Foundations Anterior Seg Flashcards
1
Q
What is the carbonic anhydase reaction equation?
A
- Catalyzes hydration of carbon dioxide to carbonic acid leading to liberation of hydrogen & bicarbonate atoms
- Enzyme immunohistochemically localized to ciliary epithelia in major processes of pars plicata region only
2
Q
How does carbonic anhydrase inhibitors work and what are they used for?
A
- NHE-1 (NHE = sodium hydrogen exchanger) and AE2 (AE = anion exchanger) antiports on the stromal side of the PCE cell membrane
- Underlie uptake of Na+ and Cl- form the ciliary body stroma, in exchange for H+ and HCO3- respectively
- Cytoplasmic carbonic anhydrase II enhances the delivery rate of H+ and HCO3- and thus facilitates Na+ and Cl- uptake for use in making aqueous.
- The Na+ and Cl- ions taken up by the PCE are passed into the NPCE via gap junction where the Na-K-ATPase pumps them into the cleft between NPCE cells
- Carbonic anhydrase inhibitors used in the treatment of glc likely reduce inflow and IOP by inhibiting the NHE-1 and AE2 antiports in the PCE
3
Q
Describe how beta-1 & 2 and alpha-2 receptors work?
A
- Phosphorylated by GTP (not ATP)
- Receptor binding by agonist = molecule binds to the receptors which lead to activation of G protein
- G protein phosphorylated by GTP - leads up up regulation of adenocyclase, ATP, kinase A
- And cascade leads to various effects - ultimately to which Na-ATPase will turn and will pump out sodium and produce aqueous humor
- B-agonist attaches to receptors = more aqueous made, IOP will increase
- B-blocker attaches to receptor = G protein cant be activated
- A2 receptor attaches to g protein (inhibitory g protein) = everything will spin down (not up) = aqueous humor production stops
4
Q
Aqueous humor outflow is ___ flow, along a __ __ __, from the anterior chamber to the ___ ___
A
Passive flow, downhill pressure gradient, episcleral veins
5
Q
IOP must over come ___ in order for aqueous humor to leave the eye
A
- Episceral venous pressure
6
Q
EVP averages approximately __ mmHg if the patient is seated and DOES NOT change with age
A
9 mmHg
7
Q
If you see a dilated episcleral vessel and elevated IOP what can this suggest? What should you ask the patients about? What can you give to reduce elevated episcleral venous pressure?
A
- Ask about recent trauma, specifically craniofacial or any head injury, that can suggest a carotid cavernous sinus fistula.
- A complete past medical history should be obtained to rule out etiologies that may cause venous obstruction, including but not limited to hyperthyroidism, amyloidosis, congestive heart failure, hypercoagulable states, vasculitis, superior vena cava syndrome and sturge-weber syndrome.
- Use of the alpha-agonist apraclonidine, the calcium channel blocker, verapamil and the new rho-kinase inhibitors reduce EVP
8
Q
Describe elevated EVP in Sturge-Weber
A
- Sturge-weber syndrome aka encephalotrigeminal angiomatosis is a rare congenital neurological and skin disorder.
- It is one of the phakomatoses and is often associated with port-wine stains of the face (A congenital hemangioma composed of excess capillaries around branches of one or more of the three division of CNV), glaucoma, seizures, intellectual disability, and ipsilateral leptomeningeal angioma (cerebral malformations and tumors)
- Elevated EVP is likely the cause of glaucoma associatd with the vascular phakomatosis sturge-weber syndrome
- Elevated EVP has not yet clearly and consistently been shown to play a contributing role in POAG
9
Q
Describe the case for pulsatile aqueous outflow
A
- non-NIH reviewed and funded research suggest that there is an ocular pulse-related pumping of aqueous out of the eye and the outflow system is NOT the passive downhill flow just described
- When doing tono you will see a pulse - easy to believe that pulse squeezes the aqueous out of the eye
- Trabecular outflow REMAINS THE SAME - the only difference is the episcleral pressure goes from in-vivo 9 mmHg to 0 mmHg and everything else scales down proportionally but maintains the same ouflow resistance and IOP
- The presence or absence of a vascular pulse makes no difference
10
Q
A
Study the Image
11
Q
A
Study the image
12
Q
Name the angle
A
13
Q
A
Study the image
14
Q
What is the most direct way out and sees the most flow? What happens in this area as we age?
