Causes of focal infiltration (“foci”) of the fundus:

• drusen
  
• cotton-wool spots
  
• hard exudates
  
• focal anomalies
  
• focal retinal and choroidal scars
  
• toxoplasmosis
  
• tuberculosis
  
• mycoses
  
• incipient toxocariasis
  
• focal scarring from laser photocoagulation
  
• acute posterior multifocal placoid pigment epitheliopathy (APMPPE)
  
• early phase of birdshot retinochoroidopathy.

Retinopathy with focal or mottled lesions often occurs in relation to anatomic vascular structures such as in the retinal capillary network or as “lobes” in the choroidal terminal vascular bed. These disorders should be differentiated from primary vascular disorders such as vasculitis even if symptoms of secondary vasculitis are observed in severe cases of focal inflammation.

White Mottled Deposits

These findings are characteristic of degenerative changes in the retina in systemic disease and a few specific diseases of the retina. Leukocytic infiltrates occurring with lymphomas and tumor metastases also lead to focal retinal changes.

Drusen in the Retinal Pigment Epithelium

Drusen are defined as gray punctate deposits beneath the retina visible on direct ophthalmoscopy or with the 78-diopter lens.

One differentiates between “hard,” “soft,” and “reticular” drusen. Soft drusen are not sharply demarcated and can be confluent.

Treatment:as hard exudates are secondary signs, they can disappear when the underlying disorder is treated.

Fig. 3.3 Hard exudates in hypertensive retinopathy occurring in a pattern known as circinate retinopathy in the setting of treated advanced diabetic retinopathy.

Canthaxanthin Retinopathy

The carotenoid preparation canthaxanthin is used orally for endogenous cosmetic skin tanning. After a while, crystalline deposits appear in the retinal pigment epithelium at the posterior pole of the eye. Defects in the pigment epithelium occur with chronic use and can lead to permanent visual impairment. In some European countries, the preparation has been taken off the market.

Sharply Demarcated, Bright, and Pigmented Areas

Posterior Staphyloma in Myopia

In severe myopia, the peripapillary crescent develops into a marked posterior evagination of the eyeball. This “staphyloma” can extend past the macular region. This area appears bright, nearly white, because the choroid and retina lining the cavity are greatly stretched and atrophic or have become very thin. There is a high risk of retinal tear with subsequent retinal detachment. In monocular funduscopy, this change appears as a large myopic cone. Binocular ophthalmoscopy reveals the full extent of the posterior evagination.

Treatment : there is no known effective treatment. If both eyes are affected, it is recommended that the patient be referred to a specialist for the visually impaired.

Fig. 3.4 Posterior staphyloma in severe myopia. Evagination of the outer layer of the globe leads to retraction of the choroid and retina, exposing the white sclera.

Choroidal Coloboma

Scars from chorioretinitis are sharply demarcated and yellowish-white when the underlying sclera shines through. If remnants of the choroid are present, a few choroidal vessels will be visible.

Lesions may include small round spots, larger scars, and broad defects. Areas of scarring can occur at any location on the fundus and may be isolated, clustered, or diffusely disseminated.

Recent Scars from Laser, Diathermy, or Cryotherapy

Fig. 3.9 Recent laser burns following photocoagulation of a retinal hole.

Fig. 3.10 Myelinated nerve fibers in the superior temporal vascular arcade.

Treatment: there is no known effective treatment.

Cotton-Wool Spots of Varying Etiology

These spots are observed at the posterior pole of the eye and in the vascular arcades, often in close proximity to the retinal vessels. They are produced by edematous nerve fibers in the retinal layer of ganglion cells that are the result of localized ischemia in the retinal capillaries. These are typical concomitant signs of other disease processes and are therefore regarded as a diagnostic feature. Soft exudates appear transiently and can disappear after a few days.

Fig. 3.11 Cotton-wool spots and retinal hemorrhage in eclampsia.

Fig. 3.12 Cotton-wool spots in hypertensive retinopathy with round and linear intraretinal hemorrhages. Note the narrow caliber in the arteries and the optic disc edema.

Cotton-wool spots are important diagnostic signs in:

Central Fetal Toxoplasmosis

The fovea centralis is rarely affected in adults. Central, usually bilateral, involvement in toxoplasmosis is typical of fetal infection during the sixth to eighth month of pregnancy. The mother usually contracts a lung infection that goes unnoticed. The newborn’s eyes will already have developed extensive scars in the central retina, visible as large white defects with a pigmented halo. This means that visual acuity is greatly reduced right from birth, leading to secondary strabismus.

