Understanding the Clinical Impressions of Common

Retinal LesionsThomas F. Freddo, O.D., Ph.D., F.A.A.O.

Professor and Former DirectorSchool of Optometry

University of Waterlootfreddo@uwaterloo.ca

Commercial Interests

None

Optos

Posterior Pole vs PeripheryPosterior Pole vs Periphery

Same retina at same magnification. Note that retinal periphery is only about 1/3 the thickness of the posterior pole.

Vascular Distribution from CRA

Major vessels travel in nerve fiber layer and give rise to two, precisely placed layers of capillaries; one at the ganglion cell layer and one at the INL/OPL interface. No retinal vessels in or below OPL.

Terminal Arcades the retinal vasculature is a closed loop system and does not reach all the way to the ora.

Typical peripheral microcystoid degeneration of the retina beyond the terminal arcades.

Peripapillary Retinal Vasculature Radial peripapillary

capillary plexus Long straight radiating

vessels with few interconnections and thus a diminished capacity for collateral flow.

This plexus serves the region where the nerve fiber layer is thickest.

The result is that the peripapillary region has a greater dependent tissue mass, relying upon a vascular supply with less capacity for collateral flow.

As such, this area is at greater risk from a given amount of vascular occlusion than elsewhere. in the retina.

Cotton Wool Spots Yellow, white

grey fluffy lesions overlying or deflecting retinal vessels and most often in the peripapillary region.

Classical description is that they result from microvascular occlusion and infarction of the nerve fiber layer.

Diseases Associated with Cotton-Wool Spots

Accelerated Hypertension Most common in

younger patients Diastolic pressures

above 130 mmHg Diabetes mellitus

In moderate background retinopathy

Collagen-Vascular Diseases Systemic lupus

erythematosus Polyarteritis nodosum Progressive Systemic

Sclerosis (scleroderma) Dermatomyositis

Hyperviscosity / Hypercoagulability states Multiple myeloma Waldenstrom’s

macroglobulinemia Sickle cell disease Leukemia

Embolic Disorders Sepsis Long bone fracture Atheromata Phlebitis

Anemia HIV Medications

I generally ask about diabetes and put a BP cuff on everybody who shows up with a CWS and then look further down the list if necessary.

HIV RetinopathyCotton Wool Spots as a Solitary Finding

Cotton-wool spots, often as a solitary finding. In any patient with this finding, who has neither HBP or DM, and who has risk factors for HIV, a work-up is indicated.

Cotton-wool spots occur in approximately 50 to 60% of patients with advanced HIV disease and are the earliest and most consistent finding in HIV retinopathy

Interferon RetinopathyCotton Wool Spots as a Solitary Finding Cotton-wool spots,

may occur with use of interferon for treatment of Hep-C/ MS. Hep-C patients often have risk factors for HIV/AIDS. If the patient reports taking interferon consider the retinal findings a side-effect of the drug before assuming HIV+

Cotton-Wool SpotsTrypsin-digest showing area of cotton-wool spot

Cytoid Bodies

Note swelling of retina, producing NFL elevation and deeper retinal layer compression.

Staining properties “cell-like” but “nuclei” do not stain blue Hence these structures that look like cells are called cytoid

bodies and it is a cluster of cytoid bodies in a focal area of swollen retina that corresponds to a CWS.

Cytoid Bodies

Cytoid Bodies are equivalents of the neurobiologist’s Cajal’s nodes

Blue arrows point to normal diameter axons

Cytoid bodies

Interruption of Axoplasmic Flow - mitochondria and membrane whorls

The Pseudonucleus

Note many blown out mitochondria and absence of nuclear membrane around area that represents the pseudonucleus seen by light microscopy.

Rethinking Cotton Wool Spots

Why cotton wool spots should not be regarded as retinal nerve fibre layer infarcts. D McLeod British Journal of Ophthalmology 2005;89:229-237.

If a CWS is truly an infarction of the nerve fiber layer, as is often taught, the legacy of these lesions would have to be substantial sectorial areas of field loss and that almost never happens.

Rethinking Cotton Wool Spots

Why cotton wool spots should not be regarded as retinal nerve fibre layer infarcts. D McLeod British Journal of Ophthalmology 2005;89:229-237.

Tso and Jampol’s definition of a CWS is “a disturbance of both retrograde and orthograde axoplasmic transport...due to focal retinal ischaemia”

But the presence of cytoid bodies shows us that there is some true infarction and not just ischaemia

Rethinking Cotton Wool Spots

Why cotton wool spots should not be regarded as retinal nerve fibre layer infarcts. D McLeod British Journal of Ophthalmology 2005;89:229-237.

Note the CWS develops not within but at the edge of the area of perfusion compromise.

Also note reduction in size and more granular appearance with time.

3 hr 3 days

3 weeks

So what is happening?

At the very center of the swollen cotton wool mass in the retina there are clearly some truly infarcted axons (cytoid bodies) but not enough to be easily documented on visual fields. Most of the mass is only ischemic and if the vascular supply is reestablished, the ischemic area resolves and the CWS disappears clinically.

Legacy of the Cotton Wool Spot

If all of this area was truly infarcted the patient would have complete loss of his inferior visual field and he had no loss.

Legacy of the Cotton Wool Spot

Dissecting the Retina with an Ophthalmoscope Large vessels

in NFL.If a lesion covers a

vessel it has to be in the NFL. If the vessel crosses the lesion, the lesion is deeper, most likely in OPL, expanding to other deeper layers.

Capillary beds Superficial in ganglion cell layer Deep at junctionof INL/OPL

Retinal Microvasculature

Capillary beds Striate hemorrhagein NFL & ganglion cell layer Dot/Blot hemorrhage andhard exudates in OPL

Retinal Microvasculature -Relationship to retinal lesions

Foveal Avascular Zone The CRA supplies

retinal layers from the internal limiting membrane down to the INL/OPL junction.

Except for the internal limiting membrane, all of the layers dependent upon the CRA are absent in the FAZ.

OPL = Nerve Fiber Layer of Henle

Hard Exudate:

Yellow punctate lesions below the levels of the retinal vessels.

Hard Exudates are found most often in diseases increasing vascular permeability affecting capillaries and veins, rather than arterioles.

They are lipoprotein edema residues that initially develop in the outer plexiform layer.

Diabetic retinopathy Coat's disease◦ Capillary hemangioma of the

retina Leber’s stellate neuro-

retinitisBut what about their presence

in Hypertension - an arterial disease?

Hard Exudate Patterns:

They can also occur in a circinate pattern

Massive exudation in Coats Disease

Hard Exudate: Macular vs Non-MacularOPL in the Macular Region = Nerve Fiber Layer of Henle

A/V Crossing A/V NickingBut what about their presence in Hypertension - an arterial disease?

Retinal Capillaries

Only 6-10 m in size RBC is 7 m

Structure: Continuous

endothelium Basal lamina Pericytes (mural

cells)

The Trypsin Digest Method

Source: Yanoff and Fine

Diabetic Microaneurysms

Trypsin digests show loss of pericytes from the walls of the microvasculature.

Abortive attempts at neovascularization?

Less common in the peripapillary region where there are fewer vessels of the type from which these lesions develop.

Roth Spot (White-centered Hemorrhage) - SBE Named for Moritz Roth,

Swiss physician, 1849-1914) originally as pathognomonic of subacute bacterial endocarditis.

The more generic term white-centered hemorrhage (the original term coined by Roth), is commonly used for such lesions caused by other than SBE.

Roth Spot (White-centered Hemorrhage)

Differential includes: Anemia or CO poisoning leukemia retinal phlebitis Candida albicans

infection vascular diseases collagen diseases bacterial sepsis shaken-baby syndrome Can also be seen in

diabetic retinopathy and hypertensive retinopathy

Roth Spot (White-centered Hemorrhage) - Leukemia

Roth Spot (White-centered Hemorrhage)Shaken Baby Syndrome -SBS

White-centered Hemorrhages in SBS Under current reporting laws, when retinal

hemorrhages (often white-centered) and subdural hematomas are found in a child, there is an immediate referral to child protective services unless the caretaker has story that comports with a 2-3 story fall or 35 mile an hour unrestrained car accident. A determining factor of whether a child receives a diagnosis of "SBS" or not (and whether a caregiver is charged) is the believability of the story.

What is the White Center? In SBE, white center was assumed to be the

embolus dislodged from the infected heart valve leaflet in SBE.

In leukemia, the white center was presumed to represent a nidus of leukemic white cells

But serial section of white centered hemorrages from all know causes show a large, fibrin-laden thrombus at the center of each lesion.

Why do these thrombi reach a size that is ophthalmoscopically visible?

Roth Spot

White, fibrin laden thrombus lies at the center of the hemorrhage

Bruch’s Membrane

a. Basal lamina of the RPE

b. Anterior collagenous (cuticular) layer

c. Elastic layer

d. Posterior Collagenous layer

e. Basal lamina of the choriocapillary endothelium

Breaks in Bruch’s Membrane

Any break in Bruch’s Membrane can give rise to a SRNVM SRNVM

Drusen - from the German word for gland or granular nodule

Commonly present in all ages in non-macular areas

The incidence and prevalence of hard drusen is not age related.

Hard drusen in the macula are not associated with increased risk for the development of choroidal neovascularization.

Almost always have distinct and well-defined border - unlike hard exudates.

Fluorescein angiogram usually demonstrates pin-point window defect.

Hereditary or Dominant Familial Drusen Hereditary drusen are an

autosomal dominant inherited disease that shows complete penetrance and variable expression.

Leads to an accumulation of metabolic break-down deposits from the retina and from the retinal pigment epithelium within the inner collagenous layer of Bruch's membrane.

Apart from the genetics and family history, familial drusen are characterized by the earlier appearance of drusen (at 20 to 30 years of age), a symmetrical distribution pattern is found O.U. There is a distinctly earlier reduction in visual acuity (50 years of age).

In 1925 Vogt described a family from the Leventine valley in the Ticino canton of southern Switzerland. This disease has had many names, including dominant radial drusen, Doyne's honeycomb choroiditis, and Malattia Leventinese.

Hereditary or Dominant Familial Drusen

55 year old white female, non-smoker

Family history of ARMD

Four routine exam VA cRx 6/6-2 Both eyes present

a similar and symmetrical pattern

HardDrusen -

Drusen Diminished capacity to catabolize

photoreceptor material.

SoftDrusen -

Their presence increases risk of development of SRNVM

Drusen

Drusen that are not Drusen Optic Nerve Drusen Symptoms: mostly asymptomatic, but

may present with visual field defects, decreased visual acuity, or transient obscuration of vision.

Signs: Discrete, multiple, amorphous or partly calcified hyaline bodies located anterior to the lamina cribrosa

Buried hyaline bodies in children or young people may simulate papilledema

Superficial drusen appear as autofluorescent bodies that are visible on fundus photographs using appropriate filter prior to fluorescein dye injection

As the progression of the drusen interferes with the blood supply of the optic nerve, several conditions may result.

Giant Drusen of the Disc in (Tuberous Sclerosis) - juvenile pilocytic

astrocytoma