aqueous humor dynamics (dr poonam)

8/7/2019 AQUEOUS HUMOR DYNAMICS (DR POONAM)

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AQUEOUS HUMOR DYNAMICSFORMATION, OUTFLOW AND

IOP

INTRODUCTION

Aqueous humor is a dynamic intra ocular fluid that is vital

to the health of eye.

It is a relatively cell free protein free fluid formed by the

ciliary body epithelium in the posterior chamber.

Major functions of the aqueous humor include

Maintains IOP and globe integrity.

Provides essential nutrients and removes

metabolites from cornea, lens and trabecular

meshwork.

Provides high concentrations of ascorbate which

helps to protect the eye against uv radiations andscavenges free radicals.

Facilitates cellular and humoral responses.

Provides colorless and transparent medium for

optical system of the eye.


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STRUCTURE OF CILIARY BODY

The ciliary body is a right triangular uveal structure lying

between the iris and choroid.

The ciliary body consists of

Muscle

Longitudinal - on contraction opens the

trabecular meshwork and schhlems canal.

Circular on contraction they relax the zonules

and helps accommodation.

Radial their function is not clear.

The ciliary muscle is innervated by

parasympathetic fibres from ciliary ganglion.

Vascular stroma formed by anastomosis between

long posterior ciliary artery and anterior ciliaryarteries

Epithelium

Pigmented epithelium

Non-pigmented epithelium

The ciliary body consists of a folded anterior portion

pars plicata, and a flat posterior portion k/a pars plana.

The pars plicata consists of 70 80 ciliary processes having a

surface area of 6 cm2, for active transport and

ultrafiltration.

The pars plana and plicata are lined on the inner surface by

two layers of epithelium

Outer pigmented layer- role in active

metabolic processes

Inner non pigmented layer- abundance of


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Na+ K+ ATPase, involved in fluid transport.

The two layers of epithelium have their apical surfaces in

apposition.

Each ciliary process is composed of central core of stroma

and capillaries covered by double layer of epithelium.

Adjacent cells in each epithelial layer and apical surfaces of

two layers of epithelium are connected by

Gap junctions

Puncta adherentia

Desmosomes

Zonulae occludens(NPE) imp component of

blood aqueous barrier

The vascular supply is by long posterior ciliary arteries

branches of ophthalmic artery. It forms a major arterial

circle by anastomosis to supply the ciliary processes.

The ciliary body has a very high blood flow of about

154l/min.

MECHANISM OF AQUEOUS HUMOR

FORMATION

Aqueous humor is formed by a complex process involving

Ultrafiltration

Active transport

Diffusion


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ULTRAFILTRATION

It is the process by which a fluid and its solutes cross a semi

permeable membrane under a pressure gradient.

In c/o ciliary body fluid movement is favored by hydrostatic

pressure difference between capillary pressure and IOP;

and resisted by difference between oncotic pressure of

plasma and aqueous humor.

As blood passes through the capillaries 4% of plasma filters

through the fenestrations in the capillary wall into

interstitial spaces between capillaries and ciliary epithelium.

Protein is expected in the stromal filtrate because of

fenestrated nature of ciliary capillaries.

ACTIVE TRANSPORT

It is an energy dependent process which selectively moves a

substance against its electrochemical gradient across a cell

membrane.

Aqueous humor formation mainly depends upon ionsactively secreted into the inter cellular clefts of non

pigmented epithelium beyond tight junctions.

These cells secrete aqueous humor to 1/3 rd of its own

intracellular volume per min.

The ions which are actively transported include sodium,

potassium and bicarbonate through a membrane bound NAK ATPase pump in the non pigmented epithelium.


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Quantitatively the net movement of a substance across a

semi permeable membrane where only diffusion occurs is

expressed by FICKS LAW

Rate of movement = K (C1 C2)

K constant which depends on the nature and permeability

of the membrane, nature of solute, solvent, temperature.