Retinochoroiditis Juxtapapillaris

Acute focal lesions appear increasingly luminous, whereas chronic scars exhibit the consistent white gleam of the sclera and choroidal vessels. In rare cases, the chorioretinitis is severe enough to produce extensive edema, or extensive lesions give rise to a diffuse and occasionally very dense vitreous opacification. In these cases, one should consult an internist and look for a systemic infection and other general diseases.

Tuberculosis

A retinochoroiditis lesion can also be caused by a tuberculoma. Ophthalmoscopy cannot distinguish this infection from other infections such as toxoplasmosis. Miliary tuberculosis is characterized by multiple, disseminated focal lesions on the fundus that are fluffy and less compact than those in toxoplasmosis. Tuberculous retinochoroiditis produces hardly any symptoms. However, in the context of the severe primary disease, it should be evaluated and treated in close cooperation with an internist. All forms of ocular tuberculosis are recurrent. When in doubt, a polymer chain reaction (PCR) with blood or, better yet, with a vitreous body biopsy specimen is recommended in addition to examination by an internist.

Treatment: once the diagnosis has been confirmed, tuberculostatic treatment must be performed.

Mycoses

Patients at high risk for intraocular mycoses:

• drug addicts
  
• patients infected with HIV
  
• immunosuppression
  
• patients with massive blood loss
  
• patients in poor general health
  
• patients with massive infections.

Treatment: antimycotics poorly penetrate the blood-retina barrier to pass into the vitreous body. Therefore, intravitreous injections and intravenous infusions of antimycotics are recommended.

• amphotericin-B
  
• fluconazole
  
• voriconazol.

Caution: 1ocal and systemic toxicity.

Small Retinal Tumors

Incipient Retinoblastomas

Retinoblastomas begin as small white focal lesions, often simultaneously at several sites. The lesions are ill defined, and are initially difficult to distinguish from retinochoroiditis. Such findings should be carefully observed in newborns and infants until a positive differential diagnosis has been made. Retinoblastomas later develop into tuberous growth. See pages 123, 168, and 173 for a detailed description.

Incipient Tumors in Tuberous Sclerosis—Bourneville Disease

Caution: the destroyed parasites can elicit a severe immune reaction. Therefore, corticosteroids are also indicated.

Echinococcus (Dog Tapeworm)

As in other worm disorders, the larvae disseminate through the body from the bowel. They then form hydatid cysts that gradually enlarge. Diagnosis is usually made based on histologic examination demonstrating typical heads (scolices) with a double hooked ring.

Treatment : surgical.

Cysticercosis—Taenia Solium (Pork Tapeworm)

In this disorder, infection occurs by ingesting tapeworm eggs. This may be the result of contamination with the feces of infected humans or animals, such as in raw manure. The larvae disseminate through the bloodstream, often infesting the eyes as well. There they form isolated subretinal oocysts that enlarge. Once they have attained a certain size, the growing organism becomes visible. As the antigenicity of these parasites is low, serologic studies are not very helpful in making a diagnosis. The adult tapeworm only arises when the meat of its host is eaten. The parasite passes to humans in food such as beef tartar or undercooked pork.

Treatment : surgical.

Fig. 3.22 Echinococcus cyst on the fundus of a 14-year-old girl. The patient and her father had pronounced eosinophilia. The father died with liver cysts confirmed in pathologic examination.

Internal Ophthalmomyiasis

Certain species of tropical flies deposit their eggs or hatched maggots on the moist surface of the conjunctiva in flight like a dive-bomber. Occasionally, the maggots migrate into the inner eye. They can pass beneath the conjunctival epithelium and from there actively migrate into deeper tissue as far as the subretinal space, where they continue to grow. They produce elongated infiltrates with a shape resembling a worm and later lead to scars of the same shape. The diagnosis is made based on the patient’s history and, possibly, from maggots found on the surface of the conjunctiva. Sequelae include areas of retinal and choroidal atrophy, exudative retinal detachment, and subretinal scars with tractional retinal detachment.

Treatment : surgical removal of the fly larvae.

Diffuse Unilateral Subacute Neuroretinitis (DUSN)

Treatment: there is no known effective treatment.

Multifocal Yellowish-White Flat Infiltrations

Infiltrations of such appearance may be caused by retinal lymphomas, which occasionally invade the choroid and the retina. Retinal oculo-cerebral lymphomas are very rare. A differential diagnosis must exclude many other disorders. However, retinal lymphomas exhibit a few characteristics that are helpful in making a diagnosis.

The major ophthalmic lymphomas include Hodgkin disease, non-Hodgkin lymphomas (oculo-cerebral lymphoma), and chronic myelogenous leukemia.

