The White Dot Syndromes

Yoko Matsumoto, MD, PHD; Sebastian P. Haen, MD; Richard F. Spaide, MD

Disclosures

Compr Ophthalmol Update. 2007;8(4):179-200. 

In This Article

Multifocal Choroiditis With Panuveitis

Multifocal choroiditis with panuveitis, the diffuse subretinal fibrosis syndrome (DSF), and PIC are similar conditions with chorioretinal inflammation. It is unclear whether they are separate entities or various manifestations of one disease.[88,89,90,91] In the United States, the incidence of MCP is 52.4/100,000 people/years.[92] The disease, typically bilateral, affects otherwise healthy individuals in their third to fifth decade. Most affected patients are myopic females. Secondary CNV is very common in patients with MCP.

The etiology of MCP is unknown. There has been one series of patients with a reported association with antibodies against Epstein-Barr virus. This could not be confirmed in another study.[9,93] A very small minority of patients shows associations with histoplasmosis, positive treponemal serology, tuberculosis, sarcoidosis, herpes infection, Lyme disease, Epstein-Barr virus, Toxocara canis, and West Nile virus infections.[9,93,94,95,96,97,98,99] Despite this, it is likely that MCP is related to a past exposure to an infectious organism with the phenotypic presentation of MCP being related to the patient's immune diathesis. Unlike the presumed ocular histoplasmosis syndrome, patients with MCP and CNV were not more likely to have HLA-DR2; in fact, they had a decreased likelihood of having the HLA-DR2 haplotype as compared with a control group of patients not affected by uveitis or CNV.[125] A second study did not specifically look at HLA-DR2, but the authors found decreased frequency of the HLA-B7 and HLA-DR1 haplotypes.[100]

Diffuse subretinal fibrosis syndrome was first described as a finding with uveitis and subretinal fibrosis by Palestine and associates in 1985.[101] Most patients with DSF present with unilaterally decreased vision, floaters, scotomas or metamorphopsia, and photopsia. However, many, if not most, of these patients have bilateral chorioretinal scars, raising the concern that DSF is a severe variant of MCP. Punctate inner choroidopathy was first described by Watzke and coauthors in 1984.[102] Punctate inner choroidopathy affects young, healthy individuals between the ages of 16 and 40. Most of the patients are female, moderately myopic, and have bilateral chorioretinal scars with no evidence of intraocular inflammation. The lesions in PIC are considered to be more numerous, but smaller in size than those seen in MCP.

Multifocal choroiditis with panuveitis can cause a variety of visual problems. Patients commonly have increased blind spots, isolated scotomata, and photopsia. If there is concurrent clinically evident cellular infiltration in the anterior chamber, patients may have mild photophobia. Cellular infiltration of the vitreous can cause foggy vision with glare. With the advent of CNV, the central visual acuity decreases and there is an increase in distortion (Figure 6).

Concurrent inflammation seen in the anterior chamber or vitreous is common in patients with MCP. Much like the presumed ocular histoplasmosis syndrome, MCP can display four principle fundus manifestations: peripapillary scarring, punched-out scars, linear aggregates of punched-out lesions, and CNV. In the acute phase, MCP lesions are yellow-white and slightly thickened (Figure 7). The chorioretinal scars later seen are usually full-thickness, punched-out scars with variable associated pigmentation (Figure 7). Patients with Northern European ancestry often have depigmented punched-out spots, while patients with African-American ancestry can have deeply pigmented spots. The spots usually range in size from 100 microns to half a disk diameter. Choroidal neovascularization develops in 25% to 39% of the eyes and may cause severe visual loss.[94,103,104]

In PIC, many of the same findings as with MCP are seen except intraocular inflammation. Clinically evident intraocular inflammation may not be readily seen in MCP for long periods of time, decreasing the utility of this finding. The lesions in PIC are usually smaller and more numerous than those seen in MCP, although the autofluorescence findings of MCP show many small RPE defects that cannot be seen clinically. This implies that there is an overlap in lesion sizes between these disorders [Haen and Spaide, unpublished data]. Diffuse subretinal fibrosis syndrome causes an acute accumulation of fibrotic subretinal scarring that often links chorioretinal scars. Most cases of DSF arise from what appears to be multiple regions of CNV becoming confluent. On occasion, patients with DSF can have what appears to be subretinal fibrin and exudation that eventually consolidates into a subretinal scar.

The central visual acuity is generally good unless MCP is complicated by CNV. Visual field testing may reveal an enlarged blind spot and peripheral visual field loss. Multifocal electroretinography typically shows a diffuse loss of function, with focal scotomata being common. Optical coherence tomography can show CME and, if present, subretinal exudation and infiltration from CNV.

In MCP, fluorescein angiography reveals early hypofluorescence with late hyperfluorescent staining in acute lesions. Old scars typically show window defects. Patients with MCP can have retinal vascular leakage and CME. Indocyanine green angiography often reveals more lesions within the choroid as compared to the number observed in fluorescein angiography or clinical examination.[34,105,106] The large hypofluorescent spots that ranged from 200 μm to 500 μm in diameter can be seen in the posterior pole, and those spots do not correspond to any clinical or fluorescein angiographically detectable lesion. The smaller hypofluorescent lesions, approximately 50 μm, can be present in the posterior pole. Both the large and small lesions are best visualized in the late phases of the ICG study.[106] In addition, broad lobular areas of late hypofluorescence can be seen in patients, and these areas often correspond to visual field defects. After treatment, the lobular areas may regress in size with corresponding improvement in the visual field. Treatment of the MCP also causes the spots seen in ICG angiography to become smaller in size and less numerous.[106]

The findings seen in DSF are similar to MCP, except for the appearance of the subretinal exudation as seen in the earlier stages. This fluid is initially hypofluorescent with variable later staining. As the organization of the subretinal exudation occurs, the edges become more scalloped, with the middle of each outer segment becoming convex. Over time, this material converts into bland scar tissue that shows more intense late staining. The angiographic findings in PIC are similar to those seen in MCP.

