Birdshot retinochoroiditis: the origins of the disease name
Birdshot retinochoroiditis (BRC) is a uveitis predominantly affecting the posterior
segment of the eye with dual, independent retinal and choroidal inflammation and almost
only seen in Caucasians.1
2 Ryan and Maumenee first described the bilateral retinochoroidal inflammatory disease
in early 1980, reporting on 13 patients.2 These authors called it ‘birdshot retinochoroidopathy’
because they found that lesions had a pattern comparable to that seen in wounds produced
by birdshot shotguns. Later in 1980, Kaplan and Aaberg published a series of four
similar cases ‘involving a choroidal and retinal pigment epithelium disease not previously
described’, which they also called birdshot retinochoroidopathy.3 In 1981, Gass described
11 similar cases and called the disease vitiliginous chorioretinitis.4
In these first articles on the disease, clinicians had no choice but to rely on fundus
examination and fluorescein angiography (FA). Therefore, the striking choroidal involvement
seen on fundus examination was at the origin of the eponym the authors chose to give
to the disease, because both ‘birdshot’ and ‘vitiliginous’ refer to the typical rice-shaped,
depigmented choroidal birdshot fundus lesions (BFLs) that strongly and specifically
characterised the condition. Of the two designations, ‘birdshot’ became the universally
used and accepted term. It is understandable that such remarkable choroidal signs
determined the naming of the disease because the retinal and FA signs were so much
less specific and pathognomonic. Nevertheless, an important FA sign was noted by Gass,
who observed retinal vasculitis of small and large vessels and the profuse leakage
of fluorescein into the retina in the early disease, as well as a reduced presence
of fluorescein in the large veins.4 He interpreted this feature as a substantial delay
in retinal arteriovenous circulation, an explanation that was later shown to be inexact,
thanks to the use of dual FA/indocyanine green angiography (ICGA) (see below).5 Retinal
involvement was accounted for by calling the disease a retinochoroiditis or a chorioretinitis.
Often the disease was also called a retinochoroidopathy or a chorioretinopathy, which
was inadequate because it is clearly inflammatory, so that the suffix ‘-itis’ should
have been used.
The importance of HLA-A29 histocompatibility antigen as a disease-defining criterion
Association of BRC with the HLA-A29 major tissue histocompatibility (MHC) antigen
was first reported in 1982, 2 years after the entity was originally described.6 The
association rate was estimated to be approximately 95% in subsequent reports.7
8 LeHoang et al
9 found that BRC was associated with the HLA-A29-2 subtype, with a subsequent study
confirming this link as well as an association with the HLA-A29-1 subtype.10 The HLA-A29
MHC antigen is present in around 7% of Caucasian populations.11 It is increasingly
likely that the association is closer to 100% rather than >95% because false negatives
were not so rare when the antibody testing method was used.12 The rate of false-negative
results could be reduced with PCR-based testing.12 The disease has no known extraocular
inflammation sites and yet features the strongest known HLA association with an MHC
antigen with a greatly increased OR of 157.5 for the disease when the HLA-A29.02 allele
is present.13 Truly HLA-A29-negative birdshot patients are a rarity if they exist
at all, and restricting the diagnosis to PCR-positive HLA-A29 patients would exclude
a very tiny proportion of cases, if any. Therefore, the presence of HLA-A29 antigen
should be considered an essential criterion for diagnosing BRC.
ICGA is essential in detecting occult choroiditis and perform early diagnosis
Together with HLA testing, the second most important element that has drastically
changed the appraisal of BRC was the fact that ICGA became available to image the
choroid. ICGA first came into clinical use in the early 1990s and enabled insight
into choroidal inflammation.14 One substantial advantage of this method was that it
made possible the detection of occult choroidal lesions that were inaccessible using
other investigational methods.15
16 ICGA allowed clinicians to subdivide choroidal inflammation into choriocapillaritis
entities (eg, acute posterior multifocal placoid pigment epitheliopathy or idiopathic
multifocal choroiditis) and stromal choroiditis (eg, Vogt-Koyanagi-Harada (VKH) disease
and BRC).17
18
ICGA findings in BRC were standardised in 1999.19 Relevant ICGA signs for diagnosis
and disease monitoring are the presence of hypofluorescent dark dots (HDDs) and fuzziness
of large choroidal vessels. HDDs were suspected to arise from space-occupying stromal
inflammatory foci, a hypothesis that Gaudio et al
20 confirmed histopathologically. Many HDDs in BRC become isofluorescent on late angiographic
frames, which indicates that (unlike in VKH) lesions do not occupy the full thickness
of the choroidal stroma and do not involve the inner choroid.21 Fuzziness of choroidal
vessels indicates vasculitis of large choroidal vessels.14
In several reports, HDDs were thought and reported to be the angiographic expression
of BFLs.22 They are not, however, because we now know that BFLs are silent on ICGA
and correspond to inactive depigmented cicatricial areas where pigment has been destroyed
by the inflammatory mechanism. BFLs can coexist with HDDs, meaning that the disease
has been present for some time and is still active (figure 1). On the other hand,
HDDs may be absent in the presence of BFLs, meaning that the disease is no longer
active and that what we see are simply areas devoid of melanocytes, marking regions
of previously active stromal choroiditis (figure 1).