Hodgkin Disease

Hodgkin lymphomas produce granulomatous choroidal infiltrates that resemble focal lesions in chorioretinitis. Isolated or multiple nodules of this sort may be present. This disorder can only be distinguished from other inflammatory disorders on the basis of systemic findings.

Non-Hodgkin Lymphomas—Diffuse Malignant Lymphomas (Ocular-Cerebral Lymphoma)

Choroidal metastases can occur with the following carcinomas:

• breast carcinoma
  
• bronchial carcinoma
  
• lung carcinoma.

Treatment: surgical and cytostatic treatment of the underlying disorder.

Fig. 3.24 Small choroidal metastases of a breast carcinoma, still flat at this stage.

Fig. 3.25 Multiple metastases of small-cell lung carcinoma, appearing as flat focal lesions. The 43-year-old patient died eight weeks later. The diagnosis was made through autopsy.

Fig. 3.26a–c Ocular histoplasmosis syndrome (POHS).a Dirty gray macular edema. A small retinal hemorrhage is visible at the margin.

Fig. 3.26c Round scars further in the periphery of the fundus so called “histo spots.”

Presumed Ocular Histoplasmosis Syndrome (POHS)

The disorder first manifests itself as distorted vision and a decrease in visual acuity to between 20/40 and 20/200. Findings on the fundus include a retinal edema in or adjacent to the macula with crescent shaped or round hemorrhages at its margin.

Fluorescein angiography reveals sharply demarcated (classic) choroidal neovascularization similar to that seen in age-related macular degeneration. Occasionally visual acuity will continue to decrease only gradually or not at all, and the patient will not necessarily lose the ability to read. Histoplasma infection is detectable by a skin test in the United States. In Europe, no pathogens have yet been identified (except for isolated cases of Borrelia burgdorferi). A chorioretinal scar develops after two to three months. Similar new lesions appear immediately or within a period of weeks to months. These new lesions may be observed directly adjacent to the scar, in the broader vicinity of the posterior pole of the eye, or further in the periphery of the fundus. They, too, heal with small yellow atrophic scars known as “histo spots.” The initial central retinal involvement and diffuse scarring represent a typical clinical syndrome.

Treatment: prolonged administration of systemic corticosteroids.

Acute Posterior Multifocal Placoid Pigment Epitheliopathy (APMPPE)

If one of these focal lesions lies directly on the fovea, visual acuity can decrease to 20/200 or less. Less often, slit lamp examination will reveal a fine cellular exudation in the vitreous body. The diagnosis is made by fluorescein angiography: the focal lesions initially remain dark, masking the fluorescence of the choroid and retinal capillaries. The exudation in the inflammatory lesions becomes luminous only in the late phase of the angiogram and remains visible for a long time. Choroidal scars with fine pigment clumping develop within a few weeks. Visual acuity often recovers, and permanent impairments are rare.

Treatment: there is no known effective treatment.

Fig. 3.a–c Acute posterior multifocal placoid pigment epitheliopathy (APMPPE). a Disseminated indistinct lesions.

Fig. 3.27b b Fluorescein angiography of APMPPE: lesions mask fluorescence in the early phase (after eight seconds).

Fig. 3.27c Fluorescein angiography of APMPPE: the inflammatory lesions appear luminescent in the choroid in the late phase (after four minutes).

Birdshot-Retinopathie

Other names for multifocal inner choroiditis and punctate inner choroidopathy:

• chorioretinopathy with anterior uveitis
  
• multifocal choroiditis with panuveitis
  
• progressive subretinal fibrosis and uveitis
  
• multifocal inner choroiditis with disciform macular degeneration
  
• inflammatory pseudohistoplasmosis.

The inflammatory process occurs within the retinal pigment epithelium and in the choriocapillaris.

One possible cause is sarcoidosis. Subclinical infections with tuberculosis, EpsteinBarr virus, syphilis, and histoplasmosis have also been discussed. Between five and 20 focal lesions appear nearly simultaneously over the entire fundus, both in the periphery and at the posterior pole. They measure from 100 to 200μm in diameter, are round to oval, sharply demarcated, and initially gray-yellow, later turning yellow-white.

Sympathetic Ophthalmia

This severe panuveitis can occur secondary to penetrating injury or surgical procedures of one eye and leads to uveitis in the fellow eye within a period of a few days to several years. In addition to diminished visual acuity and increased sensitivity to glare, the disorder is primarily characterized by anterior uveitis. Fundus findings include cells in the vitreous body and disseminated white spots on the fundus. Refinements in modern surgical techniques have made the disease rare.

