Historical note

Patients with retinopathies and choroidopathies are usually referred by their primary eye care providers to retinal subspecialists (for retinal conditions) or uveitis subspecialists (for choroidal conditions), although both groups of subspecialists see both types of patients. Occasionally, a patient may be referred to a neurologist if the primary eye care provider misdiagnoses such a condition as an optic neuropathy.

The origins of a subspecialty dealing with retinopathies and choroidopathies go back to Dr. Donald Gass, a world-class retinologist who classified most of these conditions with the help of fluorescein angiography in the 1960s. Newer diagnostic imaging techniques, such as optical coherence tomography and indocyanine green angiography, help physicians today make diagnoses that were not possible in decades past. In early publications, new diseases were described along with new manifestations of common retinal conditions to establish an ophthalmic nomenclature describing a distinct group of entities: the retinopathies and choroidopathies. Assumptions based on anecdotal personal experiences of the pioneers were eventually replaced by evidence-based data from some of the best-designed type I multicenter clinical trials, which is how most of the ophthalmic community practices today.

Anatomical considerations

The portion of the ocular fundus (the back of the eye) that includes the optic nerve and the macula is the area between the temporal arcades (superior and inferior retinal blood vessels temporal to the optic nerve) and is called the posterior pole. The center part of the posterior pole is the macula, and the most central part of the macula is the fovea, which supports the 20/20 or better visual acuity that characterizes normal sight. A capillary-free zone in the fovea is known as the foveal avascular zone (measures 400 microns or 0.61 mm in normals). The center of the universe of the retina/choroid is the macula (and the fovea contained within).

The more peripheral a lesion is relative to the macula, the more anterior the lesion is in the eye (rather than a posterior lesion as in the macula). So, progressing peripherally or anteriorly in the eye relative to the macula, lesions may involve the region within the (vascular) arcades (the posterior pole) or beyond the arcades toward the equator of the eye. The most peripheral lesions are those that involve the ora serrata, which is closest to the ciliary body. These are the anatomic landmarks within the eye for lesions in terms of how they are positioned within the fundus.

Lesions are also localized in terms of their depth within the tissues that make up the wall of the eye. If one were to take a cross section of the back of the eyeball at some distance from the optic nerve, the following layers from inside the globe to outside are: (1) the retina, which is transparent; (2) the retinal pigment epithelium and Bruch membrane; (3) the choroid, which is the most vascular layer of the eye; and (4) the relatively avascular collagenous sclera, known as the white of the eye.

The retina, or the most internal tissue, is a transparent structure consisting of 10 anatomically and physiologically distinct layers. The outer layers in the retina derive their oxygen by diffusion from the vascular choroid, and the inner layers are nourished by capillaries derived from the branches of the central retinal artery. The retinal pigment epithelium is a layer of cuboidal melanin-containing cells that perform important metabolic functions for the retinal photoreceptors, which are the light-capturing cells that make up the outermost layer of the retina.

In front of the retina and filling the center of the globe (eyeball) is the vitreous body, which is a clear, jelly-like substance in the young that undergoes syneresis in the elderly. Syneresis is a process that makes the gel of the vitreous more of a watery substance and creates irregular-shaped vitreous opacities that many people see as “floaters.”

The blood supply of the eye comes from the internal carotid artery. Above the cavernous sinus, the internal carotid artery branches into the ophthalmic artery, which ultimately supplies blood to the eye. The ophthalmic artery branches into the posterior ciliary arteries (2 or more arteries per eye) and the central retinal artery.

The blood supply to the inner two thirds of the retina (including the retinal nerve fiber layer and retinal ganglion cell layer) is from the central retinal artery. The blood supply to the outer one third of the retina (the rods and cones and outer nuclear layer) comes from the posterior ciliary arteries. The posterior ciliary arteries also supply the retinal pigment epithelium, Bruch membrane, the choroid, and the prelaminar, laminar, and part of the retrolaminar optic nerve. These levels within the cross section of the optic nerve are named in reference to the lamina cribrosa, an extension of the sclera across the optic nerve that contains many holes or canals through which the axons of the optic nerve pass.

A cilioretinal artery arising from the choroidal circulation is present in about 20% of normal individuals and supplies the inner two thirds of the retina in a small vascular territory between the optic disc and the macula. The remainder of the retina derives its inner retinal blood supply from the central retinal artery.

When a disease process involves only the retina, it is called a retinopathy; if it involves only the choroid, it is called a choroidopathy. Sometimes diseases involve both structures, in which case it is called a retinochoroidopathy or a chorioretinopathy.

The retinal pigment epithelium may be involved with some retinopathies and some choroidopathies but rarely is affected in isolation. Sometimes diseases cause accumulation of fluid at various levels; for example, subretinal fluid refers to fluid under the retina, and cystoid macular edema refers to fluid that accumulates in the outer plexiform layer within the retina.

The choroid and the retinal pigment epithelium are the only pigmented structures in the back of the eye. The amount of pigment varies by race, eg, Africans have more pigment than those with northern European ancestry. The hallmark sign of inflammation involving the choroid and retinal pigment epithelium is often funduscopicly visible hyper-and hypopigmentation in the retina. When pigment is liberated as a result of an inherited condition such as retinitis pigmentosa, it is not unusual for it to aggregate around capillaries in the retinal vascular supply giving it a linear and angular appearance. These are often referred to as “bone spicules” even though no bone is involved.

Clinical manifestations

The key symptoms of retinal or choroidal disease are:

The onset of symptoms of the retinochoroidopathies depends on the condition and can be sudden but more often has an insidious onset.

Two conditions, although not really considered retinochoroidopathies, will be mentioned here because they occur frequently and produce symptoms similar to those of the retinochoroidopathies. These conditions are posterior vitreous detachment and retinal detachment.

The most common cause of unilateral acute onset of floaters and persistent stationary flashing lights is acute posterior vitreous detachment, a disorder that predisposes the patient to retinal detachment and vision loss. Posterior vitreous detachment occurs when the vitreous body detaches from the most inner aspect of the retina and creates a floating, often spider web-like structure that is described by patients as a “floater.” A posterior vitreous detachment is benign if it does not significantly pull on and create a small tear in the retina. If a posterior vitreous detachment causes enough traction on the retina (often associated with the patient seeing light flashes), a retinal tear can develop. Once a retinal tear develops, the vitreous fluid can penetrate under the retina where accumulation of this subretinal fluid may result in retinal detachment. If left untreated, retinal detachment can lead to blindness.

Retinal detachment is a preventable cause of visual loss if the patient sees an eye care provider when their symptoms of flashes or floaters begin and if he or she is emergently referred to a retina specialist for surgery when required. New flashes and floaters are, therefore, considered an ocular emergency and should be seen by a retinal expert the same day. The risks for retinal detachment increase with age, with myopia (near sightedness), and with a history of eye trauma or eye surgery. Patients typically present with floaters, flashes, peripheral visual field loss, or blurred vision. Early intervention improves visual outcome. Non traumatic retinal detachment occurs in approximately 1 in 10,000 people per year (49).

Flashes related to posterior vitreous detachment must be distinguished from those seen in migraine. In migrainous visual aura, the area of scintillating angular figures “marches” or progresses slowly from one area to another within the visual field on one or both sides while increasing or decreasing in size over an average interval of 20 minutes. Flashes related to posterior vitreous detachment also must be distinguished from the sound-induced phosphenes that have been described in optic neuritis related to multiple sclerosis (86).

The key signs of retinal disease are:

Table 1. Presentation: Macula Versus Optic Nerve

Table 2. Examination: Macula Versus Optic Nerve

Table 3. Testing: Macula Versus Optic Nerve

Ancillary diagnostic testing

Visual field measurements can be obtained by manual types of examination (Goldmann perimetry) or by computerized automated static threshold perimetry. Quantitative visual field examination is useful in monitoring progression of disease because the examination usually has good reproducibility. Most exams will reveal a central scotoma if the problem is macular or peripheral constriction if the problem is in the retinal periphery.

Electrophysiology testing

Full-field electroretinogram (ERG). The full-field ERG is a record of the aggregate electrical response generated by neural and non-neuronal cells within the retina in response to light stimulation (typically flashes from a strobe light). The components of the ERG response are:

The electroretinogram provides measurements of waveform amplitudes and time relationships. Latency of the response refers to the time from the stimulus until the beginning of the a-wave. Implicit time is measured from the stimulus onset to the peak of the b-wave. The ERG is recorded under scotopic (dark = rods are tested) and photopic (light = cones are tested) conditions.

Markedly reduced or nondetectable ERG responses can be found in the presence of 20/20 vision in cases of retinitis pigmentosa.

Electro-oculogram (EOG). Electro-oculogram is a term introduced by Marg in 1951 (85). It measures the electrical standing or resting potential that exists between the cornea and the posterior pole of the eye. The electro-oculogram has two components:

(1) The light-insensitive component, which depends on the integrity of the retinal pigment epithelium and is independent of the functional status of the retinal photoreceptors.

(2) The light-sensitive component, which appears to be generated by depolarization of the basal membrane of the retinal pigment epithelium. Intact photoreceptor cells are necessary to generate this response.

Electro-oculography is indicated primarily for staging diseases that involve the retinal pigment epithelium, such as Best disease (88).

Multifocal electroretinogram (mfERG). Full-field ERG is not sensitive for detection of local or focal changes of retinal function because of the mass response from the entire retina. Full-field ERG abnormalities are seen with advanced or extensive disease. Multifocal ERG tests locally with focal stimulation and uses stimulus patterns that consist of between 61 and 241 hexagons.

Eighty-five percent of eyes with maculopathy have reduced or delayed mfERG responses; thus, for a patient with visual acuity of worse than 20/40, a normal mfERG indicates that the visual acuity loss is probably not due to macular disease (43).

Optical coherence tomography (OCT). Optical coherence tomography is an ocular imaging technique that enables high resolution cross-sectional imaging of tissue microstructure or in vivo histology. The technique is based on the principle of Michelson interferometry and is similar to ultrasonography (67). The distinction is that optical coherence tomography uses light and not sound to measure the variations in reflectivity within a target tissue. Since its introduction commercially in 1996, optical coherence tomography has proven to be one of the most useful noninvasive newer techniques in retinal imaging, with the newer frequency domain devices having resolution exceeding 5 μm.

Optical coherence tomography technology allows the visualization of retinal anatomy and the quantification of retinal, intraretinal, and nerve fiber layer thicknesses and abnormalities using a suggested mapping technique. Both qualitative and quantitative image analyses are possible.

One of the latest developments in existing clinical OCT instruments is the availability of OCT angiography. The imaging of retinal vasculature is accomplished by using laser light reflectance of the surface of moving red blood cells to produce an image of blood vessels down to even the smallest capillaries without the injection of a dye.

