1. Correlation of CPAP, BiPAP, and AutoPAP use with intraocular Correlation of CPAP, BiPAP, and AutoPAP use with intraocular pressure in patients with sleep apnea and glaucoma. pressure in patients with sleep apnea and glaucoma. Daniel J. Watson B.S. 1, Anita Vin M.D. 2,and Shuchi Patel M.D. 2 1 Loyola University Chicago, Stritch School of Medicine, Maywood, IL 2 2 Department of Ophthalmology, Loyola University Chicago Stritch School of Medicine, Maywood, IL Introduction Several studies have shown that obstructive sleep apnea (OSA) is related to pathology of the eye. Correlations between OSA and floppy eyelid syndrome, primary open angle glaucoma (POAG), normal tension glaucoma (NTG), nonarteritic anterior ischemic optic neuropathy (NAION), papilledema, and keratoconus have all been shown [4,12]. Our research team is interested in the relationship between obstructive sleep apnea and glaucoma (GLC). Evidence has shown that people with sleep apnea are more likely to have glaucoma and people with glaucoma are more likely to have sleep apnea [12]. OSA results in impaired oxygen supply to the optic nerve. This results in neuropathy and degeneration of retinal ganglion cells in the nerve fiber layer with concomitant loss of vision. Recently, there has been some controversy over whether or not positive airway pressure (PAP) used to treat OSA raises intraocular pressure [1,2,6,7,8]. Intraocular pressure (IOP) is currently the only modifiable risk factor for glaucoma. High intraocular pressure inhibits blood flow and trophic factors needed to support the optic nerve and retinal ganglion cells. In this study, we looked at different positive airway pressure machines and how they affected the IOPs of patients with both OSA and GLC (POAG + NTG) and in patients with just OSA. No previous research study has measured IOPs of patients with both OSA and GLC while on PAP therapy. Purpose By understanding the effects of different positive airway pressure machines on intraocular pressure, we can better manage patients who have been diagnosed with both sleep apnea and glaucoma. If our study happens to find that one machine increases intraocular pressure less, then perhaps the treatment modality for patients with both sleep apnea and glaucoma needs to be modified to prevent raised intraocular pressure and further progression of glaucoma. Methods Introduction and Purpose Background Continued Background Discussion Continued Summary References 1. Alvarez-Sala R, Díaz S, Prados C, et al. Increase of intraocular pressure during nasal CPAP. Chest. 1992 May;101(5):1477. 2. Alvarez-Sala R, García IT, García F, et al. Nasal CPAP during wakefulness increases intraocular pressure in glaucoma. Monaldi Arch Chest Dis. 1994 Dec;49(5):394-5. 3. Antonescu-Turcu A and Parthsarathy S. CPAP and Bi-level PAP therapy: new and established roles. Resp Car. 2010 Sep; 55(9):1216-28 4. Dhillon S, Shapiro CM, Flanagan J. Sleep-disordered breathing and effects on ocular health. Can J Ophthalmol. 2007; 42(2): 238-43 5.Epstein LJ et al. Clinical guideline for the evaluation, management and long-term care of obstructive sleep apnea in adults. J Clin Sleep Med. 2009 Jun 15;5(3):263-76. 6. Kiekens S, DeGroot V, Coeckelbergh T, et al. Continuous positive airway pressure therapy is associated with an increase in intraocular pressure in obstructive sleep apnea. Invest Ophthalmol Vis Sci. 2008 Mar;49(3):934-40. 7. Melki L, Haller, M, Pepin JL, et al. Sleep apnea and intraocular pressure: effects of continuous positive airway pressure treatment. Invest Ophthal Vis Sci 2005; 46: E-Abstract 4834 8. Pepin JL, Chiquet C, Tamisier R, et al. Frequent loss of nyctohemeral rhythm of intraocular pressure restored by nCPAP treatment in patients with severe apnea. Arch Ophthalmol. 2010 Oct; 128(10): 1257-63 9. Punjabi NM. The epidemiology of adult obstructive sleep apnea. Proc Am Thorac Soc. 2008 Feb 15;5(2):136-43 10. Quigley HA and Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006 Mar;90(3):262-7. 11. Sommer A, Tielsch JM, Katz J, Quigley HA, Gottsch JD, Javitt J, Singh K. Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans. The Baltimore Eye Survey. Arch Ophthalmol. 1991 Aug;109(8):1090-5. 12. Waller EA, Bendel RE, Kaplan J. Sleep disorders and the eye. Mayo Clin Proc. 2008 Nov; 83(11): 1251-61 13. Weinrab RN and Pen TK. Primary open-angle glaucoma. Lancet. 