Is the Optic Disc Cupping or Sinking in Is the Optic Disc Cupping or Sinking in GlaucomaGlaucoma? ?

Syed S. Hasnain M.D. Porterville, California, USASyed S. Hasnain M.D. Porterville, California, USAHasnain40@sbcglobal.netHasnain40@sbcglobal.net

INTRODUCTION:INTRODUCTION: The term ‘glaucomatous cupping’ which The term ‘glaucomatous cupping’ which was given 150 years ago, implies gradual enlargement of was given 150 years ago, implies gradual enlargement of the physiological cup in glaucoma. This presentation is to the physiological cup in glaucoma. This presentation is to determine whether the physiological cup is truly enlarging. determine whether the physiological cup is truly enlarging. If not, then what may be occurring to the disc and its If not, then what may be occurring to the disc and its physiological cup.physiological cup.

METHOD:METHOD: This presentation is conveyed in an This presentation is conveyed in an unconventional approach. Instead of searching for various unconventional approach. Instead of searching for various factors causing glaucoma, three puzzling questions and factors causing glaucoma, three puzzling questions and their answers, based on deductive reasoning, morphology their answers, based on deductive reasoning, morphology and histology of the glaucomatous discs will be discussed.and histology of the glaucomatous discs will be discussed.

Author has no financial interest related to this presentation.Author has no financial interest related to this presentation.

DiscussionDiscussion: Three puzzling questions of : Three puzzling questions of glaucomaglaucoma

PUZZLING QUESTION # 1PUZZLING QUESTION # 1: : Why don’t ocular hypertension (OHT) subjects Why don’t ocular hypertension (OHT) subjects develop glaucoma at high IOPs such as 30mm Hg whereas normal-tension develop glaucoma at high IOPs such as 30mm Hg whereas normal-tension subjects (NTG) develop glaucoma even at normal IOPs (10 – 21 mm Hg)?subjects (NTG) develop glaucoma even at normal IOPs (10 – 21 mm Hg)?

PUZZLING QUESTION # 2PUZZLING QUESTION # 2: Why are the arcuate axons selectively : Why are the arcuate axons selectively destroyed in early stages, whereas the macular fibers last until the end-destroyed in early stages, whereas the macular fibers last until the end-stage of glaucoma?stage of glaucoma?

PUZZLING QUESTION # 3PUZZLING QUESTION # 3: Why can’t glaucoma be halted despite : Why can’t glaucoma be halted despite maximally lowering of IOP?maximally lowering of IOP?

Discussion:Discussion: Puzzling QuestionsPuzzling Questions PUZZLING QUESTION # 1PUZZLING QUESTION # 1. . Why don’t OHT subjects develop Why don’t OHT subjects develop

glaucoma at higher range IOPs whereas NTG subjects develop glaucoma at higher range IOPs whereas NTG subjects develop glaucoma even at normal range IOPs?glaucoma even at normal range IOPs? Medical history of 100 Medical history of 100 glaucoma patients revealed that high-tension patients (HTG) were glaucoma patients revealed that high-tension patients (HTG) were usually in good health, whereas the NTG patients had cardio-usually in good health, whereas the NTG patients had cardio-pulmonary and circulatory problems. Interestingly, about 70% of NTG pulmonary and circulatory problems. Interestingly, about 70% of NTG patients were smokers. These findings suggest that NTG may be a patients were smokers. These findings suggest that NTG may be a systemic disease and glaucoma as a multifactorial disease.systemic disease and glaucoma as a multifactorial disease. Raised IOP Raised IOP is not the only cause of glaucoma. The reason some OHT subjects do is not the only cause of glaucoma. The reason some OHT subjects do not develop glaucoma, may be due to the fact that they may have only not develop glaucoma, may be due to the fact that they may have only one riskone risk factor (raised IOP)factor (raised IOP) and thus less prone to develop glaucomaand thus less prone to develop glaucoma.. This may answer question #1 as to why some OHT subjects do not This may answer question #1 as to why some OHT subjects do not develop glaucoma. The more the risk factors present, higher the develop glaucoma. The more the risk factors present, higher the likelihood of development of glaucoma.likelihood of development of glaucoma.