Ophthalmic fundus photography and angiography

These techniques have undergone incredible growth and technological advance over the past decade. Film-based fundus photography and angiography has been replaced by digital photography and angiography, which is the new standard in the ophthalmic community. Digital technology provides enhanced resolution, shorter processing time, easier manipulation, transmission, and duplication, and, most importantly, instantaneous availability of the study to the treating ophthalmologist for management issues (96). High-speed angiographic techniques can provide exquisite visualization of the choroidal perfusion.

Fluorescein angiography. Fluorescein angiography is the technique of performing rapid sequence photography of the fundus of the eye after intravenous injection of fluorescein dye. Fluorescein angiography provides the following information:

The most common indications for fluorescein angiography are detection of choroidal neovascular membranes, detection of macular edema, evaluation of diabetic retinopathy, and evaluation of idiopathic serous choroidopathy (135).

Some of the advantages of fluorescein angiography over optical coherence tomography include the following: (1) fluorescein angiography provides assessment of the choroidal and retinal circulation; (2) fluorescein angiography provides information about the perfusion and nonperfusion status of the retina; and (3) fluorescein angiography can detect choroidal neovascular membranes better than optical coherence tomography in eyes with retinal edema. This is because fluorescein angiography reveals leakage, which is not imaged by the optical coherence tomography.

Indocyanine green angiography. Indocyanine green angiography was introduced in 1973 by Flower (44) but did not reach widespread use until the 1990s. This technique, which can only be obtained using digital imaging, provides better visualization of the choroidal circulation and allows detection of early and subtle choroidal neovascular membranes in patients with exudative age-related macular degeneration, inflammatory diseases, and chorioretinal abnormalities (139). The major drawbacks relate to optimal exposures and the cost of the software program for the digital camera being used.

Fundus autofluorescence. Fundus autofluorescence is a relatively new imaging technique that highlights lipofuscin deposits to check the metabolic status of the retinal pigment epithelium. When lipofuscin is exposed to short to medium wavelengths of the visible light spectrum, it will autofluoresce. Fundus autofluorescence can be used to predict patterns, progression of disease, and elucidate better understanding of disease pathogenesis, particularly age-related macular degeneration and geographic atrophy cases (122; 11; 81).

Optical coherence tomography angiography. Optical coherence tomography angiography is a dye-free angiogram of retinal vessels that is noninvasive, motion-contrast imaging. Depth of retinal vasculature is color-coded for ease of visual assessment. It represents erythrocyte movement in retinal blood vessels. Optical coherence tomography angiogram does not replace fluorescein angiogram but, rather, complements it and does not show leaking vessels. The first optical coherence tomography angiography device was approved in the US in 2016 and in Europe in 2014 (147; 18). Possible advantages of optical coherence tomography angiography over fluorescein angiogram are the fact that no intravenous injection is needed (no risk of fluorescein dye-related side effects), higher resolution images (3 to 4 second acquisition), and that multiple retinal layers are visualized (50; 09).

The clinical advantages offered by optical coherence tomography angiogram are that it allows us to understand retinal vascular occlusions, enables us to discover diabetic retinopathy earlier, and makes the conversion from dry to wet macular degeneration easier to detect.

Ultrasonography. For over 50 years, ocular ultrasound techniques have been paramount in the diagnosis of certain types of retinal pathology. Traditionally, the contact type of ultrasound includes an A-scan and a B-scan, each with its own representative images and summary report. The evaluations include morphologic, topographic, and volumetric qualifications of normal and pathologic conditions, such as in cases of retinal detachment and intraocular tumors.

Optical disc storage and direct Internet transmission of the generated images make reviews, comparison of new and old data, and the sharing of reports simple and easy (140).

Hypertensive and diabetic retinopathy

Hypertensive retinopathy

Definition. Guidelines proposed by the European Society of Hypertension and European Society of Cardiology (ESH-ESC) Guidelines Committee and the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC7) provide classifications of blood pressure (29; 39). The two classifications have notable differences, and treatment recommendations are different in each. Both, however, emphasize the importance of maintaining low blood pressure in adults 18 years of age and older (Table 4). “Prehypertension” is considered to represent a high-risk condition, and individuals with prehypertension can prevent or delay true hypertension by practicing lifestyle modifications (29).

Table 4. Blood Pressure Classification Chart

The term hypertensive retinopathy encompasses the spectrum of retinal vascular changes secondary to hypertension. “Mild retinopathy” refers to retinal arteriolar and venular alterations, such as arteriolar narrowing or venular irregularities. “Moderate retinopathy” refers to the presence of microaneurysms, cotton-wool spots, retinal hemorrhages, retinal exudates, or combinations of these (138).

Clinical classifications. Keith, Wagner, and Barker published in 1974 a pivotal work on hypertensive retinopathy (74; 114). They classified four grades, depending on severity. Their classification emphasizes the importance of optic nerve swelling, and the 3-year survival rate decreased significantly with each grade increment. Wong and Mitchell proposed a 3-grade classification in 2004 (138). In this system, mild retinopathy refers to retinal arteriolar signs, such as arteriolar narrowing, arteriolar wall opacification, and arteriovenous nicking. Moderate retinopathy includes mild retinopathy plus flame- or blot-shaped hemorrhages, cotton-wool spots, hard exudates, or microaneurysms. Severe retinopathy indicates the presence of any of the signs of moderate retinopathy along with optic disc swelling.

Table 5. Hypertensive Retinopathy Classification Chart

Etiology. Numerous studies have confirmed the strong association between the presence of signs of hypertensive retinopathy and elevated blood pressure (137; 80). This association suggested that generalized narrowing and arteriovenous nicking are markers of vascular damage from chronic hypertension. In contrast, other signs like focal arteriolar narrowing, retinal hemorrhages, microaneurysms, and cotton-wool spots are related to acute hypertension. Keith Wagner Baker classification I and II are typically a result of chronic (essential) hypertension; III and IV are often the result of acute secondary hypertension, especially if the onset is relatively rapid. The following three references enumerate some of the diseases associated with secondary hypertension ranging from common to rare: (84; 23; 59).

Pathogenesis and pathophysiology. Robinson and colleagues studied the association between retinal circulation and systemic blood pressure after a series of isometric exercises and concluded that retinal vascular resistance adjusts to changes in ocular perfusion pressure to keep the retinal blood flow constant, given the fact that the mean ophthalmic artery pressure rises with the mean brachial artery pressure (104). When the mean arterial blood pressure rises above 115 mmHg, approximately 41% above the resting levels, retinal blood flow increases, indicating that the regulatory mechanism has been overwhelmed (104). These numbers are consistent with the sequential changes in the eye depending on the grade of hypertension. The pathophysiological changes in the initial stage include vasospasm and increased retinal arteriolar muscle tone as part of local autoregulatory mechanisms (131). Persistently elevated blood pressure leads to intimal thickening, hyperplasia of the media wall, and hyaline degeneration followed by disruption of the blood-retina barrier, necrosis of smooth muscle and endothelial cells, exudation of blood and lipids, and retinal ischemia.

Epidemiology. Epidemiologic studies show that hypertensive retinopathy is more common in the adult population 40 years of age or older, with prevalence rates of up to 14% (138).

A higher prevalence of retinopathy has been reported among African Americans compared with Caucasians, a difference that is explained in large part by the higher blood pressure levels among African Americans (114). Variations in the prevalence according to age and sex have not been consistently demonstrated.

Clinical presentation. The patient commonly presents with recurring headaches and visual disturbances, such as blurred vision, halos, blind spots, floaters, and other symptoms. Signs observed with a detailed ophthalmoscopic examination will reveal the diagnosis, and these signs will be proportional to the severity of the hypertension and the prognosis of the disease (62). To perform fundus examination, first find the optic disc, then follow the retinal vessels from the disc as far out as possible in the periphery. Always come back to the disc to begin exploration of a new vascular territory. Examine the macula last because it is the most light-sensitive area of the retina. Direct ophthalmoscopy is inexpensive and can be easily performed after the pupils have been dilated with drops (62; 93). The most commonly used dilating drops are the anticholinergic agent, 1% tropicamide; it is best to avoid the sympathomimetic agent, 2.5% phenylephrine, as this agent can increase systemic blood pressure.

The fundus features include focal and generalized arteriolar narrowing, intraretinal hemorrhage cotton-wool spots, hard exudates, microaneurysms, and optic disc swelling. Arteriovenous nicking, changes in the arteriolar light reflex, and arteriolar sheathing can be found (62). Changes from arteriosclerosis (eg, copper and silver wiring) are accelerated by hypertension. Abnormal vascular permeability can produce flame-shaped hemorrhages, retinal edema, and lipid exudates (62). The deeper blot hemorrhages appearing as dark red can be found in patients with severe hypertension and may be indicative of worsening ischemia. Fovea examination may reveal a macular star figure formed by lipid deposition in the retina surrounding the fovea (71). Nerve-fiber layer infarcts (cotton-wool spots) are caused by obstruction of the precapillary arterioles in patients with acute hypertension (62).

Regarding arteriolar narrowing, this may be due to edema in the arteriolar wall or there may be localized areas of fibrosis. The development of digital fundus photography with specific software packages has made it possible to measure the arteriole-to-venule diameter ratio (AVR) (138). The normal AVR ratio is 0.65±0.05.

Studies suggest that patients with a high AVR (arteriolar narrowing) have a high risk of developing hypertension. The odds of developing hypertension for persons with high-normal blood pressure levels and AVR in the fifth quintile of the sample were 2.31 times as high as those of people with normal blood pressure and AVR in the first to fourth quintiles (138). Independent of the AVR, persons with focal areas of vasoconstriction are also more likely to be diagnosed with hypertension than were those without focal narrowing.

Diagnostic workup. Direct ophthalmoscopy studies by Palmberg and colleagues in which patients were screened for diabetic retinopathy showed that direct ophthalmoscopy had a sensitivity of 56% for detecting hypertensive retinopathy, mostly mild or minimal retinopathy (99). When these findings were present, there was a high degree of specificity, with two false positives out of 367 patients. However, Moss and colleagues reported better results for ophthalmoscopy, with an 82% sensitivity and 95% specificity, for the presence or absence of hypertensive retinopathy in 1949 patients (91).

The gold standard for the diagnosis of hypertensive retinopathy is believed to be stereoscopic color photography. Retinal photography is extremely useful for permanent documentation and detailed quantification of the lesions. It can be carried out by technical personnel as standard color photography using photographic film or digital equipment, and “nonmydriatic” camera models can be employed (48; 16; 32).

Differential diagnosis. Diabetic retinopathy, radiation retinopathy, venous occlusive disease, carotid artery occlusive disease, perifoveal telangiectasis, or systemic illnesses such as collagen vascular disease can all present with a fundus appearance similar to hypertensive retinopathy. Besides malignant hypertension, patients who have optic nerve head swelling and a macular star may have diabetic papillopathy, radiation optic neuropathy, neuroretinitis due to inflammatory or infectious origin, central retinal vein occlusion, or rarely ischemic optic neuropathy. Severe papilledema may also result in a macular star exudate, so intracranial disease must be excluded in the presence of bilateral optic disc edema (82).