Choroidal neovascularization is quite common in MCP and can have a few different angiographic appearances. Generally, CNV is classic in nature and is usually associated with a visible chorioretinal scar. The neovascularization can surround a chorioretinal scar or may grow from a scar toward the center of the macula. It is not uncommon for several areas of CNV, even a half dozen, to grow simultaneously. These can be quite difficult to individually track. Some patients have an obvious area of CNV and, in the adjacent areas, they have small foci of what look like window defects on fluorescein angiography. These smaller window defect-like areas show increased fluorescence without significant leakage. However, after treatment with intravitreal corticosteroids, anti-VEGF agents, or both, the window defects go away. This implies that what looked like window defects were probably incipient areas of CNV. Histopathologic examination of MCP has found a predominant infiltration of B-lymphocytes and plasma cells, and a deposition of complement and immunoglobulins.[101]

The biggest mistake in MCP is to be lulled into complacency. This statement pertains to both the patient and physician. Multifocal choroiditis with panuveitis is a chronic disease and should be viewed in the same way as a rheumatoid disease. Patients with MCP are usually young, healthy, and energetic. They seemingly recover from bouts of intraocular inflammation without much difficulty, and may even recover from episodes of CNV with relatively good visual acuity by using only short-term corticosteroid treatment and anti-VEGF agents. However, the hallmark of MCP for many, if not most, patients is progressive damage. Multiple recurrences are common.[104] It is common for the CNV to eventually return or the inflammatory damage caused by the MCP to expand, causing troublesome central scotomata.

Some patients do not need to have chronic treatment. They may continue with chorioretinal scars without any complications for years. There are other patients who have been relatively quiet, but present with active CNV. It may be that the CNV arose from a chorioretinal scar and there may be no concurrent intraocular inflammation. The difficulty is known if there actually is any inflammation contributing to the formation or continuance of the CNV, or if the pre-existing scar just offered an access route for the CNV to the subretinal space. Concurrent findings may help in making this determination; suspicion should be raised if there are inflammatory cells in the vitreous, if there is retinal vasculitis, or if there is staining of the nerve in fluorescein angiography. Most of these cases are treated with corticosteroids and anti-VEGF agents.[62,107] Patients usually respond to this form of treatment.

If a patient has chronic active inflammation, progressive troublesome scotomata, retinal vasculitis, the formation of new spots, recurrent CNV, or new advent of CNV, more chronic therapy is required. Continuous use of corticosteroids has numerous complications.[108] Often, patients will not affirm the presence of neuropsychiatric symptoms unless specifically asked. Sleep disorders, the feeling of being manic or moody, and difficulty concentrating are common side effects of high-dose corticosteroids in patients with MCP. To reduce the dose of corticosteroids, long-term systemic immunomodulation is generally required. Use of immunosuppressive drug therapy can reduce the risk of posterior pole complications and poor vision prognosis.[109] Common drugs for this purpose include methotrexate and mycophenolate.

The advantage of methotrexate is that it is inexpensive and has a relatively low risk of side effects. The main side effect is liver toxicity. Folic acid analogs even inhibit the alcohol dehydrogenase. Thus, drinking alcohol should be avoided during methotrexate therapy. This can be a concern for younger people, as socializing often includes drinking alcoholic beverages.

Mycophenolate appears to be effective and does not preclude drinking. Mycophenolate is more expensive than methotrexate. It blocks selectively the proliferation of B- and T-lymphocytes. As a result, it has less systemic side effects. However, the liver function has to be monitored closely.

Corticosteroids are given concurrently; this commonly takes the form of low-dose oral corticosteroids, and if a higher dose of corticosteroids is needed, subtenon injection of triamcinolone may be helpful.

Concurrent CNV has been treated successfully with PDT, but collateral damage may occur in patients with active inflammation[106] (Figure 8). Some patients may respond to corticosteroids alone.[110] The treatment of CNV due to MCP is shifting over to anti-VEGF agents because of their apparent efficacy and lack of collateral damage. Treatment with anti-VEGF agents alone is usually not applicable because patients with MCP almost always have concurrent inflammation. As patients with MCP are young and in the productive phases of their lives, any vision loss is difficult to reverse. Therefore, it is almost never a mistake to start an aggressive treatment as early as possible to control CNV, if possible, in a minimal amount of time. Patients having recurrent leakage from CNV while on immunosuppressant agents and corticosteroids generally need the addition of an additional immunosuppressant agent such as cyclosporine or tacrolimus.[109]

Multifocal choroiditis with panuveitis tends to be a chronically progressive disorder lasting years. The visual prognosis is generally poor unless the patients are aggressively treated, particularly if they have concurrent CNV.[104,111,112] Severe visual loss may occur because of disciform macular scarring, macular fibrotic scarring, atrophy, or chronic CME. Aggressively treated patients can usually maintain good visual acuity, at least in one eye.

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