342 RETINOPATHY OF PREMATURITY born children.

Earl A. Palmer, MD, FAAP

Portland, Oregon

ETIOLOGY/INCIDENCE

Retinopathy of prematurity (ROP) is a maturational disorder of retinal blood vessels that occurs in premature infants. Its incidence varies inversely with gestational age, and ROP affects 2/3 of infants born weighing less than 1251 g. Although oxygen in excess of need can cause vaso-obliteration in the immature peripheral retina, other factors likely also play a causative role. Presumably in response to peripheral retina ischemia, neovascularization later develops just posterior to the junction of vascularized and nonvascularized retina.

COURSE/PROGNOSIS

ROP is detected best 4 to 6 weeks after birth and usually involutes spontaneously. Treatment is available if it progresses. In some cases, complications such as vitreous hemorrhage, fibrous proliferation, and retinal detachment supervene during the neovascular phase and lead to irreversible scarring. Cicatricial sequellae may range from mild dragging of the retina compatible with good visual acuity to total retinal detachment, retrolental mass of fibrovascular tissue, anterior chamber collapse, corneal opacity, and phthisis bulbi. Although these findings are generally apparent in the first year of life, retinal detachment may occur as a later sequel of severe ROP throughout childhood and adolescence.

DIAGNOSIS

Clinical signs and symptoms

Ocular or periocular

●Iris:

Because prematurity is recognized as the most important cause of ROP, prevention of ROP largely depends on public health measures designed to reduce the incidence of premature birth. Restricting light to the faces and eyes of infants may be restful, but has not been found to alter the likelihood of severe ROP.

Premature infants weighing less than 1500 g at birth, or deemed otherwise at special risk by a neonatologist, should be examined for ROP at 4 to 6 weeks of age. Infants showing ROP and those in whom vascularization of the peripheral retina is incomplete should be examined again at an interval depending on examination findings. Patients with zone I ROP or stage 3 ROP in zone II generally should be reexamined at least weekly, and other patients are seen every 2 weeks. There is considerable variation from case to case as to the significance of stage 2 or 3 ROP. Variables include: degree of prematurity, zone of vessels, clock hour extent, rate of progression, race (lower risk among Afro-Americans), and degree of oxygen dependency. Because of this, a mandatory rigid examination schedule is somewhat impractical. For most premies, examinations every week or two suffice. For a few, more frequent examination is necessary.

For examination, the binocular indirect ophthalmoscope should be used after dilation of the pupils with phenylephrine (1% to 2.5%) combined with either cyclopentolate (0.2% to 0.5%) or tropicamide (0.5% to 1.0%). A lid speculum is generally used, and the sclera is gently depressed as necessary. After involution of ROP, children with cicatricial fundus changes should be followed throughout life, particularly during childhood and adolescence, to help prevent further visual loss due to amblyopia, retinal detachment, or angle-closure glaucoma.

Ocular

No medication is known to be effective in preventing or treating ROP. Topical corticosteroids may be helpful in controlling secondary glaucoma if it occurs, and must be used judiciously due to systemic absorption.

Surgical

In 1988 cryotherapy was reported to decrease the risk of severe

tis, vascular engorgement, poor response to mydriatics;

●Involutional and cicatricial phases: anterior or posterior synechiae.

●Optic nerve: pallor, in severe cases; enlarged cup sometimes associated with periventricular leukomalacia.

●Retina: detachment, ‘dragged’ appearance, folds, attenuated vessels, dilated vessels, vascular tortuosity, hemorrhage, neovascularization, pigmentary changes, retrolental mass.

●Vitreous: haze, hemorrhage, organization, traction.

●Other: myopia, anisometropia, strabismus, amblyopia, altered angle kappa, shallow anterior chamber, band keratopathy, glaucoma, cataract, leukocoria, microphthalmos, phthisis.

TREATMENT

Systemic

Augmented supplementation of inspired oxygen once ROP develops does not significantly alter its course. Research efforts

eral nonvascularized zone of eyes with ‘threshold’ ROP (zone I or II, stage 3 ‘plus’; 5 to 8 clock-hours). Within the following decade indirect ophthalmoscopically delivered laser photocoagulation was found to yield at least equivalent results, with greater ease of application, particularly in zone 1 disease.