2004 May; 363: 1711-20 Glaucoma (GLC) is a group of diseases that result in optic nerve damage and retinal ganglion cell loss. The only modifiable risk factor of glaucoma is intraocular pressure (IOP). Obstructive sleep apnea (OSA) is the cessation of breathing during sleep due to the loss of oropharyngeal muscle tone and collapse of the airway. Positive airway pressure (PAP) splints open the airway during sleep to prevent collapse. There has been controversy over whether or not PAP therapy increases IOPs. We measured IOPs during PAP therapy with 3 different machines on patients with GLC and OSA or just OSA. This is the first study to measure IOPs of patients with both GLC and OSA while on PAP therapy. We report our anticipated results and preliminary data. We expect there to be an increase in intraocular pressure after PAP therapy; AutoPAP machines to increase IOPs the least compared to CPAPs and BiPAPs; and patients with both OSA and GLC to experience the greatest increase in intraocular pressure during PAP therapy. Risk FactorsSymptomsUntreated Complications -Obesity -Hypertension -Hypothyroidism -Anatomically narrowed airways -Large neck circumference -Alcohol/ sedatives before sleep -History of cigarette use -Snoring -Waking with a snort or while gasping or coughing -Told by others hold breath or stop breathing during sleep -Daytime somnolence -Morning Headaches -Weight Gain -Depression Cardiovascular: - arrhythmias - hypertension - autonomic dysfunction - vascular dysregulation - atherosclerosis Kidneys: nephritic syndrome Liver: hypoxic hepatitis Central Nervous System: stroke Risk FactorsSymptomsUntreated Complications -Increased intraocular pressure -Aging -Glaucoma in first degree relative -Race (higher in African Americans) -Suspicious optic nerve appearance (cupping or asymmetry) -Thin Corneas -High myopia (nearsightedness) -Diabetes -Hypertension -Eye injury or surgery -History of steroid use -Migraine headaches -Peripheral vasospasm -Sleep related breathing problems -Gender (males more likely) -Generally symptomless until the disease has progressed significantly -50% of nerve loss can occur without loss of vision -Loss of vision -Peripheral vision is lost first and then central vision Study Design Patients seen in the glaucoma clinic found to also have been diagnosed with OSA were recruited for this study. They wore a CPAP, BiPAP, or AutoPAP machine during a 2 hour session in which intraocular pressure measurements were made. Five pressure measurements were taken in sequence with each patient: 1. Seated 2. After lying supine for 15 min 3. Supine immediately after 30 min of PAP therapy 4. Remaining supine for 15 min after PAP therapy cessation 5. After returning to the seated position for 15 min. Inclusion criteria was greater than 18 years of age, diagnosed with OSA on PAP therapy, and a normal anterior chamber with an open angle. Exclusion criteria was younger than 18, inability to provide informed consent, any abnormality that prevented reliable applanation tonometry, angle closure glaucoma, and central sleep apnea. Surgeries and concomitant use of drops were not exclusion criteria. This study was approved by the institutional review board and the human research protection program. Anticipated / Preliminary Results and Discussion 1. We expect there to be an increase in intraocular pressure after PAP therapy. 3. We expect patients with OSA and GLC to experience the greatest increase in intraocular pressures during PAP therapy. 2. We expect AutoPAP machines to result in the least increase in intraocular pressure compared to CPAP and BiPAPs Glaucoma is a group of diseases characterized by a progressive degeneration of retinal ganglion cells and the optic nerve. High intraocular pressure is often the cause of retinal ganglion cell damage due to compression of blood vessels and axons transporting trophic factors to support them [13]. However, other pathologies that inhibit blood supply to the cells and the optic nerve are also implicated in glaucoma including obstructive sleep apnea [4]. Prevalence of glaucoma is 2% of the population >40 years old. It is estimated that in 2010, 44.7 million people worldwide were affected by primary open angle glaucoma with 8.4 million resulting in bilateral blindness. These numbers are projected to be 58.6 million and 11.2 million in the year 2020 [10]. Sleep Apnea Obstructive sleep apnea is characterized by the loss of pharyngeal muscle tone and the collapse of the soft palate or base of tongue into the airway during sleep (see figure 1) [12]. The prevalence of sleep apnea is 2 to 9% of the population if defined by patients having at