New Perspectives on the Pathogenesis of OSA - Anatomic Perspective. New Perspectives on the Pathogenesis of OSA: Anatomic Perspective - Disclosures

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1 New Perspectives on the Pathogenesis of OSA - Anatomic Perspective Richard J. Schwab, M.D. Professor of Medicine Interim Chief, Division of Sleep Medicine Medical Director, Penn Sleep Centers University of Pennsylvania Perelman School of Medicine New Perspectives on the Pathogenesis of OSA: Anatomic Perspective - Disclosures NIH grants - PPG (phenotyping and OSA) ResMed Grant/Registry to study OSA/CSA and CPAP in hospitalized patients Jazz clinical trial (JZP-110) for daytime sleepiness in OSA Inspire CT study to examine upper airway anatomy with hypoglossal nerve stimulation 1

2 New Insights into the Pathogenesis of Sleep Apnea: Anatomic Perspective Physical examination/anatomic risk factors for OSA Anatomic pathogenesis of OSA Increased size of upper airway soft tissues Importance of tongue fat Dynamic upper airway imaging during respiration Modified Mallampati Classification Class 1 Class 2 Class 3 Class 4 Tsai et al, AJRCCM 167, , 2003 Mallampati et al. (1985). A clinical sign to predict difficult tracheal intubation: a prospective study. Can Anaest Soc J, 32(4), ,

3 Modified Mallampati Classification What is this patient s Modified Mallampati score? Anatomic Risk Factors for Sleep Apnea Obesity and its effects on the upper airway tissues Increased neck circumference Nasal airway restriction: septal deviation, allergic rhinitis, nasal polyps Macroglossia/tongue ridging Adeno-tonsillar hypertrophy (palatine/lingual tonsils) Lateral peritonsillar narrowing Enlargement/elongation of the soft palate Recessed mandible (retrognathia)/maxilla Narrowed hard palate - overbite/overjet A combination of soft tissue and/or craniofacial risk factors is likely most important 3

4 Morphometric Measurements (Schellenberg AJRCCM 162; , 2000) Macroglossia: tongue being above level of mandibular occlusal plane Uvula enlargement: > 1.5 cm in length or > 1.0 cm in width Enlargement of lateral walls: > 25% impingement pharyngeal space by peritonsillar tissues Tonsillar enlargement: > 50% lateral impingement of posterior pharyngeal airspace Normal Upper Airway (Schellenberg et al, AJRCCM 162; , 2000) 4

5 Physical Examination and Sleep Apnea (Schellenberg et al, AJRCCM 162; , 2000) Physical Examination and Sleep Apnea (Schellenberg et al, AJRCCM 162; , 2000) 5

6 Normal Upper Airway (Schellenberg et al, AJRCCM 162; , 2000) Lateral Pharyngeal Grading System Class I = palatopharyngeal arch intersects at the edge of the tongue Class II = palatopharyngeal arch intersects at 25% or more of the tongue diameter Class III = palatopharyngeal arch intersects at 50% or more of the tongue diameter Class IV = palatopharyngeal arch intersects at 75% or more of the tongue diameter Tsai, et al. A Decision Rule for Diagnostic Testing in Obstructive Sleep Apnea. American Journal of Respiratory and Critical Care Medicine, Vol. 167, No. 10 (2003), pp

7 Physical Examination and Sleep Apnea (Schellenberg et al, AJRCCM 162; , 2000) Narrowed Hard Palate and Sleep Apnea 7

8 Physical Examination and Sleep Apnea (Schellenberg et al, AJRCCM 162; , 2000) Physical Examination and Sleep Apnea (Schellenberg AJRCCM 162; , 2000) Adjusted Odds Ratio (OR) for Sleep Apnea Physical Finding OR 95% CI Lateral Narrowing 2.6* Tonsillar hypertrophy 2.1* Macroglossia Enlarged soft palate Retrognathia *Maintained significance after adjusting for BMI/neck size 8

9 Digital Morphometrics: A New Paradigm to Assess Upper Airway Anatomical Risk Factors for Obstructive Sleep Apnea) Schwab, R. et al., (2017). Digital Morphometrics: A New Upper Airway Phenotyping Paradigm in OSA. Chest., 152(2). doi: /j.chest Quantify Anatomic Risk Factors for OSA with Digital Morphometrics/Laser Ruler Schwab, R. et al., (2017). Digital Morphometrics: A New Upper Airway Phenotyping Paradigm in OSA. Chest., 152(2). doi: /j.chest

