1

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

15

DownwardTrend

125107

119

78

16

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.

28

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???