PUZZLING QUESTION #2.PUZZLING QUESTION #2. Why are the arcuate axons selectivelyWhy are the arcuate axons selectively destroyed in early stages of glaucoma?destroyed in early stages of glaucoma? Because arcuate scotomas are Because arcuate scotomas are produced in both HTG and NTG, there should be a produced in both HTG and NTG, there should be a commoncommon site of site of injury where the arcuate axons can be injury where the arcuate axons can be selectivelyselectively destroyed in these destroyed in these two types of glaucoma. The arcuate axons can possibly be destroyed two types of glaucoma. The arcuate axons can possibly be destroyed at one of three sites: the lamina cribrosa, retina or the junctional area. at one of three sites: the lamina cribrosa, retina or the junctional area.

Search for Common Site of InjurySearch for Common Site of Injury Can the arcuate axons within the lamina cribrosa Can the arcuate axons within the lamina cribrosa

or the retina be or the retina be selectivelyselectively destroyed by any destroyed by any cause?cause?

LAMINA CRIBROSA? LAMINA CRIBROSA? Unlikely. It is not possible that high IOP, or Unlikely. It is not possible that high IOP, or any other pathology, can any other pathology, can selectivelyselectively destroy only the arcuate destroy only the arcuate axons among the one million or so densely packed axons within axons among the one million or so densely packed axons within the intricate meshwork of the lamina cribrosa. Thus, the lamina the intricate meshwork of the lamina cribrosa. Thus, the lamina cribrosa may not be the primary site of injury.cribrosa may not be the primary site of injury.

RETINA? RETINA? Unlikely. Similar to the case of lamina cribrosa, it is not Unlikely. Similar to the case of lamina cribrosa, it is not possible that high IOP, or any other pathology, can possible that high IOP, or any other pathology, can selectivelyselectively destroy only the arcuate axons within the retina in the early destroy only the arcuate axons within the retina in the early stages of glaucoma. Thus, the retina may not be the primary site stages of glaucoma. Thus, the retina may not be the primary site of injury. of injury.

Regarding Apoptosis:Regarding Apoptosis: It is unlikely that our genes are so pre- It is unlikely that our genes are so pre-programmed that they would first predict the impending chronic programmed that they would first predict the impending chronic glaucoma and then initiate apoptosis glaucoma and then initiate apoptosis selectivelyselectively with only those with only those ganglion cells which serve the arcuate axons. ganglion cells which serve the arcuate axons.

If the lamina cribrosa or retina can’t be the If the lamina cribrosa or retina can’t be the primaryprimary and and commoncommon site of injury, then the border tissue of Elschnig may be the site of injury, then the border tissue of Elschnig may be the possible site of injury.possible site of injury.

Can the border tissue of Elschnig be theCan the border tissue of Elschnig be the common site of injury for HTG and NTG? common site of injury for HTG and NTG?

Likely. The border tissue of Elschnig lies between lamina cribrosa and Likely. The border tissue of Elschnig lies between lamina cribrosa and

the sclera and secures the disc, acting as an ‘O’ ring seal, in the the sclera and secures the disc, acting as an ‘O’ ring seal, in the scleral opening.scleral opening.

The border tissue is The border tissue is exclusivelyexclusively supplied by short posterior ciliary supplied by short posterior ciliary arteries having lower pressure compared to the central retinal artery, arteries having lower pressure compared to the central retinal artery, thus it can be easily compressed by high IOP or directly reduced due thus it can be easily compressed by high IOP or directly reduced due to poor systemic circulation. IOP and arterial pressure are opposing to poor systemic circulation. IOP and arterial pressure are opposing forces. Thus, the IOP should be lower than the arterial pressure of the forces. Thus, the IOP should be lower than the arterial pressure of the border tissue for its healthy maintenance. border tissue for its healthy maintenance.