Prevention. The only prevention is screening for those who are at risk for hypertension so that early diagnosis and treatment can prevent the clinical complications of hypertension.

Prognosis and complications. Keith and colleagues found 79% mortality within a year for patients diagnosed with grade 4 hypertensive retinopathy (74).

Studies suggest that hypertensive retinopathy is associated with double the risk of coronary heart disease or myocardial infarction, independent of blood pressure and other coronary risk factors. Thus, retinal microvascular changes are an important indicator of atherosclerosis. Vision is typically not affected in grade 1 and 2 and may be mildly decreased with grade 3. In grade 4, vision is usually seriously impaired (72).

Management. The treatment goal for hypertensive retinopathy is to control the hypertension. If blood pressure is maintained within the normal limits, the fundus abnormalities will resolve in a few months. The visual loss in grade 4 hypertension may be irreversible due to vascular damage. Changes seen in chronic hypertension may remain even if blood pressure control is achieved (01).

Diabetic retinopathy

Definition. Diabetic retinopathy is a chronic progressive disease of the retinal microvasculature associated with prolonged hyperglycemia and worsened by other comorbidities, such as hypertension. It remains the most frequent cause of newly diagnosed blindness in middle-aged adults (20 to 74 years old), despite the use of laser, vitreous surgery, intravitreal injections, and more effective means of glucose and blood pressure control.

Classification.

(1) Nonproliferative diabetic retinopathy (NPDR), which exists in three stages: mild, moderate, and severe,

(2) Proliferative diabetic retinopathy (PDR), and

(3) Diabetic maculopathy: focal and diffuse edema, ischemic or mixed.

Pathophysiology. The pathogenesis of diabetic retinopathy is promoted by an individual's genetic predisposition (101) and is probably influenced by environmental factors, such as alcohol consumption (145), diet (28), and nicotine abuse, although none of these have been proven to be of relevance (20). Useful clinical markers are either familial aggregation or variation in disease frequency not fully explained by environmental, biochemical, or biological risk factors. Clinical studies on diabetic retinopathy demonstrate substantial variations in the onset and severity of retinopathy that are not fully explained by known risk factors (91).

The main proposed components for induction and progression of diabetic retinopathy include:

The biochemical pathways that link hyperglycemia and microvascular complications are: polyol accumulation associated with the development of basement membrane thickening, pericyte loss, and microaneurysm formation (46; 38), formation of advanced glycation end products shown in rats after 26 weeks of induced hyperglycemia, oxidative stress that leads to vascular damage and may result from glucose auto oxidation, protein glycation, increased flux through the polyol pathway, and prostanoid production (51), and activation of protein kinase C, which results in numerous cellular changes, including increased expression of matrix proteins and increased expression of vasoactive mediators. The changes are seen as thickening of the basement membrane, increased retinal vascular permeability, and alterations in retinal blood flow (132).

Epidemiology. An estimated 30.3 million people of all ages—or 9.4% of the U.S. population—had diabetes in 2015. This total included 30.2 million adults aged 18 years or older (12.2% of all U.S. adults), of which 7.2 million (23.8%) were not aware of or did not report having diabetes. The percentage of adults with diabetes increased with age, reaching a high of 25.2% among those aged 65 years or older. Compared to non-Hispanic whites, the age-adjusted prevalence of diagnosed and undiagnosed diabetes was higher among Asians, non-Hispanic blacks, and Hispanics during 2011–2014 (22).

Retinopathy is the most common microvascular complication of diabetes, resulting in blindness for over 10,000 people with diabetes per year. There is evidence that retinopathy starts to develop at least 7 years before the clinical diagnosis of type 2 diabetes, and as many as 100% of type 1 diabetic patients have been observed to develop some degree of retinopathy after 20 to 30 years, peaking at about 10 to 15 years after diagnosis (60).

Diabetic retinopathy is the leading cause of blindness for persons aged 20 to 65 years in the United States (136).

Clinical presentation.

Nonproliferative diabetic retinopathy. The clinical presentation of this form of diabetic retinopathy may include microaneurysms, macular exudates, blot and dot hemorrhages, venous beading, and intraretinal microvascular anomalies.

Microaneurysms result from the loss of retinal capillary pericytes associated with the accumulation of advanced glycation end products. These are hyperpermeable and are associated with the loss of the inner blood-retinal barrier, leading to retinal exudation of plasma, lipids, and blood. A superficial, flame-shaped nerve fiber layer or a deeper “dot-and-blot” intraretinal hemorrhage can be seen. Macular edema, hard exudates, and hemorrhages can be identified ophthalmoscopically. Macular edema and retinal thickness can be assessed by optical coherence tomography, which generates cross-sectional images of the retina. Thrombosis of the microaneurysms (ischemia) manifest as cotton-wool spots. Retinal ischemia is accompanied by the release of vascular endothelial growth factor from the retina. The result is retinal neovascularization on the vitreous cortex (the hallmark of proliferative diabetic retinopathy) and increased retinal vascular permeability (33).

Proliferative diabetic retinopathy. This form of diabetic retinopathy is characterized by neovascularization at the disc (NVD) or neovascularization elsewhere (NVE) as well as vitreous hemorrhage that causes subacute or acute loss of vision.

The patient may complain of floaters or veils. These hemorrhages are due to retinal neovascularization that erupt onto the surface of the retina and then grow into the vitreous cortex “scaffold” causing hemorrhages every time the vitreous moves. Organization of hemorrhage on the vitreous cortex or formation of fibrovascular tissue on the vitreous cortex and retina can cause tractional retinal detachment and permanent loss of vision (112).

Table 6. Clinical Manifestations of Diabetic Retinopathy and Differences Between Nonproliferative and Proliferative Disease

The following is a modification of a classification given by The University of Wisconsin:

Diagnostic workup. Retinal ophthalmoscopic screening examinations are essential at least once a year to identify changes that would prompt intervention.

Stereoscopic photography has helped in the standardization of the classification and documentation of diabetic retinopathy. The sensitivity of detection of eye disease by photography is believed to be 89% (95% (CI): 80% to 98%), significantly better than for direct ophthalmoscopy (65%; 95% CI: 51% to 79%) (58; 27).

The Department of Ophthalmology and Visual Sciences at the University of Wisconsin-Madison released a wide collection of photograph slides with grading standards for diabetic retinopathy. These photographs are no longer available on its website but can be purchased on a CD for a nominal fee.

Imaging for diagnosis. Optical coherence tomography is an imaging technique that creates cross-sectional images of the macula, retinal nerve fiber layer, and optic nerve head; this imaging technique is helpful in disorders such as epiretinal membranes, macular holes (134), and vitreomacular traction (63). Finally, fluorescein angiography and indocyanine green angiography both have a major importance in the diagnosis of diabetic retinopathy and other vascular abnormalities (70).

Prevention. In an epidemiologic study of more than 2000 subjects, 11% with type 1 and 7% with type 2 diabetes were identified as having high-risk proliferative diabetic retinopathy, but they had not been seen by an ophthalmologist in the previous 2 years (75).

The risk of macular exudation, edema, and ischemia increases with poor control of blood glucose levels and blood pressure, dyslipidemia, anemia, and diabetic kidney disease.

Blood glucose control. The Diabetes Control and Complications Trial Research Group suggested that in primary prevention, intensive therapy with insulin reduced the adjusted mean risk for the development of retinopathy by 76% compared with conventional therapy and slowed the progression of retinopathy by 54% and reduced the development of proliferative or severe nonproliferative retinopathy by 47% (04).

Exercise alone reduces the concentration of HbA1C by about 0.65 points and should be strongly encouraged in diabetic patients. Risks of progressive nephropathy and neuropathy are also reduced with tight glucose control.

Blood pressure control has proven to help slow the progression in patients with diabetic retinopathy, along with progressive nephropathy and neuropathy (25; 24; 02). A 10 mmHg decrease in systolic blood pressure and 5 mmHg decrease in diastolic blood pressure has been reported with a 47% reduction of moderate visual loss and death from diabetes or stroke.

Lipid treatment. There is an association between the presence of hard exudates and increased serum cholesterol levels in patients taking insulin. This can lead to loss of vision from development of fibrosis or a lipid plaque in the foveal area (28).

Diabetic nephropathy control. Erythropoietin-sensitive anemia is associated with diabetic macular edema. Induced microalbuminuria and the arterial hypertension that often accompanies diabetic nephropathy can exacerbate the macular edema.

Photocoagulation. The Diabetic Retinopathy Study showed that retinal (scatter) photocoagulation significantly reduced severe visual loss (5/200 or worse) in high-risk eyes with significant disc neovascularization or neovascularization elsewhere with vitreous hemorrhage. The risk of legal blindness was reduced by 50% to 60%.

Management. The strongest elements in the treatment of diabetic retinopathy are controlling both blood sugar and blood pressure.

Surgical management. The main goals of vitreoretinal surgery in diabetic retinopathy are to remove media opacities, to completely relieve all tractional adhesions, and to apply adequate laser treatment to the retina (64).

When neovascularization is present with partial detachment of the vitreous, ophthalmologists recommend waiting 6 to 12 months before considering surgery for diabetic vitreous hemorrhage. But in eyes with vitreous hemorrhage and anterior segment neovascularization, waiting for clearance of the hemorrhage may cause irreversible damage. Therefore, vitrectomy with intraoperative laser therapy should be performed to allow adequate control of the retinopathy (03).

In addition to the aforementioned intensive glycemic and blood pressure control, ongoing research focuses on interfering with the ischemic process that leads to neovascularization and macular edema (31).

Laser photocoagulation has been, for many years, the standard treatment for diabetic retinopathy and macular edema. Over the past several years, however, there’s been a trend away from laser treatment in favor of anti-VEGF therapy. There are three drugs that are FDA-approved for intraocular use (ie, ranibizumab, pegaptanib, and aflibercept) and one used extensively off-label in clinical practices (bevacizumab) because of its low cost and equivalent effectiveness. These anti-VEGF drugs had been used as adjunct therapies to laser treatment, but there is an increasing trend towards using them as primary treatment for retinal neovascularization and diabetic macular edema (121; 54; 125). As with the treatment for wet macular degeneration, the anti-VEGF drugs require repeated injections that are a serious burden for both the administering physician and the patient (08).

Prognosis. Eyes with a better visual acuity before photocoagulation had a better visual prognosis than those with decreased visual acuity at the time of initial treatment (37).

Diabetic retinopathy remains a major cause of blindness. With the addition of pharmacotherapy, improved visual results with less vision loss may be possible.

Central retinal vein occlusion (CRVO)

Definition. Central retinal vein occlusion can present with disc edema accompanied by dilation and tortuosity of the retinal veins and macular edema of varying degrees (Mandell and Sharma 2005).

Etiology. The causes of central retinal vein occlusion can be classified into three categories: (1) external compression of the vein, (2) vascular disease or vasculitis, (3) thrombosis.

