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Challenging the Glauocma Archetype 1
Larry J Alexander, OD FAAO
Member Optometric Glaucoma Society
NewsFlash!!!
• 528 IU/DAY D3 ASSOCIATED WITH 7-8% DECREASE IN DEATH RATE
• Therefore
DO NOT RECOMMEND VIT D3 SUPPLEMENT AS YOU WANT YOUR
GLAUCOMA PATIENT TO DIE BEFORE THEY GO BLIND
Definition of Glaucoma
GLAUCOMA IS OCULAR DEMENTIA,
INFLAMMATION, AND ISCHEMIA LEADING TO
GANGLION CELL DEATH WITH SUBSEQUENT RNFL DEATH AND COINCIDENT
FUNCTIONAL LOSS , EVEN COMPROMISE TO THE
CORTEX
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TOPICS:
HEMI-STRUCTURENEUROLOGICAL RELATIONSHIPS
HORMONESVASCULAR ISSUES
CCTSLEEP APNEA
SMOKINGOBESITY
EXERCISEINFLAMMATION
NUTRITIONAL ISSUESMANAGEMENT
Several studies have identified similarities in the pathogenic processes underlying
AD and glaucoma with a higher incidence of glaucoma in AD. The relationship may
be associated with cerebrospinal fluid pressure anomalies.
Selkoe DJ. Alzheimer's disease is a synaptic failure. Science. 2002;298(5594):789-791.McKinnon SJ. Glaucoma: ocular Alzheimer's disease. Front Biosci. 2003;8:s1140-s1156.
Guo L, Salt TE, Luong V, et al. Targeting amyloid-beta in glaucoma treatment. Proc Natl Acad Sci USA. 2007;104(33):13444-13449.Bayer AU, Ferrari F, Erb C. High occurrence rate of glaucoma among patients with Alzheimer's disease. Eur Neurol. 2002;47(3):165-168.Tamura H, Kawakami H, Kanamotoa T, et al. High frequency of open-angle glaucoma in Japanese patients with Alzheimer's disease. J
Neurol Sci. 2006;15;246(1-2):79-83.Wostyn P, Audenaert K, De Deyn PP. Alzheimer's disease and glaucoma: is there a causal relationship? [published online ahead of print
March 13, 2009]. Br J Ophthalmol. doi:10.1136/bjo.2008.148065.
COMMON CHARACTERISTICS OF NEURODEGENERATIVE DISEASES
INCLUDE AXONOPATHY BUT THE TOTAL UNDERSTANDING OF THE VARIATIONS IS
UNDER STUDY.Coleman M. Axon degeneration mechanisms: commonality amid diversity. Nat Rev Neurosci. 2005;6:889-898.
Conforti L, Adalbert R, Coleman MP. Neuronal death: where does the end begin? Trends Neurosci. 2007;30(4):159-166.Selkoe DJ. Alzheimer's disease is a synaptic failure. Science. 2002;298(5594):789-791.
Adalbert R, Gilley J, Coleman MP. Abeta, tau and ApoE4 in Alzheimer's disease: the axonal connection. Trends Mol Med. 2007;13(4):135-142.Braak H, Del Tredici K. Nervous system pathology in sporadic Parkinson disease. Neurology. 2008;70(20):1916-1925.
Fischer LR, Glass JD. Axonal degeneration in motor neuron disease. Neurodegener Dis. 2007;4(6):431-442.McKinnon SJ. Glaucoma: ocular Alzheimer's disease? Front Biosci. 2003;8:s1140-s1156.
Guo L, Salt TE, Luong V, et al. Targeting amyloid-beta in glaucoma treatment. Proc Natl Acad Sci USA. 2007;104(33):13444-13449.Jakobs TC, Libby RT, Ben Y, et al. Retinal ganglion cell degeneration is topological but not cell type specific in DBA/2J mice. J Cell Biol. 2005;171:313-325.
Soto I, Oglesby E, Buckingham BP, et al. Retinal ganglion cells downregulate gene expression and lose their axons within the optic nerve head in a mouse glaucoma model. J Neurosci. 2008;28(2):548-561.
Buckingham BP, Inman DM, Lambert W, et al. Progressive ganglion cell degeneration precedes neuronal loss in a mouse model of glaucoma. J Neurosci. 2008;28(11):2735-2744.
Libby RT, Li Y, Savinova OV, et al. Susceptibility to neurodegeneration in a glaucoma is modified by Bax gene dosage. PLoS Genet. 2008;1:17-26.Vila M, Jackson-Lewis V, Vukosavic S, et al. Bax ablation prevents dopaminergic neurodegeneration in the 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine mouse model of
Parkinson's disease. Proc Natl Acad Sci USA. 2001;98(5):2837-2842.Coleman MP, Perry VH. Axon pathology in neurological disease: a neglected therapeutic target. Trends Neurosci. 2002;25:532-537.
Whitmore AV, Libby RT, John SW. Glaucoma: thinking in new ways-a role for autonomous axonal self-destruction and other compartmentalised processes? Prog Retin Eye Res. 2005;24:639-662.
