THE FLAMMER SERIES

PART IV

IMPAIRED CEREBROSPINAL FLUID CIRCULATION IN THE DEVELOPMENT OF GLAUCOMA

INTRODUCTION

Glaucoma has no characteristic features. It is an amalgamation of signs and symptoms which form the basis for diagnosis of glaucoma in one individual but may be regarded as some other condition or even as normal in others. Richard Bannister (1622 AD) described the “glaucoma triad” of raised intra-ocular pressure (IOP), optic disc cupping and visual field (VF) changes as diagnostic of glaucoma. 

https://ourgsc.blogspot.com/2017/05/ 

However, IOP now has been thrown entirely out of the equation. Ostensibly, high IOP is just a statistical figure. It can occur in an entirely harmless way in certain individuals. It is also surprising that nearly half of all glaucoma patients who have been on apparently well controlled IOP end up with glaucomatous optic atrophy (GOA) in atleast one eye during their lifetime. Thus, IOP has become much of an enigma in the development of GOA. 

https://www.ncbi.nlm.nih.gov/pubmed/23932216

Structural changes in glaucoma probably occur late. So, GOA may not be seen until significant amount of damage has already been done. What causes GOA? Is it mechanical, vascular, biochemical molecules, translaminar pressure difference or genetic factors which make the optic nerve head vulnerable? Moreover, optic atrophy may also occur in a diverse range of other conditions such as ischemic, compressive and hereditary optic neuropathies, pointing to a possible common thread running through some of these optic nerve degenerations. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3083760/ 

What about VF changes? Why are there just a handful of techniques available to record the VF? Then too, a Humphrey VF chart may not resemble a printout from an Octopus perimeter for the same patient. Dr Hasnain mentions that glaucomatous field loss correlates fully with the arrangement of nerve fibers while in the retina, but DOES NOT correlate at all with the arrangement of nerve fibers after they have made their 90⁰ turn into the prelaminar region. The characteristic glaucomatous field loss such as arcuate scotoma and Ronnie’s nasal step cannot be produced if the primary site of injury is in the prelaminar area or lamina cribrosa and beyond, according to Dr Hasnain.  

https://ourgsc.blogspot.com/search?q=hasnain

DARC (Detection of Apoptosing Retinal Cells) technology, a technique which can identify retinal ganglion cell (RGC) damage at a very early stage, has shown random damage to RGCs which cannot explain the classical VF defects on a Humphrey Visual Field Analyzer.

https://ourgsc.blogspot.com/search?q=DARC 

How can apoptosis like this produce visual field changes seen on perimeters ?

This brings me to the current topic. Prof Flammer has published a great deal on the vascular aspects of glaucoma. However, an article co-authored by him sheds some light on the role of cerebro-spinal-fluid (CSF) pressure (intracranial pressure or ICP) in the pathogenesis of glaucoma. 

The optic nerve is regarded as an extension of the brain. Like other parts of the CNS, the optic nerve (ON) is covered by the dura, arachnoid and pia mater. The optic nerve is exposed to IOP within the eye and to ICP due the presence of CSF in the sub-arachnoid space (SAS). The lamina cribrosa demarcates these two pressurized zones (eye vs. SAS) and the pressure difference between them is called “translaminar pressure difference” (TPD) (IOP-ICP=TDP). There is increasing evidence that TDP could play an important role in the pathophysiology of glaucoma.

Disc cupping is assumed to represent a typical morphological pattern of anterograde atrophy of axons on their way from the intraocular to the retrolaminar portion of the ON. However, there is a possibility that in some cases the primary damage occurs in the ON and then a retrograde process leads to the destruction of RGCs. This direct damage to the ON is attributed to the environment of the nerve especially to the surrounding CSF.

