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Blood-Retinal Barrier (BRB)

Definition

The blood-retinal barrier (BRB) is a selective physiological barrier that separates the neural retina from the systemic circulation. It is analogous to the blood-brain barrier and maintains the specialized ionic and molecular microenvironment required for normal visual function. The BRB has two anatomically and functionally distinct components: the inner BRB (iBRB) and the outer BRB (oBRB).

1. Inner Blood-Retinal Barrier (iBRB)

Anatomical basis: The iBRB is formed by the tight junctions (zonula occludentes) between the non-fenestrated endothelial cells of the retinal capillaries.

Structure of retinal capillary walls (from inside outward):

Endothelial cells - form a single layer on the basement membrane, linked by tight junctions that constitute the actual barrier
Basement membrane - lies beneath the endothelial cells, with an outer basal lamina enclosing pericytes
Pericytes - lie external to endothelial cells, have contractile pseudopodal processes that envelop capillaries, and participate in autoregulation of microvascular circulation

Key property: Neither protein-bound nor free fluorescein can cross an intact iBRB. The basement membrane and pericytes play only a minor supporting role.

Distribution: The iBRB covers the inner two-thirds of the retina, supplied by the retinal circulation. Capillary-free zones are present around arterioles and at the foveal avascular zone (FAZ).

Inner blood-retinal barrier - (A) Intact: showing endothelial cell (E), pericyte (P), and basement membrane (B.M.); (B) Disrupted: showing leakage of molecules into surrounding tissue

Fig. 14.5 Inner BRB. (A) Intact - E = endothelial cell, P = pericyte, B.M. = basement membrane. (B) Disrupted - fluorescein molecules leak into surrounding retinal tissue. (Kanski's Clinical Ophthalmology, 10th ed.)

2. Outer Blood-Retinal Barrier (oBRB)

Anatomical basis: The oBRB is formed by the RPE cells and their intercellular tight junctions (zonula occludentes), which lie on Bruch membrane.

Structure and mechanism:

The choriocapillaris is a fenestrated capillary network - its walls allow free and protein-bound fluorescein to escape into the extravascular space
Fluorescein crosses Bruch membrane freely (Bruch membrane is permeable)
On reaching the RPE, it is blocked by the tight junctions between adjacent RPE cells
The RPE also actively pumps ions and water out of the subretinal space, maintaining the dry subretinal microenvironment

Bruch membrane (5-layered structure) separates RPE from choriocapillaris:

Basal lamina of RPE
Inner collagenous layer
Elastic fibre band
Outer collagenous layer
Basal lamina of choriocapillaris inner layer

Outer blood-retinal barrier showing the RPE layer with zonula occludentes (Z.O.) blocking passage from the choriocapillaris, with Bruch membrane (B.M.) visible

Fig. 14.4 Outer BRB - Z.O. = zonula occludentes (RPE tight junctions); B.M. = Bruch membrane; choriocapillaris below. (Kanski's Clinical Ophthalmology, 10th ed.)

3. Functions of the BRB

Function	Component
Prevents extracellular fluid leaking into subretinal space	oBRB (RPE tight junctions)
Maintains ionic homeostasis of the retinal microenvironment	Both iBRB and oBRB
Inward transport of metabolites (glucose, amino acids)	RPE (oBRB)
Outward transport of metabolic waste products	RPE via Bruch membrane
Active pumping of ions/water from subretinal space	RPE
Storage, metabolism and transport of Vitamin A (visual cycle)	RPE
Absorb stray light (via melanosomes)	RPE
Phagocytosis of shed photoreceptor outer segments	RPE
Immune privilege of the retina	Both barriers

4. Breakdown of the BRB - Clinical Significance

A. Breakdown of the Inner BRB

Caused by dysfunction or absence of endothelial tight junctions. On fluorescein angiography (FFA), this causes leakage - early hyperfluorescence that increases in both area and intensity over time.