In December, 2003, the results of the Early Treatment for ROP study showed significant benefit from earlier intervention in high risk eyes that were likely to eventually reach the traditional threshold of disease known to benefit from cryotherapy. Essentially, eyes with plus disease may be treated, with the possible exception of zone III ROP. Also, zone I ROP at stage 3 is treated even in the absence of plus disease, and zone II stage 1 could be observed even in the presence of plus disease. The definition of plus disease relies on a published standard photograph (Figure 342.1), and has been used in the major multicenter ROP clinical trials. Otherwise, there is considerable inter-examiner variation in making this diagnosis.

For eyes in which retinal detachment has developed despite laser or cryotherapy, optimal management remains controversial. Indications for scleral buckling for partial but progressive

FIGURE 342.1. Plus disease is a subjective determination. At least 4 major clinical trials have employed the standard photo shown here (upper right), originally picked for the CRYO-ROP study, as the depiction of the minimum necessary degree of dilatation and tortuosity needed to officially qualify as plus disease. Recently the term ‘preplus’ was introduced (reference) to describe what is shown here in the two examples as ‘not plus.’ (Adapted from STOP-ROP Multicenter Study Group: Supplemental therapeutic oxygen for prethreshold retinopathy of prematurity (STOP-ROP), a randomized, controlled trial. I: Primary outcomes. Pediatrics 105(2):295–310, 2000.)

traction detachment from ROP remain subject to individual specialists’ interpretation. In eyes with tractional/exudative total retinal detachment, microsurgical vitrectomy with or without lensectomy and/or scleral buckling, usually applied between 3 and 12 months of age, have been successful in reattaching the retina in many cases. Even among eyes with initial anatomic success, however, visual results usually are disappointing.

Still today, no matter what is done, some infants go blind from this disease.

tions must not be discontinued until the retinopathy has unequivocally involuted and the retina has finished vascularizing to the ora serrata at least on the nasal side. If ROP remains unresolved at the time of discharge or transfer, it is imperative that the chain of indicated examinations continue unbroken in the outpatient setting.

COMMENTS

The identification of affected infants leads to timely diagnosis and treatment. Their families should learn about ROP and its potential complications from the physicians providing care. Follow-up throughout childhood permits the detection of further complications that threaten visual loss.

Not all cases of proliferative vascular retinopathy in infancy and childhood are ROP. Other etiologic factors should be considered, particularly in infants born weighing more than 1500 g; examples include Norrie’s disease, familial exudative vitreoretinopathy, and incontinentia pigmenti.

REFERENCES

Cryotherapy for Retinopathy of Prematurity Cooperative Group: Fifteenyear outcomes following threshold retinopathy of prematurity: final results from the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity. Arch Ophthalmol 123:311–318, 2005.

Early Treatment for Retinopathy of Prematurity Cooperative Group: Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol 121:1684–1694, 2003.

Reynolds JD, Dobson V, Quinn GE, et al: Evidence-based screening criteria for retinopathy of prematurity. Arch Ophthalmol 120:1470–1476, 2002.

An International Committee for the Classification of Retinopathy of Prematurity: The International Classification of Retinopathy of Prematurity Revisited. Arch Ophthalmol 123:991–999, 2005.

STOP-ROP Multicenter Study Group: Supplemental therapeutic oxygen for prethreshold retinopathy of prematurity (STOP-ROP), a randomized, controlled trial. I: primary outcomes. Pediatrics 105(2):295–310, 2000.

PRECAUTIONS

Since topical medications may cause adverse systemic side effects in premature infants, 10% phenylephrine and 1% cyclopentolate should not be used. (See Supportive above.) Because absorption and systemic toxic effects of ocular medications occur mainly through the nasal mucosa, excess solution should be wiped away promptly.

Ophthalmoscopic examinations are both disturbing and potentially hazardous to the critically ill infant. However, the consequences of unrecognized and untreated high risk ROP are extremely severe. Because ROP progresses to ‘threshold’ for treatment at an average of 37 weeks’ postconceptional (postmenstrual) age, it is extremely important that examinations be carried out before this. It is advised that examinations begin at 31 weeks postmenstrual age or at 4 weeks from birth, whichever comes first. In particularly ill infants, if the neonatologist directs that the examination should be delayed until the infant has stabilized, this information should be explicitly stated in the medical record. In scheduling subsequent examinations during the preterm period, the examiner should err on the side of caution. If in doubt about zoning or staging, the next interval should be planned according to the worse scenario. Examina-

343 SUBRETINAL NEOVASCULAR MEMBRANES 362.16

(Choroidal Neovascularization,

Subretinal Neovascularization)

M. Vaughn Emerson, MD

Portland, Oregon

ETIOLOGY/INCIDENCE

Subretinal neovascularization (SRN), refers to the presence of blood vessels in the subretinal space. The origin of these blood vessels can be the retinal circulation, but is more commonly the choroidal circulation, with vessels extending through a defect in Bruch’s membrane or around Bruch’s membrane at the margin of the optic disc. These membranes are therefore commonly referred to as choroidal neovascularization (CNV). Although SRN can occur anywhere in the posterior pole, it most commonly presents in the macula or peripapillary retina.