The ON is distinct from other cranial nerves in that it is surrounded by CSF throughout its entire length. The subarachnoid space (SAS) enveloping the ON may become or act as a separate CSF compartment in patients with normal-tension-glaucoma (NTG). CSF-cisternography, using an iodinated contrast agent (Lopamidol), has demonstrated blockage (stasis) and impaired influx of CSF from the chiasmal cistern into the SAS of the ON in normal-tension-glaucoma.

The ON compartment syndrome (and impaired CSF turnover) develops through postulated mechanisms such as inflammatory changes and mechanical stress on the arachnoid and it’s trabeculae as well as glial cells in the ON. This leads to increased expression of MHC II cells, tumor necrosis factor-alpha (TNF-α) and endothelin.

The apices of the meningoepithelial cells (MECs) lining the arachnoid layer face the SAS. These cells are highly reactive to various stimuli such as increased ICP and inflammation due to meningitis and arachnoiditis, as well as mechanical stress.

MECs also produce a rather unique factor called L-PGDS (Lipocalin-type Prostaglandin D Synthase). Upregulation of L-PGDS is demonstrated in αβ-crystalline positive oligodendrocytes and astrocytes in chronic multiple sclerosis. Elevated L-PGDS contributes to apoptosis of PC12 neuronal cells. Conversely, L-PGDS appears to protect the perineuronal oligodendrocytes from apoptosis. Studies have shown that when high concentration of L-PGDS is added to neuronal cultures the proliferation of astrocytes can be markedly inhibited in vitro.

L-PGDS could also act through the synthesis of prostaglandins which regulate vascular tone. ON compartmentalization leads to reduced CSF turnover; accumulation of substances such as L-PGDS, beta-amyloid, peroxinitrates and TNF-α; as well as possibly an effect on mitochondrial function. These are detrimental to the health of the ON.

The concept of an ON compartment syndrome offers an entirely new approach to the understanding of the pathophysiology of visual loss in patients with NTG. A disturbance of CSF components following compartmentation would cause damage to axons, astrocytes and mitochondria. It would also severely affect the blood vessel tone of the pial plexus supplying the ON in the SAS, leading to cupping of the optic disc and retrograde atrophy with loss of VF and ultimately involve the central visual acuity.

Physiologically, the difference between IOP (avg. 14.3 mmHg) and ICP (avg. 12.9 mmHg) in the supine position is small. A higher TPD may lead to abnormal function and damage of the ON due to changes in axonal transportation, deformation of the lamina cribrosa, altered blood flow or a combination thereof, leading to GON.

A meta-analysis of TPD published in “Nature” found that ICP was significantly lower in patients with primary open angle glaucoma, particularly NTG, than in healthy subjects. TPD was almost two times higher in patients with NTG and nearly five times higher in patients with high-tension-glaucoma (HTG), compared to healthy controls.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815687/

As the optic nerve head is exposed to both IOP and ICP, the TPD becomes an important parameter and its reduction might assist in halting the progression of glaucoma.

It is easy to define glaucoma as a “multifactorial” neurodegenerative disorder. These factors unfortunately, are multiplying by each passing day. Instead of presenting a clearer picture they are muddying the waters. The only hope is that out of chaos order will come and one day a better understanding of these factors will help us in determining the pathogenesis of glaucoma and thereby lead us to more positive treatment outcomes.

ABOUT THE AUTHOR

Dr Syed Shoeb Ahmad is just a "regular guy" with an interest in glaucoma.

Correlation between glaucomatous visual field loss and arrangement of nerve fibers in retina and optic nerve head

Dr Syed S. Hasnain, MD

Dr Aziz Hasnain, JD

Porterville, USA

Abstract:

This presentation discusses the possible site of injury in chronic glaucoma by correlating the glaucomatous field loss with the arrangement of nerve fibers (NFs) in the retina and optic nerve head (ONH).  Glaucomatous visual field loss is a unique and diagnostic feature of glaucoma, since no other disease results in similar progressive field loss.  Glaucomatous field loss is produced in an orderly and predictable sequence which is the reason we do perimetry in glaucoma.

