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7/15/2015 Disclosures “Decision Making in Glaucoma: When to pull the trigger” COPE #41665-GL Financial disclosures: • Speakers Bureaus/Consultant: Alcon Allergan Optovue Zeiss-Meditec VSP B&L Ivantis Robert E. Prouty, O.D., FAAO Specialty Eye Care Parker, Colorado [email protected] • I have no personal financial interests in any of these companies Glaucoma is an Optometric Problem ~ 2.5 million Americans are diagnosed with Glaucoma Risk Factors for Glaucoma ◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦ 1% – 2 % of those > 40 years ◦ 1.6% > 40 (Framingham Eye Study) As many as 95,000 Americans lose some degree of sight to Glaucoma each year ◦ 12,000 become blind It is estimated that 1 million Americans with glaucoma are undiagnosed! Glaucoma The most common types: ◦ Primary Open Angle Glaucoma ◦ Angle Closure Glaucoma High IOP Family history of glaucoma African ancestry High myopia Cardiovascular risk Age Other: Chronic steroid use/previous eye surgery European Glaucoma Society: Terminology and Guidelines for Gaucoma, 1998:63 Primary Open Angle Glaucoma In general, patients are at risk for glaucoma if they have the following: ~2.5 million Americans have POAG ◦ About 1/3 of the POAG is undiagnosed ◦ ~ 25% of all cases of POAG are African Americans Acute or Chronic ◦ Secondary Glaucomas Pseudoexfoliation Pigment Dispersion Uveitic Angle Recession 1 7/15/2015 Risk Factors Race: African Americans ~5X > whites • Comparison of prevalence of Glaucoma in LALES Latinos and African-Americans and Whites in the Baltimore Eye Study 35 Prevalen ce (%) 30 25 21.09 21.09 20 13.8 13.8 15 LALES Whites Blacks 10 5 2.6 2.6 0 40-49 50-59 60-69 70-79 Age Groups (yrs) 80+ Varma R, Prevalence and Risk Indicators of Visual Impairment and Blindness in Latinos – The Los Angeles Latino Eye Study, Ophth. 2004;111:1132–1140 Secondary Glaucomas Pseudoexfoliation Syndrome (PEX): ◦ 1.6%-2.3% of population > 50 yo in US ◦ Pseudoexfoliative Glaucoma (PEG) most commonly occurs between 60-80 yo ◦ PEX is 2-3X more common in women ◦ PEX is reported unilateral in 50%-70% of cases on initial diagnosis Pigment Dispersion Syndrome (PDS): ~2.5% of whites in the US ◦ 20%-60% of PDS ◦ 25%-50% of PDS OHTN PDG When to pull the trigger It is my observation that many ODs question themselves as to “when to pull the trigger” ◦ To soon = mistake and meds cost $$$ ◦ To late = increases professional liability (malpractice) exposure How many ODs have been sued for starting a patient on meds too soon? Secondary Glaucomas Uveitic ◦ Estimated to be 7.6% to 23% among patients with uveitis ◦ Surgery is required in children > adults* 59% of children and in 35% of adults Angle Recession ◦ Of those eyes with angle recession, very few (~ 0-20%) develop glaucoma ◦ In those that do develop glaucoma, the onset is extremely variable * * Ocular Immunology & Inflammation, Vol 17, Issue 4 August 2009 , pgs 243 - 248 How do ODs become more accurate in diagnosis? Refined MHx assessment ◦ Remember that IOP alone does not determine glaucoma! • Poor sensitivity & specificity - Sensitivity 79% - Specificity 64% * Review by Doughty, M.J., and Zaman, M.L. Surv of Ophthalmol 2000; 44: 367 * Liu, J.H.K., Zhang, X., Kripke, D.F., and Weinreb, R.N. IOVS 2003; 44:1586 None, Nada, Zero, Zilch, The big Goose Egg! 2 7/15/2015 Time of maximum IOP 1:30 PM 9pm12am 11:30 AM 3pm6pm 7:30 AM 9am12pm 9:30 AM 3am6am 5:30 AM 0 3:30 AM 12 10 Habitual IOP of untreated glaucomatous eyes 1:30 AM 23 20 n=24 9:30 PM 10 DIURNAL/WAKE NOCTURNAL/SLEEP 11:30 PM 20 DIURNAL/WAKE 7:30 PM Number of eyes 30 26 25 24 23 22 21 20 19 18 17 16 15 14 12 10 8 6 4 2 0 3:30 PM IOP (mm Hg) Times of maximum IOP Over a 24-hr period: IOP is Higher at Night 5:30 PM Peak IOP Outside Office Hours for 2/3 of Eyes Clock Time Nakakura S, et al. J Glaucoma 2007; 16(2): 201-204 Liu JH et al. Invest Ophthalmol Vis Sci. 2003; 44: 1586-1590 Liu JH et al. Invest Ophthalmol Vis Sci. Dec 1998; Vol 39 #13 Med Effects on Diurnal/Nocturnal IOP DIURNAL/WAKE NOCTURNAL/SLEEP DIURNAL/WAKE 28 26 Refined 24 22 20 IOP (mmHg) How do ODs become more accurate in diagnosis? Baseline 18 Travoprost 0.004%1 Brimonidine 0.2%2 16 14 12 10 • Diurnal period – sitting 8 • Nocturnal period – supine 6 1:30 PM 9:30 AM 11:30 AM 7:30 AM 5:30 AM 3:30 AM 1:30 AM 9:30 PM 11:30 PM 7:30 PM 5:30 PM 3:30 PM 4 2 0 MHx assessment ◦ Remember that IOP alone does not determine glaucoma! ◦ Compromised ocular hemodynamics Vascular dysregulation The more complex the regulative system, the more susceptible it is for dysregulation and the more dramatic the potential damage • Grieshaber M, Mozaffarich M, Flammer J, What is the Link Between Vascular Dysregulation and Glaucoma, Survey Ophth #52, Supp #2, Nov 2007 1) Sit AJ, et al. Am J Ophthalmol. 