Pathogenesis and pathophysiology. Central retinal vein occlusion can be divided in nonischemic and ischemic types (103). There is an association of central retinal vein occlusion with:

Epidemiology. Venous occlusive disease is the most common disease seen in clinical practice. Its incidence is 2:1000 in patients older than 40 years of age and 5:1000 in patients older than 65 years of age.

Clinical presentation and diagnostic workup. Visual acuity ranges from hand motion to 20/20. In the case of an ischemic process, the common visual acuity is 20/100, and patients with a nonischemic process tend to be less severely affected unless there is macular edema (61). In ischemic central retinal vein occlusion, some studies have found a relative afferent pupillary defect (RAPD) greater than 1.2 log; in nonischemic patients the RAPD is usually absent. Visual fields may show peripheral constriction, and central scotomas are more common in ischemic central retinal vein occlusion cases with severe macular edema.

Fundus findings are typically seen with cotton-wool spots; the incidence of 10 or more is indicative of an increased risk of rubeosis (growth of new abnormal blood vessels formed by neovascularization found on the surface of the iris). Retinal hemorrhages, tortuous veins, and disc edema tend to disappear entirely after months. In some cases, microaneurysms can be seen with persistent macular edema and pigment irregularity.

Differential diagnosis. The diagnosis is clinical. The parameters that need to be assessed in the evaluation of the patient are visual acuity, degree of afferent pupillary defect, ophthalmoscopic findings, fluorescein angiography, and electroretinographic findings. Fluorescein angiography characteristically shows changes in vascular caliber and prolongation of filling after injection (113). Electroretinogram shows reduced B-wave amplitudes and prolonged B-wave implicit time.

Prevention. It is important to identify patients at risk with comorbidities, such as arterial hypertension, diabetes mellitus, hypercholesterolemia, previous cardiovascular accident, and heart disease.

Prognosis and complications. When the disease is mild and there is little vascular dilation and few retinal hemorrhages, the prognosis is good. On the other hand, the condition that presents with multiple hemorrhages, cotton-wool spots, macular edema, and retinal edema is likely to develop rubeosis iridis and neovascular glaucoma that is extremely hard to treat and often leads to a totally blind eye (126).

Management. Photocoagulation appears to be beneficial in preventing complications, but at the cost of destroying large areas of retina. Thrombolytic therapy and corticosteroids are added to prevent macular dysfunction. Once rubeosis develops, treatment becomes much more difficult. The reported outcome of a trial “to analyze the efficacy and safety of ranibizumab in eyes with preproliferative (ischemic) central retinal vein occlusion” was that “intravitreal ranibizumab therapy can improve retinal anatomy and vision in eyes with severe central retinal vein occlusion. Despite significant clinical benefit with antivascular endothelial growth factor therapy, the risk of neovascular complications was not ameliorated by vascular endothelial growth factor blockade but was merely delayed” (15).

The use of anti-VGEF agents for the treatment of macular edema has been more encouraging. In a study to evaluate intravitreal bevacizumab treatment in patients with central retinal vein occlusion, intravitreal bevacizumab treatment of macular edema due to central retinal vein occlusion improved standard morphological measures and electrophysiological function (47).

The Ophthalmic Technology Assessment Committee Retina/Vitreous panel of the American Academy of Ophthalmology reported Level I evidence that intravitreal anti-VEGF therapy is safe and efficient over 2 years for macular edema associated with central retinal vein occlusion. Delay in treatment was reported to be associated with worse visual outcomes. In addition, level 1 evidence showed the short-term efficacy of intravitreal corticosteroid but also showed that it was associated with a higher frequency of adverse events (142).

Currently there are two VEGF inhibitor agents that have been approved by the United States Food and Drug Administration and the European Medicine Agency for the treatment of central retinal vein occlusion: ranibizumab and aflibercept. Another VEGF inhibitor, bevacizumab, is also often used "off-label" because of price and effectiveness. The ideal treatment regimen has not been defined yet; however, several treatment regimens have been proposed in clinical trials, such as monthly and as-needed injections (17).

Branch retinal vein occlusion

Definition. Branch retinal vein occlusion is a common retinal vascular condition characterized by sectorial venous tortuosity, retinal hemorrhages, exudates, and, in some cases, macular edema (87).

Etiology. Compression of a retinal vein is believed to be the main cause of branch retinal vein occlusion. This compression of the vein is caused by a thickened artery due to atherosclerosis secondary to long-standing arterial hypertension. Inflammatory and thrombophilic conditions, such as sarcoidosis, Lyme disease, protein C deficiency antiphospholipid syndrome, lupus, gammopathies and others, can affect the retinal veins (105).

Pathogenesis and pathophysiology. Eyes with arteriovenous crossings seem to be at risk for branch retinal vein occlusion. Anatomic predisposition and comorbidity, hypertension, atherosclerosis, inflammatory or thrombotic disease may lead to retinal endovascular thrombosis (05).

Epidemiology. Branch and central vein occlusions are the second most common retinal vascular diseases, with a 1.1% prevalence in the population older than 40 years of age.

Clinical presentation. The patient typically presents with sudden, painless, decreased vision in the affected eye. Branch retinal vein occlusion can be described as acute or chronic with corresponding clinical findings, retinal hemorrhages, retinal edema, and cotton-wool spots (77). In the chronic stage, no hemorrhages are found, and some macular edema is the only sign (61).

Diagnostic workup. Most branch retinal vein occlusion cases are secondary to a microvascular disease. Occasionally, laboratory testing is necessary for those conditions mentioned in the etiology (98).

Differential diagnosis. The differential diagnosis should include hypertensive and diabetic retinopathy.

Prognosis and complications. In some cases, ocular neovascularization develops and, if untreated, leads to vitreous hemorrhage, retinal detachment, retinal breaks, or neovascular glaucoma and neovascularization at the disc (68). For this reason, fluorescein angiography is obtained 3 months after the event (once the hemorrhages have cleared) to check for neovascularization. Optical coherence tomography is helpful in the follow-up of the patient with macular edema secondary to branch retinal vein occlusion.

Management. Doses of 4 to 25 mg of intravitreal triamcinolone improve the branch retinal vein occlusion related macular edema. Scatter photocoagulation reduces neovascularization in 40% to 20% of patients (110; 100). Medical and surgical treatment options, such as intraocular injections of steroids and antivascular endothelial growth factor agents, sustained drug release devices, vitrectomy, and sheathotomy aim to reduce macular edema in the chronic stage (113).

Maculopathies

Maculopathies are distinct disorders that primarily involve the central portion of the retina known as the macula. Because of the similarity of symptoms, maculopathies are commonly confused with optic neuropathies. The common maculopathies are:

Age-related macular degeneration

Age-related macular degeneration is a degenerative disease of the macula characterized by age-related involutional changes at the level of the Bruch membrane and the retinal pigment epithelium. The hallmark lesions are choroidal yellow crystalline accumulations called drusen, which can be soft, hard, or laminar.

Etiology. Although age-related macular degeneration is believed to be an age-related problem, one literature review showed the following five concepts to be relevant to its cell biology:

Pathophysiology. Although the pathogenesis of age-related macular degeneration is not known, it is speculated that oxidative stress plays an important role (146).

Epidemiology. The prevalence of early age-related macular degeneration (drusen) is 18% of the population 65 to 74 years of age and 30% in the population older than 74 years of age. Ten percent of patients with age-related macular degeneration develop neovascularization.

Clinical presentation. Patients’ symptoms include metamorphopsia, scotomas (blind spots), or loss of central vision in the affected eye. Clinical examination reveals choroidal drusen, geographic (with irregular margins) atrophy of the retinal pigment epithelium, hard exudates bleeding, retinal pigment epithelium detachments, or grayish-green subretinal neovascular membrane.

Diagnostic workup. Clinical examination of the macula, optical coherence tomography, fluorescein angiography, and indocyanine green angiography are the techniques used to diagnose the stages of age-related macular degeneration.

Pharmaceutical trials are beginning to use other imaging systems such as scanning laser ophthalmoscopes, fundus autofluorescence, and preferential hyperacuity perimeters that allow the monitoring of treatment in a less invasive way. Although these systems seem to be useful, there are disadvantages, such as the need for new criteria and the low sensitivity and specificity in comparison to fluorescein angiography (119).

Prevention. The Age-Related Eye Disease Study (AREDS), a multicenter, randomized, placebo-controlled clinical trial demonstrated the beneficial effects of oral supplementation of high-dose antioxidant vitamins and minerals in decreasing the risk of advanced age-related macular degeneration by 25% (107).

After several revisions of the original study, when these data were analyzed, with appropriate correction for multiple statistical comparisons, it was found that “the AREDS supplements reduced the rate of age-related macular degeneration progression across all genotype groups. Furthermore, the genotypes at the complement factor H and age-related maculopathy susceptibility 2 loci did not statistically significantly alter the benefits of AREDS supplements.” Chew, in a very concise review of the age-related eye disease studies (AREDS and AREDS2), summarizes the main findings of these multi-centered studies designed to determine whether patients at risk for the neovascular macular degeneration benefited from vitamin supplements. The main conclusions for the overall experimental group suggested a 10% reduction in the chances of getting the more advanced forms of this disease for those taking the vitamins. Persons who are smokers or had a long history of smoking appeared to see 2 times greater risk for lung cancer by taking beta-carotene in the original ARADS formula. When beta-carotene was replaced with lutein and zeaxanthin in the AREDS2 formula, this risk went away.

Prognosis and complications. Age-related macular degeneration is one of the leading causes of blindness in developed countries and the most common cause of legal blindness in adults. The most dreaded complication is the development of neovascular complications, seen in 10% of patients. Among patients with choroidal neovascularization in one eye and geographic atrophy (retinal pigment epithelium changes) in the fellow eye, the cumulative incidence of choroidal neovascularization in the eye with geographic optic atrophy is 30% to 50% at approximately 5 years of follow up. Without the geographic atrophy changes, the fellow eye involvement in neovascular age-related macular degeneration is 12% per year. An anatomical relationship between the location of the retinal damage (scotoma) and retinotopic-specific damage to white matter within the optic radiations has been established using diffusion-weighted magnetic resonance imaging and tractography (144).

Aspirin and age-related macular degeneration. There have been contradictory reports on the influence of aspirin on age-related macular degeneration. On the basis of the current studies, data cannot definitely prove whether aspirin influences vision in these patients. The authors suggest regular vision checks in patients who are on aspirin in order to avoid possible risks of age-related macular degeneration development (90).

A cohort study within Comparison of Age-Related Macular Degeneration Treatment Trials (CATT) to evaluate the association between the use of antiplatelet or anticoagulant drugs and retinal or subretinal hemorrhage in patients with neovascular age-related macular degeneration revealed no significant association with hemorrhage, but there was significant association with hemorrhage in patients with hypertension (143).

