Glaucomatous Optic Atrophy

1. 1

4 April 2011



Glaucomatous Optic Atrophy


John R. Martinelli, OD, FAAO
St. George’s University School of Medicine











Abstract

Glaucomatous optic atrophy (GOA) can be characterized as an irreversible, end-stage
glaucomatous optic neuropathy with associated severe visual field loss and reduction of
acuity. Clinically apparent is advanced optic cupping, loss of neuro-retinal rim tissue, and
optic pallor. This degree of optic neuropathy and functional vision loss can be secondary
to various contributing factors including an undiagnosed, poorly managed, or poorly
controlled primary or secondary glaucoma. The development of glaucomatous optic
atrophy in properly managed cases, and particularly in normal tension glaucoma (NTG),
may also be related to genetic factors or generalized systemic or vascular disease
jeopardizing the integrity of the optic nerve and ocular micro-circulation. Poor patient
compliance with treatment is another consideration which may lead to eventual end-stage
disease. The pathogenesis and pathophysiology of secondary glaucomatous optic atrophy
can be distinguished from other forms of optic atrophy with respect to etiology and
clinical manifestations.



Keywords: Glaucoma, GOA, Glaucomatous Optic Atrophy, Glaucomatous Optic
Neuropathy, ION, Ischemic Optic Neuropathy, NTG, Normal Tension Glaucoma,
Secondary Optic Atrophy

2. 2

Introduction

Glaucomatous optic atrophy (GOA) is classified as a secondary optic atrophy arising
from contributing ocular or systemic disease. This is in contrast to the primary optic
atrophies, such as Leber’s hereditary optic atrophy or autosomal dominant optic atrophy
(ADOA), which are attributed to inheritance with a molecular-genetic basis.

Clinically, the optic disc can appear with peripapillary chorio-retinal atrophy, a large
vertical cup/disc ratio, thinning or absence of neuro-retinal rim tissue, associated NFL
defects, and marked optic pallor. Alternatively, a small or hypoplastic optic nerve without
cupping can be susceptible to end-stage glaucomatous optic atrophy with pallor due to
morphologic disadvantages. An afferent pupillary defect will be present in the affected
eye along with significant loss of visual field and acuity with no-light-perception (NLP)
possible.

The pathogenesis of this disorder and subsequent loss of optic nerve function can be the
end result of various etiologies including an uncontrolled longstanding primary
glaucoma. Examples include chronic open angle glaucoma (COAG), chronic mixed
mechanism or narrow angle glaucoma (NAG), and chronic or acute angle closure
glaucoma (ACG).

Uncontrolled secondary glaucoma’s such as uveitic glaucoma, traumatic angle recession
glaucoma, neovascular glaucoma (NVG), pseudoexfoliative glaucoma (PXE),
phacomorphic glaucoma, pupillary block glaucoma, and surgical or iatrogenic induced
glaucoma are also examples which can lead to end stage disease. Medications such as
Prednisone and Topamax (Topiramate) can create ocular hypertensive conditions leading
to secondary glaucoma which may induce optic atrophy as well.

The irido-corneal-endothelial (ICE) syndromes such as Chandler’s syndrome are an
example of congenital anterior segment disorders which can lead to secondary glaucoma
and optic atrophy if left undetected or uncontrolled.

Systemic conditions affecting the integrity of the optic disc, neuro-retinal rim, or retinal
nerve fiber layer (RNFL) will also provide opportunity for glaucomatous optic
neuropathy leading to atrophy. Vascular disease such as carotid insufficiency creating
ischemic conditions at the level of the optic nerve can contribute to glaucomatous optic
atrophy even at normal intraocular pressures. Systemic inflammatory disease including
giant cell arteritis (GCA) is another example that may produce ocular ischemia and
greater risk. Orbital compressive disease such as advanced thyroid ophthalmopathy or
orbital melanoma with optic nerve involvement is also considered a risk factor for
associated secondary glaucomatous optic atrophy.

Considering the multitude of possible clinical scenarios and etiologies, a thorough
understanding of related ocular and systemic disease is critical in recognizing and
identifying those individuals at risk. Aggressive medical and/or surgical therapy must be
instituted before atrophic progression and irreversible vision loss results.