least one clinical symptom and an apnea/hypopnea index (AHI) of >5 drainage of aqueous into Schlemm’s canal and then into the scleral veins. Drainage through the uveoscleral pathway is through the muscle fibers of the ciliary body into the scleral veins [13]. Average eye pressures are around 15mmHg while normal pressures are considered to be below 21mmHg. Pressures of 22mmHg have been shown to cause 8.6 times more damage than 21mmHg [11]. There are three major types of glaucoma. Angle-closure glaucoma (ACG) occurs when the iridocorneal angle is obstructed preventing the drainage of aqueous fluid. Primary open angle glaucoma (POAG) occurs when the iridocorneal angle is free from obstruction but IOPs are high and optic nerve changes and vision loss are detected. Normal tension glaucoma (NTG) is when IOPs are in the normal range but optic nerve changes and vision loss are still detected [13]. positive pressure. The EPAP is a therefore a lower pressure level that tries to relieve this discomfort. BiPAP machines also have spontaneous (S) or timed (T) cycling between IPAP and EPAP. [3] AutoPAP- automatic positive airway pressure machines modulate the pressure administered during the night so that only the minimum pressure is used to maintain an open airway. Maximum and minimum pressures are programmed into the machine. CPAP, BiPAP, and AutoPAP machines can have different features that improve patient comfort by modulating the pressure administered. RAMP- is a feature that gradually increases the administered pressure to the prescribed pressure over a period of time after therapy is initiated to allow the patient to fall asleep. EPR- exhalation pressure relief, is a feature that transiently decreases pressure while a patient exhales but still maintains the prescribed pressure throughout therapy. C-flex, A-flex, and Soft-X are all different types of EPR. PAP machines also can have air humidifiers that can heat, cool, or maintain the air at room temperature. Machines can also be used with different facemasks. These include nasal, nasal pillow, nasal prong, oral, hybrid (nasal and oral), or full face. Testing and Diagnosis Sleep apnea is detected with overnight sleep studies also called polysomnography. The Epworth Sleepiness Scale is also a good measure of symptoms associated with sleep apnea where 0-9 points are normal and 10+ out of 24 points are considered abnormal. Diagnosis of sleep apnea is based on the apnea/hypopnea index (AHI) or the respiratory disturbance index (RDI). Apneas are defined as the complete cessation of breathing for greater than 10 seconds. Hypopneas are partial airway collapse with 30-50% reduction in airflow accompanied by at least a 3-4% decrease in oxygen saturation or arousal. The AHI is the number of apnea and hypopnea episodes per hour whereas the RDI includes the number of respiratory event related arousals in addition to apneas and hypopneas per hour. An AHI of 30 is severe OSA [12]. [9, 5]. If just defined by an AHI >5, prevalence is 20% for the general population and it is estimated that 26% of adults are at high risk for OSA [9] Risk factors, symptoms, and complications of sleep apnea are listed below in Table 1. Treatment Treatments for OSA include weight loss, dental devices, sleep position restriction, and surgery. The most common treatment, however, is positive airway pressure (PAP) therapy. Positive air pressure acts like a splint to prevent collapse of the airway during sleep (see figure 2). There are many different PAP machines each with their own features: [1] CPAP- continuous positive airway pressure machines administer the same pressure level measured in cm of H2O during the use of the machine [2] BiPAP- bi-level, biphasic, or variable positive airway pressure machines administer different pressure levels during inspiration (IPAP) and expiration (EPAP). The greatest discomfort reported by patients is trying to exhale against Glaucoma Increased intraocular pressure is a contributing factor to the development of glaucoma. The most common cause of increased IOP is the excessive production or inadequate drainage of aqueous fluid in the eye. Aqueous fluid is produced by the ciliary epithelium and travels from the posterior chamber to the anterior chamber through the pupil (see figure 3). Drainage of aqueous fluid occurs through two routes: trabecular or uveoscleral. The trabecular meshwork is a loose fibrous connective tissue found at the iridocorneal angle which allows Testing and Diagnosis Diagnosis of