Ординатура / Офтальмология / Английские материалы / Basic Sciences in Ophthalmology_Velayutham_2009
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Ocular Pathology
INFLAMMATION
The inflammatory response involves a variety of specialized effector cells and a complex interplay of cells, mediators and biochemical reactions that protect the body against microorganisms. The inflammatory process includes mechanisms to repair and restore tissues damaged by foreign invaders, trauma or chemical and physical agents. The intact immune system, which is the corner stone of the inflammatory process, is effective in protecting us from potential invaders. This is evidenced by the wide spectrum of opportunistic infections and tumors that afflict patients who have AIDS.
Definition
Inflammation is defined as a localized protective response elicited by injury to or destruction of tissues by physical, chemical and biologic stimuli. The process serves to destroy, dilute and sequester the injurious agents and to partially isolate the injured tissue.
It is an expression of the host’s attempt to localize and eliminate metabolically altered cells, foreign particles, micro-organisms or antigens. It involves a complex series of eventsdilatation of arterioles, capillaries and venules resulting in increased blood flow and vascular permeability, exudation of fluid and plasma proteins and migration of leukocytes into the inflammatory region.
The suffix -itis is used to designate an inflammatory process. If several tissues are simultaneously involved the one that is most prominently or initially affected is designated first in the terminology.
“True” intraocular inflammatory processes must be separated from pseudoinflammatory processes in which the inciting agent is ischemic or neoplasia e.g. Pseudohypopyon produced by leukemia, retinoblastoma or pseudouveitis produced by anterior segment ischemic syndrome.
Intraocular inflammation is subdivided into acute, subacute and chronic. Acute inflammation begins within minutes of injury and lasts for several days or weeks before resolving.
There are five cardinal signs of acute inflammation:
1)Rubor or redness.
2)Calor or heat.
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Above two signs are caused by increased rate and volume of blood due to increased vascular permeability.
3)Tumor or swelling or edema is due to the exudation of the fluid and the cellular components of the blood into the extravascular space.
4)Dolor or pain is due to prostaglandin inflammatory mediators, which stimulates contraction of smooth muscle, e.g., Spasm of the ciliary muscle and sphincter muscles of the iris contributes to the pain of anterior uveitis.
5)Functio laesa or loss of function.
Effects of Increased Vascular Permeability
Aqueous humor normally is totally devoid of protein. When inflammation disrupts the blood ocular barrier, protein content rises. Inflammatory cells normally move with the convection currents in the aqueous. An absence of cellular convection currents may indicate clotting of fibrin rich aqueous in a patient with severe vascular permeability. Adhesions readily form in the fibrin rich milieu of ocular inflammation e.g., posterior synechiae and seclusio pupillae. Aggregates of inflammatory cells called keratic precipitates (KP) form on the posterior surface of cornea. KP may be small or large and lardaceous (mutton fat) as seen in chronic granulomatous inflammation.
Outline of Acute Inflammatory Response
Principal features are vasodilatation, increased blood flow, increased vascular permeability and exudation of blood proteins and leukocytes. Emigration of leukocytes into the inflammatory focus is divided into three stages:
1)Margination—leukocytes pass from the center of the vessel to contact the endothelial lining.
2)Adherence of white blood cells to the microvasculature.
3)Diapedesis or migration of leukocytes into the extra vascular space. Initially neutrophils are the predominant inflammatory cells. After 24 hours they are replaced by monocytes and macrophages. The inflammatory cells are attracted to the region of injured tissues by specific chemical mediators or chemotactic agents within the tissues- chemotaxis. Chemotaxis is followed by the process of phagocytosis, which shows three phases:
1)Attachment of phagocytes to the foreign antigenic particles.
2)Ingestion and intracellular degradation of the particle.
3)Extracellular release of the leukocyte degradation product.
The various chemical mediators of inflammation released during the process of extracellular exudation have specific actions that enhance the acute inflammatory response. Mediators that increase vascular permeability are histamines, serotonin, kinins, prostaglandins and platelet activating factors.