Management. In the early stages of age-related macular degeneration, some recommend the use of antioxidant vitamins and minerals (107) and avoidance of sun exposure and smoking. The Macular Photocoagulation Study has shown the benefits of focal laser photocoagulation in various clinical scenarios.

Photodynamic therapy with verteporfin approved by the FDA in 2000 is reserved for the treatment of predominantly classic choroidal neovascularization associated with age-related macular degeneration but is expensive and only benefits a modest subgroup of patients with overall disappointing results (127).

Work with surgical excision of the choroidal neovascular membrane has shown that this is another viable alternative in select patients being studied in the Submacular Surgery Study, a multicenter, randomized, clinical trial.

Understanding the anatomy and physiology of the retina is critical to understanding macular degeneration. The retina is a very thin structure. At its thickest, it is only 300 µm. It is an extremely complex structure with approximately 100 million receptor cells devoted to night vision and 7 million receptor cells devoted to day vision and color vision. These are connected to approximately 1.3 million ganglion cells via bipolar cells with processing by horizontal cells and amacrine cells. The retina has a very high metabolic rate as evidenced by the fact that it is sandwiched between two blood supplies (choroidal and the retinal). The choroidal supply supports the receptor layer via the retinal pigment epithelium, which provides nutrients to the receptors and removes waste products. Any compromise of retinal pigment epithelium function leads to a destruction of the photoreceptors. This is most apparent in the macula, which gives us our reading acuity. Approximately 80% of macular degeneration is the “dry” type represented by gradual loss of photoreceptors and reductions in central acuity. Approximately 10% of the time the choroid responds to the vasogenic factors produced by the anoxic retina by producing new vessels (neovascularization). These grow into the retinal pigment epithelium and the potential subretinal space. These vessels are fragile and leak, giving rise to the so-called “wet” form of age-related macular degeneration.

Although age-related macular degeneration is non-neovascular in approximately 80% of cases, according to several studies, the neovascular form is responsible for about 90% of the cases in which the disease leads to severe visual loss of 20/200 or worse. According to the National Eye Institute, age-related macular degeneration is the leading cause of severe vision loss in people older than 65 years of age in the United States, and the advanced stage currently affects one or both eyes of 1.6 million Americans (07)

Currently, the primary tool to diagnose and follow patients with macular processes is optical coherence tomography. However, fluorescein angiogram and the indocyanine green angiogram are other available testing tools.

Options to treat wet-age-related macular degeneration include photodynamic therapy using verteporfin, intravitreal triamcinolone and anecortave acetate, and intravitreal anti-VEGF therapy, which inhibits vascular endothelial growth factor-A (VEGF-A), reducing permeability of neovascular vessels and helping to reduce vessel growth and leakage (106; 65).

The current anti-VEGF agents being used are ranibizumab and bevacizumab (106; 92). VEGF Trap-eye (VTE) has been added to this list (128). Bevacizumab and ranibizumab are monoclonal antibodies that neutralize all active forms of vascular endothelial growth factor-A; these agent have been evaluated for the treatment of neovascular age-related macular degeneration (106; 92).

Petaganib was the first VEGF antagonist to be approved by the US Food and Drug Administration for use in wet age-related macular degeneration. However, patients treated with petaganib still experience visual decline. For this reason, petaganib is seldom used now (53). Until recently, ranibizumab was the only other drug the United States FDA approved for treatment of age-related macular degeneration (07), and bevacizumab is approved for treatment of certain colon cancers. Bevacizumab inhibits the activity of VEGF. It has a similar action and is related to the ranibizumab compound with respect to its structure. Bevacizumab was approved by the FDA for the treatment of metastatic colorectal cancer in 2004, but it has not been licensed for the treatment of wet age-related macular degeneration or any other ocular condition.

The MARINA clinical trial was a minimally classic/occult trial of the anti-VEGF antibody ranibizumab in the treatment of neovascular age-related macular degeneration; 716 patients were enrolled. The study showed that intravitreal administration of ranibizumab for 2 years prevented vision loss and improved mean visual acuity, with low rates of serious adverse events, in patients with minimally classic or occult (with no classic lesions) choroidal neovascularization secondary to age-related macular degeneration. The benefits apply to all angiographic subtypes of neovascular age-related macular degeneration and across all lesion sizes (14; 45; 65; 108).

Aflibercept was granted approval for the treatment of subfoveal choroidal neovascularization, in November 2011. In contrast to the antibody-based VEGF binding strategy used by ranibizumab and bevacizumab, the VTE incorporates the second binding domain of the VEGFR-1 receptor and the third domain of the VEGFR-2 receptor (128). The approval was based on two concurrent age-related macular degeneration trials: the VIEW 1 trial, which enrolled 1217 patients in North American centers, and the VIEW 2 trial, which enrolled 1240 patients in South American, European, Asian, and Australian centers. All VTE investigational arms reached the primary endpoint--noninferiority for maintenance of vision (15 or fewer letters of vision loss) compared to ranibizumab. The advantage of aflibercept, is that the ocular injections for maintenance can be bimonthly compared to the standard of care, eg, monthly injections of bevacizumab (130). But the greater expense of aflibercept rules in favor of using bevacizumab for many patients. The problem with anti-VEGF monotherapy has always been, and remains, the necessity for monthly injections. The need for repeated treatments is a burden on the ophthalmologist providing the care and even more so on the patients and their families.

In an excellent review on all forms of ocular neovascularization, Campochiaro elucidates the molecular pathogenesis of subretinal and retinal neovascularization and then discusses targets for interrupting this process. Anti-vascular endothelial growth factor (anti-VEGF), anti-platelet derived growth factor (anti-PDGF), and agents that will target hypoxia inducible factor-1 (HIF-1) might be combined to produce a much more robust therapy against this devastating disease process than presently exists. He summarizes by saying “While substantial progress has been made, the future looks even brighter for patients with retinal and choroidal vascular diseases” (19). At the time of this update, a phase 3 safety and efficacy study of Fovista^® (E10030) intravitreous administration in combination with Lucentis^® compared to Lucentis^® monotherapy is under way. Further information on this topic can be found at ClinicalTrials.gov.

Considerable effort has gone into research to see if antiplatelet-derived growth factor anti-PDGF to anti-VEGF treatment might enhance the efficacy and prolong treatment intervals. Despite initial phase 1 and 2 trial results that were very promising, phase 3 trials have found “no benefit observed on addition of pegpleranib to monthly ranibizumab regimen for the treatment of wet age-related macular degeneration” (97).

Juvenile-onset macular degeneration

In contrast with age-related macular degeneration, juvenile-onset macular degeneration can result from a number of inherited diseases and may present early in childhood or later in life. Juvenile-onset macular degeneration can be classified by the pattern of inheritance: autosomal dominant (cone dystrophy, vitelliform macular dystrophy, North Carolina macular dystrophy, etc.), autosomal recessive (Stargardt disease and cone dystrophy), X-linked (X-linked retinoschisis), and mitochondrial (maternally inherited diabetes and deafness) (95).

Cone dystrophies

These are rare, typically autosomal dominant disorders of progressive cone dysfunction heralded by decreased central and color vision in the first 3 decades of life. On the basis of their natural history, the cone dystrophies may be broadly divided into two groups: stationary and progressive cone dystrophies. The stationary cone dystrophies have received more attention, and, subsequently, our knowledge of their molecular, genetic, psychophysical, and clinical characteristics is better developed. Various methods of classification have been proposed for the progressive cone dystrophies, but none is entirely satisfactory, largely because the underlying disease mechanisms are poorly understood. Multidisciplinary studies involving clinical assessment, molecular genetics, electrophysiology, and psychophysics should lead to an improved understanding of the pathogenesis of these disorders.

Pathophysiology. The cone dystrophies are a heterogeneous group of inherited disorders that result in dysfunction of the cone photoreceptors and sometimes their post-receptor pathways.

Epidemiology. This group of diseases consists of inherited conditions that present in early adulthood with a variable inheritance pattern.

Prevention. Genetic counseling may be of benefit for patients and their families.

Clinical presentation. The major clinical features of cone dystrophy are photophobia, photopsias (flashes), reduced visual acuity, subtle central scotoma, and abnormal color vision in both eyes. There is no relative afferent pupillary defect. Ophthalmoscopy is deceiving in early cases, but as the disease progresses, one can find central pigmentary macular changes and in other cases the classic bull’s eye maculopathy. In some cases, there may be findings of temporal disc pallor and arteriolar attenuation (118).

Diagnostic workup. ERG and multifocal ERG shows reduced or absent cone responses.

Prognosis and complications. The cone dystrophies can be stationary or progressive, and some of the genes have been identified in various pedigrees. Most patients have visual decline to the 20/200 level in their 30s.

Management. Genetic studies are recommended in pedigrees and among members of the same family. Tinted lenses may help reduce the photophobia.

Best disease (vitelliform macular dystrophy, VMD2)

Best disease is a maculopathy that presents in childhood with the striking appearance of a yellow or orange yolk-like lesion in the macula. Dr. Franz Best, a German ophthalmologist, described the first pedigree in 1905 (12).

Etiology. Best disease is autosomal dominant with variable penetrance. The mutation is in the BEST1 gene, previously known as VMD2; it is found on the long arm of chromosome 11 (11q12-q13) and encodes a protein known as bestrophin-1, which functions as a calcium-dependent chloride transport protein in the retinal pigment epithelium. Mutations lead to accumulation of lipofuscin within and beneath the retinal pigment epithelium and result in the characteristic bilateral egg yolk appearance of the macula (95).

Pathophysiology. Abnormalities in the eye result from a disorder in the retinal pigment epithelium. Lipofuscin accumulates within the retinal pigment epithelium cells and in the sub-retinal pigment epithelium space, particularly in the foveal area. The retinal pigment epithelium appears to have degenerative changes in some cases with secondary loss of photoreceptors.

Epidemiology. Best disease is found in individuals of European, African, and Hispanic ancestry. No known gender predilection exists. Usual onset is between 3 and 15 years of age, with an average age of 6 years. The condition often is not detected until much later (fundus abnormalities associated with Best disease are visible within the first 2 decades of life), and visual acuity may remain good for many years. Approximately 5% of patients who carry a mutation in the bestrophin-1 gene have normal or minimally abnormal macular findings despite their genotype.

Prevention. Evaluation of family members is important for identification of carriers and individuals with the dystrophy. Both genetic counseling and career counseling should be provided.

Clinical presentation. Many patients initially are asymptomatic, with fundus lesions noted on examination. Visual symptoms can include decreased acuity (blurring) and metamorphopsia. These symptoms may worsen if the disease progresses to the atrophic stage. Hyperopia is common.

Best disease has been characterized as progressing through five stages: pre-vitelliform, vitelliform, pseudohypopyon, vitelliruptive, and atrophic (95). Findings usually are bilateral and can be asymmetric. Vision varies among stages of the disease. In the pre-vitelliform stage, visual acuity can be approximately 20/20; in the vitelliform stage with egg-yolk appearance, visual acuity can be approximately 20/50. The vitelliruptive stage, which is the break-up of the vitelliform stage, leads to the "scrambled egg" stage and may be accompanied by visual acuity deterioration.