The most common underlying etiology is age-related macular degeneration (AMD), although several other ocular disorders have been linked to SRN, including but not limited to presumed ocular histoplasmosis syndrome, choroidal scars (in multifocal choroiditis or laser scars), choroidal ruptures, angioid streaks, myopia, lacquer cracks, choroidal nevus, optic nerve head drusen, or other optic nerve head anomalies. Idiopathic SRN is not uncommon.

●The Anecortave Acetate Risk Reduction Trial (AART) is currently evaluating the efficacy of posterior sub-Tenon injection of anecortave acetate in the prevention of wet macular degeneration in eyes with drusen and pigment clumping.

●Argon laser treatment of drusen is currently being evaluated following promising results of two pilot studies. The Complications of Age-related Macular Degeneration Prevention

Trial (CAPT) will soon publish 6-year results of the effect of light grid and focal laser to eyes with = 10 large drusen.

COURSE/PROGNOSIS

Initially, SRN causes visual disturbance with a serous or hemorrhagic retinal detachment. Treatment-related or spontaneous regression of the SRN leads to disciform scar formation and visual acuity is dependent on the extent of tissue destruction and the particular area of involved retina, retinal pigmented epithelium, and underlying choroid.

DIAGNOSIS

Clinical signs and symptoms

TREATMENT

Systemic

No systemic therapy has been demonstrated to be effective in the treatment of SRN. Squalamine, an aminosterol with antiangiogeneic properties and relatively low systemic toxicity, and combretastatin A-4 Phosphate (CA4P), an antimitotic agent with both antitubulin and antivascular properties, are undergoing clinical evaluation as intravenous anti-SRN therapies.

Intravenous interferon alfa-2a, thalidomide, steroids, plasmapheresis, and many other medications and strategies have been used in an attempt to inhibit the neovascular activity in SRN.

tafoveal, extrafoveal, peripapillary, or peripheral.

●Subretinal bleeding is common and frequently outlines the SRN in a circular pattern.

●In some cases, very large subretinal hemorrhages occur, which can be mistaken for malignant melanoma of the choroid.

●Lipid exudation and serous fluid often accompany the SRN.

●Common symptoms include metamorphopsia and central or cecocentral scotomata.

Laboratory findings

●Fluorescein angiography may assist in confirming the diagnosis, guiding laser therapy, and determining the efficacy of treatment modalities.

●Optical coherence tomography has recently been employed more frequently in the initial diagnosis and monitoring of therapy. Optical coherence tomography commonly demonstrates retinal thickening with cystoid spaces, subretinal fluid, and subretinal hyperreflectivity, demonstrating the SRN.

●Indocyanine green angiography may be of use in cases in which subretinal hemorrhage or fluid blocks fluorescein.

Differential diagnosis

Central serous chorioretinopathy, vitelliform detachment due to basal laminar drusen or pattern dystrophy, choroidal melanoma or other tumor.

Prophylaxis

●Micronutrient supplementation, as studied in the Agerelated Eye Disease Study (AREDS), yields a 25% risk reduction in progression to advanced AMD (CNV or geographic atrophy) and a 19% risk reduction in moderate vision loss

over five years in patients with non-neovascular AMD with at least 1 large (>125 μm) druse or extensive medium-sized drusen. The AREDS formula includes vitamin A 25,000 IU (as beta carotene), vitamin C 500 mg, vitamin E 400 IU, zinc oxide 80 mg, and cupric oxide 2 mg. Some studies suggest a theoretical benefit to lutein dietary supplementation, although this has not been demonstrated with the same systematic rigor as the AREDS formula.

these systemic therapies have not been shown to be effective in randomized clinical trials.

Medical

●Laser photocoagulation, as studied in the Macular Photocoagulation Study (MPS) significantly decreases vision loss at 5 years for extrafoveal, juxtafoveal, and subfoveal SRN due to AMD, histoplasmosis, and idiopathic membranes when compared to observation. Most surgeons do not treat subfoveal lesions because of the risk of immediate loss of six or more lines of vision. The recurrence rate can be as high as 78% in cases of juxtafoveal SRN, usually extending into the fovea. However, laser photocoagulation remains the treatment of choice for patients with extrafoveal or peripapillary SRN, with the alternative of observation in some cases.

●Photodynamic therapy (PDT), approved by the FDA in 2000 for the treatment of predominantly classic CNV associated with AMD, ocular histoplasmosis, and myopia, involves an intravenous injection of verteporfin (Visudyne, Novartis) followed by photoactivation of the dye with a 689 nm wavelength laser. Treatment is repeated every three months, as

necessary, based on angiographic leakage. This treatment has been demonstrated to reduce vision loss (defined by = 15 ETDRS letters) in patients with predominantly classic

CNV, and is most effective in patients with no occult component. PDT is not used within 200 μm of the optic nerve, and the maximum treatable lesion size is 5400 μm in greatest linear diameter.

●Photodynamic therapy is currently commonly used in combination with intravitreal steroid injections, although this regimen has yet to be supported by a randomized, controlled clinical trial. The Visudyne with Intravitreal Triamcinolone Acetonide (VisTA) trial may clarify which patients may benefit from this treatment combination.

●Macugen (pegaptanib, Eyetech) is a single-stranded RNA molecule that binds vascular endothelial growth factor (VEGF), which was FDA-approved for the treatment of neovascular AMD in 2005. When repeated every 6 weeks, Macugen decreases the rate of moderate vision loss by one-

third. These results are similar to those of PDT in the prevention of SRN-associated vision loss at 2 years.

●Phase III studies of monthly injections of another antiVEGF agent, Lucentis (ranibizumab, Genentech), a humanized anti-VEGF antibody fragment, are ongoing. However,

1-year results have demonstrated a treatment benefit over PDT and = 15 ETDRS-letter improvement in vision in 25– 34% of patients. Avastin (Bevacizumab, Genentech), an anti-VEGF antibody has also been used intravenously and intravitreally with anecdotally positive results.

●Randomized clinical trials of low-dose radiation to SRN in AMD have shown no benefit.

Macular Photocoagulation Study Group. Laser photocoagulation of subfoveal neovascular lesions of age-related macular degeneration: updated findings from two clinical trials. Arch Ophthalmol 111:1200–1209, 1993.

Miller J, Chung CY, Kim RY, MARINA Study Group: Randomized, controlled phase III study of ranibizumab (Lucentis) for minimally classic or occult neovascular age-related macular degeneration. Program and abstracts of the American Society of Retina Specialists 23rd Annual Meeting. Montreal, Canada, July 16–20, 2005.

Submacular Surgery Trials (SST) Research Group. Surgery for subfoveal choroidal neovascularization in age-related macular degeneration: ophthalmic findings: SST report no. 11. Ophthalmology 111:1967–1980, 2004.

Surgical

●The Submacular Surgery Trial (SST) demonstrated no benefit to surgery over observation on visual acuity with the removal of SRN and evacuation of subretinal hemorrhage. Because the quality of life assessment was slightly better in patients undergoing surgery, submacular surgery may be of use in select cases.

●Neither macular translocation surgery nor the implantation of miniature intraocular telescopes has been studied in a randomized, controlled fashion, although each may be of benefit in select cases.

●Stem cell and retinal pigmented epithelium transplantation and gene therapy are other investigational treatments.

COMPLICATIONS

The introduction of intravitreal administration of pharmaceuticals has increased the rate of ocular complications, including endophthalmitis, retinal detachment, cataract, and glaucoma. As use of these therapies become more widespread, the occurrence of adverse events will increase, particularly when compounded over multiple injections. Nor are laser photocoagulation and PDT without complications, including inadvertent laser burns, absolute scotomas, retina pigmented epithelial rips, and choroidal nonperfusion.

COMMENTS

With the recent explosion of research concerning the prevention and treatment of SRN, particularly in association with AMD, treatment recommendations for SRN are evolving more rapidly than ever. It is important to tailor management to each individual case, with a thorough discussion of the treatment options, risks and benefits.

REFERENCES

Age-related Eye Disease Study Research Group. A randomized, placebocontrolled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 119:1417–1436, 2001.

Bressler NM, Bressler SB, Gragouds ES: Clinical characteristics of choroidal neovascular membranes. Arch Ophthalmol 105:209–213, 1987.

Gragoudas ES, Adamis AP, Cunningham ET, et al: Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 351:2805–2816, 2004.

