- •
HLA-A29 is very strongly associated with this entity.
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Long term the disorder can lead to severe visual handicap.
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Long-term therapy is often needed to control this disease.
The spectrum of posterior uveitic entities is quite broad, with similar or identical entities known by various names in the literature. Better definition of these entities is obviously a constant goal. Birdshot retinochoroidopathy fits the aforementioned spectrum, and fits into the broad scheme of ‘white-dot (perhaps ‘splotch’ is a better word!) syndromes.’ However, this disorder seems to have better-defined boundaries than some of the others in the white-dot group. Laboratory tests, albeit not definitive, appear to help the clinician in making this diagnosis. The entity appears to have distinct characteristics; it occurs more frequently in whites of northern European extraction and has a strong genetic association. Several reviews have described it. As this is a chronic, ongoing disease, we need to be very cognizant of the fact that it has a significant impact on the non-visual aspects of patients’ quality of life.
Clinical manifestations
Birdshot retinochoroidopathy was first described by Ryan and Maumenee in 1980 and soon after by Gass in 1981, who called it vitiliginous chorioretinitis. According to Gass – and this has been our experience as well – it is seen in healthy persons, more commonly women, with an onset somewhat later than that of other uveitic entities in the third to the sixth decades. One recent report described a patient with birdshot retinochoroidopathy as also having psoriasis; another reported a patient with birdshot retinochoroidopathy as also having an autoimmune sensorineural hearing loss; these may be chance occurrences. This disorder affects a small percentage of the patients with uveitis whom we see at the National Eye Institute. In our experience, 58% of these patients are women, whose average age is 48 years. Patients report an increased number of floaters and often have difficulty with night vision or color distinctions. In the original description by Ryan and Maumenee, the key elements of the clinical presentation are as outlined in Box 25-1 ; see also Figure 25-1 . For research purposes, the following criteria have been assembled, not really different in any major way from the clinical presentation outlined ( Box 25-2 ).
PATIENT
White
Female
Late 40s to 50s
OCULAR EXAMINATION FINDINGS
Quiet anterior chamber
Vitreal inflammation but no snowbanking
Retinal vascular leakage and cystoid macular edema
Deep circular cream-colored lesions, mostly in the posterior pole and surrounding areas
Bilateral
Low to moderate risk of subretinal neovascularization
ADDITIONAL TESTS
Abnormal electroretinogram and electrooculogram findings
Evidence of retinal autoimmunity
HLA-A29+
Required characteristics
- 1.
Bilateral disease
- 2.
Presence of at least three peripapillary ‘birdshot lesions’ *
* Cream-colored, irregular or elongated, choroidal lesions with indistinct borders, the long axis of which is radial to the optic disc. Typical lesions are illustrated in the Figure 25-1 .
inferior or nasal to the optic disc in one eye
- 3.
Low-grade anterior segment Intraocular inflammation (defined as ≤1 + cells in the anterior chamber †
† As defined by the Standardization of Uveitis Nomenclature (SUN) Working Group.
)
- 4.
Low grade vitreous inflammatory reaction (defined as ≤2 + vitreous haze ‡
‡ As defined by Nussenblatt and associates.
)
Supportive findings
- 1.
HLA-A29 positivity
- 2.
Retinal vasculitis
- 3.
Cystoid macular edema
Exclusion criteria
- 1.
Keratic precipitates
- 2.
Posterior synechiae
- 3.
Presence of infectious, neoplastic, or other inflammatory diseases that can cause multifocal choroidal lesions §
§ Patient should be evaluated for the following disorders by appropriate history taking, physical examination, or laboratory tests: sarcoidosis with panuveitis or posterior uveitis; intraocular lymphoma; acute posterior multifocal placoid pigment epitheliopathy (APMPPE); multifocal choroiditis and panuveitis; punctate inner choroidopathy (PIC); multifocal evanescent white dot syndrome (MEWDS); pars planitis syndrome; posterior scleritis; sympathetic ophthalmia; Vogt–Koyanagi–Harada disease (chronic stage); syphilis; tuberculosis.