2006; 141(6): 1131-1133 2) Liu JH et al. Ophthalmology, 2010 Nov;117(11):2075-9 How do ODs become more accurate in diagnosis? How do ODs become more accurate in diagnosis? Refined Refined MHx assessment ◦ Remember that IOP alone does not determine glaucoma! ◦ Compromised ocular hemodynamics Vascular dysregulation Primary (PVD) & Secondary (SVD) PVD = inborn tendency to inefficiently OBF respond Primarily Endothelin modulated (ET-1 dysregulation) Variable up & down regulation/perfusion SVD = systemic disease related tendency to respond More consistent down regulation/perfusion MHx assessment ◦ Remember that IOP alone does not determine glaucoma! ◦ Compromised ocular hemodynamics Vascular dysregulation Primary (PVD) & Secondary (SVD) PVD = inborn tendency to inefficiently OBF respond Women > men Academics > blue collar Low BP – Cold hands – low thirst – longer sleep onset (need feet to warm before they can sleep) 3 7/15/2015 How do ODs become more accurate in diagnosis? How do ODs become more accurate in diagnosis? Refined Refined MHx assessment ◦ Remember that IOP alone does not determine glaucoma! ◦ Compromised ocular hemodynamics Vascular dysregulation Primary (PVD) & Secondary (SVD) SVD = systemic disease related tendency to respond MS – Giant cell arteritis – Lupus – RA – Anorexia – liver cirrhosis - etc Basically all chronic inflammatory autoimmune Essentially no interference with autoregulation yet down regulated How do ODs become more accurate in diagnosis? Refined Refined MHx assessment Ocular assessment Vascular dysregulation Primary (PVD) & Secondary (SVD) PVD is a major risk but SVD is a minor risk in POAG! • Grieshaber M, Flammer J, Blood Flow in Glaucoma, Curr Opin Ophth 2005 16:79-83 (data from Satilmis M, OrgÜlS, Doubler B, Flammer J, Rate of progression of glaucoma correlates with retrobulbar circulation and intraocular pressure, AJO, May 2003 Vol. 135, Issue 5, Pages 664-669) Glaucoma Clinical Workup I only get paid once in their lifetime! AAO Preferred Practice Pattern Guidelines: ◦ Perform gonioscopy periodically (e.g., 1-5 years). o Gonioscopy Is Gonioscopy required on all glaucoma patients? Does it need to be done more than once? MHx assessment ◦ Remember that IOP alone does not determine glaucoma! ◦ Compromised ocular hemodynamics AOA Clinical Practice Guidelines: ◦ To rule out the development of an angle closure component in the glaucoma, gonioscopy should be repeated periodically. How do ODs become more accurate in diagnosis? Refined MHx assessment Ocular assessment Refined ONH assessment Refined ~ A Video Atlas ~ http://gonioscopy.org/ Wallace L.M. Alward Frederick C. Blodi Chair in Ophthalmology Director, Glaucoma Service University of Iowa Carver College of Medicine 4 7/15/2015 Five Rules for Assessment of the Optic Disc in Glaucoma 1. Observe the scleral Ring to identify the limits of the optic disc and its size Optic Disc Size Measurement of optic disc size with direct ophthalmoscope Small aperture (5 degree) of Welch-Allen direct ophthalmoscope Size of light spot ~ size of average optic disc Optic Disc Size Five Rules for Assessment of the Optic Disc in Glaucoma Size of cup varies with size of disc Large discs have large cups in healthy eyes 1.4 2.2 1.9 Small Average Observe the scleral Ring 2. Identify the size of the Rim Large Identify small and large optic discs Small discs: avg vertical diameter <1.5 mm (1.1 X 1.3 = 1.43) Large discs: avg vertical diameter >2.2 mm (1.7 X 1.3 = 2.21) “ISNT” Rule Rim width Distance between border of disc and position of blood vessel bending ISNT rule Inferior > Superior > Nasal > Temporal 1. “ISNT” Rule S N T I More recent “ISNT” research: ◦ Morgan J, Bourtsoukli I, et al, “The Accuracy of the Inferior>Superior>Nasal>Temporal Neuroretinal Rim Area Rule for Diagnosing Glaucomatous Optic Disc Damage”, Ophthalmology, April 2012, Vol 119:723-730 “The ISNT rule has limited utility in the diagnosis of open-angle glaucoma.” 5 7/15/2015 Five Rules for Assessment of the Optic Disc in Glaucoma Five Rules for Assessment of the Optic Disc in Glaucoma 1. Observe the scleral Ring 1. Observe the scleral Ring 2. Identify the size of the Rim 2. Identify the size of the Rim 3. Examine the Retinal nerve fiber layer 3. Examine the Retinal nerve fiber layer 4. Examine the Region of parapapillary atrophy Five Rules for Assessment of the Optic Disc in Glaucoma 1. Observe the scleral Ring 2. Identify the size of the Rim 3. Examine the Retinal nerve fiber layer 4. Examine the Region of parapapillary atrophy 5. Look for Retinal and optic disc hemorrhages How do ODs become more accurate in diagnosis? Refined MHx assessment Ocular assessment Refined ONH assessment Refined VF interpretation Refined Visual Fields: Poor Sensitivity A large number of RGCs often are lost prior to detectable visual field abnormalities As many as 50% optic nerve fibers can be lost prior to a standard perimetric defect 1,2 By the time there is a 5 dB loss, there is a corresponding 25% loss of RGCs2 1Quigley HA, Addicks EM, Green WR. Arch Ophthalmol. 