The Proposed Genesis of RGC/AXONAL Destruction in Glaucoma
IOP BLOCKS AXOPLASMIC FLOW @ LAMINA CRIBROSA
INTERFERENCE OF DELIVERY OF NEUROTROPHIC GROWTH FACTORS FROM THE LGN TO THE RGCS
MICROGLIA
DEATH OF RGCS ASTROCYTES
AND SPREAD TO OTHER INFLAMMATION RGCS
ISCHEMIA & IMMUNE CELL EXCESSIVE MICROCIRCULATION CHANGES GLUTAMATE COMPROMISE
RGCS DIE BEFORE RNFL
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MAYBE THE BEST WAY TO TREAT GLAUCOMA IS 15 MINUTES PER
DAY IN A HOT TUB.
WHY IN HEAVEN’S NAME WOULD I EVER SAY THAT?
LARRY IS DEFINITELY GETTING SENILE!!!!
JAMES WHITE COMES IN TO SEE YOU AND HE IS 53 YEARS OLD. HE CAN’T SEE GOOD NO MORE UP CLOSE AND HE JUST MISSED A 72
POINT BUCK AT 20 FEET CAUSE “I DIDN’T SEE HIM A COMIN.” IT IS HIS FIRST EYE
EXAMINATION AND HE IS CORRECTABLE TO 20/25 WITH THE TUMBLING E. HIS IOP IS 18 AND HE HAS CUP EROSION AND SOME VF DEFECTS. THE OCT IS COMPROMISED. HE AIN’T BEEN TO
SEE NO DOCTOR EVER.
TELL ME WHAT YOU ARE THINKIN REGARDING WHETHER OR NOT HE IS GOING TO PROGRESS
WITH OR WITHOUT TREATMENT.
I ASK YOU, HOW DO YOUARRIVE AT THE SUSPICION
OF GLAUCOMA?
Check for Diabetes?Check for Hypothyroidism?Do Diurnal IOP Variations?
Do Postural IOP Variations?Screen VF or Digitized
Imaging?Do Routine Anti-cardiolipin
Antibodies?Do Routine MRIs?
Check for Raynaud’s?
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Hemi-Structure and Hemi-Function and Sym-Metrx
HEMI-STRUCTURE
DISEASE IS OFTEN MANIFESTED AS INTER-
EYE AND INTRA-EYE STRUCTURAL ASYMMETRY
INTRA USUALLY REFERS TO ASYMMETRY OF THE SUPERIOR DISC AND THE INFERIOR DISC AND INTER
REFERS TO BETWEEN THE EYES
Example of a Congenital Optic Pit in the Right Eye and the Left Eye With a Difference in Disc Sizes. There is Inter- and Intra-Disc Structure Variation.
Alexander LJ. Primary Care of the Posterior Segment. 3rd edition. McGraw Hill. June 2002
Example of An Acquired Variation-Glaucomatous Optic Neuropathy in the Left EyeMore Advanced than the Right Eye. Note The Inferior Notch OS. There is Inter-
and Intra-Disc Structure Variation.
Alexander LJ. Primary Care of the Posterior Segment. 3rd edition. McGraw Hill. June 2002
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HEMI-FUNCTION
DISEASE IS OFTEN MANIFESTED AS INTER-
EYE AND INTRA-EYE FUNCTIONAL ASYMMETRY
INTRA USUALLY REFERS TO ASYMMETRY OF THE SUPERIOR
VISUAL FIELD AND THE INFERIOR VISUAL FIELD
Example of a Congenital and Acquired Variation-Glaucomatous Optic Neuropathy in the Right Eye More Advanced than the Left Eye and the Accompanying Visual Fields. Note the OS Disc is Larger Than the OD Disc Representing a Congenital
Variation Known as Megalopapilla. Note the Very Striking Limitation of the Visual Field Defect in the Right Eye to the Inferior Hemi-Field. Hemi-Field Defects are
Characteristic of Acquired Optic Neuropathy. In this case the Superior Disc Erosion OD Corresponds Well to the Inferior Field Defect. There is Inter- and Intra-
Disc Structure Variation.
Alexander LJ. Primary Care of the Posterior Segment. 3rd edition. McGraw Hill. June 2002
The Ganglion Cell Complex in Diagnosis and Management
The Ganglion Cell Complex in The Ganglion Cell Complex in Diagnosis and ManagementDiagnosis and Management
The Proposed Genesis of RGC/AXONAL Destruction in Glaucoma
IOP BLOCKS AXOPLASMIC FLOW @ LAMINA CRIBROSA
INTERFERENCE OF DELIVERY OF NEUROTROPHIC GROWTH FACTORS FROM THE LGN TO THE RGCS
MICROGLIA
DEATH OF RGCS ASTROCYTES
AND SPREAD TO OTHER INFLAMMATION RGCS
ISCHEMIA & IMMUNE CELL EXCESSIVE MICROCIRCULATION CHANGES GLUTAMATE COMPROMISE
RGCS DIE BEFORE RNFL
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The ganglion cell complex (ILM The ganglion cell complex (ILM ––IPL)IPL)
Inner retinal layers provide complete Ganglion cell assessment:
• Nerve fiber layer (g‐cell axons)• Ganglion cell layer (g-cell body)• Inner plexiform layer (g-cell dendrites)
Imaging Overlay of the pRNFL and GCC on the OS Retina
pRNFL
GCC
The Scanning Zones for Assessment of the Peripapillary Retinal Nerve Fiber Layer(RNFL) and Ganglion Cell Complex (GCC)
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Patient Data
• 54 yo wf• Routine Eye Evaluation• Knows doctors were concerned about her eyes years
ago and had ordered CT and MRI all of which were “normal”
• Best Corrected VA OD 20/20 OS 20/20• CCT 533, 537 IOP 17• Well defined inferior VF defects
Fundus Shots
Optic Nerve and RNFLGanglion Cell Complex
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What does she have and what do you do?