Fuerst and colleagues believed they could distinguish four patterns of birdshot-spot distribution in the nine patients they evaluated: those with (1) macular sparing or (2) macular predominance; those that were (3) asymmetric with a concentration of spots, particularly inferiorly; and those that were (4) diffuse. In our experience the lesions tend to be present in the posterior pole and extend to the equator, but not generally beyond that. The lesions themselves appear deep in the fundus, are circular or oval, and are fairly large (at times 0.75 disc diameter in area). The edges of the lesions are usually not sharply defined, and frequently do not stand out as being sharply demarcated, particularly in a ‘blond’ fundus. Often they are best observed with the indirect ophthalmoscope. The lesions themselves may have ‘substance’ to them; we have interpreted this appearance as evidence of an active lesion, whereas with time they may flatten out, giving a more atrophic appearance ( Fig. 25-2 ). The lesions can disappear. Usually the lesions in the posterior pole do not have a significant amount of pigment surrounding them and those in the periphery perhaps have even less. The overlying retina may be quite normal, although in more advanced disease an edematous or thinned retina can be perceived. In the late stages, examination of the posterior segment reveals a strikingly blond fundus, suggestive in our minds of the involvement of the outer retina and the retinal pigment epithelium. Rothova and von Schooneveld reported end-stage findings in one patient who did not receive immunosuppressive therapy. The patient’s electroretinograms (ERGs) ultimately were flat, and the retina resembled a tapetoretinal dystrophy. Using fundus autofluorescence, the hypopigmented lesions did not correspond to the white-cream colored lesions ( Fig. 25-3 ). They are however, reflective of retinal pigment epithelial damage or death and could explain the poor vision seen in some patients.
Ocular examination and ancillary clinical tests
Examination of the macula is imperative, as cystoid edema is a significant sequela to this disease. We noted it in 41% of the eyes with birdshot retinochoroidopathy we followed. Its presence is important in establishing the diagnosis and in deciding on a correct therapeutic approach. Monnet and coworkers reported that cystoid macular edema was the most common casue of a drop in visual acuity in the 80 patients they reported. Thorne et al. reported cystoid macular edema in 20% of their patient group, noting that the longer the patient had had the disease the greater the chance of developing cystoid macular edema and the greater the chance of a decrease in vision. Patients with birdshot retinochoroidopathy have a vitreal reaction, although if cystoid edema is not present visual acuity will often be quite good despite the opacities. The disease may initially be low grade, and patients may not be aware of visual alterations, with lesions being noted because of a routine examination or after cataract surgery. ,
The use of fluorescein angiography is helpful in delineating the degree of retinal vascular leakage and the severity of the macular edema. This technique very dramatically underscores the rather marked retinal vascular component of this disease, as well as inflammatory disease affecting the optic nerve head ( Fig. 25-4 ). However, as Gass first noted – as have all the investigators reporting their findings concerning this disease – the cream-colored lesions are far more prominent ophthalmoscopically than with fluorescein angiography. Although mild hyperfluorescence may be noted in the later stage of the angiogram, early photographs in the angiogram may not demonstrate either hypo- or hyperfluorescence ( Fig. 25-5 ). Optical coherence tomography (OCT) has been a useful way to determine the presence of macular edema and also to monitor for its disappearance. Ultrahigh-resolution OCT has provided us with a new and important view of the damage that can occur with the inflammatory disease of birdshot. Monnet et al. have corroborated what we showed years ago: that a drop in visual acuity is associated with macular thickness rather than the area of fluorescein leakage. They did report that the loss of the third highly reflective band (HRB) seen on OCT is associated with poorer visual acuity ( Fig. 25-6 ). Forooghian et al., using high-definition OCT, showed that foveal atrophy was a complication of many uveitic syndromes, including birdshot retinochoroidopathy.
Indocyanine green (ICG) has been used to study this disorder ( Fig. 25-7 ). Although the use of ICG will elucidate more lesions than are seen clinically, early on in its use it was suggested that it was not particularly useful in following the disease course. More recently, Herbort et al. have shown that choroidal lesions evolve differently than do the retinal lesions, with the former seeming more responsive to immunusuppressive therapy. Lommatzsch and coworkers studied choroidal blood flow using perfusion-pressure videoangiography in a patient with birdshot retinochoroidopathy. They found that in this patient fluorescein dye penetrated through the vessel walls of the large choroidal arterioles close to the short posterior ciliary arteries. These investigators thought that this leakage was the cause of the typical birdshot pattern seen in this disorder. It does not explain, however, why most patients initially may not have dramatic angiographic evidence of disease.
Many of these patients will show altered retinal function in spite of good visual acuity. The visual field and electroretinographic results are two good ways to follow the course of these patients. Visual field testing will often reveal scotomata, even in patients with good vision and minimal ocular complaints. , In a report by Thorne et al., 75% of 48 eyes had abnormal I-4 changes. Of the 28 eyes from patients receiving immunosupprssion, the rate of visual field loss prior to therapy was 107° per year for the I-4 isopter. After therapy was initiated, there was a rate of gain of 53° per year for the isopter. Therefore therapy may reverse visual field loss. Problems with night vision and color discrimination are not uncommon in patients with this disorder, sometimes despite excellent central visual acuity. They should not be taken lightly, because alterations in retinal functions other than visual acuity can be demonstrated.