A
- posterior meshwork (PM) has schlemm’s canal behind it
- With that flow, over many years, comes “wear and tear” pigment, which is phagocytized more by the TM cells in the PM than the AM
- Note abrupt reduction in pigment portion of the TM anterior to the end of schlemm’s canal. This is a normal older angle - NOT PDS
15
Q
A
- Uveal meshwork (below red line) - extends from the uveal tissue to schwalbe’s line
- Corneoscleral meshwork (between red and blue line) extends from scleral spur to the deep stroma of the cornea
- Juxtacanalicular connective tissue (JCT region - between blue line and schlemm’s canal - SC).
16
Q
What are the dimensions of the uvealmeshwork, corneoscleral meshwork, and the JCT region?
A
- As one progresses deeper into proximal portions of the conventional outflow pathway, the sizes of the open spaces are reduced
- Uveal meshwork = 25-75um
- Corneoscleral meshwork = 2-15um
- JCT region = 1-2um
- Given the sizes of the openings in the uveal and corneoscleral meshwork, neither region is considered to contribute any measurable resistance to aqueous flow
17
Q
Where does the longitudinal bundle insert (ciliary muscle)?
A
- Longitudinal bundle
- Inserts onto posterior surface of scleral spur but its tendons also extend into the meshwork and even to the inner wall of schlemm’s canal
18
Q
What is the cribriform plexus?
A
- Tendons from the tips of muscle cells in the longitudinal bundle do not all attach to the undersurface of the scleral spur (SP). Many extend into the TM and even make direct, elastin-containing connections directly to the inner wall of schlemm’s canal
19
Q
Cribriform plexus - do miotics really decrease IOP by pulling on the scleral spur and “opening up” the meshwork?
A
- Some of the longitudinal bundle attaches to the scleral spur, but most enter the TM and even connect to the inner wall of SC
- As IOP increases, SC wants to collapse. Miotics seem to work mainly by holding up schlemm’s canal, by analogy with the cordae tendinae attached to the mitral and bicuspid valves of the heart. They brace the inner wall to prevent collapse
20
Q
Most of the trabecular meshwork is composed of __ __ __ composed of a __ and __ __, wrapped by a single layer of __ __ __. As with the corneal endothelium there is an age-related __ in these cells.
A
- avascular trabecular beams
- collagen & elastin core
- trabecular endothelial cells
- decrease
21
Q
Describe the JCT region?
A
- No beam structure
- Open connective tissue matrix of collagens (C) and elastin
- Resident cells are fibroblast and not epithelial
- These cells send long extended processes that attach to the inner wall of schlemm’s canal (E) with mushroom shaped pads (small arrows). This allows JCT to spread away from the inner wall without losing contact
22
Q
Describe giant vacuoles
A
- The pressure difference across the inner wall of SC drives formation of focal detachments of endothelial cells that form “giant” vacuoles
- As pressure increases, the size and andnumber of vacuoles increase in normal eyes (less so in eyes with POAG)
- They open, release aqueous into SC and collapse
23
Q
What are the 2 types of pores?