1982; 100:135 2Quigley HA, Dunkelberger GR, Green WR. Am J Ophthalmol. 1989; 107:453 6 7/15/2015 Visual Fields: Highly Variable OHTS Visual Field Progression • 86% of visual field abnormalities not replicated on retesting* Slow progression 0 Visual Function (MD) 1st VF abnormal (GHT Outside Normal Limits) 2nd VF normal (GHT Within Normal Limits) Early intervention 15 Fast progression Later intervention Level of visual disability 3rd VF abnormal (GHT Outside Normal Limits) Birth Change Analysis Death Event Analysis Baseline Glaucoma Progression Analysis (GPA) Baseline Rate of Progression Caprioli J, The Importance of Rates in Glaucoma, AJO 2008 Vol 145, No. 2 , Pg 192 *VF defect defined as GHT outside normal limits, CPSD < .05%, or both 1 Keltner JL, Johnson CA et al. Arch Ophthalmol. 2000; 118:1187-1194 Different from baseline? Glaucoma Progression Analysis (GPA) Follow-up Multiple exams GPA has been found to have high specificity in determining glaucoma progression A recent study suggests: “GPA criterion of ‘likely progression’ has high specificity on average, but some patients are more prone to false-positive alerts than others This report may help to avoid false-positive decisions on progression in patients with uncharacteristically large variability and frequent response errors." 11/27/97 12/15/98 4/18/01 Possible Progression Likely Progression 4/18/02 11/20/02 Rate-of-progression plot Artes P, Leary N, et al, Visual Field Progression in Glaucoma. What Is the Specificity of the Guided Progression Analysis?, Ophthalmology. 2014 May 28. [Epub ahead of print] 7 7/15/2015 Visual Field Index Visual Field Index Central points weighted more heavily than on periphery Reduces cataract effect to the measurement of VF loss The VFI is less sensitive to a worsening cataract or removal of a cataract than is mean deviation index (MDI). The predictive value of VFI depends on the validity of the assumption that “past performance predicts future performance”. B A VFI = 90% Bengtsson B, Heijl A; A Visual Filed Index for Calculation of Glaucoma Rate of Progression, AJO 2008 Vol 145, No. 2, Pg 343-353 VFI = 81% B”has more damaged central points and lower VFI than “A” “ Visual Field Index Visual Field Index Current age at testing % loss to date % loss in next 5 years 100% VF Index plotted against age: • Characterizes trend significance over next 5 years Visual Field Index Bar • Aids in interpretation & patient education • Helps formulate individualized treatment decisions •Shows vision loss in terms of % •Enhanced visual presentation Summary of Functional Tests SITA SAP Advantages “Gold Standard” SITA SWAP As fast as SITA SAP Possibly more sensitive The “5Rs” of Progression FDT Matrix More portable Tolerates blur Possibly more sensitive 1. 2. Record baseline structure and function. Risk evaluation. Variability does not increase with severity Disadvantages Not sensitive enough to detect early glaucoma Limited clinical evaluation Limited clinical evaluation Variability Cataract effects Best use Baseline VF and following progression in advanced disease Early diagnosis Early diagnosis Younger patients 8 7/15/2015 Developing a Risk Profile Developing a Risk Profile Each patient must be assessed individually Establish baseline risk and reassess from exam to exam Criteria Each patient must be assessed individually Establish baseline risk and reassess from exam to exam Criteria - Stage of disease - Life expectancy ◦ Stage of disease ◦ Life expectancy ◦ Other risk factors How old is the patient? How long did the patient’s parents live? How is the patient’s overall health? Independent Risk Factors for Progression AGIS CIGTS • Elevated IOP Elevated IOP CNTGS EMGT EGPS OHTS X X X X X X X X X X Hg X 24 to 32 mm > 32 mm HgX (2 points) – – Age • CCT below 500 µm Central corneal thickness (thinner) Disc hemorrhage Independent Risk Factors for Progression X X • Disc hemorrhage (2 points) Visual field (higher PSD) Cup-to-disc ratio (greater) • Pseudoexfoliation/Pigment Visual field (greater MD) X Pseudoexfoliation Pseudoexfoliation/pigment X Low ocular perfusion pressure X – – X X X X 24 to 32 mm Hg > 32 mm Hg (2 points) • CCT below 500 µm X Abnormal baseline HRT/OCT/GDx Race (nonwhite) • Elevated IOP • • X X Disc hemorrhage (2 points) Pseudoexfoliation/Pigment Number of Points Level of Risk 0-1 2 Low Medium >2 High The “5Rs” of Progression The “5Rs” of Progression 1. Record baseline structure and function. Risk evaluation. 3. Repeat fields and imaging/photos. 