C1 concentration of substance on side of higher

concentration

C2-concentration of substance on side of lower

concentration

In c/o aqueous production lipid soluble substances are

transported by diffusion though lipid portions of cellmembrane of ciliary processes proportional to concentration

gradient across the membrane.

As the aqueous humor passes from posterior to anterior

chamber it resembles plasma more closely as diffusional

exchange occurs with surrounding tissues like iris, lens, and

cornea, vitreous.

Provides glucose, amino acids, oxygen and potassium and

removes carbon dioxide, lactate and pyruvate.


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CHEMICAL COMPOSITION

PHYSICO CHEMICAL PROPERTIES

Volume 0.31 ml

Refractive index 1.336

Density slightly denser than water 1.025 to 1.040Osmotic pressure - 3 to 5 mOsm/L

pH acidic 7.2

Rate of formation- 2 to 3 l / min

BIOCHEMICAL COMPOSITION

Relative to the plasma general characteristics of aqueous is

as follows

Slightly hypertonic

Acidic

Marked excess of ascorbate

Marked deficit of protein

Slight excess of chloride and lactic acid

Slight deficit of sodium, bicarbonate, CO2 , glucose.Other constituents include

Amino acids

Sodium hyaluronate

Norepinephrine

Coagulation factors

tPA

Latent collagenase activity


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Entry of various substances depend on a number of factors

such as molecular size, electrical charge, and lipid solubility.

Therefore large molecules like proteins penetrate the eye

poorly, and lipid soluble substances pass readily.

There are certain transport systems which actively transport

substances out of the eye hence preventing accumulation of

toxic substances in the eye.

BLOOD AQUEOUS BARRIER

It is a barrier to the movement of substances from theplasma to the aqueous humor so as to prevent large size

molecules such as protein to enter the cavities of the eye

hence maintaining the clarity of the media of eye.

The barrier include

vascular endothelium

basement membrane

stroma

pigmented and non pigmented

epithelium

Of all the above the tight junctions or the zonae occludens of

the non pigmented epithelium are considered to be the

actual site of the barrier.

Although the name signifies but the junctions are not so

tight cause they allow the passage of some small ions and

water across them.

Many exogenous and endogenous stimuli increase the

permeability of the barrier hence increasing the protein

content of the aqueous, recognized clinically as the tyndaqll

effect.


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Stimuli which break the blood aqueous barrier are as

follows

Trauma

mechanical injury

contusion

paracentesis

Chemical irritants

nitrogen mustard formaldehyde

acid , alkali

Neural activity

stimulation of the trigeminal nerve

Immunogenic activity

bovine serum albumin

Endogenous mediators

histamine bradykinin

prostaglandins

serotonin

acetylcholine

Corneal and intra ocular infections

Miscellaneous

bacterial endotoxins

x radiation

infrared radiation

laser energy

alpha melanocyte stimulating hormone


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In certain situations like intra ocular infections breach in

the barrier brings cellular and humoral immunity to the

eye

On the other hand it favours complications such as cataract

and synechia formation.

TECHNIQUES FOR MEASUREMENT OF AQUEOUS

HUMOR

1. Pressure dependent techniques

Depends on the following equation

Flow = C (Po Pv)C =facility of outflow

Po = IOP

Pv = episcleral venous pressure

tonography

suction cup

perfusion

2. Tracer method

photogrammetry

fluorescein

fluoresceinated dextrans

paraminohippurate

iodide


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FACTORS AFFECTING AQUEOUS HUMOR

FORMATION

1. Diurnal variation

Most commonly the IOP peaks in the afternoon

and is minimum at early morning and late

night.

The rate of formation is half during sleep due

to decreased stimulation of ciliary epithelium

by circulating catacholamines.

2. Age and sex

Similar rate in males and females.

Reduction in aqueous humor formation

decrease with age of 60.

3. IOP

Many investigators have postulated a feed back

mechanism but many other observations havenegated such a relationship.

4. Blood flow to ciliary body

Profound vasoconstriction decreases the rate of

aqueous flow.

5. Neural control

The stimulation of cervical sympathetic chain,

hypothalamic centres alter the aqueous production.

