Ординатура / Офтальмология / Английские материалы / Basic Sciences in Ophthalmology_Velayutham_2009
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Macular Holes
Can be lamellar or full thickness. Clinically, appear as discrete, small round areas of retinal discontinuity in the fovea. Epiretinal membrane and small drusen are often present. Hole formation is due to detachment caused by tangential vitreous traction in the macular regions.
HPEMacular holes show rounded margins. Sometimes proliferated RPE binds the margins creating a chorioretinal adhesion. Epiretinal membranes may be present. Photoreceptor segments extend close to the hole margins.
Hereditary Retinal Dystrophies
(Vitreoretinal Dystrophies)
1)Lattice degeneration: The term is derived from lattice like pattern of criss crossing sclerotic vessels seen in 12% of lesions. There are oval areas of retinal thinning, which are sharply demarcated, circumferentially oriented and located anterior to the equator.
HPEFocal areas of retinal thinning seen. Inner retinal layers are atrophic. Internal limiting membrane is absent.A pocket of liquefied vitreous overlies the discontinuity in internal limiting membrane. Thick walled vessels are present. RPE shows hypertrophy, hyperplasia and intraretinal migration. The firm vitreoretinal adhesions to the margins of atrophic retina predispose to tractional retinal breaks and rhegmatogenous retinal detachment.
2)Familial exudative vitreoretinopathy: It resembles Coat’s disease or retinopathy of prematurity. Retina has preretinal acellular fibrous membranes peripherally with retinal traction and macular dragging. Later there is intraretinal exudation, leading to total detachment. Peripheral retina is avascular.
3)Stickler syndrome: Striking feature is vitreous degeneration with syneresis (optically empty vitreous cavity). Fundus shows perivascular pigmentation overlying atrophic RPE, lattice degeneration and retinal breaks.
HPEAdvanced cases show complete retinal detachment. Preretinal membrane extends through the retinal holes into the retrolental space.
4)Wagner disease: It shows degenerative fundus changes resembling retinitis pigmentosa and gliotic membrane formation, but without retinal detachment.
Photoreceptor Dystrophies
Retinitis Pigmentosa
Early symptom is decreased night vision (nyctalopia). Fundus shows RPE atrophy and characteristic bone spicule pigmentation arranged along retinal vessels, which are markedly narrowed. Waxy pallor of optic nerve is due to decreased vascularity. Macular edema, pre retinal membrane formation and optic disk drusen may be seen. Posterior subcapsular cataract may develop. HPEshows varying degrees of photoreceptor degeneration that initially affects the rods and ultimately the cones. Earliest changes occur in the equatorial
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zone and then extend peripherally and centrally. Nuclei of photoreceptor cells migrate outward with subsequent degeneration of photoreceptors and atrophy of outer nuclear layer. RPE proliferates and invades the atrophic retina and grows in the space around retinal vessels forming perivascular cuffs of intensely pigmented cells (evident clinically as bone spicule pigmentation) and also in small clusters.
The endothelial cells of the surrounding retinal vessels become thin and develop fenestrations. Vascular walls are thickened and gliotic. The remaining retina adheres to Bruch’s membrane. Cystoid macular edema, hole formation and epiretinal membrane may be seen. Gliosis is seen overlying the optic disc with retinal gliosis in advanced cases. Inner retina remains relatively more intact, but there is some loss of ganglion cells. Overlying vitreous contains pigment epithelial cells, uveal melanocytes, macrophages, retinal astrocytes and free melanin pigment.
Stargardt's Disease And Fundus Flavimaculatus: (Yellow
Spotted Fundus)
They are part of the same disease and are a type of inherited macular dystrophy. Clinically- Retina shows poorly defined yellow white linear or fish tail opacities at the level of RPE.
HPE- Opacification of RPE is due to massive accumulation of an abnormal lipofuscin like lipopigment, which is yellow brown in colour in the cytoplasm of the RPE cells which become intensely PAS positive. RPE cells are taller than normal and their nuclei are displaced towards the apex of the cells. Groups of enlarged RPE cells surrounded by smaller, relatively normal cells may be responsible for the yellow-flecked appearance of the fundus.
All the RPE cells contain yellow brown lipopigment but the lipofuscin is hidden by a relatively normal complement of apical melanin in the smaller cells. The pisciform aggregates of larger cells appear yellow because these grossly abnormal cells are relatively amelanotic. Macrophages or detached lipopigment laden RPE in the subretinal space could also contribute to the flecked retinal appearance. The massive accumulation of pigment probably contributes to RPE dysfunction and death of subfoveal RPE cells leads to photoreceptor degeneration and atrophic macular degeneration.
Vitelliform Dystrophy (Best’s Disease)
In the early stages of the disease, a striking yellow deposit, which is smooth and round, resembling the yolk of an egg, is seen at the macula or elsewhere in the posterior pole. Visual loss develops when the egg "scrambles" becoming irregular in appearance and chorioretinal scarring develops.
Lipofuscin accumulates within the apices of the RPE cells. In the macular region an acellular fibrillar material has been found beneath the RPE. This may represent disordered shedding of photoreceptor outer segment or diffusely
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impaired metabolism of RPE cells. Secondary subretinal neovascularisation may occur. Likely cause is a gene defect for a protein expressed in the photoreceptor outer segment. Pale macular lesions are seen in the adult form of vitelliform dystrophy, which is a retinal pigment epithelial dystrophy.
HPE - RPE may show atrophy and hypertrophy with fibrosis or retinal pigment epithelial nodular proliferation.
Pattern Dystrophies
They are congenital abnormalities of the RPE. Depending on the arrangement of pigment they are-
1)Butterfly shaped dystrophy.
2)Maculoreticular dystrophy.
Choroidal Dystrophies
There is primary selective atrophy of the choriocapillaris. Loss of the choriocapillaris in turn causes loss of RPE and outer retina. Junction between involved and uninvolved regions is sharp and abrupt. Involved areas are pale with prominent sclerotic choroidal vessels.
Gyrate Atrophy
It is due to defect of the enzyme ornithine aminotransferase found in mitochondrial matrix. Fundus shows confluent, sharply demarcated areas of depigmentation in the mid periphery.
HPE- Retina shows abrupt photoreceptor and pigment epithelial loss in the atrophic area with focal pigment epithelial hyperplasia.
Parsplana Cysts
They are innocuous acquired degenerative lesions seen in 1/3 rd of normal people above 70 years of age. They are found incidentally. They are formed by detachment of the inner nonpigmented layer of ciliary epithelium and contain hyaluronic acid in normal individuals.
Multiple pars plana cysts occur in patients with multiple myeloma. The cysts contain Bence Jones protein and on fixation appear as milky white opacification due to precipitation of protein.
HYPERTENSIVE AND ARTERIOSCLEROTIC RETINOPATHY
Arteriolar sclerosis and hypertension are separate phenomena, but usually occur together. They are graded separately from grade I to IV. Hypertensive retinopathy is due to vascular incompetence and breakdown of the blood retinal barrier. Acute severe elevation of blood pressure causes retinal arteriolar narrowing and focal vasospasm which when persistent causes necrosis of the muscular and endothelial coats of the vessels.
HPE- Shows endothelial damage with resultant retinal edema and necrosis of smooth muscle and insudation of fibrin rich plasma in the vessel wall. There
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may be exudation and even serous retinal detachment. Small exudates called edema residues may form a stellate pattern around the fovea (macular star figure). Retinal hemorrhages and papilledema are additional manifestations of hypertensive retinopathy.
Grade I - There is thickening of the arterioles so that the blood column appears narrower than normal.
Grade II - There is increased narrowing and focal spasm of the arterioles. Grade III - In addition there are hemorrhages at any level of the retina, cotton wool spots (microinfarctions of the nerve fibre layer)
and hard exudates that may form a macular star. Grade IV - All the above changes along with papilledema.
Fibrinoid necrosis caused by the insudation and accumulation of plasma proteins in vessel walls may affect retinal and choroidal vessels. Microinfarctions of the nerve fibre layer (cotton wool spots) occur due to occlusion of small damaged vessels. Occasionally larger areas of retina show infarction. Focal choroidal infarction with patchy proliferation of RPE is evident clinically as Elschnig spots and Siegrist lines (increased pigmentation along a sclerotic vessel) – unknown lesions.
Arteriolar Sclerotic Changes
Grade I - Subintimal hyaline deposition and thickening of the vascular wall (increased light reflex).
Grade II - Arteriolarvenular crossing defects are seen in addition.
Grade III and IV - Above changes and increased thickening of the arteriole, so that the blood column is narrowed.
The increased light reflex gives a coppery appearance to the vessel, "copper wire" change in grade III and "silver wire" change in grade IV. Low grade chronic hypertension induces fibrosis in the walls of retinal arterioles.
HPEthe vessels are encompassed by a thick mantle of collagenous connective tissue referred to as "onionskin".
Like the surrounding neurosensory retina, the walls of the healthy retinal vessels normally are transparent. Retinal vessels are seen as columns of pigmented RBCs filling the lumina. Progressive accumulation of connective tissue in the vessel walls in retinal arteriolar sclerosis gradually obscures the blood column. The light reflex is widened and imparts an orange or coppery hue to the arterioles (copper wire in grade III lesions).
If the process is prolonged and severe, perivascular fibrosis may totally hide the blood column and vessels appear as white lines (silver wire change) in grade IV lesions. Arteriovenous crossing defects (A-V nicking) results when the opaque walls of thickened arterioles obscure part of the underlying venules. This is because the arterioles and venules normally share a common adventitial sheath where they cross. So, with thickening and increased rigidity of arteriolar wall the venular wall is compressed. Clinically, this appears as a gap in the course of the venules where the arteriole crosses it.
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OPHTHALMIC PATHOLOGY OF DIABETES MELLITUS
Pathologic features of diabetes mellitus in the eye are due to two basic and partially interrelated mechanismsthickening of the basement membranes and ischaemia.
Thickening of basement membrane is due to the activation of aldose reductase by the persistently elevated glucose levels. Ischemia may result from the pathologic thickening of the basement membrane of the retinal capillary endothelium. The most severely affected ocular tissues are the retina, vitreous, choroid and corneal epithelium.
Diabetic retinopathy is the retinal manifestation of the generalized microangiopathy that occurs throughout the body in diabetes mellitus. Three forms are recognized clinically:
1)Background retinopathyinitial stage of diabetic retinopathy marked by retinal edema, hemorrhage, exudates and capillary microaneurysms.
2)Preproliferative retinopathyShows preponderance of soft exudates or cotton wool spots heralding progressive retinal ischaemia.
3)Proliferative retinopathyRetinal and vitreoretinal neovascularisation occurs, which predisposes to blinding complications like vitreous hemorrhage and tractional retinal detachment.
Diabetic retinopathy is a disorder of the retinal vasculature characterized by thickening of the endothelial basement membrane, loss of pericytes, micro aneurysm formation, capillary closure and neovascularisation. The clinical features of diabetic retinopathy-edema, exudates, hemorrhage and cotton wool spots are secondary to these retinovascular changes and are due to breakdown of the blood retinal barrier.
Primary Retinal Changes
1)Basement membrane thickening- Earliest change in the retinal vessels is thickening of the basement membrane of the capillary endothelium, which is evident by narrowing of the lumen of the vessel. Evidenced by increased PAS positive staining.
2)Loss of pericytes- is directly related to hyperglycemia. Normal retinal capillaries are composed of endothelial cells and pericytes in a ratio of 1:1. Endothelial cells have oval pale staining nuclei. Pericytes have round dark staining nuclei. Pericytes have contractile properties that regulate capillary caliber and the flow within the retinal microcirculation. They are found in capsules in the perivascular basement membrane. Pericytes are lost preferentially in the early stages of retinopathy thus permitting formation of hypercellular microaneurysms. Totally acellular areas of retinal capillary bed devoid of both endothelial cells and pericytes are also found. HPE of such areas reveals inner ischaemic retinal atrophy.
Retinal capillary pericyte loss results in retinal capillaries losing their ability to autoregulate, leading to changes in retinal blood flow. In addition,
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pericytes have an inhibitory effect on vascular endothelial proliferation, which is mediated by transforming growth factor beta. Loss of this inhibitory effect may stimulate endothelial cell proliferation and neovascularisation.
3)MicroaneurysmsEarliest recognizable clinical feature of diabetic retinopathy. Occur most abundantly in the posterior pole and surrounding acellular capillary beds. They are a potential site for plasma leakage, which can accumulate within the retina producing macular edema and lipid exudates. They consists of fusiform or saccular dilatations at the capillary level, 50 to 100 microns in size.
HPEMicroaneurysms progress from a hypercellular endothelially lined state to an acellular hyalinized state. They occur due to weakening of the capillary wall secondary to focal pericytes loss. Walls of microaneurysm may break down producing intraretinal hemorrhages.
4)Acellular capillaries (capillary closure) - Trypsin digest preparations of retina in diabetes reveal that portion of the capillary bed consists of acellular basement membrane tubes which are due to obliteration of the lumen of the vessel by muller cell processes gaining access to the inside of these acellular tubes.