344 WHITE DOT SYNDROMES 363.15

(Acute Posterior Multifocal Placoid

Pigment Epitheliopathy, Birdshot

Chorioretinopathy, Multifocal

Choroiditis and Panuveitis, Multiple

Evanescent White Dot Syndrome,

Presumed Ocular Histoplasmosis

Syndrome, Punctate Inner

Choroidopathy, Retinal Pigment

Epitheliitis, Serpiginous Choroiditis,

Subretinal Fibrosis and Uveitis)

Lyndell L. Lim, MD

East Melbourne, Australia

Eric B. Suhler, MD

Portland, Oregon

The term white dot syndrome refers to acquired diseases that cause inflammation and multifocal lesions at the level of the outer retina, retinal pigment epithelium (RPE), and inner choroid. Nine separate diseases are commonly included in this category, associated with many acronyms. New variations or related inflammatory conditions are constantly being added in the literature, such as acute zonal occult outer retinitis and unilateral acute idiopathic maculopathy. Many argue whether some of these separate conditions are simply different manifestations of the same unidentified inflammatory insult. Nevertheless, until a unifying mechanism is identified for all of these diseases, it helps to consider the white dot syndromes as individual entities, if only to simplify diagnosis and prognosis. The white dot syndromes definitely must be distinguished from the numerous other causes of ‘white dots’ in the fundus, such as vascular problems like cotton-wool spots or degenerative changes such as Stargardt’s disease, drusen, or cobblestone degeneration. The acute, multifocal, inflammatory nature of these nine entities usually makes this distinction simple.

The entities included in this article are retinal pigment epitheliitis (RPE-itis), multiple evanescent white dot syndrome (MEWDS), acute posterior multifocal placoid pigment epitheliopathy (APMPPE), serpiginous choroiditis, presumed ocular histoplasmosis syndrome (POHS), punctate inner choroidopathy (PIC), multifocal choroiditis and panuveitis (MCP), subretinal fibrosis and uveitis (SFU), and birdshot (or vitiliginous) chorioretinopathy.

Retinal pigment epitheliitis (RPE-itis; formerly known as Krill disease)

ETIOLOGY/INCIDENCE

●RPE-itis occurs primarily in otherwise healthy patients in the third decade of life.

●This is thought to involve focal inflammation at the level of the RPE with surrounding RPE edema.

●A viral precipitant has been postulated, but none has been identified.

COURSE/PROGNOSIS

dots can be very faint and are seen best in the midperiphery. There usually is a small amount of posterior vitreous cells. The fovea of the involved eye also demonstrates a peculiar and almost pathognomonic orangish granular appearance; often, this is the only physical finding to explain the patient’s symptoms, particularly if the white spots have faded markedly.

Both the symptoms and findings are usually (80%) unilateral; however, a few spots are often seen in the fellow eye on close examination.

The white dots usually last approximately 3 weeks and then fade; however, the patient may have an enlarged blind spot on perimetry that lasts longer.

Fundus fluorescein angiogram features include early hyperfluorescence of the dots with late staining, with each spot appearing as a cluster of smaller dots arranged in a wreath-like

sentation. Symptoms usually resolve in 6 to 12 weeks with little or no sequelae. There has been one case report of a choroidal neovascular membrane (CNVM).

DIAGNOSIS

●There usually are 2–4 clusters of dark-gray spots surrounded by a hypopigmented halo.

●Fluorescein angiography may be normal, or the halo may become more hyperfluorescent with time. Fluorescein lesions have been described as ‘honeycomb’ or ‘target’ shaped.

wave and early receptor potential.

A presumptive diagnosis of this entity can therefore often be made in patients presenting with a big blind spot syndrome, a small number of posterior vitreous cells, and an orangish granularity of the fovea even if the prominent white lesions are no longer present.

TREATMENT

No treatment is required for this entity. Recovery of visual acuity is typically excellent; however, subjective visual dysfunction and an enlarged blind spot may persist for some time. A choroidal neovascular membrane is a result of MEWDS on rare occasions.

TREATMENT

●No treatment is required.

Multiple evanescent white dot syndrome

ETIOLOGY/INCIDENCE

●MEWDS occurs in younger patients, with a female preponderance.

●Patients often describe an antecedent (4 weeks) viral illness, and this entity is thought to represent a postviral RPE inflammation with secondary retinal and photoreceptor changes.

●Vision is usually moderately decreased, in the 20/40 to 20/200 range.

COURSE/PROGNOSIS

●The prognosis is excellent, and most patients recover. There usually is some mild subjective decrease in visual function that persists, and the enlarged blind spot may take months to resolve.

●Recurrences are unusual; the development of a CNVM has been reported but is rare.