10 Upper Airway Soft Tissue and Craniofacial Measurements Schwab, R. et al., (2017). Digital Morphometrics: A New Upper Airway Phenotyping Paradigm in OSA. Chest., 152(2). doi: /j.chest Intraoral Photographs with Indicated Measures Schwab, R. et al., (2017). Digital Morphometrics: A New Upper Airway Phenotyping Paradigm in OSA. Chest., 152(2). doi: /j.chest

11 Craniofacial Photograph with Laser Ruler The mandibular length is measured from the marked mandibular angle to the most prominent point on the chin Schwab, R. et al., (2017). Digital Morphometrics: A New Upper Airway Phenotyping Paradigm in OSA. Chest., 152(2). doi: /j.chest Examples of the Four Classes of Modified Mallampati Class I indicates full visibility of the uvula and tonsillar fossa Class II indicates visibility of upper portion of the uvula and partial visibility of the upper airway Class III indicates visibility of the hard palate and base of the uvula Class IV indicates visibility of the hard palate and no visibility of the soft palate Schwab, R. et al., (2017). Digital Morphometrics: A New Upper Airway Phenotyping Paradigm in OSA. Chest., 152(2). doi: /j.chest

12 Digital Morphometrics: A New Paradigm to Assess Upper Airway Anatomical Risk Factors for Obstructive Sleep Apnea - Demographics Measure All Patients Controls (AHI<10) Apneics (AHI 10) N Estimate N Estimate N Estimate p Age ± ± ± 12.8 < BMI ± ± ± 9.9 < Gender Male % % % Female % % % Race Caucasian % % % African % % % Other % % % AHI ± ± ± 29.4 < ln(ahi+1) ± ± ± 0.67 < Schwab, R. et al., (2017). Digital Morphometrics: A New Upper Airway Phenotyping Paradigm in OSA. Chest., 152(2). doi: /j.chest Digital Morphometrics: A New Paradigm to Assess Upper Airway Anatomical Risk Factors for Obstructive Sleep Apnea - Results Measure All Patients Controls (AHI<10) Apneics (AHI 10) N Estimate N Estimate N Estimate p Modified Mallampati Class I % % % Class II % % % Class III % % % Class IV % % % Airway Not Visible % % % Mouth Width ± ± ± Mouth Height ± ± ± Mouth Area ± ± ± Tongue Width ± ± ± 0.57 Schwab, R. et al., (2017). Digital Morphometrics: A New Upper Airway Phenotyping Paradigm in OSA. Chest., 152(2). doi: /j.chest <

13 Digital Morphometrics: A New Paradigm to Assess Upper Airway Anatomical Risk Factors for Obstructive Sleep Apnea - Results Measure All Patients Controls (AHI<10) Apneics (AHI 10) N Estimate N Estimate N Estimate p Mouth Width ± ± ± Tongue Width ± ± ± 0.72 <0.001 Tongue Length ± ± ± Tongue Area ± ± ± Tongue Thickness ± ± ± 0.28 < Tongue Curvature ± ± ± Airway Width ± ± ± Uvula Length (Airway) ± ± ± Uvula Width (Airway) ± ± ± Uvula Area (Airway) ± ± ± Mandibular Length ± ± ± 1.05 <0.001 Mandibular Width ± ± ± 1.04 < Schwab, R. et al., (2017). Digital Morphometrics: A New Upper Airway Phenotyping Paradigm in OSA. Chest, 152, 2017 Associations Between Photography Measurements and OSA and AHI - Conclusions Apneics had higher scores on all measures of Mallampati, less airway visibility, larger mouth width and area, and larger tongue width and thickness Also had more severe pharyngeal narrowing within the subpopulation where this measure was quantifiable Measurements of intraoral crowdedness showed the strongest associations in OSA and AHI status Apneics tended to have more crowded or less visible airways than controls Schwab, R. et al., (2017). Digital Morphometrics: A New Upper Airway Phenotyping Paradigm in OSA. Chest., 152(2). doi: /j.chest

14 Different Imaging Modalities to Phenotype the Upper Airway Morphometric examination/digital photography Cephalometrics - craniofacial skeleton Nasopharygnoscopy - awake and sleep induced (Propofol) Acoustic Reflectance - airway Optical Coherence Tomography - airway lumen Computed Tomography Magnetic Resonance Imaging Normal Subject (Mid-Sagittal View) (Schwab, Am J Resp Crit Care Med 152: , 1995) Soft Palate Tongue Airway Mandible Subcutaneous Fat Retropalatal Retroglossal Subcutaneous Fat 14