3. 3

Case Report

A 48 year old African-American gentleman presented to our center on August 8, 2005 as
a new patient for a routine examination. He had no complaints but stated he “needed new
glasses”. He reported an unremarkable ocular and systemic history. He was not aware of
a family history of ocular or systemic disease. With refraction, best corrected VA was
20/20 OD and 20/30 OS without PH improvement. Keratometry did not show evidence of
irregular corneal cylinder or distortion in either eye. Ishihara color plates were normal
OU. Stereopsis was normal. Confrontation visual fields suggested a generalized 360
degree constriction OU. Pupils were equal, round, and responsive to light and
accommodation, however, a slight grade I afferent pupillary defect (APD) was elicited
OS. Extraocular muscles were full without restriction or subjective diplopia. Red cap test
was diminished OS when compared with the fellow eye.

Biomicroscopic examination revealed a healthy anterior segment with wide open, grade
IV angles by Vonherrick technique OU. There was no evidence of keratopathy, corneal
edema, anterior uveitic disease, posterior synechia, pupillary block, or lenticular changes
in either eye. Intraocular pressure by Goldmann applanation tonometry was markedly
elevated at 42mm Hg OD and 49mm Hg OS. Sonogage central corneal pachymetry
readings were above average at 586µ OD and 599µ OS. Goldmann three mirror
gonioscopy also showed an open grade IV anterior chamber in all 4 quadrants of each
eye. Schwalbe’s line, trabecular meshwork, Schlemm’s canal, scleral spur, and ciliary
body were viewable in each quadrant OU. There was no sign of peripheral anterior
synechia (PAS), iris strands, or angle recession in either eye. Grade II pigment was
apparent within the trabeculum OU without evidence of pseudoexfoliative debris in either
eye.

Dilated 90D ophthalmoscopic evaluation demonstrated a clear vitreous without evidence
of cells or posterior inflammatory activity OU. The peripheral retina, vessels, and macula
appeared healthy; however, there was dramatic optic cupping evident in each eye along
with mild parapapillary atrophy present OU. A c/d of 0.7/0.8 OD and 0.9/0.9 OS was
viewed with loss of neuro-retinal rim tissue more evident in the left eye. Early optic
pallor was observed OS. Optic nerve head Heidelberg retinal tomography (HRT) analysis
produced results corresponding to advanced glaucomatous cupping with significantly
reduced rim area, volume, and thickness in each eye. Notably, the OS was quite reduced
in comparison with the fellow eye and far outside of normal parameters. The same was
found for the global cup shape measure (CSM) in each eye with the OS CSM confirming
more advanced disease progression in that eye. Considering the above findings, a
diagnosis of advanced chronic open angle glaucoma with glaucomatous optic neuropathy
OU and early secondary glaucomatous optic atrophy OS was determined. He was started
on Travatan (Travoprost 0.004%) 1gtt HS OU and was educated regarding the advanced
stage of the disease. The likelihood of adjunctive topical treatment was discussed as was
the importance of compliance and follow-up visits. SLT laser treatment was also
recommended for each eye with the left eye scheduled to be performed at his first follow-
up visit. Depending on the efficacy of in-office therapy, the possibility of additional
surgical treatment such as endoscopic cyclophotocoagulation (ECP) or trabeculectomy

4. 4

would be considered. He was scheduled for a 1 week follow-up visit to re-assess his IOP,
perform formal threshold visual field testing, and proceed with SLT treatment OS.


Follow-up #1

Unfortunately, he returned approximately 1 ½ years later on February 20, 2007 with a
chief complaint of “cannot see out of my left eye and my glasses don’t help”. He
conveyed that because “the drops didn’t help”; he never returned for his follow-up visit
and had only used the drops for a few days. His ocular and systemic history was
otherwise unchanged and unremarkable.

With a new refraction, best corrected VA’s were 20/20 OD and 20/CF@10’ OS without
PH improvement. Pupils were equal, round, and responsive to light and accommodation,
however, a dramatic grade IV APD OS was now apparent. Versions were full with good
alignment and without subjective diplopia. Biomicroscopic examination remained
unremarkable with grade IV angles in each eye via Vonherrick technique. Goldmann
applanation tonometry was elevated at 37mm Hg OD and 38mm Hg OS. Digital
stereophotography of the optic discs revealed advanced end-stage glaucomatous optic
cupping OU, greater OS, with predominant optic pallor OS. The infero-temporal cupping
in the right eye showed quite dramatic progression as did the degree of optic pallor
present in the left eye. Optic nerve head HRT analysis demonstrated advancement of all
parameters, confirming progression of the neuropathy in each eye and secondary atrophy

5. 5

in the left eye. Oculus 30-2 threshold visual field exhibited a characteristic glaucomatous
Bjerrum scotoma along with an extensive peripheral nasal depression with corresponding
probability map defects OD. The OS visual field was unobtainable due to his non-
responsiveness to testing due to CF acuity.