Acute posterior multifocal placoid pigment epitheliopathy

ETIOLOGY/INCIDENCE

APMPPE usually affects patients in the third decade of life. About one-third of patients report an antecedent viral syndrome, and this condition may represent some sort of postviral hypersensitivity process.

The pathology is thought to be a choroidal microvasculitis with choroidal lobule closure and secondary RPE changes.

COURSE/PROGNOSIS

Patients usually present with a fairly rapidly progressive decrease in vision, the severity of which depends on whether lesions are present directly under the fovea. Involvement is also usually bilateral, with the second eye being involved in days to weeks.

Symptoms usually resolve in 1 to 2 months and the prognosis is generally good, with most patients recovering 20/30 vision or better, although the vision may be much worse if there is extensive subfoveal scarring. Even with good visual return, there may be lingering metamorphopsia or scotomata. Recurrences and secondary CNVM are rare.

FIGURE 344.1. Color fundus photo of the right eye demonstrating the classic creamy white lesions seen in APMPPE.

with corticosteroids and believe that this therapy provides more rapid regression. There are no controlled studies to support either of these approaches. Patients with severe or complicated cases require systemic investigations (see below).

COMPLICATIONS

Of note, this syndrome is the only white dot syndrome that has been associated with death; there have been case reports of death from associated cerebral vasculitis. Other systemic associations include systemic vasculidities such as Wegener’s granulomatosis, acute nephritis, thyroiditis, hearing changes, erythema nodosum, headache, and cerebrospinal fluid pleocytosis. Most patients do not have these systemic associations; however, if a patient complains of a particularly severe headache or neurologic symptoms, he or she should be referred for appropriate workup.

Serpiginous choroiditis

FIGURE 344.2. Color fundus photo of the same eye shown in Figure 344.1 several weeks later showing complete resolution of the acute creamy lesions with residual pigmentary changes at the level of the RPE.

infiltrates may form one large central lesion. This disease is remarkable for the rate at which pigment changes develop; they usually begin in 1–2 weeks, and variations in pigment reaction can occur on almost a daily basis (Figure 344.2).

Several associated ocular findings have been noted, including papillitis, serous retinal detachment, retinal vasculitis, macular edema, superficial retinal hemorrhages, corneal infiltrates, and episcleritis. There usually are few anterior chamber or vitreous cells.

Fluorescein angiography of these creamy lesions shows a classic early hypofluorescence and late hyperfluorescence with leakage.

TREATMENT

APMPPE usually resolves without the need for treatment. Some believe that severe vision loss or significant vitreous cells merit the use of corticosteroids. Others routinely treat all patients

ETIOLOGY/INCIDENCE

●The average age is in the fifth decade, which is somewhat older than for most of the other white dot diseases.

●There is no clear racial or sexual predisposition and no known systemic association.

●The disease usually starts at the disk and spreads centripetally with recurrent episodes of inflammation. The active areas are gray-white and usually occur at the edge of previous atrophy. The active edge may remain active for weeks to months, gradually resolving to RPE mottling and atrophy. Twenty percent of patients may have isolated macular lesions as the initial site of involvement. Multifocal noncontiguous recurrences can also occur. Focal phlebitis and retinal neovascularization have been described on rare occasions.

COURSE/PROGNOSIS

The course is characterized by recurrences at intervals ranging from weeks to years. Progression may be asymptomatic if the macula is not involved, and this may explain why these patients present at older ages than patients with other white dot syndromes. CNVMs occur in up to 25% of patients. Early serpiginous choroiditis may be difficult to differentiate from other focal inflammations, such as toxoplasmosis, APMPPE, or idiopathic peripapillary CNVMs. Usually, the diagnosis becomes clear as the patient is followed and the disease recurs. In general, the prognosis is fair, with useful vision preserved in at least one eye. The prognosis can be very poor if foveal involvement or a CNVM develops.

DIAGNOSIS

●Patients present with blurred vision, floaters, or both.

●Histopathology shows aggregates of lymphocytes in the choroid, presumably causing focal choriocapillaris and RPE damage.

●The fluorescein angiogram is characteristic, with the atrophic areas showing staining along the edge where functional

COURSE/PROGNOSIS

Overall, these patients tend to have a slowly and relentlessly progressive loss of vision over a long period of time (i.e. years). Often, this loss is detectable on electrophysiologic testing (e.g. ERG and dark adaptation) and visual field monitoring long before a drop in visual acuity is seen.

The most common cause of vision loss is cystoid macular edema, which occurs in up to 50% of patients, with associated vitreal haze often present. Other less common complications include optic nerve edema and atrophy, epiretinal membranes, CNVM and retinal vasculitis resulting in neovascularization and vitreal hemorrhage.