The above circulatory balance would be reversed either due to an The above circulatory balance would be reversed either due to an increase in IOP or due to reduction in arterial pressure resulting from increase in IOP or due to reduction in arterial pressure resulting from poor systemic circulation. In the latter scenario, even normal range poor systemic circulation. In the latter scenario, even normal range IOP would become too high and would compress the weak-pressured IOP would become too high and would compress the weak-pressured blood vessels of the border tissue leading to chronic ischemia and blood vessels of the border tissue leading to chronic ischemia and atrophy of border tissue and thus sinking of optic disc.atrophy of border tissue and thus sinking of optic disc.

Can the arcuate axons be Can the arcuate axons be selectivelyselectively destroyed if optic disc is sinking?destroyed if optic disc is sinking?

LikelyLikely.. As the border tissue of Elschnig which lies between As the border tissue of Elschnig which lies between the lamina cribrosa and the sclera atrophies, the lamina the lamina cribrosa and the sclera atrophies, the lamina would become loose and begin to sink in the scleral canal. would become loose and begin to sink in the scleral canal. Since the disc is usually temporally tilted, the temporal Since the disc is usually temporally tilted, the temporal lamina would sink below the scleral edge first. lamina would sink below the scleral edge first.

As the lamina sinks below the scleral edge, all the temporal As the lamina sinks below the scleral edge, all the temporal axons consisting of sup. & inf. arcuate and macular axons axons consisting of sup. & inf. arcuate and macular axons (prior to their entry in to lamina), would be stretched (since (prior to their entry in to lamina), would be stretched (since one end of the axon is still attached to the retina and other one end of the axon is still attached to the retina and other to the sinking lamina) and axotomized against the scleral to the sinking lamina) and axotomized against the scleral edge edge simultaneously.simultaneously. However, the arcuate axons being However, the arcuate axons being fewer in number, would be depleted earlier, giving rise to fewer in number, would be depleted earlier, giving rise to double arcuate scotomas, whereas the macular axons being double arcuate scotomas, whereas the macular axons being abundant would last until the end-stage of glaucoma. abundant would last until the end-stage of glaucoma. This may answer question #2 as to why are the arcuate This may answer question #2 as to why are the arcuate axons selectively destroyed in earlier stages and the axons selectively destroyed in earlier stages and the macular axons last until the end-stage.macular axons last until the end-stage.

Axotomy of axons in glaucomaAxotomy of axons in glaucoma

Fig. 1. Arcuate axons (blue) and macular axons (black) are being axotomized simultaneously due to disc sinking.

Fig. 2. Arcuate axons, being fewer, will be depleted earlier giving rise to arcuate scotomas

Fig 3. Hogan & Zimmerman. Intermediate stage. Empty spaces in temporal lamina cribrosa due to disappearance of axons as a result of axotomy.

Fig 4. Becker & Shaffer. End-stage glaucomatous disc. Empty crater (unique to glaucoma) due to axotomy of all the axons.

Early to end-stage glaucomatous discsEarly to end-stage glaucomatous discs

Fig 5. Early stage glaucomatous disc. Right eye. Splinter hemorrhage at 7 o’ clock. No change in the contour of the physiological cup

Fig 6. Advanced stage glaucomatous disc. Left eye. Same patient as in Fig. 5

Fig. 7 Intermediate stage glaucoma. Physiological cup obliterated due to confluence of its normal pallor with the pallor (from destruction) in the rim area. Arcuate scotoma present.

Fig. 8 End-stage glaucomatous disc. Marked kinking of the blood vessels due to loss of axons.

What happens as the sinking of the disc What happens as the sinking of the disc continues?continues?

Retinal axons anchor the optic disc in place as roots anchor a tree. Retinal axons anchor the optic disc in place as roots anchor a tree. As the axons are being axotomized and depleted, the optic disc As the axons are being axotomized and depleted, the optic disc becomes more loose and sinks further, resulting in severing of becomes more loose and sinks further, resulting in severing of additional axons. The axons in the retina are arranged in a way that additional axons. The axons in the retina are arranged in a way that those originating from the extreme peripheral retina lie deepest and those originating from the extreme peripheral retina lie deepest and exit from the most peripheral part of the disc (closest to the scleral exit from the most peripheral part of the disc (closest to the scleral edge) whereas the axons originating closest to the disc lie most edge) whereas the axons originating closest to the disc lie most superficial (closest to the vitreous) and exit from the most central superficial (closest to the vitreous) and exit from the most central part of the disc. part of the disc.