6. 6

The severity of progression and danger of continued
loss of vision was once again explained. He was placed
on Cosopt (Dorzolamide 2%/Timolol 0.5%) 1gtt Q12H
OU and Travatan Z (Travoprost 0.004%) 1gtt HS OU.
He was also scheduled for 360º SLT laser treatment in
each eye, with the left eye performed first at his 1 week
follow-up visit.

Follow-up #2

He returned on schedule for his 1 week follow-up visit
and reported proper compliance with his topical
treatment. Corrected VA remained 20/20 OD and
20/CF@10’ OS. Goldmann applanation tonometry
showed a greatly reduced IOP of 21mm Hg OD and
26mm Hg OS. A 400µ/100 spot SLT treatment @
40mw was applied 360º to the OS trabeculum. To
enhance the post-operative effect, he was not placed on
any additional topical medications and was instructed to
continue his current therapeutic regimen. He was
scheduled for a 10 day follow-up visit for repeat IOP
measurements and OD SLT treatment.

Follow-up #3

He returned as scheduled for his 10 day follow-up visit. He maintained proper
compliance with his topical treatment. Corrected VA was stable at 20/20 OD and
20/CF@10’ OS. IOP OD was slightly less at 20mm Hg. The OS demonstrated a
noticeable response s/p SLT treatment at 21mm Hg, representing a nearly 20% reduction.
A 400µ/100 spot SLT treatment @ 40mw was also applied 360º to the OD trabeculum.
His post-operative instructions were identical to the other eye without additional topical
treatment recommended. He was scheduled for a 10 day follow-up visit for IOP
measurements.

Follow-up #4

He returned on schedule for his 10 day follow-up visit reporting good compliance with
his topical treatment. Corrected VA was unchanged at 20/20 OD and 20/CF@10’ OS.
IOP OD was 17mm Hg s/p SLT treatment, a 15% improvement. IOP OS was slightly less
at 20mm Hg. Considering the advanced stage of progression with secondary optic
atrophy, a target pressure of ≤ 12 was recommended despite a favorable response to the
current treatment. Therefore, he was additionally placed on Alphagan P (Brimonidine
0.15%) 1 gtt Q12H OU and instructed to continue his other current topical medications.
He was asked to return again in 1 week to re-assess his IOP and consider further
treatment options.

7. 7

Follow-up #5

He returned as scheduled for his 1 week follow-up IOP check. He was now compliant
with all topical medications including Cosopt, Alphagan P, and Travatan. IOP OD
continued to drop to 15mm Hg. IOP OS was now at 17mm Hg. To achieve our target
pressure goal of ≤ 12 OU, the possibility of requiring either surgical ECP or
trabeculectomy was explained. Considering his much improved condition and the
possibility of further IOP reduction often seen several weeks s/p SLT treatment, it was
recommended to re-evaluate his IOP after a one month period while maintaining his
current treatment regimen. He was scheduled for this visit and was again reminded of the
importance of treatment.

Discussion

As exhibited in this case, the formation of progressive secondary glaucomatous optic
atrophy (GOA) can be a visually devastating result of patient non-compliance to therapy.
Early detection and optimal treatment of underlying contributing ocular and systemic
conditions is critical to its prevention. Based on recent epidemiologic analyses of the
primary glaucoma’s, progression to this advanced stage of pathology leading to blindness
will continue to become more prevalent. By 2010, 60 million people will have open angle
glaucoma (OAG) and angle closure glaucoma (ACG), and it will be the second leading
cause of world blindness.1 The number estimated blind from OAG in 2010 is 4,472,083
and from ACG is 3,936,241 for a combined total of 8,408,324.1 While only 24% of those
with primary glaucoma have ACG, the number of ACG blind is nearly equal to that of
OAG because of the greater estimated morbidity of this disease.1

Predictive factors leading to progression in OAG have been found to vary depending on
the level of intraocular pressure during the course of the disease. For patients with
elevated intraocular pressure, significant predictive factors for eventual progression were
older age, advanced perimetric damage, smaller neuroretinal rim, and larger area of beta
zone of parapapillary atrophy.2 In contrast, patients with normal intraocular pressures, a
significant predictive factor was the presence of disc hemorrhages at baseline.2 Within
patients with elevated intraocular pressure, primary open-angle glaucoma and secondary
open-angle glaucoma results did not differ in predictive factors for progression.2 In
addition, progression of glaucomatous optic nerve head changes in OAG has been found
to be independent of the size of the optic disc and alpha-zone of parapapillary atrophy
and retinal vessel diameter.3

Many ocular or systemic conditions affecting the integrity of the optic nerve can lead to
glaucomatous optic neuropathy with potential for end stage disease and blindness. The
pathogenesis may involve several inter-related factors including structural effects of the
optic nerve related to intraocular pressure, inherent susceptibility of the optic nerve itself,
micro-vascular pathology or ischemia at the level of the optic nerve, as well as orbital
disease.