Treatment: high doses of systemic corticosteroids and immunosuppressive agents.

Literature

Prominence of the Macula

Secondary Macular Edema

Causes of macular edemas:

• age-related macular degeneration
  
• Irvine–Gass syndrome
  
• retinal vein occlusion
  
• diabetic retinopathy
  
• arterial hypertension
  
• uveitis
  
• Leber miliary aneurysms
  
• Coats disease
  
• Behçet disease
  
• Eales disease
  
• retinal periphlebitis
  
• discontinuous reversible arteriopathy (Kyrieleis disease)
  
• retinitis pigmentosa
  
• birdshot retinochoroidopathy
  
• inflammatory processes
  
• retinal detachment
  
• macular pucker
  
• possibly idiopathic.

Fig. 3.29a and b Cystoid macular edema following to cataract surgery (Irvine-Gass syndrome). a Typical stellate exudation around the fovea centralis appears in the late phase of fluorescein angiography (after five minutes).

The cystoid macular edema occurs relatively often together with:

In a few of the disorders mentioned above, the cystoid macular edema gradually develops over a period of weeks to months. Visual acuity gradually decreases until the patient is unable to read. It is highly probable that cystoid macular edemas occur under the influence of prostaglandins. Once the frequently associated inflammatory symptoms have disappeared, a cystoid macular edema can resolve over a period of months and visual acuity can improve, especially in juvenile patients.

Fig. 3.29b Optical coherence tomography (OCT) demonstrates the anatomic position of the cysts.

Macular Edema with Aphakia or Pseudophakia (Irvine-Gass Syndrome)

Cystoid macular edema occurs in 10–20 % of all cases following intracapsular cataract operations, less frequently after extracapsular operations (2 %). Its incidence increases significantly secondary to rupture of the posterior capsule of the lens. Cystoid macular edema also occurs secondary to other procedures that lead to decreased intraocular pressure (paracentesis effect).

Macular Edema with Posterior Uveitis

Cystoid macular edema is a long-term complication of chronic inflammation. It often manifests itself with the symptoms described above after an insidious clinical course of several months. Fluorescein angiography is indicated if visual acuity decreases without correlating ophthalmoscopic findings.

Fig. 3.30b Late phase of fluorescein angiography (after five minutes) showing the parafoveal fluorescence typical of macular edema. The hyperfluorescence of the optic disc is a sign of the inflammatory process..

Fig. 3.31a and b Intermediate uveitis—pars planitis. a The inferior periphery of the fundus exhibits typical preretinal “snowball” infiltrates also retinal and choroidal lesions posterior to them. b Fluorescein angiography: the retinal and choroidal lesions appear brightly luminous.

Macular Edema with Intermediate Uveitis—Pars Planitis

Cystoid macular edema often determines the prognosis for the underlying disorder with respect to visual acuity.

Treatment

• treatment of the underlying disorder
  
• cyclo-oxygenase inhibitors
  
• systemic and peribulbar corticosteroids where indicated.

Macular Edema with Retinal Vascular Disease

Macular Edema in Diabetic Retinopathy

Fig. 3.32b-c entral serous chorioretinopathy. b Fluorescein angiography: a focal area of hyperfluorescence appears in the venous phase. c Fluorescein angiography: within a few minutes, the fluorescence expands upward in the classic “smokestack” sign.

Fig. 3.33 Chronic central serous chorioretinopathy. Fluorescein angiography: defects in the pigment epithelium with slow exudation.

Diffuse Retinal Pigment Epitheliopathy (Chronic Serous Chorioretinopathy)

Treatment: there is no known effective treatment.

Macular Edema from Choroidal Neovascularization

Clinical signs of exudative age-related macular degeneration include subretinal bleeding, hard exudates, fibrovascular or serous pigment epithelium detachment, and fibrovascular scars. Choroidal neovascularization is occasionally detectable by ophthalmoscopy as a greenish-gray prominence with surrounding edema and hemorrhages or as hyperpigmentation. A positive diagnosis can be made by fluorescein or indocyanine green angiography (Dobberstein and coworkers 1998). Choroidal neovascularization may be angiographically subdivided into so-called classic and occult forms.

Classic Choroidal Neovascularization

In the classic form, the early phase of fluorescein angiography reveals a focal area of hyperfluorescence and occasionally a fine vascular network. In the late phase of angiography, increasing homogeneous leakage is observed in the vicinity of the choroidal neovascularization. This form of choroidal neovascularization is further subdivided according to its position relative to the center of the fovea. It is specified as extrafoveal (more than 200 μm from the center), juxtafoveal (1–199 μm from the center), or subfoveal (beneath the center). Extrafoveal or juxtafoveal classic choroidal neovascularization is accessible to thermal (argon) laser photocoagulation, whereas photodynamic therapy may be considered for subfoveal choroidal neovascularization.