15 Normal Subject (Axial View) (Schwab, Am J Resp Crit Care Med 152: , 1995) Airway Tongue Pharyngeal Wall Mandible Mandible Parapharyngeal Fat Pad Parotid Pharyngeal Wall Spinal Cord Subcutaneous Fat Sagittal Upper Airway MR Images (Schwab, Am J Resp Crit Care Med 152: , 1995) Normal Subject Apneic Patient 15

16 Axial Upper Airway MR Images (Schwab, Am J Resp Crit Care Med 152: , 1995) Normal Subject Apneic Patient Schwab et al, AJRCCM 168; , 2003 Tongue Mandible Parapharyngeal Fat Pads Airway Normal Subject Soft Palate Pharyngeal Walls Tongue Mandible Parapharyngeal Fat Pads Airway Patient with Sleep Apnea Soft Palate Pharyngeal Walls 16

17 Volumetric Anatomic Risk Factors for Sleep Apnea (Cases/Controls: N = 96) (Schwab et al, AJRCCM 168; , 2003) Adjusted Odds Ratio (OR) for Sleep Apnea: Soft Tissue Volume OR 95% CI Fat pads Lateral Walls 6.01* Soft Palate Tongue 6.55* Total Soft Tissue 6.95* Adjusted for gender, ethnicity, age, craniofacial size and visceral neck fat * = Significant Why are Upper Airway Soft Tissue Structures Enlarged in Apneics? Edema from negative pressure Changes in blood flow/redistribution leg edema Muscle disorder/function/exercise Vibration/snoring/surface tension Weight gain/obesity Gender Ethnicity Genetic factors 17

18 Airway Airway Airway Normal Airway Apneic We Still Do Not Understand the Effect of Obesity on Upper Airway Tissues Increased volume of adipose tissue (several studies have demonstrated this) In parapharyngeal fat pads increased tissue pressure?? Within tongue does this size and function? Fat under mandible and subcutaneous Increased muscular tissue with weight gain? Increase in size of lateral walls, tongue, soft palate 18

19 Images from the Nashi autopsy study [Laryngoscope 117; , 2007]. Left panel (A) shows a sagittal image of the tongue demonstrating a significant amount of fat in the posterior third of the tongue and in the sublingual region below the intrinsic tongue muscles; bottom (B) is a schematic demonstrating the percent of tongue fat in the anterior, posterior and sublingual regions in 121 tongue autopsy specimens. The right panel demonstrates another autopsy specimen with a significant amount of tongue fat. Psoas muscle Tongue Histomicrographs of psoas muscle (A: top) and tongue (B: bottom) in an obese subject. Note there is greater fat in the tongue than the psoas muscle. Nashi Laryngoscope 117; ,

20 Anterior and posterior percentage tongue fat correlates with increasing body mass index Nashi et al, Laryngoscope 2007; 117: Study Objectives (Kim et al, Sleep 37; , 2014) The primary goal of this study was to identify alterations in fat deposition within the tongue of obese apneics in comparison to obese subjects without sleep apnea using the three-point Dixon method (a method for fat/water discrimination) Compared tongue fat to fat in the masseter muscles Examined tongue fat topography Compared men and women 20

21 Kim et al, (Sleep 37; , 2014) 21

22 Demographics of Case and Control Subjects (Kim et al, Sleep 37; , 2014) Apneics (n=90) Controls (n=31) Factor Mean SD Mean SD t test (p value) Age, years BMI, kg/m < AHI, events/hour < Gender, M:F 42:48 10: Race, C:AA 39:51 18: Definition of abbreviations: AHI=apnea/hypopnea index; BMI=body mass index; C=Caucasian; AA=African American 22

23 Comparison of Muscle Volumes and Intramuscular Fat in Case and Control Subjects (Kim et al, Sleep 37; , 2014) Apneics (n=90) Controls (n=31) Soft Tissue Volume Mean SD Mean SD t Test (p value) 2 p Tongue, mm 3 101,193 17,651 85,542 13,813 < Tongue fat, mm 3 32,791 9,175 23,390 5,511 < Tongue fat, % Left masseter, mm 3 16,204 6,633 14,517 6, Left masseter fat, mm Left masseter fat, % Significant differences (p < 0.05) are presented in bold. 2 p indicates after adjustment for age, BMI, gender, and race Comparison of Muscle Volumes and Intramuscular Fat in Apneics and Controls (Kim et al, Sleep 37; , 2014) Tongue volume and tongue fat increased in apneics compared to controls. No differences in masseter volumes or masseter fat volume 23