Is it congenital or acquired?Is there any relationship to
glaucoma?Does the RNFL match the
GCC?
Topless Disc Syndrome or Superior Optic Nerve HypoplasiaSowka J, Vollmer L,Reynolds S. Superior segmental optic nerve hypoplasia: The topless disc syndrome. Optometry 2008;79:576-580.Hashimoto M, Ohtsuka Kenji, Nakagawa T, Hoyt W. Topless optic disk syndrome without maternal diabetes mellitus. Am J Ophthalmol 1999,128:111-112
Patient DataPatient Data• 35 Year Old White Female• 14 Year History of Diabetes With
Hemoglobin A1C of 6.4• Best VA of 20/20 O.U.• Normal IOP not Being Treated for
Glaucoma
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Case GL 109Case GL 109
O.D. AND O.S. NOTE LOSS OF RNFL REFLEX SUPERIORO.D. Inferior Arcuate Loss O.S. Inferior Arcuate Loss
Case GL 109Case GL 109
SuperiorRNFL and GCCloss OU
Abnormal RNFLTSNIT graphO.U.
Abnormal RNFLParameters O.U.Abnormal GCCParameters O.U.
The Cup
The Rim
RNFL, Optic DiscRNFL, Optic Disc And GCC Results And GCC Results Case GL 109Case GL 109
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O.D. VF Compared to RNFL and GCC Case GL 109Case GL 109
O.S. VF Compared to RNFL and GCC Case GL 106Case GL 106
Conclusions Case GL 109Case GL 109
• In this case we have– RNFL OU does correlate very well with VF
as does superior GCC
– This case has severe loss of structure and function secondary to developmental issues
Patient DataPatient Data•• 25 year old Pakistani female25 year old Pakistani female•• C/O blurred vision that seems to be getting worseC/O blurred vision that seems to be getting worse•• ““Should I continue in College or am I goingShould I continue in College or am I going blind?blind?””
Dad doesnDad doesn’’t see too well and was told he has macular t see too well and was told he has macular degeneration.degeneration.
•• BCVA O.U. 20/30 with O.D. BCVA O.U. 20/30 with O.D. --4.754.75--1.25 X 155 and O.S. 1.25 X 155 and O.S. --3.503.50--2.25X 0052.25X 005
•• IOP 20 mm Hg O.U.IOP 20 mm Hg O.U.•• 20/20 vision in the past, confirmed by call to previous 20/20 vision in the past, confirmed by call to previous
doctordoctor
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STRUCTURAL LOSS?
SUGGESTION OF TEMPORAL OPTIC ATROPHY
FUNCTIONAL COMPROMISE
POSSIBLE VISUAL FIELD DEFECT
STRUCTURAL LOSS VERIFIED STRUCTURAL LOSS FURTHER CORROBORATED
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What does she have and what do you do?
Is it congenital or acquired?Does she need neuroimaging?
Does the RNFL match the macular thickness?
Patient DataPatient DataHer DADHer DAD
•• 66 year old Pakistani male Cardiovascular 66 year old Pakistani male Cardiovascular surgeon still in practicesurgeon still in practice
•• BCVA O.D. 20/70 O.S. 20/200BCVA O.D. 20/70 O.S. 20/200•• IOP 15 mm Hg O.U.IOP 15 mm Hg O.U.•• Cataracts removed with BCVA post surgery at Cataracts removed with BCVA post surgery at
20/70 O.U.20/70 O.U.•• Hypertension and thyroid issuesHypertension and thyroid issues•• Was told in past ARMDWas told in past ARMD
STRUCTURAL LOSS
TEMPORAL OPTIC ATROPHY
FUNCTIONAL LOSS
POSSIBLE EARLY VF DEFECTS
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STRUCTURAL LOSS VERIFIED Autosomal Hereditary Dominant Optic Atrophy
Vision loss typically begins as the affected individual reaches school age.The onset and progression are insidious – most patients are unable to identify a precise age of onset. As many as 50% of patients with Dominant Optic Atrophy experience a progressive loss of vision with advancing age. Dyschromatopsia (color blindness) is frequently present but its manifestations are variable. Initially, Dominant Optic Atrophy was thought to be most closely associated with blue color vision deficits ( Kline 1979), but more recent studies have demonstrated that mixed color deficits are most common (81%) ( Votruba 1998).
Optic disc pallor is one of the defining characteristics of Dominant Optic Atropy. About half of the affected individuals have disc pallor that is limited to the temporal side of the disk while the remaining patients have diffuse disc pallor. The degree of pallor tends to correlate with the severity of vision loss. In a recent series of patients with proven OPA1 mutations (see below), 69% had peripapillary atrophy, 31% had a temporal grey crescent, and 48% had a cup to disc ratio of >0.5 ( Votruba 2003). The most common visual field defects are central or cecocentral scotomas, although altitudinal defects also have been described in patients with documented OPA1 mutations ( Brown 1997). Histopathologic studies have shown loss of retinal ganglion cells, especially in the papillomacular bundle, and diffuse atrophic changes of the optic nerve (Johnston 1979).