It is the final stages of geographic retinal pigment epithelium atrophy with possible development of choroidal neovascular membrane that is associated with further deterioration in acuity. The atrophic stage usually occurs after 40 years of age.

Diagnostic workup. A hallmark of the disease is a clinically normal ERG and markedly abnormal electro-oculogram, with a reduced or nonexistent light to dark ratio (95). The optical coherence tomography also shows characteristic changes.

Prognosis and complications. The lesion evolves through several stages over many years, with increasing potential for adverse visual outcome. These patients can develop neovascularization and scarring with permanent severe visual loss. In general, most affected patients will maintain reading vision in at least one eye throughout life. In a study, 88% of patients retained 20/40 or better visual acuity, and only 4% of them had 20/200 or worse visual acuity in the better eye. The deterioration of vision usually is very slow and is not significant in most individuals until after 40 years of age.

Management. No treatment exists for vitelliform macular dystrophy. Secondary choroidal neovascularization can be managed with direct laser treatment and anti-VEGF injections. A phenotypically similar adult-onset form of this disease (adult-onset vitelliform macular dystrophy, AVMD) also exists. The genetics of AVMD are not fully understood, but it is sometimes associated with the PRPH2 gene. Age of onset is a major criterion for distinguishing VMD2 from AVMD. AVMD is also usually less debilitating. Genetic testing for these genes is now readily available at very reasonable prices and is advised when identifying nonphenotypic carriers or when genetic counseling is desired (102; 89).

Central areolar choroidal dystrophy

Etiology. Central areolar choroidal dystrophy is inherited as an autosomal dominant trait and shows genetic heterogeneity.

Pathophysiology. Mutations in the peripherin-RDS gene on chromosome 6 have been reported in affected members of families transmitting the disease. A new locus at chromosome 17p13 was identified by a genome-wide linkage search in members of a large Northern Irish family (79).

Epidemiology. Central areolar choroidal dystrophy is an inherited condition.

Prevention. Genetic counseling may be of benefit for patients and their families.

Clinical presentation. Central choroidal dystrophy is characterized by lack of large parts of the central choroid. In the dystrophic region, outer retinal layers also are involved, whereas inner retinal layers may be unaffected. These cases are predominantly bilateral asymmetrical, with a few case reports of unilateral disease. The patients have metamorphopsia and reduced central acuity in their 40s, which progresses to severe central visual loss in their 60s. Initial ophthalmoscopy shows mottling of the retinal pigment epithelium in the macular area with granularity; but in later stages, circular zones of retinal pigment epithelium and choriocapillary atrophy are evident.

Diagnostic workup. The visual field test shows bilateral temporal scotomas simulating a bitemporal hemianopia. The amplitude of the electroretinogram initially is normal, and late in the disease is reduced according to the extent of the defect in the neurosensory epithelium. Multifocal ERG identifies the defective areas of the macula earlier, and these appear as depressed responses (40).

Fluorescein angiography identifies areas of hyperfluorescence with easy visualization of the large choroidal vessels.

Prognosis and complications. Patients will be legally blind with irreversible macular changes by the time they reach their 50s or 60s.

Management. Genetic counseling may be of benefit for patients and their families.

Stargardt disease (fundus flavimaculatus)

Etiology. Stargardt disease is the most common cause of autosomal retinal disease in humans. The disease is caused by a mutation in the ABCA4 gene located in the short arm of chromosome 1 (57).

Pathophysiology. The gene ABCA4 codes for a member of the ABC transmembrane protein located in the rim of the photoreceptor discs and is involved in the transport of all-trans retinal through the disc membrane. ABCA4 protein dysfunction causes accumulation of all-trans retinal in the photoreceptors and in the retinal pigment epithelium. All-trans retinal is then converted to N-retinylidene-N-retinylethanolamine (A2E), a major component of lipofuscin, which is toxic to the retinal pigment epithelium and photoreceptors. With the progression of the disease, the accumulated lipofuscin causes cellular damage to the retinal pigment epithelium, which leads to atrophy of the retinal pigment epithelium, photoreceptors, and choriocapillaris (57).

Epidemiology. Molecular genetic studies indicate that Stargardt disease and fundus flavimaculatus may represent a spectrum of the same disease (55). The disease affects individuals of any sex, race, and age, affecting approximately 1 in 8000 to 1 in 10,000 people in the United States (57).

Prevention. Genetic counseling may be of benefit for patients and their families.

Clinical presentation. Stargardt disease presents in patients between 10 and 20 years of age with slowly progressive bilateral vision loss, which can range from 20/30 to 20/200. Later in life, there is night blindness and acquired red-green dyschromatopsia.

Noble and Carr used the fundus appearance at the time of the presentation to classify the disease into four types: macular degeneration without flecks, macular degeneration with perifoveal flecks, macular degeneration with diffuse flecks, and diffuse flecks without macular degeneration. In any patient, the type of disease can change to another as the disease progresses (57).

The hallmark of the disease is the yellowish-white-colored flecks at the level of the retinal pigment epithelium. The flecks are usually present in the posterior pole, inside and outside the macula. These fish-like flecks can appear similar to drusen; however, they are usually irregular in shape, and they do not fluoresce with fluorescein angiography. The flecks evolve following a pattern of radial expansion from the fovea to the periphery. Macular pigmentary changes may present or can develop later in the disease course. Retinal pigment epithelium atrophy is commonly seen in the macula around the fovea, giving the bull’s eye appearance to the macula. In later stages, patients can develop atrophy of the extramacular retinal pigment epithelium and choriocapillaris (57).

Fundus exam shows a “beaten bronze” appearance in the macula. Later, geographic atrophy is noted. Some patients present with flecks in the posterior pole up to the equator.

Diagnostic workup. Stargardt disease is usually diagnosed from clinical findings, particularly the appearance of the ocular fundus. Fundus autofluorescence visualizes distribution of lipofuscin in the retinal pigment epithelium, which is increased in the fundi of patients with Stargardt disease (57). Fluorescein angiogram shows obscuring of choroidal fluorescence, which is described as the “dark choroid or choroidal silence” effect. Electro-oculogram is abnormal, and ERG is normal early in the disease. Optical coherence tomography shows characteristic findings. A genotyping microarray has been designed and is capable of detecting 400 variants of ABCA4 gene. In a Stargardt cohort study, the efficiency of the array to detect disease-associated alleles was 54% to 78% (57).

Prognosis and complications. Most patients have reduced visual acuity of 20/200 or worse by the third decade of life. Ophthalmologists should encourage patients with Stargardt to wear dark glasses and hats when exposed to prolonged bright light to reduce the rate of formation of all-trans retinol in photoreceptors. High-dose vitamin A supplements, including AREDS vitamins, should be avoided due to their potential to increase formation of bisretinoids in the retina (57).

Management. Currently, there is no treatment available for patients with Stargardt disease. However, there is ongoing research in genetics, disease mechanism, gene therapy, and cell replacement. Transplant of stem cell retinal pigment epithelium, intravitreous injection of dobesilate (synthetic fibroblast growth factor inhibitor), and topical ramipiril 2% have been used on patients with Stargardt disease with reports of improvement of visual acuity. However, the safety and efficacy of these interventions have not been demonstrated in a large number of patients (57).

Juvenile retinoschisis

Juvenile retinoschisis is an X-linked disorder characterized by visual distortion and classic foveal schisis (separation of retinal layers) or spoke-wheel appearance of the macula.

Etiology. X-linked juvenile retinoschisis has been related to a mutation in the gene RS1 (117).

Prevalence. Estimates of the prevalence of X-linked juvenile retinoschisis vary from 1 in 5000 to 1 in 25,000 (117).

Clinical presentation. The disease presents in the first decade of life, in some cases as early as 3 months of age. Affected males typically have vision of 20/60 to 20/120 on first presentation. Visual acuity may deteriorate during the first and second decades of life, but then remain relatively stable, with very slow progressive reduction from macular atrophy until the fifth or sixth decade.

Appearance of foveal lesions varies from largely radial striations, microcystic lesions, and honeycomb-like cysts to noncystic appearing foveal changes, including pigment mottling, loss of the foveal reflex, or an atrophic-appearing lesion (117).

Diagnosis. The diagnosis is made in a young male with bilaterally reduced visual acuity, abnormal fundus exam, foveal schisis and thinning of the retina on spectral domain optical coherence tomography, family history consistent with X-linked inheritance, and a pathogenic variant in RS1.

The findings on fundus examination are as follows: areas of schisis in the macula in a spoke wheel pattern, schisis of the peripheral retina predominantly inferotemporally, and, on occasion, the Mizou phenomenon (color change in the retina after dark adaptation with the onset of light) (117).

Management. Currently there is no available treatment for X-linked retinoschisis. Treatments like gene therapy are currently under investigation (117).

Familial drusen

The macula of these patients contain drusen that are bilateral and numerous, and they tend to coalesce and cause visual distortion. The condition can evolve into choroidal neovascularization and severe loss of central vision.

Central serous chorioretinopathy

Central serous chorioretinopathy is a disorder characterized by the development of a small, shallow neurosensory detachment in the central macula.

Etiology. The etiology of central serous chorioretinopathy is controversial. It has been suggested that corticosteroids may act as an inciting drug (21). Also noted is a predominance of type A behavioral characteristics in affected patients.

Pathophysiology. An alteration of the retinal pigment epithelium is believed by many to be the inciting event. Others think that an abnormality in the choroidal circulation with choriocapillaris hyperpermeability is the problem. Studies with multifocal electroretinography have demonstrated bilateral diffuse retinal dysfunction when the disease is active only in one eye. These studies support the belief of diffuse systemic effect on the choroidal vasculature. Indocyanine green angiography has shown both multifocal choroidal hyperpermeability and hypofluorescent areas suggestive of focal choroidal vascular compromise. Some believe that initial choroidal vascular compromise subsequently leads to secondary dysfunction of the overlying retinal pigment epithelium. For an expanded discussion of the pathophysiology of central serous chorioretinopathy, the reader is referred to a survey article on this topic (94).

Epidemiology. Central serous chorioretinopathy is a disease of young men with A-type personality and is associated with the use of steroids as well as with systemic hypertension. It appears uncommon among African Americans but may be particularly severe among Hispanics and Asians. It is common in male patients aged 20 to 55 years. This condition affects men 6 to 10 times more often than it affects women.

A strong association with pregnancy seems to be related to the presence of subretinal fibrinous exudates (75% to 100%) (109). One study found that pregnancy is a risk factor strongly associated with the development of central serous chorioretinopathy (odds ratio of 7.1 in pregnant women versus their age-matched counterparts with no history of pregnancy) (56).