Cytokines are synthesized and secreted by inflammatory cells and include interleukins, interferons and colony stimulating factors. The balance of synthesis and degradation of these mediators of inflammation helps to determine the nature, time course and severity of the inflammatory response.
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Thus, acute inflammation may subside with complete resolution and the area of inflammation is healed by scarring or abscess formation. The inflammation may persist or may change and progress to subacute or chronic inflammation.
Subacute inflammation: Destructive force or inciting agent continues to elicit a modified inflammatory response over a period of weeks or months.
Chronic or recurrent intraocular inflammation: Usually follows an acute or subacute form. Some inflammatory process presents a chronic appearance throughout their entire course.
Histopathologically inflammation is categorised as acute or chronic, based on the type of inflammatory cells found in the tissue or exudates. Acute inflammation is characterized by presence of polymorphonuclear leukocytes and pus (exudates composed of numerous polymorphs and tissue destruction). Presence of pus is called suppurative inflammation. Hypopyon is seen in acute keratitis and endophthalmitis. Vitreous abscess is seen in acute purulent endophthalmitis.
Chronic inflammation may be nongranulomatous or granulomatous. Chronic non-granulomatous inflammation shows lymphocytes and plasma cells and denotes involvement of the immune system. Presence of numerous eosinophils is suggestive of an allergic reaction or parasitic infestation. Mast cells or tissue basophils can be seen in allergic disorders, e.g., vernal conjunctivitis and also in neurofibromas.
Chronic granulomatous inflammation is characterized by activated macrophages or epithelioid histiocytes and inflammatory giant cells. Epithelioid cells are derived from blood monocytes. It refers to inflammation in which granulomas are present and occurs in response to certain infectious agents. Granuloma is a mass or nodule less than 2 mm in diameter, composed of macrophages known as epithelioid cells and may contain multinucleated giant cells. HPE- the lesion is surrounded by a rim of lymphocytes. Actively growing fibroblasts and small capillaries may be seen within a granuloma.
Chronic granulomatous inflammation can be induced by—
1)Infection—Bacteria (tuberculosis, syphilis, leprosy), Mycoses (candida, toxoplasmosis, histoplasmosis, cryptococcosis), Parasites (toxocara, cysticercosis) (Fig. 14.1).
2)Reaction to autologous intraocular tissue—phacoanaphylactic endopthalmitis, resolving vitreous hemorrhage, cholesterol granuloma, sympathetic ophthalmia, chalazion (lipogranulomatous inflammation).
3)Immunological processes of unclear etiologysarcoidosis, Still’s disease, scleritis in rheumatoid arthritis, juvenile xanthogranuloma.
4)Intraocular foreign bodies.
Three histological patterns are seen in granulomatous inflammation:
•Nodular pattern seen in tuberculosis.
•Zonal pattern seen in phacoanaphylactic uveitis.
•Diffuse pattern seen in sympathetic ophthalmia (Fig 14.2).
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Fig. 14.1: Shows cystic structure with a scolex showing papillary infoldings and hooklets
During inflammation epithelioid cells aggregate forming giant cells. Inflammatory giant cells are of three types:
1)Langhan's giant cell seen in tuberculosis. Nuclei are arranged around the periphery (Fig. 14.3).
2)Foreign body giant cellnuclei are randomly arranged throughout the syncytium. May contain foreign material.
3)Touton giant cellshows a rim of cytoplasm that contains lipid peripheral
to the ring of nuclei.
Granulation tissue forms during the reparative phase of inflammation and plays an important part in wound healing. Granulation tissue is composed of proliferating capillaries, activated fibroblasts with contractile properties called
Fig. 14.2: Dalen Fuchs nodule showing collection of epithelioid histiocytes beneath the RPE
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Fig. 14.3: Tuberculous endophthalmitis—shows numerous caseating epithelioid cell granulomas in vitreous and sclera
myofibroblasts and a mixture of polymorphs, lymphocytes, plasma cells, macrophages and eosinophils. Myofibroblasts are involved in scar contraction. Pyogenic granuloma is an exuberant proliferation of granulation tissue seen after surgery or minor trauma.