glaucoma is made when changes in the optic nerve are visualized such as an increased cup- to-disc ratio, asymmetry of cupping between eyes, hemorrhage of optic disc, pigment and rim changes, and retinal nerve fiber layer thinning (see figure 4). Diagnosis is made after a dilated fundus exam to visualize the optic nerve, applanation tonometry to measure IOPs, gonioscopy to visualize the iridocorneal angle, perimetry to assess the visual field, and retinal nerve fiber layer analysis. Treatment Treatment for glaucoma is usually through the use of eye drops. Beta blockers, prostaglandin analogues, alpha-adrenergic agonists, and carbonic anhydrase inhibitors either reduce the production of aqueous fluid or increase its drainage. Patients with severe glaucoma can undergo various surgeries and procedures aimed at lowering intraocular pressure. Acknowledgements: This work was supported by the Richard A. Perritt Charitable Foundation and the Illinois Society for the Prevention of Blindness. Table 1. Table 2. Figure 1. Figure 2. Figure 3. Figure 4. Data Collection Intraocular pressure measurements were taken via two methods: Perkins and Tono-Pen. The Perkins tonometer is a handheld version of the Goldmann tonometer (figure 5) which is considered the gold standard for IOP measurements. The Tono-Pen (figure 6) is handheld instrument that gives a digital pressure reading with a confidence interval. Both are forms of applanation tonometry which involves contact with the front of the eye after administration of a topical anesthetic drop. Figure 5 (above) & 6 (below). Preliminary Data Due to ongoing status of this study, only general observations of the data can currently be made. Recruitment and data gathering are still in process in order to obtain statistical significance or non-significance. Anticipated Results Preliminary data has shown an increase in intraocular pressures after PAP therapy. Other studies have shown a significant increase in IOPs after PAP therapy. Concern was first reported by Alvarez-Sala, et al. in 1992 and followed with a study by the clinicians in 1994. They found a significant increase in IOP in patients with primary open angle glaucoma (POAG) but no significant increase in non-glaucomatous (non-GLC) subjects. Recently, Kiekens, et al. 2008 and Pepin, et al. 2010 reevaluated the correlation between CPAP therapy and an increase in IOP. Both research teams studied non-GLC patients recently diagnosed with OSA and each found a significant increase in IOPs. However, the studies had contradicting conclusions: Kiekens, et al. reported that CPAP machines may be involved in the increase of IOP and Pepin, et al. reported that CPAP machines restore normal IOP rhythms and that the dangers of CPAP use can be discarded [1,2,6,7,8]. AutoPAP machines modulate the pressure administered during the night so that only the minimum pressure is used to maintain an open airway. This is the first study to compare intraocular pressure measurements between CPAPs, BiPAPs, and AutoPAPs. Alvarez-Sala 1992 and 1994 have already reported significant increases in intraocular pressure among patients with glaucoma after PAP therapy. We believe patients with both OSA and GLC will have increases beyond these findings because patients with OSA have more connective tissue flexibility which may allow for a greater increase in intrathoracic pressure and subsequently increased intracranial pressures and intraocular pressure. Raw Data Snapshot Table 3 shows data from 5 patients enrolled in the study. The number furthest left corresponds to the pressure measurements described in the methods section above. The values are given first for the right eye (Tono-Pen, Perkins) then for the left eye. All patients had OSA and their GLC status is listed along with their machine type and settings. Table 3 Figure 7. Figure 7 shows the delicate interplay between GLC, OSA, and PAP therapy. Sleep apnea causes vascular dysregulation which can cause ischemic damage to the optic nerve. PAP therapy can prevent the ischemic episodes of OSA but may also increase intraocular pressure which damages the optic nerve by decreasing axonal transport of trophic factors and cutting off blood supply. It has been proposed that PAP therapy increases intraocular pressure by first raising intrathoracic pressure and intracranial pressure. The rise in intracranial pressure increases venous circulation pressure and reduces aqueous humor outflow subsequently resulting in increased intraocular pressure [2, 4, 13].