Case CA 1
61 YO Glaucoma
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THE TEMPLATE
Lower Limit of Normal on RNFL 5%-AVERAGE 87.88 OD OS
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The Lower Hemi StructureThe Lower Hemi Structure RNFL Limit at 5%RNFL Limit at 5%
Hemi Structure RNFL Average of the 3 Studies
Overall Average RNFL 82.17
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7591
60
74
SSI
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THE TEMPLATE
Ganglion Cell Complex (GCC) Lower Limit of Normal (bottom 5% cut-off)
AVERAGE OF 82.04
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7792
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DownwardTrend
125107
119
78
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No DownwardTrend
10295
7
DownwardTrend
Case CA 5
72 YO Glaucoma
17
7673
100
79
ApparentStability
9263
29
18
DownwardTrend
7776
81
62
SSIVariability
7972
7
19
DownwardTrend
MYOPIA AND GLAUCOMA
Prevalence of Glaucoma as Related to Axial Length
Surv Ophthalmol 1970;15:1
11.224%19626.5 to 33.6 mm
3.125%19220.0 to 26.4 mm
Total Subjects with Glaucoma
Total SubjectsAxial Length in mm
Responses to Topical Corticosteroids Am J Ophthalmol 1966;62:1039
NOTE 9% -5D HAD IOP OVER 21 MM HG
29%59%12%17> - 5 D
26%52%22%50POAG Siblings
22%68%10%100POAGOffspring
92%8%0%50POAG 4%26%70%100Volunteers
> 31 mm Hg
20-31 mm Hg
<20 mm Hg
N
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Pigmentary Glaucoma and Refractive Error Trans Am Acad Ophthalmol Otolaryngol 1970;74:984
1.98%-10.00 to -13.50 D1.98%-7.00 to -9.00 D19.80%-4.25 to -6.75 D23.27%-2.25 to -4.00 D31.19%-.50 to -2.00 D14.85%-.25 to +.25 D6.44%+.5 to +2 D0.49%+3 D
% of Eyes withPigmentary Glaucoma -78.22 % Myopic
Refractive Error
POAG LTG and Refractive Error Br J Ophthalmol 1973;57:499
19.8 mm Hg34.3 mm HgMean Max IOP
25.2 mm22.9 mmMean AL
-5.1 D0.0DMean Refract
6371Mean Age
LTGPOAG
I Would Argue That Statistically Glaucoma Is a Greater Concern Than Retina in the Moderate to High Myopic
Patient
Need IOPNeed RNFLNeed GCC
R/O Pigmentary IssuesConsider Axial Length
In longer eyes the sampling location of the RNFL layer is
further away from the center of the ONH yielding artificially thinner
measurements.Rauscher FM, Sekhon N, Feuer WJ et al. Myopia affects retinal nerve fiber layer measurements as determined by optical coherence tomography. J Glacuoma
2009;18:501-505
Signal strength and scan circle placement affects RNFL
measurements.Vizzeri G, Bowd C, Medeiros FA et al. Effect of signal strength and improper alignment on the variability of stratus optical coherence tomography retinal nerve fiber layer thickness
measurements. Am J Ophthalmol 2009;148:249-255
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Statistically significant differences in the structure of ONH and peripapillary
retina in non glaucomatous high myopes compared to on glaucomatous
emmetropes. OCT measurements of RNFL thicknesses different in non
glaucomatous with tilted discs.Tsutsumi T, Tomidokoro A, Saito H et al. Confocal scanning laser ophthalmoscopy in high myopic eyes in a population-based setting. Invest Ophthalmol Vis Sci 2009;50:5281-5287
Law SK, Tamboli DA, Giaconi J, Caprioli J. Characterization of retinal nerve fiber layer in nonglaucomatous eyes with tilted discs. Arch Ophthalmol. 2010 Jan;128(1):141-2.
Funky Discs and The Impact on Diagnosis
26 yo black female 20/20 no complaints
Case 4
58 yo
58 YO GLAUCOMA O.S. AND GLAUCOMA SUSPECT O.D.
NOTE INTER-EYE + OS HEMI-STRUCTURE RNFL DIFFERENCES
102104
7469
Megalopapilla OD
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NOTE HEMI-STRUCTURE DIFFERENCES WITHO.D. NEGATIVE SUPERIOR THINNER AND O.S. POSITIVEINDICATING INFERIOR THINNER
THIS IS CONSISTENT WITH THE INTER-EYE RNFL DIFFERENCES WITH OS MORE ADVANCED THAN OD
96108-11.84
76679.19
Comparisons
21+ 9- 12Difference4167108GCC I207696GCC S35/1.072/0.98Difference3569104RNFL I2874102RNFL S
Inter Eye Difference
OSOD
Conclusions:
1. Dominant Inter-Eye Asymmetry on RNFL and GCC
2. Intra-Eye Asymmetry on Mild on RNFL and Moderated on GCC
3. OS Appears More Advanced by Inter Eye
Conclusion???
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SYSTEMIC DISORDERS AND GLAUCOMA There is a clear beneficial effect of
the use of glaucoma medication on the likelihood of death.