4. Rate of progression. 1. 2. 2. dB Loss per Year Rate of Progression < 0.5 0.5-1.5 Low Moderate > 1.5 High Record baseline structure and function Risk evaluation 3. Repeat fields and imaging/photos 4. Rate of progression 5. Reassess and revise management plan and re-establish baseline 9 7/15/2015 How do ODs become more accurate in diagnosis? Refined MHx assessment Refined Ocular assessment Refined ONH assessment Refined VF interpretation Refined NFL assessment 3 Imaging technologies have been shown to be effective in detecting and managing ocular pathologies Light Polarizer Two polarized components Birefringent structure (RNFL) Retardation Scanning Laser Polarimetry (SLP) Confocal Scanning Laser Ophthalmoscopy (CSLO) Optical Coherence Tomography (OCT) Glaucoma Clinical Workup Tomography - CSLO Digital Tomography Deficiencies 2D measurement are stacked to achieve a 3D assessment An inferred estimate of the RNFL height is based on a depth of 50 microns All estimates of glaucoma status are based on a multivariate analysis This regression analysis (Moorfields regression analysis) also compensates for age and identifies glaucomatous eyes with a relatively high level of sensitivity and specificity Chong G, Lee R, Glaucoma versus red disease: imaging and glaucoma diagnosis, Curr Opin Ophthalmol 2012, 23:79–88 GDx Basic Principles GDx Basic Shortcomings Light Polarizer The crystalline lens and cornea have significant birefringence which is highly variable.1 As such, the macula was used as a reference to variably compensate in the interpretation of the reflected RNFL birefringence (GDx VCC). It measures NFL thickness but only inferentially measures loss based on normative database. Two polarized components Birefringent structure (RNFL) Retardation The amount of retardation from the RNFL is directly proportional to the RNFL thickness1 1 Weinreb et al. Arch Ophthalmol 1990; 108: 557-560 540 healthy eyes with 271 glaucomatous eyes 18-82 yo in healthy with 25-89 yo glaucomas Chong G, Lee R, Glaucoma versus red disease: imaging and glaucoma diagnosis, Curr Opin Ophthalmol 2012, 23:79–88 10 7/15/2015 GDx Basic Shortcomings Ocular movement such as nystagmus can render GDx measurements meaningless. Older patients, high myopia, or lightly pigmented fundus eyes, are subject to increased birefringence with an abnormal s/n ratio which can provide erroneous readings. Correlation of the Deviation Map with Visual Fields PPA can be a confounding factor if it falls within the measurement circle. The circle can be enlarged to avoid scanning the PPA region and increase the reliability of measurements yet that adds variability From Normal to Advanced Glaucoma Chong G, Lee R, Glaucoma versus red disease: imaging and glaucoma diagnosis, Curr Opin Ophthalmol 2012, 23:79–88 Correlation of the Deviation Map with Visual Fields But GDx does NOT assist in differentiating in congenital NFL decreases or myopic ONH decreases Basically it measures but does NOT interpret Scans & Analysis Fast RNFL (Bilateral) - Three circular scans with a 3.4mm diameter are used to image the peripapillary region of the ONH to create a TSNIT image. Fast Optic Disc (Monocular) Utilizes a 6 line starburst scan (4mm) through the ONH at each 12 clock hours. Each individual scan can be reviewed. Fast Macula (Bilateral) - The Stratus uses a 6 line radial pattern to image the macula (6 mm). Chong G, Lee R, Glaucoma versus red disease: imaging and glaucoma diagnosis, Curr Opin Ophthalmol 2012, 23:79–88 TD Stratus OCT Deficiencies Acquisition times are slow so movement artifact affects accuracy Database is VERY limited in patients >80 yo Database is VERY limited in patients outside -12.00 or +8.00 RNFL Thickness Average Analysis Black line is patient’s RNFL thickness Highly myopic eyes have a wide range of “normal” RNFL thickness Moderately myopic individuals may have thinner peri-papillary RNFL at the superior and inferior poles when measured by OCT. Interpreting a myopic glaucoma suspect’s RNFL status needs to take into account these limitations. Chong G, Lee R, Glaucoma versus red disease: imaging and glaucoma diagnosis, Curr Opin Ophthalmol 2012, 23:79–88 11 7/15/2015 Fourier Domain OCT Advantage Fourier Domain OCT Advantage Faster speed also allows for greater density of sampling points and reduces artifacts from eye-movements ◦ RTVue FD OCT has 26,000 A scans/sec vs Stratus TD OCT with 400 A scans/sec FD OCT has twice the depth resolution as TD OCT ◦ 5 microns vs 10 microns Allows imaging and segmentation of: ◦ Cornea ◦ Angular structures ◦ Macular Ganglion cell layers Ganglion Cell Loss in the Macula Macular Ganglion cell density Histologic studies have shown ganglion cell loss in the macula Desatnik et al, found macular ganglion cells are lost in