Sequelae of Ocular Inflammation
Intraocular fibrosis and membranes are caused by the organization of inflammatory debris. Contraction of cyclitic membrane causes tractional detachment of ciliary body and retina. Disorganization and destruction of intraocular structures results in ocular hypotony and shrinkage. Clinically the term "phthisical" refers to blind hypotonous eyes that are soft, partially collapsed and have vague cuboidal shape due to rectus muscle traction.
Pathologically, eyes that are markedly atrophic and disorganized and have thickened folded sclera are designated phthisis bulbi. Interior of such phthisical eyes usually are filled with scar tissue. Intraocular structures are unrecognizable.
The term "atrophic bulbi with shrinkage" is used if intraocular structures can be identified. Intraocular ossification (osseous metaplasia of the retinal pigment epithelium) may be seen in atrophic and phthisical eyes that have chronic retinal detachment.
Aggregates of inflammatory cells called Keratic precipitates form on the posterior surface of cornea. KP may be small or large and lardaceous. The latter are called mutton fat keratic precipitates and are seen in eyes with chronic granulomatous inflammation.
Phases of The Inflammatory Process
All inflammatory processes show the following phases
1)Exudative phasecells and serum proteins migrate from intravascular space to extravascular space.
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2)Acute adaptive phase—there is cytotoxicity and tissue necrosis. Varies in severity and duration. Ultimately progresses to sub acute or chronic inflammation.
3)Reactive phase of homeostasis restoration. There is reactive proliferation and restoration of tissue substance with newly formed parenchymal tissue, scarring, fibrosis or granulation tissue.
Exudation
In anterior uveitis, there is exudation of lymphocytes, plasma cells or polymorphs into the anterior chamber-Hypopyon.
Inflammatory exudate in the stroma of the iris inhibits free movement of the iris-causes miosis in iritis.
Inflammation of the ciliary body leads to decreased production of aqueous humor and ciliary muscle spasm.
Posterior uveitis results from exudation into the vitreous.
Bacterial infections cause diffuse infiltration of the vitreous with extensive liquefactive necrosis.
In contrast, mycotic infections cause multifocal microabscesses. Exudation beneath the retina or choroid may result in retinal and choroidal
detachments. Serous detachment of the sensory retina results in degeneration of photoreceptors and outer retinal layers, due to reduction of oxygen and nutritional supply from the choriocapillaris.
Edema also may be present within the retina. Cystoid macular edema results when fluid accumulates in the outer plexiform layer or Henle’s nerve fiber layer. Retinal vasculitis and perivasculitis are common features associated with intraocular inflammatory processes.
Cytotoxicity and Tissue Necrosis
Cytotoxic immunologic mechanisms while destroying noxious agents often result in some destruction of normal host tissue.
Inflammatory exudates in the anterior chamber often become adherent to the corneal epithelium and can cause focal destruction of the corneal epithelium with swelling of the corneal stroma.
In granulomatous inflammation or viral induced inflammation, the stroma and pigment epithelium of the iris and ciliary body show sectoral or diffuse iris necrosis, but remain intact in nongranulomatous inflammatory processes.
Chronic recurrent inflammations of any type can lead to focal or diffuse atrophy of the iris and ciliary body.
Choroid shows severe changes in bacterial endophthalmitis, but is spared in viral retinopathies.
Toxoplasmic retinochoroiditis causes marked focal destruction about the retina and the choroid.
The pigment epithelium and outer layers of the retina are damaged secondarily in primary choroidal inflammatory diseases. The inner retinal layers remain intact due to the external limiting membrane.
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In contrast, primary inflammations affecting the retina (retinits) are characterized by cewllular infiltrates throughout the entire retinal structure.
