatment and treatment of internal medicine for lifestyle-related diseases such as diabetes mellitus for such cases.

 b. Central Mechanism of SAS and the Effect of Oral Appliances
It is necessary to consider the cortical control activity over the stomatognathic system and have a perception of the oropharynx region when considering the occurrence of sleep apnea. The author measured movement-related cortical potential and contingent negative variation to examine cortical control with jaw movement [130, 131]. Contingent negative variation accompanying a jaw and tongue protrusion task, was measured revealing a difference in the amplitude and distribution of response in SAS patients [9, 124]. Magnetoencephalography has a very high time and space resolving power. The author used a magnetometer to assess the soft palate and record a somatosensory magnetic field, and observed the reaction in second somatosensory field on both sides [132], as well as the reaction reduction during sleep [9, 124]. In addition, the authors measured the brain blood volume with near-infrared spectroscopy, jaw closing and opening movements, tongue protrusion movement, a measurement at the time of pronunciation, brain blood volume changes during sleep, and those in the frontal lobe during a word fluency task [124]. In the future, such non-invasive brain function measurements will provide new information on the central mechanism of SAS occurrence, its changes related to oral appliance therapy, and choice of oral appliance therapy.

 c. Future oral Appliance
The author has treated over 2,000 patients with SAS using mainly oral appliances [9, 19, 22, 39]. The patients sometimes experienced a transitory discomfort of the masticatory muscle or temporomandibular joint, excessive salivation, and transient tooth discomfort after first using the device. It would be very meaningful to develop a new treatment device with fewer complications for safe and long-term use. The author aims to develop a device which allows free jaw movements during sleep and advance the mandible if sleep apnea occurs based on respiratory pattern sensoring. The device could be combined with CPAP. When sleep apnea occurs, the device protrudes the mandible, and even if the apnea disappears, the positive airway pressure additionally works to diminish any remaining upper airway obstruction. The device could minimize the airway pressure because it prevents patients from mouth breathing, air-leak, and upper airway collapse by advancing the lower jaw. Many patients with severe SAS have been intolerant to CPAP because of discomfort related to the high pressure sensation and air-leak. This device will be highly beneficial for such patients and patients with poor compliance with standard CPAP or other oral appliances [124].