5)Intraretinal microvascular abnormalities (IRMA) - they are flat, intra-retinal vessels that extend from the terminal arterioles and venules towards zones of acellular capillaries. They may be single vessels or may be arranged in branching patterns or arcades. They have a markedly increased number of endothelial cells.
6)NeovascularisationIt is the defining characteristic of proliferative diabetic retinopathy and may develop intraretinally, preretinally or on the optic nerve head. The latter two are important clinically because these are the sites where vitreous traction on the neovascularisation may occur and subsequently result in vitreous hemorrhage and tractional retinal detachment.
Angiogenesis or formation of new vessels is stimulated by hypoxia due to closure of the retinal capillary bed and is mediated by various growth factors and inhibitors present in the retina and vitreous. Factors that play a role in neovascularisation in diabetes are-
1)Vascular endothelial growth factor (VEGF).
2)Basic fibroblast growth factor.
3)Acidic fibroblast growth factor.
4)Platelet derived growth factor.
5)Insulin like growth factor.
6)Endothelial stimulating angiogenic factor.
7)Transforming growth factor beta.
8)Various inhibitors of neovascularisation.
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VEGF has been identified in ocular fluid from patients with active retinal and anterior segment neovascularisation. Neovascularisation originates from the venules and extends into the preretinal space. The new blood vessels become intimately associated with the collagen of the cortical vitreous.
The adherence of the adventitia of the new blood vessels to the vitreous collagen promotes preretinal and vitreous hemorrhage at the time of posterior vitreous detachment. The blood vessel growth is accompanied by the migration of other cellular elements into the vitreous cavity, many of which contains intracytoplasmic actin and is capable of cell-mediated contraction. Because the neovascular complex is tethered at one end by the retina and to the vitreous at the other, cell mediated contraction can result in tractional retinal detachments.
Secondary Retinal Changes
1)Edema and exudates: Retinal edema is due to leakage of plasma through microaneurysms and other vascular abnormalities. Water and electrolytes in the leakage are removed by RPE and retinal vascular endothelial transport mechanisms. But lipid remains in the retina in the form of "hard exudates". Microglial cells phagocytose lipid. Both edema and exudates are most abundant in the outer plexiform layer. Also present in inner nuclear and ganglion cell layer.
2)Hemorrhages: Hemorrhages in the nerve fibre layer of retina are linear because the extravascular blood becomes aligned parallel to the axons within this layer. Round dot-and-blot hemorrhages are seen in the nuclear and plexiform layer where they displace the neurons and glial cells and are limited at the periphery by undamaged neuronal and Muller cells. Clinically preretinal or vitreous hemorrhage is the most important type of hemorrhage. This hemorrhage may initially be limited to the preretinal space, however, it usually diffuses into the vitreous cavity. Blood within the vitreous cavity is broken down into hemoglobin globules and ghost cells. The ghost cells gain access to the anterior chamber and result in ghost cell glaucoma.
3)Cotton wool spots: They are microinfarctions of the nerve fibre layer. The ganglion cell layer and nerve fibre layers are thickened by a sharply circumscribed lesion and contain cytoid bodies, which are globular structure 10-20 microns in diameter. After resolution of the cotton wool spots, inner retinal ischemic atrophy may produce a local area of retinal thinning.
4)Traction retinal detachment: Persistent traction on the retina by a partially detached vitreous or cell mediated contraction from preretinal neovascular complexes can result in
a)Schisis cavities within the retina.
b)Avulsion of a retinal vessel.
c)Detachment of the retina from the underlying RPE producing a tractional retinal detachment.
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With prolonged detachment of the retina, the photoreceptor layers atrophy and the glial cells proliferate.
Histopathology of diabetic retinopathy treatment following argon laser photocoagulation:
There is variable destruction of the inner retina, destruction of the RPE and occlusion of choriocapillaris. These lesions heal by proliferation of the adjacent RPE to heal the defect and by glial scarring. Bruch’s membrane is ruptured in few cases. Choroidal neovascularisation is a rare complication. Xenon photocoagulation results in full thickness retinal injury.
Surgical Treatment
Following vitrectomy to remove vitreous hemorrhage or to repair a traction detachment of the fovea, there is atrophy of the neovascular complexes on the optic nerve head and in the posterior retina. The peripheral vitreous is never completely removed. In some cases there is neovascularisation of the remaining anterior vitreousanterior hyaloidal fibrovascular proliferation, which can extend across the posterior lens capsule and be the source of post vitrectomy hemorrhage and anterior tractional retinal detachment.