Viral induced retinitis (Herpes simplex and Herpes zoster retinitis and Toxoplasma induced retinitis) are characterized by necrosis of all retinal layers.
Reactive Proliferation and Chronic Inflammatory Changes
Third phase of inflammation is generally reparative in nature.It involves reactive proliferation of parenchymal tissue and replacement with fibrous tissue. The reparative process may result in restoration of normal function, but more often results in destructive sequelae.
Reactive proliferation of the retinal pigment epithelium can result in the formation of chorioretinal scars, cyclitic membranes and Dalen Fuchs nodules. The proliferating pigment epithelial cells undergo metaplasia, lose their melanin granules and assume a spindle shape. There is extensive deposition of collagen fibres due to fibrous metaplasia of the pigment epithelium. Basement membrane material is found within the fibrous bundles because pigment epithelium has the capability to produce basement membrane material. Osseous metaplasia of the RPE may occur especially in phthisical eyes.
Proliferation of iris pigment epithelium can cause posterior synechiae formation between the iris pigment epithelium and anterior lens capsule. Secondary proliferation and fibrous tissue metaplasia of the lens epithelium can produce anterior capsular cataract.
Cyclitic membranes are formed by proliferation of nonpigmented ciliary epithelium and may extend across the entire width of the eye. Proliferation of the pars plana epithelium anterior to the ora serrata is associated with long standing retinal detachment. The mounds of proliferated RPE beneath the detached retina is known as ringschwiele.
Perivascular pseudoretinitis pigmentosa occurs secondary to several types of disease entities including various inflammatory processes. Proliferating retinal pigment epithelium migrates into the retina in a perivascular fashion.
Dalen Fuchs nodules are focal cellular accumulations that often take the form of a pile of cannon balls that accumulate between Bruch’s membrane and an elevated RPE. Typically seen in sympathetic ophthalmia. It consists of collection of epithelioid histiocytes beneath the RPE (Fig. 14.2).
Reactive proliferation of vascular connective tissue also occurs. Potential sites of neovascularisation and the proliferation of fibrovascular tissue are:
1)Anterior surface of iris stroma producing rubeosis iridis.
2)Inner surface of the ciliary body producing cyclitic membrane.
3)The surface of peripheral retina as in pars planitis.
4)Surface of the posterior retina and optic nerve head producing vasoproliferative retinopathy.
5)The choriocapillaries producing subretinal neovascular membrane.
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Rubeosis Iridis
It consists of neovascular budding from the anterior surface of the iris stroma. Appears most often at the pupillary margin or on the surface of the far peripheral iris. This fibrovascular membrane on the anterior iris surface may undergo contraction, that results in tugging of the posterior iris pigment epithelium from the posterior surface of the iris around the pupillary margin onto the anterior surface resulting in ectropion uvea.
Chronic inflammatory process of the pars plana typically causes proliferation of the ciliary epithelium and fibrovascular tissue. These epithelial and fibrovascular elements migrate along the anterior hyaloid surface towards the equator of the lens eventually forming the complete cyclitic membrane in the retrolental space. Contraction of the myofibroblasts within the membrane may exert traction on the ciliary body and produce a ciliochoroidal detachment.
PROLIFERATIVE VITREO RETINOPATHY
Proliferative vitreoretinopathy is characterized by proliferation of fibrovascular tissue and neovascularisation and is due to -
1)Organization of intraocular hemorrhage, exudates, inflammatory infiltrates and other noxious substances with associated formation of granulation tissue.
2)Retinal neovascularisation resulting from intraocular hypoxia or ischemia. Neovascularisation generally occurs as a response to relative lack of oxygen. The combined presence of both viable tissue in the affected region and partial hypoxia induces the formation of an angiogenic factor that initiates the neovascularisation process. Clinically and histopathologically proliferative vitreoretinopathy has two distinct characteristics:
1)An abnormal location in which new vessels are present, where they normally do not exist.