In reports investigating psychophysical and electrophysiologic testing of patients with this entity, disturbances in both the electroretinogram and the electrooculogram have been noted. Fuerst and colleagues reported a b-wave amplitude reduction and an implicit time prolongation. We have seen abnormal ERGs in the majority of patients we have tested, results similar to those reported by others ( Fig. 25-8 ). Several electrophysiologic changes have reported. Holder et al. reported that the cone-mediated flicker ERG responses are delayed before therapy initiation. Sobrin and coworkers also saw the cone b-wave flicker implicit time alterations and that they seemed to improve with therapy. Zacks et al. suggested that the bright scotoptic response amplitudes and the 30 Hz flicker implicit times were associated with recurrence of disease as immunosuppressive therapy is tapered. Robson et al. suggest that post-phototransduction involvement of the optic nerve pathway may be seen as well. Color-vision alterations can be found, and some patients complain of colors being ‘washed out’ or faded. Others may note a difference in color discrimination between their two eyes. Holland et al, using the desaturated Lanthony 15-Hue Test, showed that 49 of 80 patients tested (61.3%) had abnormal color confusion scores, and this included patients with normal vision. Dark adaptation thresholds are invariably abnormal. Indeed, Kappel and coworkers evaluated birdshot patients with contrast sensitivity testing. Reduced contrast sensitivity is a common finding in these eyes, being abnormal in 92% of 126 eyes tested. Although they are often related to poor vision, these authors also found that of the 38 eyes tested with normal vision, 31 (82%) had abnormal contrast sensitivity. A meta-analysis of several studies describing the clinical features of the disease can be seen in Table 25-1 .
| Authors | Shah et al. 2005 | Monnet et al. 2006 | Kiss et al. 2005 | Thorne et al. 2005 | Becker et al. 2005 | Rothova et al. 2004 |
|---|---|---|---|---|---|---|
| Design | Review | Cross-sectional | Retrospective | Retrospective | Retrospective | Retrospective |
| Period of study | 1980–2002 | 2002/2003 | 1980–2003 | 1984–2004 | 1985–2001 | 1990–2001 |
| Number of patients | NA | 80 | 28 | 40 | 11 | 55 |
| Female (%) | 54 | 64 | 50 | 42.5 | 54 | 47 |
| HLA-A29+ (%) | 95.7 | 100 | 96.4 | 85.7 | 100 | 100 |
| Age diagnosis (years) | NA | 52.4 | 50.6 | 56 | NA | 53 |
| Study time (years) | 53 | 55.6 | NA | NA | 45 | NA |
| Follow-up (months) | NA | NA | 81.2 | 30 | 72 (treated patients) | NA |
| Range (months) | NA | NA | 12–276 | 0–246 | 8–156 | 12–120 |
| Main outcome measures | NA | Birdshot lesion symptoms, VA | VA, ERG complications | VA, visual field complications | VA, treatment | VA, systemic diseases, visual fields, angiography, treatment |
| VA | ||||||
| Baseline | 20/40 (LP-20/15) | 0.8 a (CF-1.2) | 0.64–0.59 a (R-L) | 20/32 | NA | NA |
| ≤20/200-LP (% eyes) | 14.4 | 5 | NA | 12.8 | NA | 8 |
| End follow-up | 20/30 | NA | 0.74–0.71 a | NA | NA | NA |
| ≤20/200-LP (% eyes) | 20.6 | NA | NA | 20 (at 5 years) | NA | 30 (at 5 yrs) |
| Cystoid macular edema | ||||||
| Baseline | NA | 23.8 b | NA | 20.5 c | NA | NA |
| At any point (cumulative incidence) | 70.4% | NA | 35.7% b | 50% b (5 years) | NA | 84% b (5 years) |
| Treatment (percentage of patients treated) | ||||||
| Systemic steroids | NA | 35 | 46 | 67 | 100 | 65 |
| Immunosuppressive agents | NA | 41 | 100 | 54 | 45 | 53 |
| Cl | Cl, MM, AZ, others | Cl, MM, AZ, MTX | AZ, MTX, MM, Cl, IVIG | Cl, MTX, AZ, others | ||
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