Patients taking topical PGAs, a-agonists and B-blockers for
confirmed POAG associated with a 74% reduction in death.
Stein JD, Newman-Casey PA, Niziol LM et al. Association between the use of glaucoma medications and mortality. Arch Ophthalmol 2010;128:235-240
NEUROLOGY AND GLAUCOMA
When the RNFL Dies, The Brain DiesWhen the RNFL Dies, The Brain Dies
When the BrainWhen the Brain Dies, The RNFL DiesDies, The RNFL Dies
The Optic Nerve isThe Optic Nerve is Part of the BrainPart of the Brain
StuffStuff That is Good for the Brain is Also GoodThat is Good for the Brain is Also GoodFor theFor the RNFL RNFL
Degeneration of RGC and axons represent a substantial loss of neural activity in the
brain as 50 % to 60 % of the cerebral cortex spread over 40-45 visual areas represent visual function. This RGC degeneration
entails downstream caspase and mitochondrial dependent apoptotic
cascades resulting in actual loss of cortex.Quigley HA. Neuronal death in glaucoma. Prog Retin Eye Res. 1999;18:39-57.
Nickells RW. From ocular hypertension to ganglion cell death: a theoretical sequence of events leading to glaucoma. Can J Ophthalmol. 2007;42(2):278-287.Van Essen DC. Towards a quantitative, probabilistic neuroanatomy of cerebral cortex. Cortex. 2004;40(1):211-212.
Tatton WG, Chalmers-Redman RM, Tatton NA. Apoptosis and anti-apoptosis signaling in glaucomatous retinopathy. Eur J Ophthalmol. 2001;11(suppl 2):S12-S22.Tahzib NG, Ransom NL, Reitsamer HA, McKinnon SJ. Alpha-fodrin is cleaved by caspase-3 in a chronic ocular hypertensive (COH) rat model of glaucoma. Brain Res Bull. 2004;62:491-495.
Huang W, Dobberfuhl A, Filippopoulos T, et al. Transcriptional up-regulation and activation of initiating caspases in experimental glaucoma. Am J Pathol. 2005;167(3):673-681.Huang W, Fileta JB, Dobberfuhl A, et al. Calcineurin cleavage is triggered by elevated intraocular pressure, and calcineurin inhibition blocks retinal ganglion cell death in experimental
glaucoma. Proc Natl Acad Sci USA. 2005;102(34):12242-12247.
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Grey density reduction occurs in the primary visual cortex in patients with advanced glaucoma.Boucard Boucard CC, CC, Hernowo Hernowo AT, Maguire RP, et al. AT, Maguire RP, et al. Changes in cortical grey matter Changes in cortical grey matter density associateddensity associated with longwith long--standing retinal visual field defects. Brain standing retinal visual field defects. Brain 2009;132:18982009;132:1898--19061906
Measuring the optic nerve diameter at the orbital apex (15 mm behind the eye) shows significant correlation with RNFL loss.
Lagreze WA, Gaggi M, Weigel M et al. Retrobulbar optic nerve diameter measured by high-speed magnetic resonance imaging as a biomoarker for axonal loss in glaucomatous optic atrophy. Invest Ophthalmol Vis Sci 2009;50:4223-4228
Progressive visual field lossin NTG is associated with silent cerebral infarcts as defined by CT.
Leung DYL, Tham CCY, Li FCH, et al. Silent cerebral infarct and visual field progression in newly diagnosed normal-tension glaucoma. Ophthalmology 2009;116:1250-1256
CEREBROSPINAL FLUID PRESSURE AND GLAUCOMA
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ICP is significantly lower in patients with POAG and NTG and higher in those with OHT without glaucoma. Minor differences of IOP have been
associated with progression.Ren R, Jonas JB, Tian G, et all. Cerebrospinal fluid pressure in glaucoma: a prospective study. Ophthalmology 2010;117:259-266.
Wu SY, Leske MC. Associations with intraocular pressure in the Barbados Eye Study. Arch Ophthalmol. 1997;115:1572-1576.Berdahl JP, Allingham RR, Johnson DH. Cerebrospinal fluid pressure is decreased in primary open-angle glaucoma. Ophthalmology. 2008;115(5):763-768.
Berdahl JP, Fautsch MP, Stinnett SS, Allingham RR. Intracranial pressure in primary open angle glaucoma, normal tension glaucoma, and ocular hypertension: a case-control study. Invest Ophthalmol Vis Sci. 2008;49(12):5412-5418.
Nemesure B, Honkanen R, Hennis A, et al. Incident open-angle glaucoma and intraocular pressure. Ophthalmology. 2007;114:1810-1815.Suzuki Y, Iwase A, Araie M, et al. Risk factors for open-angle glaucoma in a Japanese population: the Tajimi Study. Ophthalmology. 2006;113:1613-1617.
The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration.The AGIS Investigators. Am J Ophthalmol. 2000;130:429-440.
Sommer A, Tielsch JM. Risk factors for open-angle glaucoma: the Barbados Eye Study. Arch Ophthalmol. 1996;114:235.Magnaes B. Body position and cerebrospinal fluid pressure. Part 1: clinical studies on the effect of rapid postural changes. J Neurosurg. 1976;44:687-697.