DIAGNOSIS

●Patients present with floaters and blurred vision. They may develop problems with nyctalopia and decreased color vision in later stages.

●The vision is usually mildly decreased. The disease is almost always bilateral but can be asymmetric.

●Most patients have vitreous cells and haze; anterior segment inflammation is not a common feature and if present, it is mild.

patient does not have a disseminated infection that is causing a multifocal choroiditis. In general, patients with a white dot syndrome are healthy, although in some cases there may be an antecedent viral infection. Patients who are sick, debilitated, or immunosuppressed should raise concern for another etiology, such as an endogenous endophthalmitis or systemic infectious disease. A careful review of systems looking for evidence of systemic disease is mandatory in these patients, and patients with suspicious symptoms may need to be referred for a medical evaluation. Multifocal infections, such as bacterial sepsis, Mycobacteria infection, syphilis, Lyme disease, fungal infections, and pneumocystis, must be considered depending on the clinical situation. In general, multifocal infectious entities have much more fluffy lesions with denser vitreous debris than any of the white dot syndromes. Most infectious causes also have a much more fulminant course than the more indolent white dot syndromes. As in all ocular inflammatory diseases, the history is of paramount importance in guiding the medical workup for potential masquerades. One test that should always be ordered is an FTA-Abs to exclude syphilis, the classic masquerading infectious disease.

Autoimmune diseases

Certain autoimmune diseases should be considered in the dif-

They may be very subtle, particularly in blond fundi, and may be more readily apparent with the indirect ophthalmoscope than with high diopter lenses. The lesions are most often found around the disk and nasal periphery. They appear to radiate outward from the disk into the periphery (Figure 344.5). The macula is not usually involved with the lesions.

present with a panuveitis simulating multifocal choroiditis or primarily posterior disease similar to birdshot. In cases where there is a high suspicion for sarcoidosis, a high resolution chest CT should be performed, as this modality has been shown to detect pulmonary sarcoidosis that can be missed on chest X-ray. In such cases, a tissue diagnosis via a transbronchial biopsy may be considered. Other tests that may be useful include

cal lesions. The lesions themselves are usually less visible on fluorescein angiography than on color photography, due to their deep level in the choroid and minimal interference with the RPE and choriocapillaris.

TREATMENT

The decision regarding when to start treatment in these patients is still a subject of some debate. Previously, some authors felt that treatment should be reserved for flare-ups or late complications that significantly decrease vision. However, severe deficits on ERG and visual field testing may occur well in advance of a drop in visual acuity, leading others to advocate the commencement of treatment as soon as such abnormalities are detected. Therefore, regular ERGs and visual field examinations may be useful for monitoring early disease progression.

Corticosteroids, either orally or as periocular or intravitreal injections, are generally the mainstay of treatment for severe exacerbations or complications such as cystoid macular edema. More recently, the use of cyclosporin A has been advocated for long term therapy to stabilize the course of this disease and maintain visual acuity. The use of other immunosuppressives, including antimetabolites and biologic therapies, has also been reported to be useful.

Differential diagnosis

Disseminated infection

When entertaining the diagnosis of one of the white dot syndromes, it is of paramount importance to ensure that the

sion capacity (PFTs with DLCO), conjunctival or lacrimal gland biopsy, and/or a gallium scan.

Most of the other systemic autoimmune diseases that can affect the posterior part of the eye, such as Behçet’s disease or systemic vasculitis, do not present as multifocal choroidopathies. Instead, these entities usually present with diffuse intraocular inflammation and retinal vasculitis. As a result, unless the patient has a very suggestive history, laboratory tests to evaluate for these entities are not done. A patient’s complete blood cell count and chemistry profile are often checked, not so much as a diagnostic maneuver but rather to assess their general medical status, particularly if immunosuppressive therapy is considered. Purified protein derivative skin testing is included, more to define the patient’s tuberculosis (TB) status before immunosuppression than to look for a TB-associated multifocal choroiditis, which would be unusual in an otherwise healthy patient. If the diagnosis of birdshot choroidopathy is entertained, testing for HLA-A29 should be done. If the patient presents with an appearance that is typical for one of the milder white dot syndromes (e.g. MEWDS), it may not be necessary to perform any laboratory testing.