24 Kim et al, (Sleep 37; , 2014) Correlations between Muscle Volumes and Intramuscular Fat and AHI in Apneics (Kim et al, Sleep 37; , 2014) Increases in tongue volume and tongue fat increased the AHI 24

25 Main Findings (Kim et al, Sleep 37; , 2014) Obese apneics have enlarged tongue volumes and increased fat within the tongue in comparison to obese normal subjects after adjustment for differences in age, BMI, gender, and race There is a heterogeneous distribution of fat within the tongue Tongue fat distribution in apneics is increased in specific locations of the tongue (greater in the retroglossal region) Tongue size and tongue fat are correlated with AHI No difference in tongue fat between apneic men and women Importance of Tongue Fat (Kim et al, Sleep 37; , 2014) Increased tongue fat increases AHI by increasing the size of the tongue (affects airway collapsibility and size) but may also adversely affect muscle function Increased intramuscular fat may contribute to changes in contractile performance or tongue shape What is the purpose of tongue fat? Why do some individuals have greater tongue fat deposition - genetic/high fat diet? Is this visceral fat? New therapeutic options (upper airway exercises, weight loss, hypoglossal nerve stimulation, dietary 25

26 Anatomical Imbalance The interaction between upper airway soft tissue structures and craniofacial structures Watanabe, et al. AJCCM 165:260, 2002 Icelandic Sleep Apnea Cohort (ISAC) (Schwab et al, in preparation) All patients diagnosed with OSA in Iceland and referred for CPAP treatment at the Landspitali University Hospital in Reykjavik, Iceland, from September August subjects had MRI (upper airway, neck and abdomen) and PSG (Embletta) All apneics with wide range of severity - AHI/ODI Three BMI categories < 30, 30-35, > 35 kg/m 2 Men and women but mostly men 26

27 Intra-Mandibular Volume (IMV): the Amount of Tissue within the Box (Schwab et al, in preparation) Severity of AHI: Based on Craniofacial and Soft Tissue Interactions in Men in ISAC (Schwab et al, in preparation) Total Soft Tissue (mm 3 ) IMV (mm 3 ) AHI n = ,241 ± 24, ,539 ± 32,518 AHI n = ,874 ± 26, ,533 ± 32,669 TST/IMV Ratio 1.12 ± ± 0.12 AHI 50 n = ,314 ± 26, ,042 ± 27, ± 0.13 Unadjusted p *Adjusted p *Adjusted for BMI and age The ratio of the total soft tissue (TST) to intramandibular volume (IMV) was significantly greater in the patients with the most severe apnea 27

28 Relationship of Tongue Size, Mandibular Length and AHI in ISAC Schwab et al, in preparation Log AHI was greatest when tongue volume was largest and mandibular length was smallest Dynamic Upper Airway Imaging During Wakefulness in Obese Subjects with and without Sleep Apnea (Feng et al, AJRCCM conditionally accepted) Methods: Subjects included 157 obese apneics and 46 obese controls Dynamic magnetic resonance imaging was performed during wakefulness in the midsagittal and three axial upper airway regions (retropalatal, retroglossal, epiglottal) Differences in measurements were examined using linear regression 28

29 Dynamic Upper Airway Imaging During Wakefulness in Obese Subjects with and without Sleep Apnea (Feng et al, AJRCCM conditionally accepted) A) Mid sagittal image showing the location of the axial images (RP, RG and Epi) B) Mid sagittal image showing the upper boundary set through the top of hard palate and lower boundary through the bottom of C4; the airway between these two boundaries represents the mid sagittal airway area and the perpendicular distance between two boundaries is the length of airway. Dynamic Upper Airway Imaging During Wakefulness in Obese Subjects with and without Sleep Apnea (Feng et al, AJRCCM conditionally accepted) C E are examples of images in the three axial regions: retopalatal (C),retroglossal (D) and epiglottal (E). F shows an example of the method used to measure airway lateral and anterposterior dimensions. The lateral and anterposterior dimensions are measured in the three axial regions. RP = retropalatal, RG = retroglossal, EPI = epiglottal, AA = airway area, AL = airway length, UB = upper boundary, LB = lower boundary, AP = anterposterior, LAT = lateral 29