Schwarz S, Georgiadis D, Aschoff A, Schwab S. Effects of body position on intracranial pressure and cerebral perfusion in patients with large hemispheric stroke. Stroke. 2002;33:497-501.
Carlson GD, Oliff HS, Gorden C, et al. Cerebral spinal fluid pressure: effects of body position and lumbar subarachnoid drainage in a canine model. Spine. 2003;28:119-122.Carlson KH, McLaren JW, Topper JE, Brubaker RF. Effect of body position on intraocular pressure and aqueous flow. Invest Ophthalmol Vis Sci. 1987;28:1346-1352.
Kiuchi T, Motoyama Y, Oshika T. Relationship of progression of visual field damage to postural changes in intraocular pressure in patients with normal-tension glaucoma. Ophthalmology. 2006;113:2150-2155.
Ozcan MS, Praetel C, Bhatti MT, et al. The effect of body inclination during prone positioning on intraocular pressure in awake volunteers: a comparison of two operating tables. Anesth Analg. 2004;99:1152-1158, table of contents.
Lamina separates two distinctive pressurized zones, IOP 10-21 mm Hg and ICP 5-15 mm Hg. Average IOP is
16 and Average ICP is 12 and the
IOP-ICP is called the Trans-laminar pressure.
Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:701-
713; discussion 829-730.Morgan WH, Yu DY, Alder VA, et al. The correlation between cerebrospinal fluid pressure and retrolaminar tissue pressure. Invest
Ophthalmol Vis Sci. 1998;39:1419-1428.Goetz C, ed. Textbook of Clinical Neurology. Philadelphia: Saunders; 2003:511-529.
Alteration of Trans-laminar pressure may bow the lamina creating a
pinching of axons. Both intraocular fluid and intracranial fluid are created by carbonic anhydrase reactions and
ultrafiltration.Anderson DR, Hendrickson AE. Failure of increased intracranial pressure to affect rapid axonal transport at the optic nerve head. Invest Ophthalmol Vis Sci. 1977;16:423-
426.Quigley HA, Guy J, Anderson DR. Blockade of rapid axonal transport. Effect of intraocular pressure elevation in primate optic nerve. Arch Ophthalmol. 1979;97:525-531.
Quigley H, Anderson DR. The dynamics and location of axonal transport blockade by acute intraocular pressure elevation in primate optic nerve. Invest Ophthalmol. 1976;15:606-616.
Levy NS. The effects of elevated intraocular pressure on slow axonal protein flow. Invest Ophthalmol. 1974;13:691-695.Minckler DS, Tso MO, Zimmerman LE. A light microscopic, autoradiographic study of axoplasmic transport in the optic nerve head during ocular hypotony, increased
intraocular pressure, and papilledema. Am J Ophthalmol. 1976;82:741-757.Jonas JB, Berenshtein E, Holbach L. Anatomic relationship between lamina cribrosa, intraocular space, and cerebrospinal fluid space. Invest Ophthalmol Vis Sci.
2003;44:5189-5195.Jonas JB, Mardin CY, Schlotzer-Schrehardt U, Naumann GO. Morphometry of the human lamina cribrosa surface. Invest Ophthalmol Vis Sci. 1991;32:401-405.
Jonas JB, Berenshtein E, Holbach L. Lamina cribrosa thickness and spatial relationships between intraocular space and cerebrospinal fluid space in highly myopic eyes. Invest Ophthalmol Vis Sci. 2004;45:2660-2665.
Both IOP and ICP affected by BP. ??? Systemic Hypotension??? CAI use for glaucoma
??? Positional Effects
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OTHER Neurological ISSUES• EXCESSIVE GLUTAMATE FORMATION
ISSUES INCLUDE:– STROKE– MIGRAINE– CNS TRAUMA– EPILEPSY– PD, AD, HD– HIV DEMENTIA– ALS, MS(Clin Ther 2004;26:615, Curr Alzheimer Res 2004;1:249, Neurochem Res 2007;32:757, Proc Natl
Acad Sci USA 2007;104:13444, IGR 2007;9:23)
WHITE MATTER LESIONS
• 1/3 NTG HAD WMLs ON MRI WITH INF VF DEFECTS (Ophthalmology
1995;102:1632, Jpn J Ophthalmol 2004;48:340)
• CEREBELLAR WML IN MIGRAINE ASSOC WITH AURA (Invest Ophthalmol Vis Sci 1985;26:1105, Ophthalmology 1997;104:1714, AmJ Ophthalmol 2003;136:820, JAMA 2004;291:427)
• CSVD AND ATHEROMA WITH WML 3X INCIDENCE OF STROKE, AND LARGE RET VEIN DIAMETER WITH WML (Dement Geriatr Cogn Disord 2003;15:143, Brain 2005;128:2034, Stroke 2003;34:1126, Brain 2006;129:182)
• MIGRAINE/WML? (Am J Ophthalmol 2001;131:699, Arch Ophthalmol 2002;120:714, Invest Ophthalmol Vis Sci 1985;26:1105
MIGRAINE OCCURS IN 43% OF WOMEN AND 18% OF MEN. AURA IN 25%. CNTGS STATES MIGRAINE WAS RISK FACTOR FOR PROGRESSION OF GLAUCOMA.