Diffuse unilateral subacute neuroretinitis and toxoplasmosis

Two other local ocular entities must be kept in mind. Diffuse unilateral subacute neuroretinitis occurs when certain nematodes enter the subretinal space. Patients have severe visual loss in only one eye with scattered whitish lesions that ultimately form marked pigment changes associated with optic atrophy. Any patient with such a clinical picture should be carefully

inspected for the presence of a small worm in the subretinal space, and fluorescein angiography will often reveal pathognomonic diffuse hyperfluorescent lesions in areas of previous worm tracks. Toxoplasmosis is another disease that may present with one or more small outer retinal white lesions (punctate outer retinal toxoplasmosis). These are unilateral in immunocompetent patients, and there usually is evidence of previous scarring from toxoplasmosis. A toxoplasmosis titer may be helpful, and treatment for this entity may be necessary if lesions threaten the optic nerve, macula, or retinal vasculature.

Masquerade processes

Finally, masquerade processes such as ocular lymphoma, metastatic disease, and choroidal lymphoproliferative diseases may present as a multifocal process. They often have larger, more mass-like lesions that differ from the smaller lesions of the white dot syndromes. Usually the ultrasound examination, the systemic status, or a lack of response to treatment will suggest this type of process.

Observation

Once the clinician is satisfied that the patient has one of the idiopathic white dot syndromes rather than a systemic disease, differentiation is usually fairly simple and depends largely on the clinical appearance and degree of severity. Sometimes a period of observation is required for all the clinical manifestations of the disease to become apparent. For instance, both PIC and MCP can present initially as a multifocal process. With follow-up, MCP usually demonstrates more intraocular inflammation and tends to be recurrent and to require immunosuppression. Serpiginous choroiditis may also be problematic initially, particularly if it starts in one localized area and the characteristic pattern of scarring is not present. The diagnosis usually becomes apparent with follow-up as recurrent, gradual spread of the inflammation occurs.

responder, posterior sub-Tenon’s injections of 20 to 40 mg triamcinolone acetonide may be useful for disease exacerbations.

COMMENTS

A few important points must be kept in mind when treating patients with the white dot syndromes. It is very important to use both the clinical history and physical examination to eliminate a systemic infectious cause for a multifocal choroiditis; only then can the clinician be assured that immunosuppressive treatment can be performed safely. Any multifocal process that progresses despite presumably appropriate treatment requires reevaluation for an infectious cause. A lymphoproliferative process must be considered, particularly if there appear to be masses or deposits in the subretinal or sub-RPE space, or in the presence of suspicious systemic (especially neurologic) symptoms.

In disease processes such as MCP, SRF, serpiginous choroiditis, and birdshot choroidopathy, early recognition is important due to their more chronic and sometimes aggressive courses, often requiring systemic immunosuppression.

One must constantly reassess the risks and benefits of the therapy in these entities. If continuous treatment is found to be required, strong consideration should be given to the use of immunosuppressive agents such as cyclosporin A to prevent complications from chronic steroid use. Consultation with a uveitis expert, or an internist or rheumatologist, should be obtained to assist with this.

Finally, the patient must be warned about the late development of a neovascular membrane, particularly if the patient has one of the multifocal choroidopathies (POHS, PIC, MCP, SFU) or serpiginous choroidopathy. If a subfoveal membrane develops, many investigators believe that surgical removal may be beneficial, although controlled studies are lacking.

GENERAL THERAPEUTIC APPROACH

Although there are a number of white dot syndromes, the overall therapeutic approach is very similar. Basically, if there is little inflammation and the vision is not markedly decreased, no treatment is required. If there is more inflammation or more significant visual loss, immunosuppression may be necessary, usually with depot or oral corticosteroids. Those entities that have a high risk of a CNVM, such as POHS, PIC, and MCP, require continuous monitoring with the Amsler grid and laser or photodynamic treatment if necessary. More chronic diseases, such as birdshot or MCP, have the potential to damage peripheral vision, and this parameter should also be monitored.

More specific guidelines for therapy include the use of topical steroids and cycloplegics if there is significant anterior chamber reaction. If the decision to use systemic corticosteroids has been made, the patient should be started on a dosage of 0.5 to 1 mg/kg (usually 60 to 80 mg) daily of prednisone or its equivalent. The patient should be seen in 1 to 2 weeks. The steroids can be gradually tapered depending on the clinical response. Depending on severity, flare-ups may require a return to the initial dose or simply going back to the lowest dose at which inflammation was controlled. However, long term high dose (= 10mg/day) oral prednisone will almost always result in severe side effects and therefore patients who are unable to be weaned below this dose without flares should be referred for commencement of a steroid sparing agent. If the patient is not a steroid

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