early glaucoma Yucel et al, showed loss of cells in the parvocellular layers of the LGN implicating central ganglion cell loss Disc fovea • 50% of ganglion cells located in central 4.5mm (16º) • Peak ganglion cell density is 15,000 cells/mm2 in macula (white region left) • Area represents only 7.3% of total retinal area • RTVue Ganglion cell complex map covers central 6mm area Desatnik H, Quigley HA, Glovisnky Y. J Glaucoma 1996; 5: 46-53 Yucel YH, Zhang Q, Weinreb RN, Kaufman PL, Gupta N, Prog Retin Eye Res 2003; 22:465-481 • • Diagnostic Accuracy with TD OCT: Macula vs RNFL Progression: Macula vs RNFL Medeiros et al, found the diagnostic accuracy of peripapillary RNFL thickness was significantly more accurate than macula thickness Wollstein et al, found similar results where RNFL thickness was significantly more accurate for detecting glaucoma than macula thickness Using TD OCT, Medeiros et al, compared the accuracy for detecting progression using RNFL versus macula thickness and found the RNFL was significantly more sensitive and specific than macula thickness RNFL curve Macula curve • • • Medeiros FA, et al. Invest. Ophthalmol Vis Sci 2009; 50:5741-5748 Medeiros FA, Zangwill M, Bowd C et al. Am J Ophthalmol. 2005; 139:44-55 Wollstein G, Ishikawa H, et al. Am J Ophthalmol 2005; 139: 39-43 12 7/15/2015 TD OCT Study Limitations GCC Thinning in Glaucoma Major disadvantage in these studies is that TD OCT typically measures full retinal thickness only (does not isolate ganglion cells) TD OCT does not have enough depth resolution to image and segment the ganglion cells accurately and reliably Overlay of the RNFL and GCC GCC Normal GCC Glaucoma with thinner GCC GCC Report: Normal Patient Information Exam Date and Quality GCC Thickness Map pRNFL Deviation Map GCC Fovea Mask Significance Map Parameter Table GCC Deviation Map GCC Deviation Map % loss = actual scan value – normal value normal value color coded map Percent loss value at each pixel location relative to normals (based on age-adjusted normative database) of over 300 healthy eyes color coded map shows regions where the change from normal reaches statistical significance ◦ Green = values within normal range (p-value 5% to 95%) ◦ Blue = thinning 20%-30% relative to normal ◦ Yellow = borderline results (p-value < 5%) ◦ Black = 50% loss or greater ◦ Red = outside normal limits (p-value <1%) David Huang, MD, PhD www.AIGStudy.net David Huang, MD, PhD www.AIGStudy.net 13 7/15/2015 GCC Change Analysis Revisiting the Macula Thickness Maps Can imaging the ganglion cells in macula with FD OCT improve glaucoma detection? Deviation Maps Significance Maps Trend Analysis GCC parameter change analysis Diagnostic Accuracy: GCC vs FD OCT RNFL Rao et al, found GCC had similar accuracy levels as FD RNFL Seong et al, found similar results Kim et al, found values were higher for RNFL vs GCC in a group of advanced glaucoma patients, but GCC values were higher than RNFL in a group of early glaucoma patients • • • Rao HL, Zangwill LM, Weinreb RN et al. Ophthalmology 2010; in press. Seong M, Sung KR, Choi EH, et al. Invest Ophthalmol Vis Sci 2010; 51:1446-1452. Kim NR, Lee ES, Sung GJ, et al. Invest Ophthalmol Vis Sci 2010 GCC Summary GCC thickness correlates well with VF More reproducible and more accurate for detecting glaucoma than macula thickness with TD OCT Similar accuracy for detecting glaucoma as FD OCT RNFL thickness Best in early glaucoma 14 7/15/2015 What value is digital technology? How do ODs become more accurate in diagnosis? Refined MHx assessment Refined Ocular assessment Refined ONH assessment Refined VF interpretation Refined NFL assessment Refined Management selection They offer an expert opinion but the new generation OCTs are far superior Medicinal Management Prostaglandin Derivatives Topical CAI’s Adrenergics Beta-Blockers Combos Cholinergics/Anticholinesterases Oral CAI’s The “Prosta-somethings” Travoprost (Travatan™) Latanoprost (Xalatan®) Tafluprost (Zioptan™) Bimatoprost (Lumigan™) The “Prosta-somethings” The most common 1st line Tx in nearly all glaucoma types!! Increased uveoscleral outflow Topical CAI’s IOP decr about 9%-20% ◦ Depending on the iris color ◦ tid use ◦ ~30%-40% mean IOP decr ◦ qhs use Often used bid Brinzolomide is equivalent to Dorzolamide (Trusopt®) ◦ More physiologic pH less burning on use 15 7/15/2015 Adrenergics Alpha2 agonist (Brimonidine 0.15% & 0.2%) ◦ 16% allergy rate (10% for Alphagan P!!) Decreased aqueous production & increased uveoslceral outflow Minimal tachyphylaxis reported Beta-Blockers Non-selectives 20%-30% IOP reduction Available as a generic Qday use (best in am!) ◦ Timolol maleate ◦ Timolol Gel (Timolol-XE®) ◦ 21% IOP decr ◦ tid use Gel formulation increase contact time-penetrance ◦ Timolol Hemihydrate (Betimol®) bid as effective & best compliance A levoisomer of Timolol Beta-Blockers Beta-Blockers Non-selectives 20%-30% IOP reduction Available as a generic Qday use (best in am!) ◦ Levobunolol (Betagan®) ◦ Metipranolol (Optipranolol®) ◦ Carteolol (Ocupress®) Combinations Cosopt® (was Merck but now is Akorn) ◦ Timolol 1/2% & dorzolamide As effective as separate dosing (?) ◦ Better convenience & compliance Still stings!! B1 Selective ◦ Selectivity = less efficacy 15%-25% IOP reduction Available as a generic bid use ◦ Betaxolol (Betoptic®-S) “S” = styrene molecule that increases contact time and penetrance Combinations Simbrinza™ (Alcon) ◦ Brinzolamide 1% & Brimonidine 0.2% ◦ As effective as separate dosing ◦ Better convenience & compliance Less sting!! ◦ 32%-38% IOP decr ◦ 21%-35% IOP decr ◦ bid use ◦ tid use Cosopt PF® (was Merck but now is Akorn) Used bid in Europe ◦ Preservative Free!! 16 7/15/2015 Cholinergics Anticholinesterases Pilocarpines Oral CAI’s Acetazolamide (Diamox) ◦ 1/2%, 1%, 2%, 4%, 6% concentrations ◦ Generic available ◦ NOT to be used with iritis! ◦ Significant side-effects ◦ Decreases secretion of aqueous ◦ Sulfonamide derivative ◦ Significant side-effects ◦ Doseages: start lower % and increase to max effect ◦ qid use Diamox: 250mg bid –qid Sequels: 500mg bid Oral CAI’s Methazolamide (Neptazane) Oral CAI’s ◦ Topical CAI cross-sensitivity is being re-thought ◦ Sulfonamide derivative ◦ Doseages: ◦ So the use of topical CAIs may be safely used with sulfonamide allergy depending on severity of allergic response Hives, swelling of throat, etc. is probably NOT safe! ◦ General atopy is probably LESS safe 50mg-100mg bid to tid Back to the Future! Sulfonamide sensitivity ◦ Decreases secretion of aqueous Nutritional Treatments: ◦ Blood flow enhancers Mirtrogenol® (120 mg b.i.d.) commercial composition of Bilberry extract (Mirtoselect®) and French maritime pine bark (Pycnogenol®) Gingko biloba (80 mg b.i.d.) also works as an antioxidant Back to the Future! Nutritional Treatments: ◦ Blood flow enhancers Mirtrogenol® (120 mg b.i.d.) Gingko biloba (80 mg b.i.d.) ◦ Calcium channel blockage (i.e. Nifedipine) Increase blood flow therefore poss neuroprotection Significant SE’s noted in studies (1/3 dropout from SE’s) HA’s, flushing, dizziness, swelling, low BP, nausea Lomerizine HCl (Santen’s DE-090) Only CA++ antagonist being developed as oral glaucoma treatment Excellent safety and minimal SEs to date 17 7/15/2015 Back to the Future! Back to the Future! Vitamin Treatments: ◦ Magnesium: (<350 mg qday is well tolerated) ◦ ◦ ◦ ◦ Considered “Nature’s calcium channel blocker” Usually 125 mg bid (d/c with oral antibiotic use) ◦ Vitamin B-complex (water soluble) In combination with E and Omega 3 (DHA), shown to stabilize VF Early ‘14 study supported association of Vit. D deficiency with presence of glaucoma No supplementation needed but may want to test for deficiency in NTG Prostaglandins New MOAs AR-13324 (Aerie) ROCK/NET Inhibitor (qday) Phase 3 K-115 (Kowa) ROCK Inhibitor (bid) Phase 3 (Japan) AMA0076 (Amaken) ROCK Inhibitor (bid) Phase 2a INO-8875 (Inotek) Adenosine-A1 agonist (bid) Phase 2 OPA-6566 (Acucela) Adenosine-A2a agonist (bid) Phase 1/2 SYL040012 (Sylentis) RNAi beta blocker (bid) Phase 2 Magnesium: (<350 mg qday is well tolerated) Vitamin B-complex (water soluble) Vitamin D Vitamin E (fat-soluble): Diet alone is sufficient Not > 400 IU daily ◦ Vitamin D Glaucoma Medications in the Pipeline Vitamin Treatments: Current commercial PGAs all bind to the PGFP2α receptor ◦ Bimatoprost may also bind to PGEP1 Newest research is in PGEP2-4 ◦ Early studies suggest a decrease in IOP that was long-lasting and greater than PGFP2α PGEP2 was less stable in aqueous solution New PGAs BOL-303259 (B&L) NO donating latanoprost (qday) NCX 470 (Pfizer) NO donating bimatoprost (qday) Phase 1 DE-117 (Santen) EP2 agonist (qday) Phase 2a ONO-9054 (Ono) FP/EP3 agoniist (qday) Phase 1 Phase 3 Nitric Oxide Donation In the past, nitric oxide (NO) was considered “toxic” as one of several environmental pollutants (i.e. cigarette smoke & smog) ◦ ≠ nitrous oxide (N20) “Laughing Gas” ◦ Allergan’s Butaprost binds to PGEP2 ◦ ONO Pharmaceuticals’ ONO-0476 Prodrug of prostanoid EP2 NO-Prostaglandins Nitric Oxide-Donating Prostaglandin F2-Alpha PGA s: ◦ Pfizer/Nicox Research are investigating NO-Donating Bimatoprost 0.004% (NCX 470) By late ’90s, it was determined that NO is a fundamental player in general body physiology as a messenger molecule ◦ Essential to daily functions ranging from BP regulation & digestion to antimicrobial defense 18 7/15/2015 Rho Kinase Inhibitors Rho Kinase Inhibitors Several companies with phase I to III trials Likely not to be packaged with BAK Amenable to alternative delivery modes: ◦ Rhokinase is a