Causes:

Dysfunction/loss of existing tight junctions: Background diabetic retinopathy (DR), retinal vein occlusion (RVO), cystoid macular oedema, disc swelling
Primary absence of tight junctions: Macular neovascularization (MNV), proliferative diabetic retinopathy, Coats disease, tumours

B. Breakdown of the Outer BRB

Caused by RPE tight junction disruption. On FFA, this causes pooling in anatomical spaces.

Causes and FFA patterns:

Subretinal pooling: Central serous chorioretinopathy (CSC) - small leak that slowly increases in intensity and area
Sub-RPE pooling: Pigment epithelial detachment (PED) - early hyperfluorescence that increases in intensity but not in size

5. Key Diseases Linked to BRB Disruption

Diabetic Retinopathy (DR)

The most common cause of iBRB breakdown. In DR:

Pericyte loss is the earliest histological change (before clinically apparent retinopathy)
The endothelial-to-pericyte ratio normally is ~1:1 in retinal capillaries; selective pericyte dropout occurs in diabetes
Loss of pericytes leads to loss of retinal blood flow autoregulation
Subsequent endothelial dysfunction and tight junction loss cause capillary leakage
Results in retinal oedema, hard exudates, and ultimately macular oedema (most common cause of visual loss in DR)
Microaneurysms - the earliest clinical sign - may leak plasma constituents into the retina through BRB breakdown

Other Conditions

Disease	BRB Component Affected
Central serous chorioretinopathy	Outer BRB (RPE leak)
Age-related macular degeneration	Outer BRB (RPE/Bruch membrane)
Retinal vein occlusion	Inner BRB (endothelial damage)
Irvine-Gass syndrome (post-cataract surgery CMO)	Inner BRB (inflammatory)
Coats disease	Inner BRB (absent endothelial tight junctions)
Hypertensive retinopathy	Inner BRB (endothelial damage)
Uveitis	Both (inflammatory mediators)

6. BRB and Fluorescein Angiography (FFA)

The integrity of the BRB is the basis for interpretation of FFA:

Intact iBRB: Neither bound nor free fluorescein crosses - no leakage seen
Intact oBRB (RPE): Fluorescein that escapes from fenestrated choriocapillaris is stopped at RPE tight junctions - no pooling in subretinal space
Bruch membrane is permeable to fluorescein - it does not form part of the barrier
Window defect (RPE atrophy): Gives hyperfluorescence due to unmasking of choroidal fluorescence (not true leakage) - early, doesn't enlarge

7. Molecular Basis of BRB Tight Junctions

Tight junctions of both the endothelium and RPE are composed of:

Occludin and claudins (transmembrane proteins forming the actual seal)
ZO-1, ZO-2, ZO-3 (scaffolding/zonula occludens proteins linking to the actin cytoskeleton)
JAM (junctional adhesion molecules)

In disease states (especially DR), VEGF (vascular endothelial growth factor) is a major mediator of BRB breakdown - it phosphorylates occludin, leading to tight junction disassembly and increased permeability. This is the rationale for anti-VEGF therapy in diabetic macular oedema.

Summary Table

Feature	Inner BRB	Outer BRB
Location	Retinal capillary endothelium	Retinal pigment epithelium (RPE)
Tight junction type	Zonula occludentes between endothelial cells	Zonula occludentes between RPE cells
Supporting cells	Pericytes, basement membrane	Bruch membrane
Blood supply	Retinal circulation (inner 2/3 retina)	Choriocapillaris (outer 1/3 retina)
FFA: if intact	No leakage	No pooling in subretinal space
FFA: if broken	Leakage (area + intensity increase)	Pooling in anatomical space
Key disease	Diabetic retinopathy	Central serous chorioretinopathy, AMD

References: Kanski's Clinical Ophthalmology: A Systematic Approach, 10th edition - Chapters on Retinal Anatomy, Macular Disease, and Fluorescein Angiography; The Wills Eye Manual, 8th edition.

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