8. 8

With respect to high-pressure related OAG, characteristic histopathologic features have
been described leading to atrophy even in the absence of cupping. Diffuse and centrally
intense hydropic axonal degeneration and central blocked retrograde axoplasmic
transport explain loss of central acuity, generalized contraction of visual field, and
generalized optic atrophy without glaucomatous cupping in eyes with prolonged high-
pressure secondary glaucoma.4

Recent research has found genetic factorial influences in progressive normal-pressure or
normal-tension open angle glaucoma (NTG). Examples include the optic atrophy 1 gene
(OPA1) IVS 8 +32 T/C polymorphism, which has been associated with secondary
glaucomatous optic atrophy in NTG and may be used as a marker for this disease
association.5 This polymorphism also influences the phenotypic feature in patients with
high tension glaucoma (HTG) and should be considered a genetic risk factor not only for
NTG, but also for HTG.5 Individuals with an E50K mutation in the optineurin gene
(OPTN) were found to have NTG that appeared to be more severe than in a control group
of subjects with NTG without this mutation.6 A mutation of the GLC1A gene has also
been implicated in the formation of NTG and HTG.7

Systemic cardio-vascular disease, circulatory insufficiency, ischemia, diabetes, and
hypertension are examples that can have a direct affect on optic nerve function and
possibly propagate glaucomatous progression to optic atrophy. Generalized inflammatory
or auto-immune conditions can be a contributor to end stage disease as can systemic
metabolic disorders. Orbital retro-bulbar compressive optic neuropathies will also pre-
dispose the eye to GOA. Examples include conditions such as carotid stenosis leading to
non-arteritic ischemic optic neuropathy (NAION) which will pre-dispose the optic disc to
secondary glaucomatous optic atrophy. Giant cell arteritis (GCA) with associated
temporal arteritis (TA) can create pathology producing arteritic ischemic optic
neuropathy (AION) which will likewise only initiate or enhance progression. Elevated
blood-serum levels of C-reactive protein (CRP), an inflammatory marker linked with
atherosclerotic vascular disease, may also be a sign of ocular ischemia potentially
advancing the disease.8 Metabolic syndrome and insulin resistance have been associated
with diurnal variations in IOP which may have an implication in allowing progression to
glaucomatous optic atrophy.9,10 Advanced orbital thyroid disease leading to Grave’s
ophthalmopathy with retro-bulbar compressive optic neuropathy is an example which can
mechanically allow for glaucomatous progression as well.
Unfortunately, there is no treatment to reverse the effects of secondary end-stage
glaucomatous optic atrophy. In its most advanced state, visual acuity and visual field loss
can decline to a no-light-perception (NLP) level. Aggressive ocular and systemic
treatments are preventative measures and must be instituted in high-risk individuals
before atrophic progression.

Preventative therapy includes topical ocular hypotensive medications providing for
maximum lowering of IOP. Target pressures must be set significantly lower at the onset
of treatment to provide optimal protection. In high risk individuals, at least 30% - 35%
reductions with IOP’s consistently ≤ 12mm Hg is not an unreasonable goal to attain.

9. 9

Pachymetry measurements indicating reduced central corneal thickness and the possible
associated RNFL implications must also be considered in the aggressiveness of the
treatment plan. Caution must be noted with the beta-blockers in the event of
contraindicative systemic conditions such as cardio-vascular or pulmonary disorders
which may very well be present in advanced optic nerve disease. Likewise, the
prostaglandin analogues must be avoided in the case of the uveitic glaucoma’s. However,
at risk NTG individuals may have additional benefits with prostaglandin analogue
treatment as there has been some evidence in the literature suggesting increased ocular
bloodflow.11 Depending on the form of glaucoma and responsiveness to medical
treatment, selective laser trabeculoplasty (SLT), argon laser trabeculoplasty (ALT), or
peripheral iridotomy (PI) are also options. If in-office therapy proves to be inadequate,
out-patient surgical procedures such as endoscopic cyclophotocoagulation (ECP) or
trabeculectomy may be alternatives for proper pressure control.

