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.
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
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.
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.
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.
 |
| 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/
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.
Glaucoma is caused due to abnormally increased pressure inside your eyes.
ReplyDeleteThe human body maintains normal ocular blood flow in the OA and other ocular vessels when arterial blood pressure rises during a workout. It is considered as a form of ocular hemodynamic regulation that prevents the eye from over perfusion. Dr. Anin Sethi, who is currently working at Mirchia’s Laser Eye Clinic, Chandigarh, tells on SimpliHealth platform that the possibility of regulation impairment in patients is with glaucoma. On the increase of PCO2 artificially, the ocular blood flow differences between glaucoma controls and patients are no longer essential, illustrating that the differences might result from vasospasm. Also, glaucoma patients have an altered endothelial response to endothelin-1 and nitric oxide, which is deprived of comparing NTG and POAG patients with controls. Eye vision is the priority and cannot be lost with casual behavior. It needs the proper treatment and so the understanding of issues such as glaucoma. Seek doctors on time and understand the eye problems.
ReplyDeleteClick here to watch the video