30 Mid-Sagittal Dynamic MRI Mid-Retropalatal Dynamic MRI 30

31 Mid-Retroglossal Dynamic MRI Demographic Characteristics of the Study Sample Measure Overall AHI 5 AHI 15 p N Age, years 48.9 ± ± ± 10.5 < Male, % 44.8% 37.0% 47.1% Race, % Caucasian 43.4% 43.5% 43.3% African American 53.2% 52.2% 53.5% Other 3.5% 4.4% 3.2% BMI, kg/m ± ± ± 7.8 < AHI, events/hour 33.4 ± ± ± 27.3 < Significant (p<0.05) differences shown in bold; p-value from T-test or chi-squared test comparing OSA vs. controls for continuous or categorical variables, respectively. Dynamic Upper Airway Imaging During Wakefulness in Obese Subjects with and without Sleep Apnea (Feng et al, AJRCCM conditionally accepted) 31

32 Dynamic Airway Measurements in Apneics and Controls Measurement AHI 5 AHI 15 N Mean ± SD N Mean ± SD p Mid-Sagittal Average airway area, mm ± ± CV of airway area, % ± ± Airway length in slice with maximum area, mm ± ± Airway length in slice with minimum area, mm ± ± Maximum airway area corrected for length, mm ± ± Minimum airway area corrected for length, mm ± ± Middle Soft Palate (Retropalatal) Average airway area, mm ± ± CV of airway area, % ± ± Maximum airway area, mm ± ± Minimum airway area, mm ± ± Lateral distance at maximum area, mm ± ± Lateral distance at minimum area, mm ± ± AP distance at maximum area, mm ± ± AP distance at minimum area, mm ± ± Significant or suggestive (p<0.05) differences shown in bold. p-value from T-test comparing dynamic measure between apneics and controls. CV = coefficient of variation. Dynamic Upper Airway Imaging During Wakefulness in Obese Subjects with and without Sleep Apnea (Feng et al, AJRCCM conditionally accepted) Dynamic Airway Measurements in Apneics and Controls Measurement AHI 5 AHI 15 N Mean ± SD N Mean ± SD Middle Tongue (Retroglossal) Average airway area, mm ± ± CV of airway area, % ± ± Maximum airway area, mm ± ± Minimum airway area, mm ± ± Lateral distance at maximum area, mm ± ± Lateral distance at minimum area, mm ± ± AP distance at maximum area, mm ± ± AP distance at minimum area, mm ± ± Middle Epiglottis (Epiglottal) Average airway area, mm ± ± CV of airway area, % ± ± Maximum airway area, mm ± ± Minimum airway area, mm ± ± Lateral distance at maximum area, mm ± ± Lateral distance at minimum area, mm ± ± AP distance at maximum area, mm ± ± AP distance at minimum area, mm ± ± Significant or suggestive (p<0.05) differences shown in bold. p-value from T-test comparing dynamic measure between apneics and controls. CV = coefficient of variation. Dynamic Upper Airway Imaging During Wakefulness in Obese Subjects with and without Sleep Apnea (Feng et al, AJRCCM conditionally accepted) p 32

33 Dynamic Upper Airway Imaging During Wakefulness in Obese Subjects with and without Sleep Apnea (Feng et al, AJRCCM conditionally accepted) Conclusions: Upper airway caliber during respiration was significantly narrower in obese apneics than obese controls in the retropalatal region There were strong correlations between AHI and dynamic airway caliber in the retropalatal and retroglossal regions These findings provide further evidence that retropalatal airway narrowing plays an important role in the pathogenesis of OSA in obese subjects New Perspectives on the Pathogenesis of OSA: Anatomic Perspective - "Take Home Messages" Increased volume of upper airway soft tissue structures is an important risk factor for sleep apnea Reduction in mandibular size is also an important risk factor for OSA The combination of increased upper airway soft tissue structures and reduced craniofacial skeleton increases OSA risk Tongue fat may explain the relationship between obesity and sleep apnea During respiration upper airway caliber is significantly narrower in obese apneics than obese controls in the retropalatal region 33

34 New Perspectives on the Pathogenesis of OSA - Anatomic Perspective Thank you for your attention! Any Questions? 34