Equally important is working in conjunction with the primary care physician and
appropriate medical specialists. The ultimate goal of systemic treatment is allowing for
and maintaining proper ocular hemodynamics, ocular profusion, structure, and thus
integrity of the optic nerve as it relates to generalized pathology.

Conclusion

The development of end-stage secondary glaucomatous optic atrophy leading to
permanent vision loss is a disease process which may be proceeding at many levels.
Certain ocular, genetic, and systemic conditions are most probably intertwined depending
on the individual. The goal of therapy is to prevent progression and subsequent
irreversible loss of vision. Therefore, a multi-disciplinary approach for the prevention,
control, and management of the at-risk patient is mandatory. The importance of
aggressive ocular treatment, proper diagnostic laboratory studies, and possibly genetic
counseling must not be underestimated. The prompt initiation or maintenance of
treatment for contributing systemic conditions is crucial as is the timely and proper
communications with appropriate members of the health care team. Finally, as evident in
this case, patient communication, understanding, compliance, and follow-up care are
critical to the final outcome.

10. 10

Bibliography

1. Quigley HA, Broman AT.
The number of people with glaucoma worldwide in 2010 and 2020.
Br J Ophthalmol. 2006 Mar;90(3):262-7.

2. Martus P, Stroux A, Budde WM, Mardin CY, Korth M, Jonas JB.
Predictive factors for progressive optic nerve damage in various types of chronic
open-angle glaucoma.
Am J Ophthalmol. 2005 Jun;139(6):999-1009.

3. Jonas JB, Martus P, Horn FK, Junemann A, Korth M, Budde WM.
Predictive factors of the optic nerve head for development or progression of
glaucomatous visual field loss.
Invest Ophthalmol Vis Sci. 2004 Aug;45(8):2613-8.

4. Knox DL, Eagle RC Jr, Green WR.
Optic nerve hydropic axonal degeneration and blocked retrograde axoplasmic
transport: histopathologic features in human high-pressure secondary glaucoma.
Arch Ophthalmol. 2007 Mar;125(3):347-53.

5. Mabuchi F, Tang S, Kashiwagi K, Yamagata Z, Iijima H, Tsukahara S.
The OPA1 gene polymorphism is associated with normal tension and high tension
glaucoma.
Am J Ophthalmol. 2007 Jan;143(1):125-130. Epub 2006 Oct 23.

6. Aung T, Rezaie T, Okada K, Viswanathan AC, Child AH, Brice G, Bhattacharya
SS, Lehmann OJ, Sarfarazi M, Hitchings RA.
Clinical features and course of patients with glaucoma with the E50K mutation
in the optineurin gene.
Invest Ophthalmol Vis Sci. 2005 Aug;46(8):2816-22.

7. Ikezoe T, Takeuchit S, Komatsu N, Okada M, Fukushima A, Ueno H, Koeffler
HP, Taguchi H.
Identification of a new GLC1A mutation in a sporadic, primary open-angle
glaucoma in Japan.
Int J Mol Med. 2003 Aug;12(2):259-61.

8. Stefan C, Nenciu A, Melinte D, Malcea C, Nae I, Afanasiuc O.
[Protein C reactive and glaucoma]
Oftalmologia. 2006;50(4):82-5. Romanian.

9. Oh SW, Lee S, Park C, Kim DJ.
Elevated intraocular pressure is associated with insulin resistance and
metabolic syndrome.
Diabetes Metab Res Rev. 2005 Sep-Oct;21(5):434-40.

11. 11

10. Perlman JI, Delany CM, Sothern RB, Skolnick KA, Murray D, Jacobs RW, Shue
JL, Kaplan E, Friedman NC, Nemchausky BA, Ryan MD, Kanabrocki EL.
Relationships between 24h observations in intraocular pressure vs blood
pressure, heart rate, nitric oxide and age in the medical chronobiology aging
project.
Clin Ter. 2007 Jan-Feb;158(1):31-47.

11. Inan UU, Ermis SS, Orman A, Onrat E, Yucel A, Ozturk F, Asagidag A, Celik A.
The comparative cardiovascular, pulmonary, ocular blood flow, and ocular
hypotensive effects of topical travoprost, bimatoprost, brimonidine, and
betaxolol.
J Ocul Pharmacol Ther. 2004 Aug;20(4):293-310.