A
- I-pores (Intracellular-left)
- B-pores (border right)
- These are found as tiny openings through I or between B inner wall cells. It is through pores that aqueous enters SC
- Pores of obth types decrease significantly in glc but without a change in pore diameter
- The pores in the inner wall tend to be widely spaced, approx 20-30um apart
24
Q
A
The distal outflow pathway from SC to the EPV
25
Describe the distal pathway
* There are about 30 unevenly distruted collector channels that leave the outer wall of SC
* These external collector channels each branch, initially into three vessels (recall this reduces resistance) to join tortuous vessels of the deep scleral plexus
* These in turn branch some more, joining the more superficial intrascleral venous plexus. These vessels wind their way through the remainder of the scleral thickness to join the episcleral veins on the surface of the sclera
26
As we increase IOP, areas of good flow become more and more \_\_, invariably the last areas to close are right near __ \_\_ \_\_
* restricted, invariably the last ares to close are right near the collector channel ostia
* If you perfuse the AC and distal pathway with fluorescein intra-opertively you can see striking non-uniformity of outflow (right). and the hi flow regions can change to low flow regions over time
27
What can cause blockage of the collectors channel? (distal pathway of glc)
* We have long assumed that the added resistance that elevates IOP in glc was the result of adding more resistance to sites of resistance in the normal eye But now data is saying part of added resistance is related to the collector channel
* As **pressure is increased** in normal eyes, portions of JCT and inner wall are forced into the ostia of collector channels like hernias.
* If **pressure is reduced**, they slide back out, but with age, even in normals, some of these herniations fuse into the opening of collector channels
* **But far greater number of collector channel opening are blocked by herniations in age matched eyes with POAG**
* Surgeons doing canalostomies now commonly believe that the frequent points of resistance they must break through when passing the catheter through Schlemm's canal are these fused herniations
28
Flow is determined by what 2 factors?
* Pressure difference between 2 ends of a vessle (between AC and episceral venous pressure)
* Resistance to vessel flow (resistance from fluid viscosity and resistance created by the vessel wall)
* Resistance created by the tissue between the AC & episceral vein
* In the vascular system = physiology ensure **CONSTANT FLOW**, allowing pressure and resistance to vary up and down to ensure constancy - **high BP is dysregulation of this system**
* In the eye = physiology ensure **CONSTANT PRESSURE**, allowing resistance and flow to vary up and down to ensure constancy - **glc is a dysregulation to this system**
29
What is the goldmann equation?
30
What is the goldmann equation (remember that ouflow facility is simply the mathematical inverase of outflow resistance)
31
What is the goldmann equation (the slightly complex version that takes uveoscleral facility ouflow into account)
32
As the vessel branches further divide this will decrease __ and \_\_
* **resistance and pressure**
* When vessels branch, resistance decreases, cleverly serving to prevent loss of flow, even as the volume is now distributed into multiple branches
* And the addition of another branch further **decreases** resistance thus sustaining flow, (literally by the path of least resistance) in all branches and does not increase resitance. The converse is equally true
* In the eye, recall that many areas of SC are receiving no flow at any given moment. What this means is the outflow resistance (and therefore PRESSURE) will DECREASE if we can open up more schlemm's canal to flow
* It is the equivalent of branching vessels. And leaving SC, collector channels further divide. As those vessels further divide resitsance keeps decreasing all the way to the episcleral veins
33
T/F uveal and corneo-scleral produces resistance
* F, the uvela and corneo-scleral meshwark are too large to present any significant resistance
* Even the matrix within JCT region cannot account for significant fraction of outflow resistance on its own
* Similarly, the inner wall and its pores cannot account for 10% of normal outflow resistance. So, even when added all together, in series, these elements cannot generate even the necessary levels of resistance to maintain IOP in a normal eye
34
What causes resistance to aqueous flow?
* These widely spaced pores constrain aqueous flow to limited preferential pathwyas, forcing flow through the JCT matrix to converge upon each pore as though it was the tip of a funnel
* Using darcy's law, it was shown that this non-uniform flow results in a dramatic increase in the effective hydraulic resistance of this region
* Using parameters in this formula appropriate for anormal human eye, a **30 fold increase in JCT resistance** was predicted, compared to simply adding individual resistance in series. This model would also predict that the decrease in pore numbers in a glaucomatous eye could contribute to increased resistance in a significant way
35
What are Rho-kinase (ROK) inhibitors?