Clinical presentation. Patients present with acute, painless loss of vision in one eye with distortion (metamorphopsia and micropsia) and central positive scotoma. There is usually no relative afferent pupillary defect; photostress test is delayed; and changes in the macula of elevation due to fluid can be easily missed in an undilated eye exam. The condition is the result of abnormal leakage of fluid from the choroid into the subretinal spaces.

Diagnostic workup. The best clinical diagnostic test is slit lamp biomicroscopy with high magnification, which will show loss of foveal reflex associated with a round, well-demarcated serous elevation of the neurosensory retina. Optical coherence tomography is especially helpful in identifying subtle, even subclinical, neurosensory macular detachments.

Fluorescein angiogram shows the retinal pigment epithelium leak or leaks and the characteristic neurosensory detachment in the macular area (78). Indocyanine green angiography may show multiple areas of leakage that are not evident clinically or on fluorescein angiography.

Prevention. Suggested preventive measures include stress reduction, smoking cessation, steroid avoidance, and high blood pressure control. Systemic associations include exogenous steroid use, endogenous hypercortisolism (Cushing syndrome), systemic arterial hypertension, systemic lupus erythematosus, pregnancy, gastroesophageal reflux disease, use of sildenafil citrate, organ transplantation, and use of psychotropic medications (56).

Prognosis and complications. Although the disease seems to be self-limited, even when it resolves it leaves patients with some degree of visual distortion.

Prospective randomized clinical trials using focal laser photocoagulation directed at the site of the leakage have demonstrated shortening of the course of the disease, but no long-term visual benefit or decrease in the rate of recurrence or development of chronic disease. Recurrence is seen in 40% to 50% of patients. A subset of patients (5% to 10%) may fail to recover 20/30 or better visual acuity. These patients often have recurrent or chronic serous retinal detachments, resulting in progressive retinal pigment epithelium atrophy and permanent visual loss to 20/200 or worse. The final clinical picture represents diffuse retinal pigment epitheliopathy.

Risk of choroidal neovascularization from previous central serous chorioretinopathy is considered small (less than 5%) but has an increasing frequency in older patients diagnosed with central serous chorioretinopathy.

Patients treated with steroids are at risk of worsening their disease course, and this type of treatment is contraindicated. For this reason, it is very important not to confuse this entity with an episode of optic neuritis.

Management. Most cases resolve spontaneously within 2 to 6 months. Treatment with steroids worsens the condition and is, therefore, contraindicated. Some evidence suggests that patients with chronic central serous chorioretinopathy (diffuse retinal pigment epitheliopathy) may have better prognosis with laser treatment. Intravitreal bevacizumab injection for the treatment of chronic central serous chorioretinopathy has also been explored. Five eyes in five patients with chronic central serous chorioretinopathy were intravitreally injected with bevacizumab. The intravitreal injection of bevacizumab was well tolerated and resulted in reduced foveal thickness and a modest improvement in acuity (69).

Cystoid macular edema

This is a common ocular abnormality characterized by fluid accumulating in the outer plexiform layer of the retina.

Etiology. There are multiple causes, such as cataract surgery (most common), diabetes, chronic uveitis, retinal vein occlusion, radiation, and severe arterial hypertension, among others.

Pathophysiology. Prostaglandins have been singled out as the most likely inflammatory mediators involved due to their tendency to increase capillary permeability.

Epidemiology. The most common type, associated with cataract surgery, occurs 4 to 12 weeks after surgery and most often resolves without treatment (66).

In diabetics, cystoid macular edema needs to be distinguished from clinically significant macular edema where there is thickening of the macula and ischemic maculopathy due to perfusion abnormalities.

Prevention. During cataract surgery, preventing vitreous loss and using UV blocking intraocular lenses are helpful in reducing the incidence.

Clinical presentation. Patients complain of blurred central vision with distortion, difficulty reading, and small shallow scotomas. There is usually no relative afferent pupillary defect.

Diagnostic workup. Contact lens biomicroscopy reveals absence of the foveal reflex, and on occasion the macular edema is visible. Most cases require fluorescein angiography, which shows the classic petaloid (like a flower’s petals) pattern of fluid accumulation in the outer plexiform and inner nuclear layer in the affected eye. Optical coherence tomography can also show characteristic cystic changes.

Studies performed by Fine and Brucker and confirmed by Yanoff and colleagues suggested that Müller cells’ intracytoplasmic swelling leading to liquefaction necrosis can be correlated to this petaloid configuration (42; 141).

Prognosis and complications. Most cases resolve spontaneously if related to cataract surgery. Some cases have a chronic course that leads to subsequent photoreceptor loss. On occasion, the cystic spaces coalesce and advance to produce a lamellar macular hole causing loss of vision.

Management. Nonsteroidal anti-inflammatory agents, topical or periocular steroids, and oral acetazolamide and pars plana vitrectomy have been tried with variable success. The use of ranibizumab in the treatment of patients with diabetic macular edema is currently undergoing a number of clinical trials with an emphasis on using it in combination with other treatments. The initial results appear encouraging (10; 54).

Diabetic macular edema revisited

Diabetic retinopathy is a leading cause of vision loss in working-age patients around the world. Diabetic retinopathy is related to 1% of all cases of blindness worldwide. The main cause of vision impairment in diabetic patients is diabetic macular edema (125); hence, there has been a growing focus on its treatment. Anti-VEGF ocular injections have proved effective in reducing diabetic macular edema and significantly improving visual acuity. Both ranibizumab and bevacizumab proved effective with the caveat that prolonged frequent treatments are necessary (36; 125).

Toxic macular edema

Fingolimod is a sphingosine-1-phosphate receptor modulator released in the United States in September 2010 as an oral drug for the treatment of relapsing-remitting multiple sclerosis to reduce the frequency of clinical exacerbations at a dose of 0.5 mg daily.

Fingolimod has been associated with macular edema. In multiple sclerosis controlled studies involving 1204 patients treated with fingolimod 0.5 mg, macular edema occurred in 0.4% of patients predominantly in the first 3 to 4 months of therapy (73).

In two double-blinded, randomized controlled studies, macular edema was reported in a total of 13 patients (30). In the FREEDOMS study, seven patients were noted to have macular edema. All seven patients were receiving 1.25 mg of fingolimod (n=429). In five of the seven patients, the macular edema occurred within 3 months of starting therapy. In the TRANSFORMS study, a total of six patients developed macular edema. Four of these patients were receiving the 1.25 mg dose of fingolimod (n=420), and two of the patients were receiving the 0.5 mg dose of fingolimod (n=429). The macular edema occurred within 4 months of initiating treatment in five of the patients. Four patients had complete resolution of the macular edema within 3 months of discontinuing the medication. No patients who developed macular edema in either study were re-challenged with the medication. In patients with uveitis and diabetes mellitus, risk of macular edema is increased. When these conditions are associated with multiple sclerosis, fingolimod should be used with caution.

Due to the above findings, an eye exam should be performed at baseline and 3 to 4 months after treatment initiation. If patients report visual disturbances at any time during therapy, an additional eye exam is needed.

Macular holes

Degeneration of the inner retinal layers at the central fovea may predispose the eye to macular hole formation. Current imaging studies, especially using optical coherence tomography, indicate a likelihood that focal anteroposterior traction mechanisms are related to hole formation (120).

Macular holes have been described in association with direct trauma to the eye, severe arterial hypertension, accidental laser burns, and proliferative diabetic retinopathy among other etiologies. Several clinical stages have been described, from stage 1A to 4; these are important for deciding on treatment algorithms. A clinical challenge has been to accurately diagnose early macular holes. This is being facilitated by the use of the optical coherence tomography instrument. The theoretical mechanism concepts have implications for the type of macular hole surgery to be used in a particular patient.

Optic disc edema with a macular star (ODEMS)

Strictly speaking, the macular star associated with edema of the optic disc is not a macular disease. The acronym ODEMS has come to replace the older term for this condition, Leber idiopathic stellate neuroretinitis. This entity is typically a unilateral neuroretinitis with exudates in the outer plexiform layer (Henle nerve fiber layer) that surrounds the macula, producing a star-like configuration that can be either complete or partial.

Etiology. Anything that causes optic disc edema can lead to a leakage of plasma and lipid products that surrounds the macula, producing a star. A partial list from the literature includes hypertensive retinopathy (111), Rocky Mountain spotted fever (133), cat-scratch disease (123), and tuberculous neuroretinitis (124). Sarcoidosis and systemic lupus are also known to produce this condition. For the purposes of this discussion, we will focus on cat-scratch disease because it frequently presents in young individuals and can be confused with the optic neuritis associated with multiple sclerosis. A macular star may take several days to form after onset of the other signs and symptoms. If a macular star is present, multiple sclerosis should not be a primary concern.

Pathophysiology. Edema at the nerve results in exudates being deposited in the outer plexiform layer (Henle nerve fiber layer) that surrounds the macula.

Epidemiology. Bartonella henselae is a gram-negative bacillus that has been associated with a self-limiting lymphadenopathy associated with a cat scratch or bite.

Clinical presentation. In humans, a small erythematous papule occurs in upwards of half of infected individuals at the site of inoculation, followed by symptoms of fever, malaise, fatigue, and lymphadenopathy during the following days or weeks. These are typically self-limiting. The eye is the most commonly infected non-lymphatic organ in patients with cat-scratch disease. However, not all patients demonstrate the prodromal symptoms or a history of cat or flea exposure (34).

Diagnostic workup. Diagnosis of cat-scratch disease is straightforward when typical neuroretinitis and macular star formation are both present. The star formation may not develop for several days following the initial onset, however. A history of prodromal symptoms, lymphadenopathy, and cat exposure is helpful. Serologic evaluation for anti-B henselae antibodies can aid in the diagnosis (129).

Prognosis and complications. This condition is typically self-limiting, and full recovery without treatment is the norm. Antibiotic therapy appears efficacious in immune-depressed patients, however.

Pigmented lesions of the retina

Two layers of the retina contain melanin, the retinal pigment epithelium and the choroid. The amount of pigment in both layers is highly correlated with the overall pigmentation of the individual. Very lightly complexioned individuals may have little or no pigment (eg, a person of northern European descent), and very darkly pigmented individuals will have a great deal (eg, African descent). Any disruption of these layers, regardless of etiology, is likely to give rise to maldistribution of pigment and, hence, a pigmented lesion. Toxoplasmosis is the archetypical example of an infectious inflammatory condition that frequently produces a significant pigmentary disruption of the retina, with a predilection for the posterior pole.

Toxoplasmosis

Toxoplasma gondii is an obligate intracellular protozoan parasite that infects a wide range of warm-blooded animals, including humans.

Epidemiology. T gondii has a complex life cycle. The asexual cycle can occur in almost any warm-blooded animal and is characterized by the establishment of a chronic infection in which rapidly dividing tachyzoites differentiate into bradyzoites that persist within the host tissues. The sexual cycle of this organism results in excretion of infectious oocysts in feces. Cats, both domestic and wild, are the definitive host for this reproductive cycle.