Glaucomatous field loss correlates fully with the arrangement of NFs while in the retina, but does not correlate at all with the arrangement of NFs after they have made their 90 degree turn into the prelaminar region.  The horizontal orientation of the NFs in the retina is changed into a vertical orientation of the NFs in the prelaminar region.  Therefore the characteristic glaucomatous field loss such as arcuate scotoma and Ronnie’s nasal step can’t be produced if the primary site of injury is in the prelaminar area or lamina cribrosa (LC) and beyond in glaucoma.

In conclusion, the nerve fibers are vertically arranged and the temporal retinal horizontal raphe is no longer present in the LC.  Furthermore, the arcuate fibers are no longer isolated and the macular fibers have become centrally placed in the LC. Therefore, the characteristic glaucomatous field loss such as arcuate scotoma and Ronnie’s nasal step can’t be produced if the LC is the site of injury in glaucoma. Although the LC is widely believed to be the primary site of injury in glaucoma, there is no correlation of glaucomatous field loss with the arrangement of NFs in the lamina cribrosa.  In view of aforementioned, the LC can’t be the primary site of injury in glaucoma.

This article suggests that the primary site of injury in glaucoma is where the retinal nerve fibers make their 90 degree turn and become prelaminar NFs.  Furthermore, the kind of injury appears to be stretching and severance of NFs at this 90 degree turn.

Arrangement of Nerve Fibers in the Retina

Before we discuss the above question, it is imperative to briefly summarize the arrangement of nerve fibers in the retina and optic nerve head (ONH) and the way visual field defects are produced in glaucoma. 

In the retina, the NFs are arranged in a characteristic way (Figures 1 & 2).  One million or so NFs are stacked in layers superficial to deep.  The NFs originating from the most peripheral retina lie deepest (closest to sclera) and exit closest to the edge of the scleral opening whereas the NFs originating closest to the optic disc lie most superficial (closest to vitreous) and exit from the most central part of the ONH.  As a result, the deepest retinal NFs make their 90 degree turn closest to the scleral edge to become prelaminar fibers, whereas the retinal NFs originating closest to the ONH lie most superficial on the anterior surface of the ONH (closest to vitreous) and make their 90 degree turn in the most central part of the ONH. 

Figure 1. Schematic Diagram: The arrangement of nerve fibers in the retina and optic disc. The most peripheral fibers (5) originate farthest from the optic disc, lie deepest (closest to sclera) and exit closest to the scleral edge. The most central fibers (1) originate closest to the disc, lie most superficial (closest to vitreous) and exit from the most central part of the disc. 

The nasal NFs enter the nasal part of the disc.  The NFs originating from the nasal macular area go directly to the temporal part of the ONH whereas the NFs originating from the temporal macular area and horizontal raphe arch above and below the macular NFs to reach the ONH.  These are the arcuate nerve fibers. (Figure 2) 

Figure 2. Schematic Diagram: The arrangement of nerve fibers in the retina. The arcuate fibers arch above and below the macular fibers to reach the poles of the optic disc.

Four parts of ONH.

1)      Retinal or superficial NFs lying horizontally

2)     Prelaminar region - after the retinal NFs have made the 90 degree turn

3)     Laminar region

4)     Retrolaminar region

The 360 degrees of retinal NFs converge on the ONH as a superficial surface layer and are arranged on the anterior surface of the ONH in the same way as in the retina.  After making the 90 degree turn, the retinal NFs become prelaminar NFs.

In the prelaminar region, the loose NFs begin to get arranged in bundles. The macular NFs start shifting to occupy the central position, thus the arcuate fibers lose their arcuate pattern.  The arcuate NFs get mixed with the rest of the temporal fibers and become indistinguishable.  Moreover, the NFs in the prelaminar region become vertically oriented and thus the temporal retinal horizontal raphe disappears.  In the lamina cribrosa, the bundles of NFs get fastened in its pores and the arrangement of NFs becomes drastically different in the LC compared to while the NFs were in the retina.  In the laminar region, the arcuate fibers are no longer distinguishable and the horizontal raphe also disappears.   

Glaucomatous Visual Fields

Glaucomatous field defects are produced in an orderly and predictable sequence which is the basis for perimetry in glaucoma.  In glaucoma, the peripheral NFs are destroyed first resulting in peripheral field constriction.  But the peripheral field loss has poor diagnostic value since many other diseases such as cataract can also result in peripheral field loss.  In the early stages of glaucoma along with peripheral field constriction, the isolated scotomas begin to appear in both superior and inferior paracentral areas (10 to 20 degrees) which are very diagnostic of glaucoma.  As glaucoma progresses, the isolated scotomas become more frequent and ultimately coalesce to form sharply-defined double arcuate field defects.

The superior arcuate scotoma usually appears first.  Both superior and inferior arcuate scotomas start from the blind spot and end sharply at the horizontal nasal hemifield giving rise to Ronnie’s nasal step.  Meanwhile the peripheral field loss is also progressing towards the center and ultimately joins the double arcuate scotoma.  When this occurs, only about 10 degrees of central vision remains which ultimately is also lost and a subject becomes 100% blind.

1.  Can the glaucomatous field defects be produced if the lamina cribrosa is the primary site of injury in glaucoma?

Unlikely.  Although the lamina cribrosa is widely believed to be the primary site of injury in glaucoma, the glaucomatous field defects contradict LC as the site of injury.  It is theorized that elevated IOP causes posterior bowing of the LC (cupping) resulting in distortion and misalignment of its pores, thereby impeding the axoplasmic transport leading to death of RGCs.  But this theory can’t be valid in context of the orderly loss of NFs in glaucoma.  The following are arguments against LC being the site of injury:

1)  It is inconceivable that the multilayered rigid connective tissue LC, densely packed with NFs is so fragile that it will start bowing posteriorly with an elevation of only 5-10 mmHg of IOP, yet it wouldn’t bow in cases of acute glaucoma in which the IOP becomes extremely elevated. There is no acute cupping occurring in acute glaucoma.

2)  There is no histology supporting the posterior bowing of LC.  Instead, we have confirmed evidence of posterior migration of the LC from the early stages of glaucoma.  It is inconceivable that a loosened and detached LC while migrating posteriorly could also become posteriorly bowed, especially with elevation of only 5-10 mmHg of IOP.

3) If the LC was indeed bowing posteriorly, then its central part should be affected first resulting in the loss of central vision, initially.  Thus, there should be doughnut-shaped field defects.  But in actuality, peripheral vision is destroyed first and central vision remains until the end-stage in glaucoma. 

4) Most importantly, the glaucomatous field defects closely follow the arrangement of NFs while in the retina.  But after making the 90 degree turn, the NFs become vertically oriented in the prelaminar region and in the lamina cribrosa.  In the LC, neither the arcuate fibers are isolated nor is the horizontal raphe present as they were in the retina.

In view of the re-orientation of NFs in the lamina cribrosa, the glaucomatous field loss such as the sharply-defined arcuate field defects and Ronnie’s nasal step can’t be produced if LC is the primary site of injury in glaucoma.  In view of the aforementioned, the LC can’t be the site of injury in glaucoma.

2. Can the glaucomatous field defects be produced if retina was the primary site of injury? 

Unlikely.  Although glaucomatous field defects conform to the arrangement of nerve fibers in the retina, it is inconceivable that elevated IOP would destroy the retinal NFs in an orderly fashion from peripheral to central and not destroy the entire retinal NFs at once.  In glaucoma, the NFs are being destroyed in an orderly sequence spreading over several years staring with the most peripheral NFs and ending with the central fibers.  Therefore, the retina itself can’t be the primary site of injury in glaucoma.

We face a dilemma.  We have ruled out that the nerve fibers while in the retina or even as a superficial layer of the ONH can’t be the site of injury, although the glaucomatous field loss fully correlates with the arrangement of retinal NFs.  Furthermore, we have also ruled out that the prelaminar and laminar region also can’t be the site of injury in glaucoma because of the lack of correlation of glaucomatous field loss with the arrangement of NFs in these regions.  Then, why does the characteristic glaucomatous field loss correlate with the arrangement of nerve fibers in the retina?  

3. Can the scleral edge be the primary site of injury in glaucoma?

We are only left with the area where the retinal NFs cross the edge of the scleral opening and make a 90 degrees turn into prelaminar region.  After the retinal NFs cross the scleral edge they are supported underneath by the lamina cribrosa. 

The LC is firmly kept in place in the scleral opening by the border tissue of Elschnig (BT) and also by retinal NFs as roots anchor a tree.  In normal circumstances, the LC provides a good underneath support to the NFs during lifetime. However, if the BT degenerates and the LC starts sinking, then serious consequences can occur to the NFs after they cross the scleral edge.

Glaucoma:  A Two-Stage Disease.

It is hypothesized that glaucoma is a two-stage disease. The first being a biological stage, followed by a second, mechanical stage.

The First (Biological) Stage

In the biological stage, there is degeneration of the border tissue of Elschnig due to chronic ischemia resulting from the chronic compression of BT circulation by elevated IOP.  Ciliary perfusion pressure supplying the BT and IOP are opposing forces.  Normally, the ciliary circulatory pressure supplying the BT should be higher than IOP for its good perfusion and healthy maintenance.  However, if this healthy relationship is reversed either due to a rise in IOP (ocular problem) or if perfusion pressure of the BT becomes lower than the IOP due to conditions such as chronic hypotension (systemic problem), then even the normal range IOP will take the upper hand and act as an elevated IOP.  This would lead to chronic ischemia and degeneration of the BT, thus resulting in normal-tension glaucoma in the systemically compromised subjects (Figure 3).

Figure 3. Graphic diagram: The interaction between ciliary pressure and IOP. Normally, the ciliary pressure supplying the border tissue should be higher than IOP for its good perfusion and healthy maintenance as in column (A). In column (B) the IOP is increased to 30 mmHg due to an ocular problem whereas the ciliary pressure is still the same at 25, resulting in high-tension glaucoma. In column (C) the ciliary pressure is decreased to15 due to problems such as systemic hypotension so even normal IOP at 20 will act as an elevated IOP in this scenario so resulting in normal-tension glaucoma.

Due to degeneration of BT, the lamina cribrosa becomes loose and starts sinking in the scleral canal.  This is the beginning of the second or mechanical stage.  This may also be called perimetric glaucoma.

The Second (Mechanical) Stage:

Due to sinking of the LC, the most peripheral and deepest retinal NFs (being closest to the scleral edge) will be stretched and broken against the scleral edge first (Figure 4, NF 5).

Figure 4. Schematic diagram: Due to sinking of the LC the most peripheral and deepest prelaminar nerve fibers (5) are stretched and severed against the scleral edge first. The next-in-line fiber (4) will move towards the scleral edge and also gets severed. This process will continue in an orderly sequence until the most central fiber (1) is severed.

The next in line fiber (NF 4) will move towards the edge to occupy the space vacated by the preceding severed fiber and will also get stretched and broken.  This process will continue in an orderly sequence until the most central fiber has moved towards the scleral edge and gets severed.

The actual site of injury appears to be when the retinal NFs make the 90 degree turn into the prelaminar region.  The sinking of the LC will result in loss of underlying support and the loss of continuity of nerve fibers.  This scenario would result in stretching and severance of the NFs. The severance of NFs would result in further sinking of LC as NFs are anchoring the LC as roots anchor a tree.  This process will become self-propagated until all the NFs are severed and gone. This is probably the reason glaucoma can’t be halted despite maximal lowering of IOP.  Glaucoma may not be an optic neuropathy but an optic disc axotomy.

Conclusion

Glaucomatous field defects such as the arcuate scotoma and Ronnie’s nasal step correlate fully with the arrangement of nerve fibers while in the retina or before the nerve fibers make the 90 degree turn into the prelaminar region. Therefore the site of injury to the NFs has to be either at the 90 degree turn or before but not after the NFs have made the 90 degree turn into the prelaminar region.

In the prelaminar region, the NFs become vertically oriented and the macular NFs start shifting to the central part.  The arcuate NFs get mingled with the rest of the temporal fibers and lose their arcuate pattern.  Furthermore, the loose NFs begin to form bundles in the prelaminar region which become fastened in the pores of the LC so it would be unlikely any injury could produce minute isolated paracentral scotomas which ultimately coalesce to form the arcuate scotoma. 

In the laminar region the NFs become vertically oriented, the arcuate NFs are no longer isolated and the horizontal raphe also disappears.  In other words, the arrangement of NFs in the LC is drastically different than the arrangement of NFs in the retina.  Glaucomatous field loss such as the arcuate scotoma and Ronnie’s nasal step can’t be produced if the primary site of injury is in the lamina cribrosa. If the LC was the site of injury then we should have seen doughnut-shaped field defects due to loss of central vision initially.

We have ruled out not only the prelaminar and laminar region but also the retina as the primary site of injury in glaucoma.  Thus, we are left with the area where the NFs cross the scleral edge on to the LC.  This is a weak and vulnerable area where the NFs cross the scleral edge and enter into the prelaminar area.  In normal circumstances, the LC plate provides a good underneath support to the NFs. However, due to sinking of the LC the NFs lose their firm underneath support which is important for their 90 degree angulation and continuity.  As a result of sinking of the LC, the NFs are stretched and severed against the scleral edge.

Analogy: a road is made of NFs which converge on the manhole cover in the middle of a road.  If the manhole cover begins to sink due to deterioration of its border area, then the road NFs due to loss of their continuity, will be stretched and broken at the edge.  The similar phenomenon appears to be occurring in the glaucomatous disc. The sinking of the LC and the severance of NFs will become self-propagated and would continue until all the NFs are severed in an orderly sequence from peripheral to central in glaucoma.

In summary, the site of injury to the NFs in glaucoma appears to be where the NFs are making a 90 degree turn.  This will still produce glaucomatous field defects correlating with the arrangement of NFs while they are in the retina.  Once the NFs have made the 90 degree turn into prelaminar region, their arrangement changes drastically therefore any injury to NFs in the prelaminar region and lamina cribrosa  cannot produce the classical glaucomatous field defects. In view of the aforementioned, the lamina cribrosa can’t be the site of injury in glaucoma. Furthermore, due to severance of NFs, glaucoma may not be an optic neuropathy but an optic axotomy.

REFERENCES

1. Hasnain SS. Scleral edge, not optic disc or retina is the primary site of injury in chronic glaucoma. Medical Hypothesis 2006; 67(6) ;1320-1325

2. Hasnain SS. Scleral edge, not optic disc or retina is the primary site of injury in chronic glaucoma. Medical Hypothesis 2006; 67(6) ;1320-1325

3. Hasnain SS. Optic Disc may be Sinking in Chronic glaucoma. Ophthalmology Update. Pakistan Oct-Dec. 2010; 8 (4); 22-28.

4. Hasnain SS. Pathogenesis of Arcuate Field Defects in Glaucoma. Highlights of Ophthalmology, Panama 201240(6)

5. Yang H. et al. Posterior (outward) migration of the lamina cribrosa and early cupping in monkey experimental glaucoma. Invest Ophthalmol Vis Sci 2011;52:7109-21 11.

6. Yang H. Optic Nerve Head(ONH) Lamina Cribrosa Insertion Migration and Pialization in Early Non-Human Primate Experimental Glaucoma. Poster Presentation ARVO meeting May 03, 2010.