Ординатура / Офтальмология / Английские материалы / Ocular Pathology_6th edition_Yanoff, Sassani_2009

A

C

E

C.Early, anterior chamber angle neovascularization causes a secondary open-angle glaucoma that progresses rapidly to a closed-angle glaucoma caused by peripheral anterior synechiae.

As the fibrovascular tissue on the anterior iris surface contracts, ectropion uveae may develop. The new blood vessels tend to bleed easily, hence the misused

B

D

Fig. 15.5 Neovascularization of iris. A, Clinical appearance of rubeosis iridis. Histologic section (B) and scanning electron microscopy (C) of another case show peripheral anterior synechia, secondary angle closure, and tissue anterior to the anterior border layer of the iris; the last, which constitutes iris neovascularization, is shown with increased magnification in D and E. (C and E, Courtesy of Drs. RC Eagle, Jr and JW Sassani.)

and poor term hemorrhagic glaucoma; neovascular glaucoma is the preferred term so as not to confuse the entity with glaucoma secondary to traumatic hemorrhage. Even without the development of iris neovascularization, an increased incidence of both primary openand closed-angle glaucoma exists in diabetes.

CILIARY BODY AND CHOROID

I.Basement membrane of ciliary pigment epithelium (external basement membrane of ciliary epithelium; Fig. 15.6)

A.The multilaminar basement membrane of the pigment epithelium is di usely thickened in the region of the pars plicata.

B.The di use thickening of the external basement membrane of ciliary pigment epithelium in diabetic patients is di erent from the “spotty” or “patchy” thickening that may be seen in nondiabetic subjects.

II. The multilaminar basement membrane of ciliary nonpigmented epithelium (internal basement membrane of ciliary epithelium) is not a ected.

III.Fibrovascular core of ciliary processes (see Fig. 15.6)

A.Fibrosis results in obliteration of capillaries in the “core” of the ciliary processes.

B.The capillary basement membrane is often significantly thickened.

IV. Choriocapillaris, Bruch’s membrane, and retinal pigment epithelium (Figs 15.7 and 15.8)

A.Periodic acid-Schi –positive material thickens and may partially obliterate the lumen of the choriocapillaris in the macula.

B.The cuticular portion of Bruch’s membrane (basement membrane of the retinal pigment epithelium; basal laminar-like deposits) may become thickened, and the lumen of the choriocapillaris narrowed by endothelial cell proliferation and basement membrane elaboration.

The incidence of choriocapillaris degeneration is approximately fourfold greater in diabetic patients than in nondiabetic subjects.

C.Drusen are common.

D.Scanning electron microscopy of choroidal vascular casts shows increased tortuosity, dilatation and narrowing, hypercellularity, vascular loop, and microaneurysm formation, “dropout” of choriocapillaris, and formation of sinus-like structures between choroidal lobules.

V.Arteries and arterioles of choroid (see Figs 15.7 and

15.8)

Arteriosclerosis occurs at a younger age in diabetic patients than in the general population.

1.The incidence increases sharply beyond the 15th year of the disease.

2.The change is reflected in atherosclerosis and arteriolosclerosis of the choroidal vessels.

NEUROSENSORY RETINA

I.The cause(s) of DR,Table 15.1 (see also discussion of PDR later in this section)

A.Although DR is usually discussed relative to the characteristic and clinically apparent vascular changes, recent evidence suggests that DR involves alterations in

all of the retinal cellular elements, including: vascular endothelial cells and pericytes, glial cells including macroglia (Müller cells and astrocytes) and microglia, and neurons, including photoreceptors, bipolar cells, amacrine cells, and ganglion cells (Table 15.2, p. 607). Each of these elements makes unique contributions to visual function, and participates in multiple homeostatic relationships to the other cellular elements.

B.Damage to multiple retinal neuronal elements through apoptosis, and accompanying glial cell reactivity and microglial activation, suggests that DR might be classified as a neurodegenerative disorder, and not simply as a vasculopathy.

Support for the concept of a neurodegenerative process in diabetes is found in the fact that neurovisual tests are abnormal in type 1 diabetic individuals prior to the onset of clinically apparent retinopathy. Viewed from this perspective, it is doubtful that the entity that we call “diabetic retinopathy” is the manifestation of a single pathophysiologic disturbance or of the malfunction of one cell type. Rather, as can be seen in Table 15.2, multiple pathophysiologic mechanisms come into play in DR, including structural alterations, cell death, inflammation, cellular proliferation, and atrophy. These apparent alterations must require the participation of numerous biologically active mediators. For example, in DR advanced glycation end products (AGEP) and/or lipoxidation end products form on the amino groups of proteins, lipids, and DNA, and may impact the retina by modifying the structure and function of proteins and/ or cause intramolecular and intermolecular cross-link formation. AGEP not only alter structure and function of molecules, they also increase oxidative stress. AGEP with polyol pathway activation may mediate the direct impairment of retinal endothelial cell barrier function caused by high glucose levels.

C.Apoptosis probably contributes to retinal ganglion cell death in DR and glial cells may modify the expression of such apoptosis.

D.Given the multiple pathways contributing to the development of DR, gene therapy holds promise for modifying key contributing mechanisms.

II.The diagnosis of DR—the best way to diagnose DR is by means of a thorough fundus examination through a dilated pupil.

Ancillary studies can be very helpful in demonstrating the scope of retinal involvement. For example, retinal thickness, as measured by the Retinal Thickness Analyzer, has been found to be abnormal diffusely in the retina and not just in the areas exhibiting clinically apparent retinopathy.

The vascular lesions in diabetes are not uniformly distributed across the retina. Microaneurysms, acellular capillaries, and pericyte ghosts are more numerous in the temporal retina than in the nasal retina; however, retinal capillary basement membrane thickness does not exhibit such regional variation.

III.Specific constellation of vascular findings—clinical BDR A. Loss of capillary pericytes (see Fig. 15.1)

A

r

B

Fig. 15.7 Choroidopathy. A, Histologic section of the foveomacular region shows diffuse thickening of choroidal vessels, especially involving the choriocapillaris, which are partially occluded by periodic acid–Schiff-positive material. B, Electron micrograph shows choroidal arteriole apposed to characteristic basement membrane material of outer layer of Bruch’s membrane. Note red blood cell (r) in small lumen of vessel. Endothelial cells swollen and junctional attachments (arrows) present. Smooth-muscle cells in arteriole wall also present.

Capillary pericytes probably contribute to the mechanical stability of the capillary wall.

1.In the normal retinal capillary, the pericyte-to- endothelial-cell ratio is 1 :1.

2.In the diabetic retinal capillary, the pericyte-to- endothelial-cell ratio is less than 1 :1 because of a selective loss of pericytes.

Pericytes have a contractile function, regulate microvascular retinal blood flow, are excitable cells, and react to several vasoactive substances (e.g., norepinephrine and histamine). Pericytes contain aldose reductase, and show the presence of the sorbitol pathway. They may influence the neural retinal microvasculature through their production and release of prostacyclin. The viability of cultured retinal capillary pericytes is decreased by high concentrations of glucose, probably by inhibiting phospholipase C activity of pericytes through a guanine nucleotide-depen- dent and pertussis toxin-insensitive regulatory pathway. Glycolytic metabolites activate three of the major biochemical pathways implicated in the pathogenesis of DR. These pathways are the hexosamine pathway, the advanced glycation end product formation pathway, and the diacylglycerol–protein kinase C pathway. Benfotiamine, a thiamine derivative, inhibits these three pathways simultaneously, and prevents DR in experimental animals.

3.Pericyte death is accompanied by morphologic nuclear changes and lack of inflammation characteristic of apoptosis (see p. 23 in Chapter 1).

Activation of nuclear factor-kappaB, induced by high glucose in diabetes, may regulate a proapoptotic program in retinal pericytes.

Evidence suggests that hyperglycemia followed abruptly by euglycemia triggers the process of apoptosis, resulting in retinal capillary pericyte death. This finding explains why DR sometimes develops, or accelerates rapidly, in patients who had been under poor or moderate control, and are placed rapidly on tight, excellent control.

B.Capillary microaneurysms (Figs 15.9 and 15.10)

1.Many more retinal capillary microaneurysms

(RCMs) are detected microscopically and by fluorescein angiography than are seen clinically with the ophthalmoscope.

Optical coherence tomography (OCT) may provide a noninvasive tool for the detection of early diabetic retinal changes in patients lacking clinically apparent retinopathy. Mean macular thickness, as measured by OCT, correlates with visual acuity in DR. Retinal thickness is increased in diabetic individuals without clinically apparent retinopathy compared to nondiabetic control subjects. In individuals with type 2 diabetes and mild nonproliferative retinopathy, areas of increased retinal thickness are associated with retinal vascular leakage at those sites. Similarly, perimetry can provide more useful information than visual acuity testing relative to functional loss in diabetes.

2.An increase in the number of RCMs can be directly correlated with the loss of pericytes.

3.RCMs are formed in response to a hypoxic environment in which abortive attempts at neovascularization or regressed changes, or both, have been made in a previously proliferating vessel.

Aldose reductase inhibitors (clinical trials in retinopathy and neuropathy thus far have been unsuccessful)

Aspirin (ineffective in the Early Treatment Diabetic Retinopathy Sudy, but did not increase vitreous hemorrhage; therefore not contraindicated in patients with diabetes who require it for other reasons); corticosteroids (intravitreal injection or slow-release implants for macular edema now being tested)

Clinical trials of a protein kinase Cβ isoform inhibitor in retinopathy have thus far been unsuccessful

Antioxidants (limited evaluation in clinical trials)

Altered expression of critical gene or genes

Apoptotic death of retinal capillary pericytes, endothelial cells

VEGF

PEDF

Growth hormone and IGF-1

May be caused by hyperglycemia in several poorly understood ways. May cause long-lived alteration of one or more critical cellular pathways

Reduces blood flow to retina, which reduces function and increases hypoxia

Increased by retinal hypoxia and possibly other mechanisms; induces breakdown of blood– retinal barrier, leading to macular edema; induces proliferation of retinal capillary cells and neovascularization

Protein normally released in retina inhibits neovascularization; reduction in diabetes may eliminate this infection

Permissive role allows pathologic actions of VEGF; reduction in growth hormone or IGF-1 prevents neovascularization

None at present

None at present

Reduction of VEGF by extensive (panretinal) laser photocoagulation; several experimental medical therapies being tested

PEDF gene in nonreplicating adenovirus introduced into eye to induce PEDF formation in retina (phase I clinical trial ongoing)

Hypophysectormy (now abandoned); pegvisomant (growth hormone receptor blocker); (brief clinical trial failed); octreotide (somatostatin analogue, clinical trial now in progress)

D.Arteriolovenular connections (“shunts”: actually, collaterals; Fig. 15.12)

1.Arteriolovenular connections (collaterals) are secondary phenomena (i.e., secondary to the surrounding environmental hypoxic stimulus).

2.The arteriolovenular connections have a decreased rate of blood flow, unlike true shunts.

E.Other findings

1.Often, an irregular, large foveal avascular zone is present (its irregularity and greater size with BDR are even more pronounced with PDR).

TABLE 15.2 Diabetic Alterations in Retinal Cellular

Elements

Modified from Gardner TW et al. Diabetic retinopathy: More than meets the eye. Surv Ophthalmol 47 (Suppl 2):S253, © Elsevier, 2002.

2.Diabetic patients show an abnormal macular capillary blood flow velocity, and decreased entoptically perceived leukocytes, over age-matched nondiabetic subjects. Conversely, choroidal blood flow is significantly decreased in the foveal region, particularly in diabetic macular edema (DME).

a.Pulsatile ocular blood flow is una ected in early

DR, increases significantly in eyes with moderate to severe nonproliferative DR, and decreases following laser treatment of PDR.

3.Partitions of the larger retinal venules by a double layer of endothelial cells anchored to a thin basement membrane are associated with the formation of venous loops and reduplications that are caused

by gradual venous occlusion.

IV. Exudative retinopathy

A.“Hard”or “waxy”exudates (Fig. 15.13; see also Figs 15.9 and 15.12)

1.Hard or waxy discrete exudates are collections of serum and glial–neuronal breakdown products located predominantly in the outer plexiform (Henle) layer.

One of the earliest changes in the neural retina in diabetic patients, often before BDR is evident clinically, is a breakdown of the blood–neural retinal barrier in the retinal capillaries. Fluorescein angiography and vitreous fluorophotometry can show “leakage” of fluorescein from retinal capillaries in diabetic patients who do not show signs of DR when examined by conventional clinical methods. In patients who have BDR, elevated serum lipids are associated with an increased risk of retinal hard exudates.

2.The discrete exudates are removed by macrophages in 4 to 6 months; it may take a year or more if the exudates are confluent.

3.When they are distributed around the fovea, hard exudates may form a macular “star.”

Although macular edema is common in diabetic patients, macular star formation is uncommon, unlike in grades III and IV hypertensive retinopathy, where a macular star is quite common.

B.Macular edema

1.Clinically significant macular edema (CSME) is the greatest single cause of vision impairment in diabetic patients.

a.The overall incidence of CSME is approximately 3% to 8% in the diabetic population after 4 years’ follow-up from the baseline examination.

b.The greater incidence is associated with younger age or more severe DR at the baseline examination, increased levels of glycosylated hemoglobin, increased duration of the diabetes, and an absence of posterior vitreous detachment.

c.Systemic factors that can contribute to CSME in diabetes include poor metabolic control of the diabetes, elevated blood pressure, intravascular

fluid overload, anemia, and hyperlipidemia.

Fluid overload is relative, and may reflect decreased serum oncotic pressure, such as from decreased serum albumin.

2.Morphologic evidence suggests that macular edema may be caused by functional damage to the retinal vascular endothelium (e.g., hypertrophy or liquefaction necrosis of endothelial cells of the retinal capillaries or venules; see Fig. 15.11); pericyte degeneration probably also plays a role.

a.Fluid leaks out of the retinal vessels, enters

Müller cells, and causes intracellular swelling.

b.Mild to moderate amounts of intracellular fluid collections in Müller cells may result in macular edema (Fig. 15.14), a reversible process.

c.Excessive swelling (ballooning) and rupture or death of Müller cells produces pockets of fluid and cell debris (i.e., cystoid macular edema), a process that may be irreversible.

d.Adjacent neurons undergo similar changes secondarily.

e.Intravitreal steroid injections hold promise for the treatment of CSME. The success of this therapy supports the possibility that inflammatory mechanisms may play a significant con-

tributory role in the development of CSME.

Nevertheless, other mechanisms are probably also pathogenic in CSME because vitrectomy with internal limiting membrane peeling can be an e ective treatment.

1.Support for hypoxia as a causative or contributing factor in the pathogenesis of CSME is found in the fact that supplemental inspired oxygen can improve DME.

2.The presence of a cilioretinal artery may worsen DME.

C.Microcystoid degeneration of the neural retinal macula (see Fig. 15.14)

1.Exudates or edema fluid, or both, may cause pressure atrophy of the neural retina or enlargement of the intercellular spaces, and result in microcystoid degeneration, especially in the macular area.

2.Microcystoid neural retinal degeneration may progress to macular retinoschisis (cyst), and even partial (inner layer of schisis) or complete macular hole formation.

D.“Soft” exudates or “cotton-wool” spots (see Figs 11.9, 11.11, 11.14, and 15.12)

1.The cotton-wool spot observed clinically is a result of a microinfarct (coagulative necrosis) of the nerve fiber layer of the retina and is not a true exudate.

2.They are present most commonly in the preproliferative or early part of the proliferative stage of DR, especially during a phase of rapid progression.

3.Cotton-wool spots are formed at the edges of microinfarcts of the nerve fiber layer of the neural retina (see p. 404 in Chapter 11) and represent back-up of axoplasmic flow.

4.Cytoid bodies are the characteristic histologic counterpart of the cotton-wool spot, and are caused

by the swollen ends of ruptured axons in the nerve

fiber layer in the infarcted area.

5.Cotton-wool spots usually disappear from view in weeks to months.

V.Hemorrhagic retinopathy (Fig. 15.15).The clinical appearance of a retinal hemorrhage is determined by the microanatomy of the retinal layer in which the hemorrhage is located.

A.Dot-and-blot hemorrhages

1.Dot-and-blot hemorrhages are relatively small hemorrhages located in the inner nuclear layer that spread to the outer plexiform layer of the neural retina.

2.In three-dimensional view, they appear serpiginous.

B.Splinter (flame-shaped) hemorrhages are small hemorrhages located in the nerve fiber layer.

C.Globular hemorrhages are caused by the spread of dot- and-blot hemorrhages in the middle neural retinal layers.

D.Confluent hemorrhages are large and involve all of the neural retinal layers.

E.Massive hemorrhages may break through the internal limiting membrane to extend beneath or into the