Etiology. It is thought that ingestion of bradyzoites in raw or undercooked infected meat is an important transmission route of Toxoplasma. People from cultures that are typically vegetarian do not appear to be less frequently infected, suggesting that other vectors exist. These may include eggs, unpasteurized milk, unwashed fruits and vegetables, and drinking water. Most ocular manifestations of toxoplasmosis are thought to be the result of an acquired disease in utero. This is thought to be true even when the ocular manifestations have an adult onset. Transplacental transmission of T gondii to the fetus occurs only with new-onset maternal infection. The growing impression, however, is that some ocular sequelae do occur with postnatally acquired disease, especially in the immune-suppressed patient.

Clinical presentation and diagnosis. The diagnosis of ocular toxoplasmosis is often made by clinical examination alone (76). Although not strictly pathognomonic, the fundus appearance is often so typical that it and the case history are sufficient. Serologic studies may be helpful in some cases, but a positive serology does not, in itself, confirm the diagnosis because of the very high rate of seropositive individuals found worldwide. A negative serology can assist in eliminating the disease from the differential list, but false negatives do occur. The active and cicatricial forms of toxoplasmosis present very differently. The active phase presents with a well-demarcated retinal necrosis (148). A granulomatous reaction in the choroid appears as a white elevated lesion surrounded by an inflammatory cell reaction in the retina and vitreous, giving rise to the description of the ophthalmoscopic presentation as a "headlight in the fog." The cicatricial phase is void of cellular debris and presents as hyper- and hypopigmentation at the level of the choroid and retinal pigment epithelium accompanied by white fibrotic tissue. These lesions have a predilection for the posterior pole with devastating consequences for visual acuity.

Differential diagnosis. The differential for toxoplasmosis in an adult includes syphilis, sarcoidosis, pars planitis, retinal necrosis, endogenous bacterial or fungal infection, and tubercular chorioretinitis.

Treatment. Toxoplasmic chorioretinitis in immunocompetent individuals often does not require treatment, as the ocular manifestations are frequently self-limiting. An exception is made if the lesion is sight-threatening (eg, involving the macula). The potential benefits of treatment need to be balanced against the risks associated with therapy as the drugs that are used have serious side effects. These drugs include pyrimethamine, sulfadiazine, clindamycin, and prednisone, and two, three, or all four of these drugs can be used in combination. No treatment is efficacious when the disease is inactive.

Benign pigmented lesions of the retina

There are three benign retinal lesions that deserve mentioning because their appearance can cause unnecessary concern. All three involve an increase in the amount of pigment in the retina but without insult to the retinal tissue.

Congenital hypertrophy of the retinal pigment epithelium (CHRPE). CHRPE lesions are found in 1% to 2% of the general population. They are well-demarcated pigmented lesions in the retinal pigment epithelium and can present in three different ways. They are usually asymptomatic and detected only on routine fundus examination.

The first type is the typical unifocal CHRPE. It is a gray to black, well defined, minimally elevated fundus lesion in the retinal pigment epithelium having a diameter in the range of 2 to 6 mm. (The average optic nerve is 1.5 mm in diameter.)

Pathology. The retinal pigment epithelium (RPE) cells are thicker than those of the surrounding RPE and when pigmented look darker that the adjacent RPE. They can also present as lighter than the surrounding RPE due to a loss of pigment in the affected RPE cells. These lighter areas within the CHRPE are called lacunae and appear to grow with age. Studies with OCT scanning laser show a significant loss of receptor cells in the overlying neural retina, which produces an absolute scotoma (116).

The second type of CHRPE is unilateral, multifocal, clustered lesions of hypertrophy that are sometimes called "bear tracks." These first two presentations are probably not associated with familial adenomatous colorectal polyposis (Gardner syndrome). When the pigmented lesions are bilateral, widely dispersed, (occurrence in multiple quadrants), pisiform shaped, have irregular borders, and present with a depigmented halo around them, the association with colon polyposis and Gardner syndrome becomes much stronger. Care must be exercised when interpreting pigmented fundus lesions of the RPE in order to ascertain that they are truly CHRPE and the type associated with colon cancer (26).

Differential diagnosis. The two most common differentials are a hyperplasia due to a disruption of the RPE or choroid (as with toxoplasmosis) and choroidal nevi.

Treatment. No treatment of these lesions is required except to photograph and follow them for change. Any significant change would suggest an alternative diagnosis. Identification of patients with familial adenomatous polyposis–associated CHRPE from de novo APC mutations is especially important as there is a high probability of invasive adenocarcinoma at a younger age prior to the initiation of average-risk screening colonoscopies (35).

Choroidal nevi. Choroidal nevi are made up of a benign proliferation of melanocytes in the normally pigmented choroid. Because they are beneath the pigmented RPE they often appear slate gray with feathery borders and can be completely hidden by a well-pigmented RPE when viewed with visible light (but remain visible with infrared imaging of the type used for viewing in non-mydriatic fundus cameras and instruments like the Zeiss OCT.) Most choroidal nevi are 5 mm or less in diameter and 1 mm or less in thickness, but they can attain a diameter of 10 mm or more, and a thickness of 3 mm or more. Because the chief concern about nevi as malignancy, larger nevi garner more attention. Drusen are often seen in the overlying RPE layer above a nevus. These suggest that the increased number of melanocytes have compromised the RPE, possibly due to a decrease in nutrients available to the RPE in that area. Although this compromise to the RPE in itself is not good, the presence of drusen can be taken as a sign that the nevus is long-standing and, by extrapolation, absent malignant growth. Shields and colleagues have examined the neural retina overlying choroidal nevi in 120 eyes of 120 patients. Their findings include the following: overlying retina edema (15%), subretinal fluid (26%), retinal thinning (22%), drusen (41%), and RPE detachment (12%). The overlying retina thickness was normal (32%), thinned (22%), or thickened (45%), with photoreceptor loss or attenuation noted in 51% of cases (115).

These data show that the overlying retina is often compromised by nevi but not to the extent that it is in CHRPE. Size is a concern because of the risk for malignancy in the larger lesions. There is considerable size overlap between larger nevi and smaller melanomas. Attempts to classify melanocytic choroidal tumors as benign versus malignant on the basis of tumor size can result in significant false-positive and false-negative errors (06).

Diagnostic testing. Choroidal nevi that raise the suspicion for malignancy can be further evaluated by ultrasonography and fluorescein angiography. Ultrasonography can assess the thickness of the lesion, identify its reflectivity pattern, and rule out scleral invasion and transscleral tumor extension. Fluorescein angiography and indocyanine green angiography can assess the presence of prominent blood vessels within the tumor. Most choroidal nevi do not have prominent intralesional blood vessels; most choroidal melanomas do. Consequently, most choroidal nevi appear totally hypofluorescent throughout the angiogram except where drusen and retinal pigment epithelial depigmentation has occurred. Fine-needle biopsy can be used to determine the pathologic nature of the tumor before therapeutic intervention.

Treatment. The treatment of choice is to photograph and follow these lesions.

Differential diagnosis. The most important differential is a malignant tumor of the choroid. Because the prognosis for metastasis does not appear to change with treatment, these tumors are often documented and followed until vision or ocular comfort are compromised, even if malignancy is suspected.

Melanocytoma. Melanocytoma can be considered a subset of a choroidal (uveal tract) nevus. They arise out of the optic nerve and can obscure the view of the nerve when they are large. They are dark brown to jet-black. Histopathologically, melanocytomas are composed of intensely pigmented round to oval nevus cells with benign features. They are typically relatively stationery lesions but have been shown to exhibit some enlargement in 10% to 15% of cases and can cause minor visual loss, eg, enlargement of the blind spot in the visual field. In rare instance, they can induce severe visual loss due to spontaneous necrosis of the lesion or compressive optic neuropathy. Approximately 1% to 2% of these lesions have shown transformation to malignancy (116).

Diagnosis. The diagnosis is made by clinical appearance.

Treatment. Melanocytomas should be photographed and followed for growth. Very slow growth may occur. Rapid growth would suggest a melanoma.

Peripheral retinal disorders

Rod-cone dystrophies or retinitis pigmentosa

This is a group of hereditary retinal conditions with a variable inheritance pattern in which the patients present with slowly progressive peripheral vision loss and prominent night blindness.

Genetics. Pedigrees have been found that have mutations in the rhodopsin or peripherin gene.

Clinical presentation. Patients complain of progressive night blindness and constriction of the peripheral visual fields, and clinical examination shows variable visual acuity with ring scotomas on perimetry that progress to tunnel vision in late stages. In young children, the presenting symptoms are limited to photophobia, so early screening is recommended when there is family history of such disorders. The fundus shows pigmentary changes known as bone spicules, and ultimately the condition causes thinning of the arterioles and waxy optic atrophy as secondary phenomena.

Diagnostic workup. The test used for diagnosis is the full-field ERG, which is attenuated flat. ERG changes can precede ophthalmoscopically visible fundus disease in all genetic patterns.

Prognosis and complications. Retinitis pigmentosa leads invariably to blindness.

Management. Low vision aids may enhance visual acuity.

Systemic associations. Retinitis pigmentosa may be associated with a wide variety of systemic conditions constituting specific syndromes such as Usher syndrome (deafness+ retinitis pigmentosa), Refsum disease (cerebellar ataxia + peripheral neuropathy + retinitis pigmentosa), Bassen-Kornsweig disease or abetalipoproteinemia (ataxia + retinitis pigmentosa), and Lawrence-Moon-Biedl syndrome (mental retardation + spastic paraplegia + hypogenitalism + retinitis pigmentosa).

Associations with mitochondrial diseases

Kearns-Sayre syndrome. Retinal degeneration in Kearns-Sayre syndrome is akin to retinitis pigmentosa and chronic progressive external ophthalmoplegia and is related to mitochondrial DNA deletions.

Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS). This neurologic syndrome may be associated with pigmentary abnormalities in the macula, mostly causing minimal to no symptoms. The condition results from the mutation at position 3243 of the mitochondrial DNA.

Future therapies

Gene therapy clinical trials. First-generation genetic testing for the genes that cause inherited retinal dystrophies has been expensive and hit or miss. Next generation genetic sequencing holds out the promise for simultaneous analysis of approximately 250 genes with a better than 50% hit rate, sensitivities of 98%, and specificities of 100%. Until now, identifying genes was more about genetic counseling then treatment. At present, there are gene replacement human clinical trials for the treatment of Leber congenital amaurosis, Stargardt macular dystrophy, choroideremia, Usher syndrome type I, X-linked retinoschisis, MERTK-associated retinitis pigmentosa, Leber hereditary optic neuropathy, and achromatopsia (13). Treatment of these diseases is confounded by the fact that many of these conditions are the result of multiple genetic defects, and even in an autosomal recessive condition like Stargardt, the patient can be homozygous for two defective genes but heterozygous for the mutations. The other problem is cost. The first commercially available gene therapy for the treatment of congenital amaurosis of Leber, LUXTURNA™ (voretigeneneparvovec-rzyl), costs $425,000 per eye.