At present the mechanisms are unclear

6. Hormonal effects

Systemic corticosteroids are responsible for the

circadian variations of IOP.

7. Intra cellular regulators like cAMP and cGMP can

also alter the rate of secretion.


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8. Pharmacologic agents

Stimulants of aqueous secretion adrenergic

agents, endogenously administered corticosteroids

and pilocarpine.

Decrease of aqueous secretion caused by variety of

drugs e.g. carbonic anhydrase inhibitors,

adrenergic antagonists etc

9. Surgery

Cyclocryotherapy and cyclodiathermy reduce

aqueous formation.

AQUEOUS HUMOR OUTFLOW

ANATOMY OF THE OUTFLOW SYSTEM

The major pathway from anterior chamber to venous

system include

Trabecular meshwork

Juxtacanalicular tissue

Schlemm s canal

Aqueous veins

Episcleral veins

TRABECULAR MESHWORK

It is a sieve like structure through which aqueous humor

leaves the eye.

It bridges the scleral sulcus and converts it into a tube which

accomodates the schlemms canal


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It consists of three parts

1. UVEAL MESHWORK

It is the inner most part of trabecular meshwork extending

from iris root and ciliary body to the schwalbes line.

The trabeculae are cord like and 2 to 3 layers thick having

irregular openings of 25 to 75 .

2. CORNEO SCLERAL MESHWORK

It forms the larger middle portion extending from scleral

spur to lateral wall of scleral sulcus.

The size of elliptical openings vary from 5 to 50 .

3. JUXTA CANALICULAR MESH WORK

It forms the outer most portion of trabecular mesh work

and offers the normal resistance to aqueous outflow.

It consists of a layer of connective tissue lined on either

side of endothelium and connects corneo scleral mesh

work with schlemms canal. (2 -20 m thick).


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SCHLEMM S CANAL

It is an endothelial lined circular channel which runs

circumferentially around the globe.

It resembles lymphatic channel in its structure.

The endothelial cells of its inner wall are irregular spindle

shaped and contain giant vacuoles.

The outer wall of schlemms canal has a single layer ofendothelium that lacks pores or vacuoles.

Generally it has a narrow slit like lumen that is 190 to 370

in diameter.

COLLECTOR CHANNELS

Schlemm s canal is drained by a series of collector channelswhich in turn drain into a complex system of intra scleral,

episcleral, and subconjunctival venous plexuses.

EPISCLERAL VEINS

Most of the aqueous vessels drain into these veins.

The episcleral veins ultimately drain into cavernous sinus

via anterior ciliary and superior ophthalmic veins.


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PHYSIOLOGY OF THE OUTFLOW SYSTEM

Aqueous humor flows from posterior chamber to the

anterior chamber through the pupil against slight

physiologic resistance.

In the anterior chamber there exists convection (thermal)

current which results from a temperature gradient between

anterior and posterior parts of the anterior chamber, ascornea is cooler than the iris due to evaporation.

From the anterior chamber the aqueous is drained by two

routes

Trabeculocanalicular outflow

Uveoscleral outflow

TRABECULOCANALICULAR OUTFLOW

It is the main outlet for aqueous accounting for 75 to 90 %of

drainage.


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Most of the aqueous passes

Uveal meshwork

Corneoscleral meshwork

Juxtacanalicular tissue

Endothelial lining of canal

Collector channels

Intrascleral venous plexus

Episcleral venous plexus

Anterior ciliary veins

Llobet, A. et al. News Physiol Sci 18: 205-209 2003;doi:10.1152/nips.01443.2003

FIGURE 1. Schematic diagram of the aqueous humor cycle


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The trabecular meshwork schlemm s canal has been

described as a sponge like one way valve for egress of

aqueous humor as it permits bulk flow in one direction but

restricts flow in opposite direction.

It is therefore considered as a crucial part of the blood

aqueous barrier.

Also the trabecular endothelial cells have s phagocytic

function so it acts as the reticulo-endothelial system of the

eye.

MECHANISMS OF AQUEOUS TRANSPORT ACROSS

INNER WALL OF SCHLEMMS CANAL

1. vacuolation theory

It has been suggested that aqueous humor enters the

schhlems canal by traversing the trans-cellular channels in

the endothelial cells

These channels form and recede in a cyclic fashion

The cycle begins with the invaginations on the trabecular

side of the endothelial cells and progresses to a trans cellular

channel with a small pore opening into the schlemms canal


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At one time only a small fraction of invaginations open into

the canal and they account for majority of normal resistance

to outflow.

2. leaky endothelial cells

3. sondermans channels

4. contractile micro filaments

5. pores in endothelial cells

Newer advances- it has been suggested that there is

involvement of extracellular matrix of the trabecular

meshwork in aqueous humor outflow.

A pressure gradient between IOP and intrascleral venous

pressure is responsible for unidirectional flow of aqueous.


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UVEOSCLERAL OUTFLOW

It is responsible for 10 to 25 % of total aqueous flow

Aqueous passes across ciliary body into the suprachoroidal

space and is drained by venous circulation in the ciliary

body, choroid, sclera into the orbital tissues.

The main resistance to the uveoscleral outflow is the tone of

ciliary muscle.

Therefore pilocarpine which contracts the ciliary musclelowers the uveoscleral outflow.

Atropine relaxes the ciliary muscle and increases the

outflow.

Uveoscleral outflow is raised significantly by the

prostaglandins therefore they are the most potent low dose

IOP lowering agents.

METHODS FOR MEASURING THE OUTFLOW

FACILITY

The facility of outflow can be measured by the goldmann

equation

C = F/Po - Pv

C = facility of outflow (l/min/mmHg)

F = aqueous humor production (l/min)

Po = IOP (mm of Hg)Pv = episcleral venous pressure (mm of Hg)


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The following methods are used for measuring outflow

facility

Tonography

Perfusion

Suction cup

TONOGRAPHY

It is a non invasive technique for determining the facility of

aqueous outflow.

During tonography a schiotz tonometer is placed on the

cornea for a few mins.

The weight of the tonometer increases the IOP and increases

the outflow of aqueous above its normal rate. The tonometer

is connected to a continuous recording device.

Using tables one can infer the change in IOP readings to beinferred as the volume of aqueous displaced from the eye

(V).

Rate of fluid outflow = V/t

If the tonometer raises IOP from initial P0 to average value

of Pt the outflow facility, C

C = V/t

-----------

Pt - P0


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ASSUMPTIONS

1. An acute rise in IOP alters nothing besides the rate

of aqueous humor flow.

2. All eyes respond with similar distension of the ocular

coats to acute rise in IOP.

3. Raising IOP does not affect the ocular blood volume.

ERRORS

1. operator errors2. patient errors

3. instrument errors

4. reading errors

CLINICAL IMPLICATIONS OF FACILITY OF

OUTFLOW

The mean outflow facility in normal eyes range from 0-22 to

0.28 l/min and mean Po ratio ranges from 55 to60

Both the above variable are not distributed in a normal or

Gaussian fashion and there is a considerable overlap

between normal and glaucomatous eyes

Therefore tonography is neither sufficiently sensitive no

specific to make the diagnosis of glaucoma.

Thus clinicians abandoned the test because the added value

of the test was minimal when compared with time and effort

it took to obtain quality results.


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Some other uses of tonography are as follows

1. To predict the development of POAG

2. To assess the adequacy of anti glaucoma therapy

3. To detect the wide diurnal swings of IOP

4. To help diagnosis of angle closure glaucoma

5. To determine the mechanism of action of ocular

hypotension medications and different glaucoma

operations

FACTORS AFFECTING THE FACILITY OF OUTFLOW

1. AGE

Modest decline in aqueous formation as well as outflow

with age

2. HORMONES

Corticosteroids administered topically, systemically or

periocularly would outflow facility

Other hormones such as prostaglandins, progesterone,

thyroxin, relaxin, and chorionic gonadotrophin are

postulated to influence the outflow facility

3. CILIARY MUSCLE TONE

tone of the muscle the outflow facility which can

occur during the following conditions

Accommodation

Electric stimulation of the oculomotor nerve

Posterior depression of the lens

Administration of parasympathomimetics eg

pilocarpine

4. DRUGS


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6. DIURNAL FLUCTUATION

Considerable controversy

7. GLAUCOMA

Outflow facility is reduced in most forms of glaucoma

Primary infantile laucoma

Angle closure glaucoma

Secondary open angle glaucoma

POAG

Episcleral venous pressure

It can be measured using

Pressure chambers

Torsion balance devices

Force displacement transducers

Air jets

Direct canulation

Normally ranges from 8 to 11.5 mm of Hg

INTRA OCULAR PRESSURE

The IOP refers to the pressure exerted by intraocular

contents on the coats of the eyeball.


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The normal level of IOP is maintained by a dynamic

equilibrium between aqueous humor formation , outflow

and episcleral venous pressure.

Normal IOP varies between 10.5 and 20.5 mm of Hg with a

mean pressure of 15.5 2.57 mm of Hg

The IOP serves as the tissue pressure of vascularized

internal structures of the eye and is thus much higher than

the tissue pressure elsewhere in the body (5 mm of Hg)

Normal IOP is pulsatile reflecting its vascular origin and

effects of blood flow on the ocular structures

INSTRUMENTS FOR MEASURING IOP

Direct method manometry

Indirect method tonometry

Tonometry is broadly divided into two types

Indentation tonometry

Measures the force required to flatten a small standard

area of the cornea

Applanation tonometry

Measures the amount of deformation or indentation ofthe globe in response to a standard weight applied to the

the cornea .

Indentation instruments

Schiotz tonometer


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Electronic schiotz tonometer

Applanation instruments

Goldmann tonometer

Perkins tonometer

Draeger tonometer

MacKay Marg tonometer

Pneumatic tonometer

Noncontact tonometer

Maklakow tonometer

DISTRIBUTION OF IOP IN THE GENERAL

POPULATION

Several population based studies have been done to

comment on the frequency distribution of normal IOP

The most frequently cited study is that of Leydhecker and

associates and the conclusions drawn are as follows:

The distribution of pressures observed resembled a

Gaussian curve but was skewed towards the right

It has been assumed that perhaps two different

population groups account for skewed distribution ; a

large normal group and a smaller group that was felt

to be glaucomatous without any optic nerve head

damage The mean IOP of the normal group was 15.5 2.57 mm

of Hg

95 %of the population had an IOP between 10.5 and

20.5 mm of Hg


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Some important conclusions drawn from the other

population based studies are as follows

a slight increase of mean IOP in each decade over 40

yrs

a slight higher pressure exists in women than men in

population above 40 yrs

IOP difference between right and the left eye rarely

exceeds 4 mm of Hg

Level of IOP is inherited as a polygenic multi factorial

trait

FACTORS AFFECTING IOP

1. AGEMean IOP increases with increasing age

2. SEX

Higher IOP in women

3. RACE

Higher IOP among blacks

4. HEREDITY

Polygenic trait

5. DIURNAL VARIATION

IOP varies an average of 3 to 6 mm of Hg in normal

individuals

Max pressure in mid morning hours

Min pressure at late night or early in the morning

However some individuals show no consistent pattern


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6. SEASONAL VARIATION

Higher IOP in winter months

7. CARDIOVASCULAR FACTORS

IOP increases with BP

8. EXERCISE

Strenuous exercise produces a transient reduction in IOP

9. POSTURE

IOP from sitting to supine posture

10. NEURAL FACTORS

As of today there is no proof for this hypothesis

Cholinergic and adrenergic input alters the IOP

11. HORMONES

corticosteroids the IOP.

Diabetics have higher IOP

12. DRUGS

13. REFRACTIVE ERROR

Myopes have higher IOP

14. OTHERS

Eyelid movements, lid closure, inflammation and surgery

also alter the IOP

aqueous humor dynamics (dr poonam)

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