OTHER STUDIES REPORT NO STATISTICAL RELATIONSHIP.
Stewart W, Wood C, Reed M, et al. Cumulative lifetime migraine incidence in women and men. [published online ahead of print July 15, 2008]. Cephalagia.Stewart WF, Linet MS, Celentano DD, et al. Age- and sex-specific rates of migraine with and without visual aura. Am J Epidemiol. 1991;134:1111-1120.
Phelps CD, Corbett JJ. Migraine and low-tension glaucoma. A case control study. Invest Ophthalmol Vis Sci. 1985;26:1105-1108.Drance S, Anderson DR, Schulzer M; Collaborative Normal-Tension Glaucoma Study Group. Risk factors for progression of visual field abnormalities in normal-tension
glaucoma. Am J Ophthalmol. 2001;131(6):699-708.Anderson DR, Drance S, Schulzer M; Collaborative Normal-Tension Glaucoma Study Group. Factors that predict the benefit of lowering intraocular pressure in normal
tension glaucoma. Am J Ophthalmol. 2003;136:821-829.Klein BE, Klein R, Meuer SM, Goetz LA. Migraine headache and its association with open-angle glaucoma: The Beaver Dam Eye Study. Invest Ophthalmol Vis Sci.
1993;34(10):3024-3027.Wang JJ, Mitchell P, Smith W. Is there an association between migraine headache and open-angle glaucoma? Findings from the Blue Mountains Eye Study.
Ophthalmology. 1997;104:1714-1719.Leske MC, Heijl A, Hussein M, et al. Factors for glaucoma progression and the effect of treatment: the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2003;121:48-56.Canadian Glaucoma Study Group. Canadian Glaucoma Study: 1. Study design, baseline characteristics, and preliminary analyses. Can J Ophthalmol. 2006;41:566-575.
Chauhan BC, Mikelberg FS, Balaszi G, et al. Canadian Glaucoma Study. 2. Risk factors for the progression of open angle glaucoma. Arch Ophthalmol. 2008;126:1030-1036.
• NEURO INVESTIGATION FOR FOLLOWING ISSUES– Young age– Sudden vision loss– Reduced central vision that is progressive– Vertically aligned visual field defects or VF
defects atypical for glaucoma– VF defects out of proportion to cupping– Eyes with optic atrophy exceeding
cupping – Atypia
NEUROLOGICAL DIFFERENTIALNEUROLOGICAL DIFFERENTIAL
27
Conclusion???HORMONES AND
GLAUCOMA
IOP was significantly lower in women taking HT than in those who had never taken HT, even after removing other possible influences on IOP. Tint NL, Alexander P, Tint KM, et al. Hormone therapy and intraocular pressure in nonglaucomatous eyes. Menopause 2010;17:157-160
Data in a recent study suggest a possible role for declining sex hormone levels in the genesis of primary open angle glaucoma. This study also found that current use of estrogen with progestin was associated with a reduced risk of POAG. Pasquale LR, Rosner BA, hankinson SE, Kang JH. Attributes of female reproductive aging and their relationship to primary open-angle
glaucoma:a prospective study. J Glaucoma 2007;16:598-605.
Suggestions that estrogens are neuroprotective in degenerative disorders and possibly withinthe retina and in glaucoma. Kumar DM, Simpkins JW, Agarwal N. Estrogens and neuroprotection in retinal diseases. Mol Vis 2008;14:1480-1486. Nakazawa T, Takahashi H, Shimura M. Estrogen has a neuroprotective effect on axotomized RGCs through ERK signal transduction pathway. Brain Res 2006;1093:141-149.
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ESTROGEN LEVELS MAY HAVE SOME EFFECT ON GLAUCOMA GEORGIAN MEDICAL NEWS 2005; 9: 33
ESTRADIOL LEVELS 1/2 IN GLAUCOMA VERSUS NORMALS IGR 2007;9:13
ESTRADIOL POTENTIATES FLOW, TESTOSTERONE INHIBITS FLOW ACTA OPHTHALMOLOGICA SCANDINAVICA 2003; 81: 617, J GLAUCOMA 2007;16:598
RIM STRUCTURE ALTERED DURING MENSTRUAL CYCLEACTA OPHTHALMOLOGICA SCANDINAVICA 2004; 82:741
SUGGESTION THAT FEMALE SEX HORMONES MAY BE PROTECTIVE OF THE OPTIC NERVE. VAJARANANT TS, NAYAK S, WILENSKY JT, JOSLIN CE. GENDER AND GLAUCOMA: WHAT WE KNOW AND WHAT WE NEED TO KNOW. CURR OPIN OPHTHALMOL 2010;21:91-99.
There are suggestions that “Topical estrogen drops may be a new alternative treatment of glaucoma.” Ozcura F, Aydin S. Med Hypotheses 2007;69:456.
Conclusion???
VASCULAR SYSTEM AND GLAUCOMA
29
THE DRANCE HEMORRHAGE
IS THE DEMON OF GLAUCOMA.
FACT OR FICTION?
OHTS study photo review 84% detection of disc heme, observation gave 16%. Disc heme related
to age, CCT, family history and smoking.Presence of heme increased risk of progression
by 6 X and 13.6% in eyes with previous heme 5.2% without previous heme.
BUT!!!87% of eyes with disc hem did not progress in
the 31 month follow-up.