serine/threonine kinase that serves as an important downstream effector of Rho GTPase ◦ It plays a critical role in regulating the contractile tone of smooth muscle tissues in a calciumindependent manner ◦ ROCK inhibitors reduce IOP by enhancing aqueous humor drainage through the trabecular meshwork ◦ Punctal plugs, gel vehicle etc. Rho Kinase Inhibitors Current status: Mechanism: Rho Kinase Inhibitors ◦ April 2014: Rhopressa Phase 3 Trial (Rocket 1) Misses Primary Endpoint Current status: ◦ Roclatan: Essentially, Rhopressa + Latanoprost All end points of subjects <26 were met but not about above FDA allowed modification of study endpoints Phase 2 as met and Phase 3 is underway ◦ AMA0076 (Amakem) goes forward Rho Kinase Inhibitors Current status: ◦ Roclatan: Essentially, Rhopressa + Latanoprost June 2014, Phase 2b results: All clinical endpoints met Efficacy >Latanoprost by 1.6-3.2 mm Hg. at all time points Hyperemia remains the #1 adverse reaction reported Adenosine Receptor Agonists Like ROCK inhibitors, these molecules can work on the TM but much less is known of them A3 adenosine receptor (A3AR) agonists: ◦ A3 agonists have been found to protect normal cells from undergoing apoptosis via the down regulation of death signals Therefore, potentially neuroprotective 19 7/15/2015 Adenosine Receptor Agonists A1 receptors: Adenosine Receptor Agonists ◦ Stimulation of A1 adenosine receptor in the TM causes a improvement in metabolic activity which helps to clear the pathway for the aqueous to flow out of the eye (lowering IOP) A1 Adenosine receptor agonists: ◦ Trabodenoson (Inotek INO-8875) Appears to work primarily by increasing the outflow of aqueous via the TM pathway This metabolic activity takes the form of an increase or upregulation of proteases - such as Protease A or MMP2 - that digest and remove accumulated proteins which can block the flow of aqueous humor out of an eye with glaucoma RNAi (RNA Interference) Interference RNA (RNAi) is a promising technology with therapeutic applications ◦ Sylentis is developing a treatment based on silencing the action of genes involved in aqueous humor production and/or genes which regulate its drainage, so as to reduce IOP Discovered in plants in the 1990s, RNAi consists of highly efficient selective & specific inhibition of gene expression Drug Class Prostaglandins ROCK Inhibitors Sustained Delivery Other RNAi (RNA Interference) RNAi is mediated by small fragments of double-stranded RNA, consisting of 1923 nucleotides, which promote degradation of mRNA, thus inhibiting synthesis of the proteins for which they code As this mechanism is used naturally by cells to regulate gene expression in a way that is both non-toxic and highly effective, RNAi has great therapeutic potential Product (Company) PF-4217329 (EP2-agonist, Pfizer) d/c’ed EP2-agonist, (Allergan’s Butaprost) NCX 116 (B&L’s Vesneo) NCX 470 (Nicox & Pfizer) Latanoprost & AR-13324 combo (Aerie’s Roclatan) AR-13324 (Aerie’s Rhopressa) AR-12286 & AR-13165 (Aerie) d/c’ed AMA0076 Amakem K-115 (Kowa’s Ripasudil (Glanatec) in Europe) H-1337 (Isoquinoline Sulf ROCK by D.Western Therpeutics) Y39983/SNJ1656/RKI-983 (Senji-Novartis) d/c’ed DE-104 (Santen-Ube) d/c’ed ATS907 (Altheos) d/c’ed DDS subtenon implant (Allergan) Punctal plugs Latanoprost (Mati) Punctal plugs Travoprost (Ocular Therapeutix) AC-262271 Muscarinic selective compounds (Acadia-Allergan) SAD 448 (cannabinoid CV 1/2 agonist, Novartis) d/c’ed INO-8875 (adenosine-1 agonist, Inotek’s Trabodenoson) Clinical Ophthalmology 2014:8 20 7/15/2015 Surgical Management Interpreting the GLT Results Is ALT/SLT a better option than primary Tx than medication? Early decisions were based on the Glaucoma Laser Trial (GLT) of 1995 SLT as an alternative to PGAs SLT vs. latanoprost for IOP control in OHT and POAG 12-month study 90°, 180°, 360° SLT Success criterion Initial treatment with ALT is at least as effective as initial treatment topical medication in patients with POAG in terms of control of IOP, optic disc and visual field Ultimately, ALT will need to be supplemented with other modes of intervention What about SLT???? SLT as an alternative to PGAs Results ◦ More 360° SLTs (60%) achieved success criterion ( > 30% IOP reduction) than did 90° or 180° ◦ Latanoprost-treated eyes achieved success criterion in more cases than 90° or 180° and did as well as 360° in maintaining diurnal IOP reduction ◦ 20% - 30% IOP reduction from baseline Nagar M, et al. Br J Ophthalmol 2005;89:1413–1417 Controversies in Treatment Dude….Can you prescribe medical marijuana for my glaucoma? Nagar M, et al. Br J Ophthalmol 2005;89:1413–1417 History of MJ use Since 1996, voters have approved the medical use of marijuana ◦ These state ballot initiatives, and the wider discussion they spawned