Changes In Iris In Diabetes Mellitus
There is non-progressive neovascularisation, which usually starts near the pupillary border and in the angle producing mild ectropion uvea. Neovascularisation may be more severe after vitrectomy resulting in peripheral anterior synechiae formation and subsequent development of neovascular glaucoma,
HPEshows the presence of fine vessels on the anterior iris surface and ectropion uvea. With time the iris surface vessels may become covered with a basement membrane structure resembling Descemet's membrane. This membrane can extend across the trabecular meshwork creating a "pseudo angle". In chronic hyperglycemia, there is accumulation of glycogen in cystoid spaces within the iris pigment epithelium- lacy vacuolization.
Ciliary Body
There is thickening of basement membrane of the pigmented ciliary epithelium.
Choroid
Choroidal vascular changes in diabetes mellitus are-
a)Capillary dropout.
b)Beaded capillaries.
c)Arteriovenous anastomosis.
d)Neovascularisation.
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Cornea
There is thickening of the corneal epithelial basement membrane, which can predispose to sheet like desquamation of corneal epithelium during vitreoretinal surgery. Patients are predisposed to recurrent corneal erosions and healing of epithelial defects is prolonged.
Risk of Infection
Mucormycosis can complicate diabetes mellitus. Mucor is normally a saprophytic fungus and can become pathogenic in poorly controlled diabetics who are acidotic. Infection begins in the paranasal sinuses and invades the orbital tissues secondarily. It can cause central retinal artery occlusionunilateral or even bilateral.
Descriptive Terminology In Histopathology Reports
Acanthosis: Thickening of prickle cell layer of epidermis. It is a reactive phenomenon to underlying inflammatory, infectious or neoplastic processes. Acantholysis: Intercellular spaces between squamous cells are widened due to intercellular and intracellular edema.
Atrophy: Decreased thickness of epidermis or dermis.
Atypia: Abnormal atypical appearance of the nuclei of individual cells in a disease process. Nuclear enlargement, hyperchromasia, irregularity of nuclear outline, prominent nucleoli, coarse granularity of intranuclear chromatin and enlarged nuclear to cytoplasmic ratio.
Dyskeratosis: Abnormal premature keratinisation of epithelial cells. Normal keratin is elaborated at the epidermal surface by mature squamous epithelial cells.
Dysplasia: Disordered arrangement of epithelium. Term is applied to a population of cells and should not be used in reference to a single cell. Dysplastic epithelium is characterized by a disturbance of the normal keratinocytic maturation sequence and is a common finding in actinic keratosis.
The individual cells within a dysplastic population is not necessarily atypical. Hyperkeratosis: Increased thickening of the anucleate stratum corneum. Hyperplasia: Increase in the number of cells in any given tissue. Hypertrophy: Increase in cell size in any given tissue.
Papilloma: Any nipple shaped growth caused by an upward proliferation of subepidermal papillae e.g., seborrheic keratosis and verruca vulgaris. It shows fibrovascular core surrounded by acanthotic epithelium (Fig. 14.6).
Parakeratosis: Increased thickening of stratum corneum with incomplete keratinisation. It is a histologic evidence of rapid cell turnover. So epithelial cells retain their nuclei in contrast to hyperkeratosis. It is associated with underdevelopment or absence of the granular layer.
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Fig. 14.6: Verruca vulgaris showing hyperkeratosis, papillomatosis and acanthosis with fibrovascular core
Pseudo epitheliomatous (carcinomatous hyperplasia): Irregular downward extension of acanthotic epidermis that mimics carcinoma.
BENIGN LESIONS OF EYELID
Benign Epidermal Lesions
True cysts—they have a circumscribed cavity lined by some type of epithelium and a cyst lumen that collects desquamated cells, cellular debris and cellular products (sebum, keratin, hair).
Epidermal inclusion cyst (Epidermoid cyst, Infundibular cyst)
It is the most common cystic eyelid lesion. Due to occlusion of infundibulum adjacent to the eyelash or accidental or surgical trauma, there is a sequestrum of epidermis trapped beneath the epidermal layer. Viable surface epithelium continues to shed keratin flakes and desquamated cells into the expanding unilocular cyst lumen. Cyst is lined by surface epithelium. The chronic mechanical effect of the cyst enlargement flattens the epithelial lining and promotes pseudocapsule formation. If the cyst ruptures, it usually incites a host foreign body giant cell inflammatory reaction.
Milia
They are small epidermal inclusion cysts less than 2 mm in diameter that arise at the base of the infundibulum of vellus hairs at the level of sebaceous duct. Histologically, similar to epidermal inclusion cysts.