Kass MA, Heuer DK, Higgenbotham EJ et al. The ocular hypertension treatment study: a randomized trial determines that topical ocular hypertensive medication delays the onset of primary
open-angle glaucoma. Arch Ophthalmol 2002;120:701-713.Gordon MO, Beiser JA, Brandt JD et al. The ocular hypertension treatment study: baseline factors
that predict the onset of primary open-angle glaucoma. Arch Ophthalmol 2002;120:714-720
Conclusion???
Simvastatin significantly protected against the
development of progression of visual fields in a cohort of
121 patients with normal tension glauoma.
Leung DY, Li FC, Kwong YY et al. Simvastatin and disease stabilization in normal tension glaucoma: a cohort study. Ophtahlmology 2010;117:471-476.
30
WHY?
VASCULAR PERFUSION IS AN ISSUE. DIFFERENCE OF SYSTOLIC AND
DIASTOLIC IOP IS OCULAR PULSE AMPLITUDE (OPA) AND IS LOWER IN
PATIENTS WITH POAG AND NTG. AVE OPA IS 2.09 TO 2.8 MM HG
OPTOMETRY 2010;81:408-413ARCH OPHTHALMOL 2002;120:954-959OPHTHALMOLOGY 2007;114:1965-1972
OPHTHALMOLOGY 2008;115:85-93OPHTAHLMOLOGY 2000;107:1287-1293ARCH OPHTHALMOL 1995;113:216-221ARCH OPHTHALMOL 2007;125:805-812
BR J OPHTHALMOL 1996;80:864-867J GLAUCOMA 1997;6:23-32
AM J OPHTHALMOL 1998;126:42-51ACTA OPHTHALMOLOGICA 2009;87:323-328
CURR EYE RES 2006;31:851-862BR J OPHTHALMOL 2001;85:678-682
EYE 1997;11:485-488BR J OPHTHALMOL 2000;84:1282-1284
CURR EYE RES 1981;1:19-23J GLAUCOMA 2008;17:403-407
GRAEFS ARCH CLIN EXP OPHTHALMOL 2008;246:559-565J GLAUCOMA 2007;16:700-703OPTOMETRY 2009;80:169-174
This Vascular Perfusion Stuff is All over the Place.
Logic Dictates it is an Issue, But the Issue is Yet to Be
Defined.
ASSOCIATIONS WITH POAG AND NTG
• TREATED SYSTEMIC HTN ESPECIALLY WITH Ca BLOCKERS (Current Eye Research 2007;32:153, Ophthalmology 2007;114:2221)
• DIAS PERFUSION PRESSURE = DIAS BP - IOP SHOULD BE > 30 (Memarzadeh et al at The 18th Annual AGS Meeting, March 2008, Ophthalmology 2008;115:85, Glaucoma Today 2008;6:31, Ophthalmology 2000;107:1287, Int Ophthalmol 1998;22:19, Invest Ophthalmol Vis Sci 2005;46:561, N Engl J Med 1973;288:392, Surv Ophthalmol 1999;43:S10, Am J Ophthalmol 1994;117:603, Arch Ophthalmol 1995;113:216, Arch Ophthalmol 1995:113:918 )
• ADD NIGHT-TIME, BETA BLOCKER ISSUES, CV RELATIONSHIP TO AD (Ophthalmology 2007;114:1965, American Geriatrics Society 2008 Annual Scientific Meeting: Abstract P10. Presented May 1, 2008)
31
BLOOD FLOW• VASCULAR DYSREGULATION
– ABERRANT AUTOREGULATION– POSTURAL INDUCED– INCR VF PROGRESSION– IMPACTS ON MITOCHONDRIA
(Ophthalmology 2008;115:85, Surv Ophthalmol 2007;52:S144, Exp Eye Res 1997;64:737, Ophthalmology 2008;115:246, (Invest Ophthalmol Vis Sci 1997;38:1563, Invest Ophthalmol Vis Sci 1997;38:643, Invest Ophthalmol Vis Sci 1997;38:652, Prog Retin Eye Res 2002;21:359, Fortschr Ophthalmol 1990;87:S187, Klin Monatsbl Augenheilkd 2001;218:290, J Physiol 2003;552:335, Proceedings of the Sixth Annual Scientific Meeting of the Optometric Glaucoma Society)
BLOOD FLOW• SVP GONE 46% GLAUCOMA AND
PRESENT 98% CONTROLS. (Br J Ophthalmol 2007;91:405, ARVO 2007 Abstract 2879)
• CCT AND INCR IN RVO (ARVO 2007 Abstract 3080/B587)
• GLAUCOMA HAS LOWER OCULAR SURFACE TEMP (Br J Ophthalmol. 2007;91:878)
DORZOLAMIDE AS A VASOREGULATOR
• MAY INCREASE BLOOD VELOCITY AND FLOW (Microvasc Res 2006;72:101)
• DOES THIS ALSO LOWER ICP AND ALTER THE TRANS-LAMINAR PRESSURE GRADIENT?
• SHOULD NOT USE IN PATIENTS WITH A DEFECTIVE CORNEAL PUMP (Arch Ophthalmol 2007;125:1345)
SO SHOULD WE LOOK AT WAYS TO IMPROVE BLOOD
FLOW???
32
Conclusion???