about appropriate national policies regulating marijuana, have been sharply divisive ◦ 2010 = 12 states (3 provisionals) ◦ 2012 = 16 states + D.C. 30 states looking to modify laws by 2013 21 7/15/2015 History of MJ use The director of the White House Office of National Drug Control Policy (ONDCP) asked the Institute of Medicine (IOM) to review the evidence for the potential benefits and risks associated with the use of marijuana History of MJ use The report of the 18-month IOM study was first released to both the ONDCP and the public in March 1999 ◦ There is remarkable consensus about the potential of cannabinoid drugs for medical use ◦ There are far less convincing data about proven medical benefits ◦ The IOM is a non-governmental, apolitical, nonprofit organization of scientists MJ & Glaucoma MJ & Glaucoma Glaucoma ranks among the most frequently cited reasons for using medical marijuana and is one of the indications for which the federal government once granted permission for compassionate marijuana use Research findings from as early as the 1970s show that both marijuana and THC reduce IOP Despite its illegality, millions of Americans use marijuana regularly Reported medical uses of marijuana MJ & Glaucoma The first such reports generated considerable interest because at the time conventional medications for glaucoma caused a variety of adverse side effects ◦ Pilocarpine and Diamox were among the few drugs available to treat glaucoma in the late 1970s Currently other treatments for the disorder have since eclipsed marijuana-based medicines MJ & Glaucoma Several clinical studies have found that synthetic cannabinoids or marijuana reduce IOP as well as do most conventional glaucoma medications ◦ This is true whether administered orally (eaten), intravenously or by inhalation ◦ NOT when they are applied directly to the eye ◦ In most trials a single dose of marijuana or cannabinoid maintained this effect for three to four hours 22 7/15/2015 MJ & Glaucoma MJ & Glaucoma Researchers have yet to explain how marijuana and cannabinoids reduce IOP Marijuana reduces blood pressure and reduced blood pressure could decrease blood flow to the optic nerve, counteracting the benefits of reducing IOP MJ & Glaucoma MJ & Glaucoma There is no question that marijuana-based medicines can be used to lower IOP but, like several other glaucoma medications that have fallen into disuse, their drawbacks outweigh their benefits This was not the case when the first reports of marijuana's effects on IOP were published in the 1970s when there were relatively few drugs (all of which caused troubling side effects) were available to treat the condition Societal Concerns Societal Concerns So for glaucoma….. ◦ There are far better management regimens now available The short duration of effect means that marijuana-based medicines must be taken up to 8 X per day, which most patients are unlikely to do! ◦ Other medicines reduce IOP equally well and need only be taken once or twice a day This is an important difference because patients need to control IOP continuously due to the progressive nature of glaucoma Those drugs have since been superseded by more effective and less problematic medications which seems the likely fate of marijuana-based treatments for glaucoma as well The use of Medical Marijuana is currently being worked through 3-4 hr efficacy ≠ good control Constant intoxication ≠ good citizens Health concerns ≠ future safety profile ◦ Colorado ODs can be certified for DEA Schedules 3 narcotic – 5 Marijuana is still Schedule 1 23 7/15/2015 Societal Trends May 7, 2015: “Texas could be on board with legalized cannabidiol before the end of this session, as the Texas Senate voted 26-5 to approve SB 339…. Epilepsy patients in Texas would have access to medicinal oils containing a therapeutic component found in marijuana …” Societal Trends Societal Trends April 16, 2015: “Georgia Governor Signs "Haleigh's Hope Act" on CBD Oil for Kids.” ◦ The bill takes effect immediately, and allows the possession of of up to 20 ounces of cannabis oil if a doctor signs off on the treatment Societal Concerns Wide Variability In Potency Plagues Medical Marijuana Edibles, JAMA Study (Forbes 6/23/2015 @ 5:06PM) Full legalization of marijuana…. ◦ According to a paper published this morning in JAMA…shows that the active chemicals in edible cannabis products can vary from 1% to 155% the amount listed on the product label I will leave THAT to your personal politics! Things we already know… Third party insurers have greatly changed the medical care environment Nationwide, nearly 65% of the average ODs gross income is coming from a third party insurer Older adults make up >1:6 patients and >1:7 practice revenue dollars Glaucoma can be “owned” by Optometry! 24