As the disc sinks in its entirety, the deepest prelaminar axons (prior As the disc sinks in its entirety, the deepest prelaminar axons (prior to entry in to lamina), will be stretched and severed against the to entry in to lamina), will be stretched and severed against the scleral edge first. scleral edge first.

As the peripheral axons are being severed, the axons lying in the As the peripheral axons are being severed, the axons lying in the central part of disc would move towards the periphery to occupy central part of disc would move towards the periphery to occupy the space vacated by severed axons and thus also axotomised at the space vacated by severed axons and thus also axotomised at the scleral edge. This will result in disintegration of the physiological the scleral edge. This will result in disintegration of the physiological cup. Loss of anchorage of the disc from severed axons will create a cup. Loss of anchorage of the disc from severed axons will create a self-propagated cascade of loosening and sinking of the disc which self-propagated cascade of loosening and sinking of the disc which would continue until all the axons are axotomized at the scleral would continue until all the axons are axotomized at the scleral edge. Thus, the sinking of the disc would become unstoppable akin edge. Thus, the sinking of the disc would become unstoppable akin to a sinking ship. to a sinking ship. This may answer question #3 as to why can’t This may answer question #3 as to why can’t glaucoma be halted despite maximally lowering of IOP.glaucoma be halted despite maximally lowering of IOP.

ConclusionConclusion Since the axons originating closer to disc lie superficial and exit from central part Since the axons originating closer to disc lie superficial and exit from central part

of the disc, these central vision axons should be destroyed first if the physiological of the disc, these central vision axons should be destroyed first if the physiological cup is truly enlarging. Instead, peripheral vision axons because of their deeper cup is truly enlarging. Instead, peripheral vision axons because of their deeper location are destroyed first in glaucoma, consistent with sinking optic disc.location are destroyed first in glaucoma, consistent with sinking optic disc.

Axons may not being atrophied but axotomized in glaucoma. Axons are being Axons may not being atrophied but axotomized in glaucoma. Axons are being severed prior to their entry into the lamina cribrosa.severed prior to their entry into the lamina cribrosa.

The primary and common site of injury may not be the lamina cribrosa but the The primary and common site of injury may not be the lamina cribrosa but the border tissue of Elschnig for both HTG and NTG. border tissue of Elschnig for both HTG and NTG.

Glaucoma is a multifactorial disease and NTG a systemic disease.Glaucoma is a multifactorial disease and NTG a systemic disease.

Continuous severing of prelaminer fibers due to self-propagated sinking of disc Continuous severing of prelaminer fibers due to self-propagated sinking of disc would result in progressive thinning of the RNF layer – as revealed by OCT. would result in progressive thinning of the RNF layer – as revealed by OCT.

Sinking disc may also explain the thinning of macular ganglion cell complex since Sinking disc may also explain the thinning of macular ganglion cell complex since macular axons are also being axotomised along with both groups of arcuate axons. macular axons are also being axotomised along with both groups of arcuate axons.

Total disappearance of the optic disc and the disc area replaced with an empty Total disappearance of the optic disc and the disc area replaced with an empty crater as revealed by end-stage histology suggests that axotomy (unique to crater as revealed by end-stage histology suggests that axotomy (unique to glaucoma), but not atrophy, of the axons may be occurring in glaucoma.glaucoma), but not atrophy, of the axons may be occurring in glaucoma.

Reference: Reference: Hasnain SS. Scleral edge, not optic disc or retina is the primary site of injury in chronic glaucoma.Hasnain SS. Scleral edge, not optic disc or retina is the primary site of injury in chronic glaucoma. Medical Hypotheses. 2006;67;1320-1325Medical Hypotheses. 2006;67;1320-1325