2)Increased vascular permeability.
In contrast normal retinal vessels have an intact lining with tight junctions formed by zonula occludens, which prevent the leakage of fluid into the surrounding retina. These tight junctions are absent in neovascular vessels and extravasation of fluid and lipid occurs. The vascular channels break through the internal limiting membrane of the retina and grow along the surface of the retina. In addition to this flat growth the buds often proliferate anteriorly onto the vitreous scaffolding forming the arborizing fibrovascular fronds, which are typical of proliferative retinopathy.
The preretinal membranes are composed of proliferating vascular elements, vitreous hyalocytes, retinal glial elements and macrophages derived from the blood. When simultaneous retinal defects are present, metaplastic proliferating retinal pigment epithelium may grow through these holes to form fibrovascular membrane.
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Sub retinal neovascularisation: It is a common sequelae of inflammation of the retina and choroid. Almost all focal inflammatory processes of the choroid and retina can induce neovascularisation derived from the choroid. This is particularly true when basement membrane attachments to the RPE are compromised or there is interruption of Bruch’s membrane. Sub-retinal neovascularisation can lead to subretinal hemorrhages.
Reactive gliosis: refers to reactive proliferation of glial tissue occurring in response to damage to the pigment epithelium. The cells of the RPE are strongly inclined towards reactive hyperplasia in contrast to the elements of sensory retina. Massive retinal gliosis of retina is a relatively unusual process. It involves a massive proliferation of retinal glial tissue often simulating a tumor. It may occur following hemorrhage or severe intraocular inflammation.
Fungal Granuloma
Fungal infection of retina, choroid and vitreous may be seen in post-operative patients, patients with systemic mycotic infections, IV drug users and patients with surgical or non-surgical ocular trauma. It can occur as chronic panuveitis or as fungal endophalmitis. There are fluffy deep retinal or choroidal yellow white lesions and the vitreous may contain fungal abscesses. Commonly isolated organisms are candida, fusarium, aspergillus and mucormycosis.
Candida endophthalmitis is most common cause of disseminated fungal infection. It begins as focal yellow white, deep retinal or choroidal infiltrative lesions. Usually multiple, often there are one or more associated vitreal abscesses or vitreous fluff balls. HPE reveals neutrophils, macrophages, lymphocytes and either yeast forms or pseudohyphae consistent with Candida. Non-purulent granulomatous intraocular inflammation can also be seen with lymphocytes, macrophages, multinucleated giant cells and fibrosis.
Mucor mycosis is a saprophytic fungus. It can complicate diabetes. Infection begins in the paranasal sinuses and then invades the orbital tissue secondarily. Large non-septate hyphae invade vessels producing thrombosis and necrosis. Other organisms causing endogenous fungal endophthalmitis include coccidiodomycosis, cryptococcus, histoplasmosis, and blastomycosis (Figs 14.4 and 14.5).
CORNEAL DYSTROPHIES
Dystrophy denotes an inherited, relatively symmetric bilateral disease that is unassociated with vascularisation or inflammation in its early stages. Pathology appears to be localized to an ocular tissue. It is not evident at birth but becomes clinically evident later in life.
Topographic Classification
1)Epithelial-
a)Epithelial basement membrane dystrophy.
b)Meesman's dystrophy.
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Fig. 14.4: Rhinosporidiosis showing multiple sporangia in varying stages of maturation—mature sporangia contain endospores
Fig. 14.5: Hydatid cyst shows outer non-nucleated layer composed of laminated hyaline layers
2)Bowman's layer / superficial stroma (subepithelial)
c)Familial subepithelial amyloidosis.
d)Reis Buckler's dystrophy.
3)Stroma
e)Central crystalline dystrophy.
f)Fleck dystrophy.
g)Granular dystrophy.
h)Lattice dystrophytype1, type2, type3, type3a.
i)Macular dystrophytype1, type2.