* Rho-kinase inhibitors such as rocklatan affect actinomysin cytoskeletal networks and have been shown to sig increase outflow facility in without obvious toxicity
* they alter cytoskeleton of TM and inner wall cells such as pressure attempts to collapse SC, the JCT region becomes more distended.
* The "cherry-picker" arms on the JCT cells limit this expansion
* This is the anatomical correlate for the increase in outflow facility produced by this class of meds
36
How does distention of the JCT region produce an increase in outflow facility?
* By loosening the cytoskeleton, the JCT region distends
* When it does that, that disrupts the funneling effect
* This is equivalent of increasing the branching in a vascular system, or increasing the amt of inner wall of SC available for flow.
* The result is a decrease in total resistance
37
Rhopressa inhibits both __ and \_\_
* Rock and NET (norepinephrine transporter inhibitor)
38
What is NET?
* NET (norepinephrine transporter inhibitor) is a monoamine transporter and is responsible for the sodium-chloride dependent reuptake of extracellular NE from synaptic cleft
* used in tx of ADHD
* Dexedrine, Adderal, and Ritalin fall roughly into this category. They block reabsorption of norepinephrine through monoamine transporters (including NET), thereby sustaining levels of these neurotransmitters in the synaptic cleft
* **Overabundance of NET in the brain is associated with ADHD**
* The notion is that by reducing NE re-uptake in adrenergic neurons supplying the vessels of the ciliary body, vasoconstriction is sustained. By doing that, there is reduced blood flow and tus less fluid made available from which the ciliary body can make aqueous humor form
* In about 10-25% of cases pt will develop **vorticeal keratopathy**
39
What is the difference between conventional vs uveoscleral outflow?
* Aqueous that enters the uveal face of the meshwork **above** the scleral spur enters the **conventional pathway**
* Aqueous that enters the uveal face of the meshwork **below** the scleral psur enters the **uveoslceral outflow pathway**
40
Describe the uveoscleral outflow pathway
* Aqueous entering the ciliary body band, flows along the connective fascicles that interweave among the smooth muscle cells of the longitudinal bundle until it reaches the supraciliary space
* The supraciliary and suprachoroidal spaces are the same space with a name change at the ora
* Aqueous continues along the suprachoroid to finally leave the eye through the sclera or the emissarial canals through the sclera used by the vortex veins (ex. uveovortex outflow)
* Current estimates suggest that uveoscleral outflow accounts for up to 22% total in normals and decreases with age
41
Describe the effect of prostanoids on uveoscleral outflow
* Normal CT turnover results formmatrix metaloproteinases (MMPs) breaking down old matrix. Tissue inhibitors of metaloproteinases (TIMPS) inhibit MMPs and allow new matrix to be bulit
* Prostaglandins are arachidonic acid metabolites that are elevated by inflammation (e.g. anterior uveitis). Natural prostaglandins increase uveoscleral outflow much in the same way that xalatan does
* Prostaglandins dysregulate the balance between MMPs and TIMPs, favoring dissolution of the CT matrix in the ciliary muscle. As this matrix lessens, it becomes more permeable. Uveoscleral outflow increases and IOP decreases
42
What regulates conventiona outflow resistance?
* MMPs and TIMPs and eNOS
* In the normal eye, the system responds to elevated pressure by sensing tissue strain (ex stretch) within the JCT region and shear stress along the wall of SC
* The compensatory changes to either increase or decrease resistance as needed are translated into action by array of singaling pathways and matricellular proteins that modify intracellular cytoskeletal rigidity, the amt and tensioning of extracellular matrix, or both. All of these are now targets for therapeutic intervention of glc
* Final effects of these pathways include altering the balance between MMPS and TIMPS, with MMPs degrading matrix to increase facility or being inhibited from doing so, resulting in more resistance. The shear within the SC causes release of eNOS, aand then nitric oxide, a vasodilator. Shear also modifies endothelial cytoskeletal rigidity to further relax SC, reducing shear and increasing flow