Localization of classic choroidal neovascularization relative to the fovea (distance from the center of the macula):

• extrafoveal: more than 200 μm
  
• juxtafoveal: 1–199 μm
  
• subfoveal: directly beneath the macula.

Fig. 3.36 Sketch of localization of macular lesions: subfoveal, juxtafoveal, and extrafoveal.

Fig. 3.39c Late phase (after 5-10 minutes): the serous fluid absorbed fluorescein and remains fluorescent for a long time.

End Stage of the Wet Form of Age-related Macular Degeneration (AMD)

Left untreated, exudative age-related macular degeneration develops into a fibrovascular scar that can cover the entire posterior pole of the eye (pseudotumor). This end stage of the disorder is referred to as a disciform lesion or Junius–Kuhnt degeneration. This stage is usually associated with a large absolute central scotoma and greatly reduced visual acuity.

Treatment: there is no effective treatment for the end stage.

Fig. 3.40 The advanced stage of age-related macular degeneration (disciform lesion or Junius–Kuhnt degeneration). Glial scar surrounded by hard exudates.

Fig. 3.41b Fluorescein angiography (late phase, after 10 minutes): exudation over a broad area.

Fig. 3.42 The advanced stage of untreated age-related macular degeneration. Retinal hemorrhages are surrrounding the macular edema.

Choroidal Neovascularization of Other Causes

• primary disorders
  
  
  
  • presumed ocular histoplasmosis syndrome (POHS)
  
  
• secondary disorders
  
  
  
  • severe myopia
    
  • angioid streaks
    
  • punctate inner choroidopathy
    
  • multifocal inner choroiditis
    
  • serpiginous choroiditis
    
  • adult vitelliform dystrophy

Literature

Proliferation, Scarring, and Holes in the Macula

Epiretinal Membranes (Macular Pucker)

Epimacular membrane formation after posterior vitreous separation is termed macular pucker. This term is used to describe wrinkles of the surface of the retina as a result of contracting epiretinal membranes. The membranes consist of macrophages, pigment epithelial cells, glia, fibroblasts, and myofibroblasts. The pathogenesis of macular pucker is not understood. Epimacular formation of contractile membranes without posterior vitreous separation is called “vitreo-macular traction syndrome”. More subtle expressions of epimacular traction are clinically termed: “cellophane or surface wrinkling maculopathy”.

Causes of macular pucker:

• Retinal tear without or without retinal detachment
  
• Severe ocular trauma
  
• Retinal vein occlusion
  
• Minor hemorrhages
  
• Other vascular processes
  
• Idiopathic

The fine gray strands indicative of thickening of the preretinal structures are not always immediately visible. A typical finding is distortion of the perimacular blood vessels, which may occasionally include the major temporal vessels. Contraction of the scar-like tissue causes the retinal vessels to follow abnormal, often bizarre courses. This also places traction on the macula, which in turn appears torn and often displaced in the direction of the bizarre retinal vessels. The retinal structures often appear ill-defined due to edema.

Macular pucker cannot cause retinal detachment. It often occurs secondary to other retinal disorders and vitreoretinal surgery. It can be readily managed by vitrectomy.

Treatment: Cyclooxygenase inhibitors and corticosteroids have only limited effect. The method of choice is surgical removal of the connective tissue membrane from the surface of the retina.

Idiopathic Macular Hole

Idiopathic macular holes are presumably caused by tractional forces in the vitreo–retinal interface at the posterior pole. The causative mechanism is thought to initially involve posterior–anterior tractional forces and later tangential tractional forces within the cortex of the vitreous. If such forces produce a macular hole, the foveola initially becomes detached (stage I according to Gass) and later the foveal tissue will radially retract (stage II and higher). Despite a clinically visible hole, there is no loss of retinal tissue. These holes practically never give rise to a retinal detachment. The edges of the hole are usually slightly raised. Yellow pigments will often be visible on the floor of the macular hole.

Fig. 3.44 A macular pucker in a 64-year-old woman.

Fig. 3.45 Fluorescein angiography in macular pucker. The early venous phase demonstrates bizarre vascular structures. Exudation appears only in the late phase after 5–10 minutes.

Fig. 3.46 Optical coherence tomography (OCT) with macular pucker.

Gass classification of macular holes: