Diabetes Mellitus (Lecture 2)

Slide 1 · Diabetes Mellitus

Diabetic retinopathy and ocular complications

Retinal microangiopathy • Neovascularization • Clinicopathologic consequences

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Recognize the microscopic lesions of diabetic retinal microangiopathy.

Distinguish intraretinal pathology from vessels that cross the internal limiting membrane.

Explain edema, vitreous hemorrhage, tractional detachment, and neovascular glaucoma mechanistically.

Link ischemia and VEGF to the rationale for retinal ablation and VEGF inhibition.

Slide 3 · The eye: The relevant diabetic lesions

Anterior structures

Retinal microvasculature

Secondary complications

Diabetes affects the lens, iris, ciliary body, and retina.

This unit concentrates on retinal microangiopathy and its secondary effects.

Posterior-segment ischemia also drives pathology in the anterior segment.

Slide 4 · Retinal architecture determines disease patterns

Vitreous

Posterior hyaloid

ILM

Nerve fiber layer

Outer plexiform

RPE

Schematic, not a histologic section

Retinal vessels lie within the neurosensory retina.

The internal limiting membrane (ILM) is its inner boundary toward the vitreous.

The retinal pigment epithelium (RPE) lies external to the neurosensory retina.

Slide 5 · The ILM separates two pathogenetic stages

Vitreous

Posterior hyaloid

ILM

Nerve fiber layer

Outer plexiform

RPE

Boundary determines category

Nonproliferative vascular pathology remains within the retina, beneath the ILM.

Proliferative retinopathy is defined by new vessels crossing the ILM.

This anatomic distinction is more precise than vessel abundance alone.

Slide 6 · The ciliary body carries a chronic diabetic signature

Chronic diabetes

Thickened epithelial basement membrane

Histologic marker in pars plicata

The pars plicata produces aqueous humor.

The basement membrane of its epithelium can become markedly thickened in chronic diabetes.

This microscopic change with diabetic glomerular mesangial change.

Slide 7 · Retinopathy accumulates with diabetes duration

60%–80%

15–20 years after diagnosis

Robbins 11th edition estimate

Retinopathy in approximately 60%–80% of patients 15–20 years after diagnosis.

This is a textbook estimate, not a contemporary screening-population prediction.

Duration describes exposure; Fundus pathology establishes the ocular phenotype.

Slide 8 · Two vascular failures coexist in diabetic retina

LEAKAGE

Barrier dysfunction

Edema / exudate

CLOSURE

Micro-occlusion

Ischemia / VEGF

Slide 9 · The retinal vascular basement membrane thickens

Lumen

Pericyte

Basement membrane

Altered wall architecture

Diabetic retinal vessels typically show increased basement-membrane thickness.

This is a structural manifestation of systemic diabetic microangiopathy.

Thickened basement membrane does not imply normal barrier function.

Slide 10 · Pericytes become depleted relative to endothelium

Lumen

Pericyte

Basement membrane

Relative pericyte loss

The number of pericytes decreases relative to endothelial cells.

Pericyte loss accompanies the retinal microvascular structural lesion.

Evaluate vessel wall support together with lumen patency and leakiness.

Slide 11 · Basement-membrane change and pericyte loss coexist

Lumen

Pericyte

Basement membrane

Relative pericyte loss

The same capillary network may show thickened walls and relative pericyte depletion.

These changes are not alternative diagnostic categories.

Their downstream manifestations include microaneurysms and vascular dysfunction.

Slide 12 · Microaneurysms are a major microangiopathic lesion

Lumen

Pericyte

Basement membrane

Focal dilation

Microaneurysms are focal dilatations of retinal microvessels.

They are a prominent manifestation of diabetic retinopathy.

A capillary-level lesion may have important visible retinal consequences.

Slide 13 · An ophthalmoscopic red dot needs interpretation

MICROANEURYSM

Focal microvascular dilation

Often below direct resolution

MICROHEMORRHAGE

Extravasated erythrocytes

Can resemble a tiny red dot

Slide 14 · Blood–retinal barrier dysfunction causes leakage

Abnormal retinal vessel

Blood–retinal barrier failure

Fluid / solute escape

Retinal tissue changes

Structural microvascular injury is associated with functional barrier breakdown.

Fluid and plasma-derived material leave abnormally permeable vessels.

Edema and exudates represent different consequences of vascular leakage.

Slide 15 · VEGF links ischemia with permeability

Nonperfusion

Retinal hypoxia

↑ VEGF

Leakage + angiogenesis

VEGF is induced by hypoxic retina.

VEGF was originally termed vascular permeability factor.

Its biological effects connect retinal ischemia, leakage, and angiogenesis.

Slide 16 · Macular edema is a major pathway to visual loss

Vitreous

Posterior hyaloid

ILM

Nerve fiber layer

Outer plexiform

RPE

Retinal fluid

Leakage into the retina produces tissue edema.

Edema involving the macula compromises central retinal function.

Macular edema as a common cause of visual loss in diabetes.

Slide 17 · Exudates accumulate in the outer plexiform layer

Vitreous

Posterior hyaloid

ILM

Nerve fiber layer

Outer plexiform

RPE

Exudate

Abnormal permeability produces retinal exudates.

The outer plexiform layer is a characteristic location for their accumulation.

The retinal layer explains the clinical distribution of exudate.

Slide 18 · Retinal hemorrhage shape reflects its depth

SUPERFICIAL

Nerve fiber layer

Flame-shaped profile

DEEPER

Deeper retinal layers

Dot/blot profile

Slide 19 · Cotton-wool spots signal focal axonal ischemia

Arteriolar insufficiency

Nerve fiber layer infarct

Axoplasmic transport block

Cotton-wool spot

A cotton-wool spot is an infarct of the retinal nerve fiber layer.

Disrupted axoplasmic transport produces swollen axonal endings (cytoid bodies).

The finding is not diabetes-specific: Other occlusive retinal diseases also cause it.

Slide 20 · Retinal micro-occlusion produces nonperfusion

Microvascular obstruction

Local nonperfusion

Tissue hypoxia

Angiogenic response

Diabetic capillaries may become obstructed despite being hyperpermeable elsewhere.

A nonperfused region is deprived of effective microcirculatory delivery.

Micro-occlusion supplies the ischemic stimulus for neovascularization.

Slide 21 · Fluorescein can reveal two opposite abnormalities

VASCULAR INCOMPETENCE

Fluorescein leakage

Abnormally permeable vessel

VASCULAR NONPERFUSION

Absent capillary filling

Ischemic retinal territory

Slide 22 · Hypoxia upregulates retinal VEGF

Capillary loss

Ischemic retina

VEGF upregulation

New vessel growth

The central driver of pathological new-vessel formation is retinal hypoxia.

Hypoxic retina increases VEGF expression.

Angiogenesis can first be intraretinal before surface neovascularization develops.

Slide 23 · Diabetic retinopathy has two principal categories

NONPROLIFERATIVE

Intraretinal lesions

Leakage ± nonperfusion

PROLIFERATIVE

Preretinal new vessels

Fibrovascular complications

Slide 24 · Nonproliferative retinopathy: The lesion set

Wall remodeling

Leakage

Microvascular closure

Microaneurysms and microhemorrhages reflect focal vessel abnormality.

Leakage causes edema and outer plexiform exudates.

Closure causes nonperfusion and secondary ischemic change.

Slide 25 · Nonproliferative disease remains beneath the ILM

Vitreous

Posterior hyaloid

ILM

Nerve fiber layer

Outer plexiform

RPE

Dilated vessels, leakage, and small hemorrhages lie within the retina.

Intraretinal angiogenesis does not itself meet the proliferative definition.

A clear ILM landmark prevents overcalling preretinal proliferation.

Slide 26 · Capillary incompetence drives the exudative phenotype

Damaged capillary wall

Barrier incompetence

Retinal leakage

Edema / exudate

Microvascular structural injury can destabilize normal retinal compartmentalization.

The resulting leak produces edema and exudative deposits.

This pathway does not require visible preretinal neovascularization.

Slide 27 · Macular involvement determines functional importance

MACULAR EDEMA

Leakage-related visual impairment

May occur without PDR

SURFACE NEOVESSELS

Evidence of proliferative stage

Risk of hemorrhage / traction

Slide 28 · Edema and exudate are not interchangeable

EDEMA

Fluid in retinal tissue

Disturbs retinal structure

EXUDATE

Deposited leakage products

Often outer plexiform layer

Slide 29 · Intraretinal angiogenesis precedes the ILM breach

Vitreous

Posterior hyaloid

ILM

Nerve fiber layer

Outer plexiform

RPE

Within retina

Nonperfused retina produces a proangiogenic environment.

New vascular channels may develop within the retina.

Intraretinal angiogenesis differs anatomically from surface retinal neovascularization.

Slide 30 · IRMA is not identical to preretinal neovascularization

INTRARETINAL MICROANGIOPATHY

Contained beneath ILM

Retinal compartment

PRERETINAL NEOVESSELS

Crosses ILM

Retinal / disc surface

Slide 31 · A classification exercise: Trace the vessel

Vitreous

Posterior hyaloid

ILM

Nerve fiber layer

Outer plexiform

RPE

Within retina

Start by identifying the retinal surface and ILM.

If the vascular process remains entirely intraretinal, describe an intraretinal lesion.

If newly formed vessels cross the ILM, classify retinal neovascularization.

Slide 32 · The proliferative transition crosses the ILM

Vitreous

Posterior hyaloid

ILM

Nerve fiber layer

Outer plexiform

RPE

Surface vessels

Pathologic new vessels extend through the retinal internal limiting membrane.

They grow on the retina or optic disc surface.

This crossing—rather than edema or exudate—defines proliferative retinopathy.

Slide 33 · NVD: Neovascularization of the optic disc

Ischemic retina

VEGF-mediated angiogenesis

New vessels at optic disc

NVD

NVD refers to new vessels arising on the optic nerve head surface.

The optic disc is a distinct anatomic site for proliferative growth.

The site and amount of neovascularization influence ophthalmic management.

Slide 34 · NVE: Neovascularization elsewhere

Ischemic retina

VEGF-mediated angiogenesis

New vessels elsewhere

NVE

NVE describes new vessels along the retinal surface away from the disc.

Both NVE and NVD are surface-neovascular phenomena.

Location and extent of new vessels contribute to management decisions.

Slide 35 · NVD and NVE: Different sites, shared biology

NVD

Optic nerve head surface

Disc location

NVE

Retinal surface outside disc

Elsewhere location

Slide 36 · A neovascular membrane contains more than vessels

Abnormal new vessels

± fibrous / glial stroma

Neovascular membrane

Bleeding / fibrosis risk

An angiogenic membrane contains newly formed vascular channels.

Fibrous or glial supporting stroma may be substantial or minimal.

Its stromal component is important for organization and traction.

Slide 37 · The ILM breach changes mechanical relationships

Vitreous

Posterior hyaloid

ILM

Nerve fiber layer

Outer plexiform

RPE

Surface vessels

Intraretinal vessels are embedded within retinal substance.

Preretinal membranes grow into the interface with the vitreous.

Abnormal tissue in this interface becomes vulnerable to traction during vitreous movement.

Slide 38 · The posterior hyaloid borders the preretinal space

Vitreous

Posterior hyaloid

ILM

Nerve fiber layer

Outer plexiform

RPE

The posterior hyaloid is the posterior boundary of vitreous humor.

A potential plane lies between posterior hyaloid and retinal ILM.

With the hyaloid intact, fibrovascular membranes may extend along this plane.

Slide 39 · Posterior vitreous detachment can disrupt new vessels

Preretinal fibrovascular membrane

Posterior vitreous separation

Vessel disruption

Vitreous hemorrhage

The vitreous may later separate from the ILM.

Attached abnormal vessels may be pulled or torn during separation.

The result can be extensive vitreous hemorrhage.

Slide 40 · Preretinal hemorrhage occupies a superficial plane

Vitreous

Posterior hyaloid

ILM

Nerve fiber layer

Outer plexiform

RPE

Blood above ILM

Blood may collect beneath the posterior hyaloid and above the ILM.

This is distinct anatomically from hemorrhage within retinal layers.

The relation to neovascular tissue explains the superficial location.

Slide 41 · Vitreous hemorrhage follows rupture of fragile membranes

Vitreous

Posterior hyaloid

ILM

Nerve fiber layer

Outer plexiform

RPE

Vitreous blood

The abnormal neovascular network can be disrupted mechanically.

Blood enters the vitreous cavity and may interfere with visual transmission.

The source of blood lies at the retinal–vitreous interface, not necessarily within the retina.

Slide 42 · Neovascular membranes can organize into scars

Surface neovascular membrane

Fibroglial organization

Scar contraction

Retinal deformation

Fibrovascular tissue may undergo organization and contraction.

Scarring exerts force along retinal and vitreous interfaces.

The clinical consequence depends on retinal deformation and traction.

Slide 43 · Retinal wrinkling distorts photoreceptor alignment

Vitreous

Posterior hyaloid

ILM

Nerve fiber layer

Outer plexiform

RPE

Retinal wrinkling

Contraction can wrinkle the retina.

Disrupted alignment of retinal photoreceptors can distort vision.

Vascular disease therefore causes visual impairment through a mechanical pathway as well as edema.

Slide 44 · Contractile force can lift neurosensory retina

Vitreous

Posterior hyaloid

ILM

Nerve fiber layer

Outer plexiform

RPE

Neural retina lifts

Fibrovascular contraction exerts traction on the underlying retina.

Sufficient traction separates neural retina from the RPE.

This is tractional retinal detachment.

Slide 45 · Tractional detachment need not involve a retinal break

NONRHEGMATOGENOUS

No retinal break required

Contractile traction

RHEGMATOGENOUS

Full-thickness retinal break

May follow severe traction

Slide 46 · Severe traction may eventually tear the retina

Membrane contraction

Tractional lifting

Retinal tear

Combined traction + break

Traction may progress from elevation to retinal tearing.

Once a tear develops, a rhegmatogenous component is present.

Robbins explicitly describes this progression in advanced diabetic disease.

Slide 47 · Retinal detachment disrupts the RPE interface

Vitreous

Posterior hyaloid

ILM

Nerve fiber layer

Outer plexiform

RPE

Neural retina lifts

Neurosensory retina normally lies apposed to retinal pigment epithelium.

Detachment separates those layers.

The resulting alteration threatens normal photoreceptor support.

Slide 48 · Proliferative disease creates two injury mechanisms

HEMORRHAGIC

Neovascular vessel disruption

Preretinal / vitreous blood

TRACTIONAL

Membrane organization

Wrinkling / retinal detachment

Slide 49 · Ischemic retina can signal the anterior segment

Ischemic retina

Increased VEGF

Anterior chamber / aqueous

Iris neovascularization

Retinal hypoxia increases VEGF.

VEGF in aqueous humor is implicated in iris-surface neovascularization.

Thus a posterior-segment vascular lesion can produce anterior-segment disease.

Slide 50 · Iris neovascularization adds an abnormal membrane

Retinal VEGF stimulus

Iris surface neovessels

Contractile membrane

Outflow obstruction

New vessels and associated membrane may grow over the iris surface.

The lesion is driven indirectly by retinal ischemic signaling.

Surface membrane contraction can compromise normal aqueous outflow.

Slide 51 · Anterior synechiae obstruct aqueous drainage

Iris fibrovascular contraction

Anterior synechiae

Trabecular outflow blocked

Elevated intraocular pressure

Contracting iris neovascular membrane promotes iris–trabecular adhesions.

These anterior synechiae impair access to the trabecular meshwork.

A major aqueous outflow pathway becomes mechanically compromised.

Slide 52 · Neovascular glaucoma is an ischemic consequence

Retinal nonperfusion

VEGF-driven iris vessels

Synechial angle closure

Neovascular glaucoma

An iris neovascular membrane can lead to angle closure.

Outflow impairment elevates intraocular pressure.

The resulting neovascular glaucoma is therefore downstream of retinal vascular ischemia.

Slide 53 · Posterior and anterior neovascular disease differ

RETINAL NEOVESSELS

Retinal / optic disc surface

Vitreous bleeding and traction

IRIS NEOVESSELS

Iris surface and angle

Anterior synechiae / glaucoma

Slide 54 · Locate every lesion before naming the complication

Within retina

At vitreoretinal interface

At iris–angle interface

Intraretinal microvascular lesion → nonproliferative compartment.

Cross-ILM membrane → proliferative retinal compartment.

Iris-angle membrane → neovascular glaucoma pathway.

Slide 55 · Visual loss can result from distinct mechanisms

Macular edema

Vitreous blood

Retinal traction / detachment

Macular edema disturbs central retinal tissue architecture.

Vitreous hemorrhage impairs clear visualization through the media.

Retinal deformation or detachment disrupts normal photoreceptor position.

Slide 56 · Fluorescein tests permeability and perfusion

LEAK

Permeability defect

Macular edema association

NONPERFUSION

Occlusion / ischemia

VEGF-driven angiogenesis

Slide 57 · Retinal ablation can reduce angiogenic signaling

Nonperfused retinal tissue

Retinal ablation

Reduced proangiogenic drive

Vessel regression

Laser photocoagulation or cryopexy to nonperfused retina may induce regression of neovascularization.

Retinal and iris vessel regression supports ischemia as the driving stimulus.

The pathology principle is suppression of the hypoxia-driven neovascular response.

Slide 58 · Intravitreal VEGF inhibition targets a defined mechanism

VEGF-dependent processes

Intravitreal VEGF blockade

Less pathological permeability

Control of neovascularization

VEGF contributes to vascular permeability and neovascularization.

Intravitreal VEGF inhibitors are used for diabetic macular edema and retinal neovascularization.

Targeted therapy follows from the pathological VEGF mechanism.

Slide 59 · Morphologic classification guides interpretation

NPDR

Intraretinal changes

Edema / hemorrhage / ischemia

PDR

Preretinal membrane

Hemorrhage / traction / detachment

Slide 60 · Diabetic and hypertensive retinopathy can overlap

DIABETIC

Pericyte reduction; Microaneurysms

Leakage ± neovascularization

HYPERTENSIVE

Arteriolar narrowing / sclerosis

Arteriovenous crossing change

Slide 61 · Teaching vignette: Edema without proliferation

Identify the leakage lesion

Identify the boundary

Explain visual impairment

A diabetic retina has leakage, exudates, and macular thickening.

No vessels are described crossing the ILM.

Interpret the visual threat and the retinopathy category separately.

Slide 62 · Teaching vignette: Intraretinal angiogenesis

Localize the channels

Identify the ILM

State why IRMA ≠ PDR

A capillary bed shows nonperfusion and abnormal new channels within the retina.

No vascular membrane is present above the ILM.

What prevents classification as proliferative disease?

Slide 63 · Teaching vignette: Surface neovascularization

Recognize NVD

Link ischemia to VEGF

Predict possible hemorrhage

New vessels are seen extending onto the optic disc surface.

The adjacent retina shows zones of nonperfusion.

Classify the lesion and explain its angiogenic stimulus.

Slide 64 · Teaching vignette: Progressive vitreoretinal traction

Membrane disruption → bleeding

Scar contraction → traction

Potential retinal detachment

A fibrovascular membrane is followed by posterior vitreous separation.

Hemorrhage and retinal wrinkling develop.

Identify the two distinct mechanical complications.

Slide 65 · Teaching vignette: Neovascular glaucoma pathway

Retinal ischemia → VEGF

Neovascular iris membrane

Synechial angle obstruction

Advanced retinal nonperfusion coexists with iris neovascularization.

Peripheral iris–trabecular adhesions are present.

Explain why intraocular pressure may rise.

Slide 66 · Integrated sequence: Capillary injury to complications

Capillary wall injury

Leakage + nonperfusion

Hypoxia → VEGF

Neovascular growth

Hemorrhage / traction / glaucoma

Microangiopathy produces leakage and/or retinal nonperfusion.

Ischemia drives VEGF and may generate retinal and iris surface neovascular membranes.

Edema, bleeding, traction, detachment, and glaucoma are mechanistically distinct endpoints.

Slide 67 · Essential structural checkpoints

Capillary wall

ILM / hyaloid

Iris / angle

Basement membrane thickening and relative pericyte loss characterize diabetic microangiopathy.

The ILM is the boundary used to distinguish retinal neovascularization from intraretinal disease.

Posterior hyaloid interaction explains bleeding and traction; Iris-angle scarring explains glaucoma.

Slide 68 · References and source boundaries

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th edition (2026). Chapter 29, The Eye: Diabetes Mellitus, pp. 1201–1203.

Adjacent anatomical context: Retina and Vitreous, pp. 1198–1201; associated figures and captions on pp. 1202–1205.

All retinal diagrams in this lecture are original editable schematics, not photomicrographs, fundus photographs, or reproduced textbook figures.

The source-based therapeutic discussion explains mechanisms; it is not a current clinical treatment guideline.