Figure 1
Birdshot fundus lesions (BFLs) do not correspond to hypofluorescent dark dots (HDDs).
Case of birdshot retinochoroiditis that lasted for >5 years before the patient agreed
to treatment. Top left: untreated patient; many BFLs are present in the fundus. Bottom
left, indocyanine green angiography (ICGA) frame, the presence of numerous HDDs indicating
active disease; however, there are more angiographically silent BFLs than HDDs. Top
right: the fundus after 7 years of treatment with persisting BFLs. Bottom right: ICGA
frame showing that neither resolved HDDs nor BFLs appear on ICGA (angiographically
silent).
HDDs resolved in treatment-naïve patients with BRC having BFLs without affecting substantially
their size or number,23 precisely because BFLs correspond to areas of depigmentation
that no longer have any active inflammation once the stromal pigment islets have been
‘digested’. This explains why BRC fundus lesions are angiographically silent. The
third scenario that can arise consists of HDDs without BFLs, indicating early disease
before cicatricial depigmentation has occurred (see below) (figure 2).
Figure 2
(A) Case of birdshot retinochoroiditis diagnosed before birdshot fundus lesions (BFLs)
were visible. Top: fundus pictures of the right and left eye. No BFLs seen. Middle:
indocyanine green angiography (ICGA) showing numerous HDDs on both sides. Bottom:
diffuse retinal vasculitis involving veins of all sizes with diffuse leakage. (B)
Same case as (A) after 10 years of immunosuppressive therapy. Top: fundus pictures
of right and left eye showing absence of typical BFLs. Middle: ICGA shows a totally
normal choroid indicating that the choroid is responding easily to immunosuppressive
therapy with resolution of all lesions. Bottom: fluorescein angiography (FA) shows
that retinal vasculitis is substantially improved; however, discreet leakage is still
present, and there is bilateral disc hyperfluorescence.
ICGA also demonstrated that choroidal and retinal inflammation develop independently,
showing that areas of retinal capillary leakage seen on FA do not correspond to HDDs.24
Dual FA/ICGA makes it clear that choroidal inflammation promptly responds to therapy,
whereas retinal inflammation is more resistant and is responsible for most of the
symptoms and morbidity caused by the disease.25
ICGA also made it possible to explain the apparent perfusion delay of retinal veins
reported by Gass, which in fact is a ‘pseudo-delay’ caused by massive extrusion of
fluorescein into the retina, while ICGA retinal arteriovenous circulation time is
normal.5
ICGA, crucial for early diagnosis/early treatment, modified the phenotype of BRC
By far the most important impact of ICGA in BRC was that choroidal involvement can
be detected before the typical choroidal birdshot lesions are seen on funduscopy (figure
2).26 Moreover, among patients treated before the development of BFLs, the appearance
of such lesions could be prevented altogether in five of six cases treated within
a mean of 6.5 months of the onset of symptoms. In addition, such lesions were not
observed during a mean follow-up period of 10 years under treatment, implying a change
in the phenotype of BRC (figure 2).23 In this regard, BRC behaved like VKH, another
stromal choroiditis in which early, aggressive and prolonged treatment can prevent
the development of sunset glow fundus.27 The preponderant role of ICGA in BRC has
been reported by several groups in Europe and recently also in the USA.19
28–30 Indeed, prevention of BRC fundus lesions requires early diagnosis, which is
not possible with the present diagnostic criteria.
The need for appropriate diagnostic criteria of BRC
In 2006, a group of experts published research criteria for the diagnosis of BRC.31
However, these criteria fail to truly characterise BRC, especially early stage disease.
The major shortcomings are the omission of ICGA signs, which are present in 100% of
cases19
23; the lack of any reference to the visual field changes that are present in almost
100% of cases at presentation, depending on the onset of symptoms32
33; the characterisation of HLA-A29 antigen as a merely supporting factor, even though
it is present in almost 100% of cases when PCR testing is used and the lack of acknowledgement
that keratic precipitates cannot be an exclusion criterion because they are present
in 15.8%–23% of treatment-naïve patients.2
4
34 In our series, the 3/19 (15.8%) patients with keratic precipitates had been evolving
for more than 3 years without treatment.34
There is an urgent need for new and proper diagnostic criteria for the appropriate
appraisal and management of BRC, especially for early disease. In our studies, we
used the following criteria for the diagnosis of BRC: (1) presence of vitritis and
retinal vasculitis in one or both eyes, (2) visual field anomalies in one or both
eyes, (3) stromal choroiditis as evidenced by ICGA in both eyes (required), HLA-A29
antigen positivity (required) and absence of extraocular inflammation sites. An additional
(but not any more requested) strongly suggestive criterion is the presence of BFLs.
Such criteria are to be recommended for use in clinical practice as they correspond
to the reality of the disease presentation (box 1).
Box 1
Global diagnostic criteria for birdshot retinochoroiditis (BRC)/HLA-A29 uveitis
Presence of vitritis in one or both eyes (required)
Presence of retinal vasculitis in one or both eyes (required)
Stromal choroiditis, as evidenced by ICGA, in both eyes (required)
HLA-A29 antigen positivity (required)
Visual field anomalies in one or both eyes (supportive)
Absence of extraocular inflammatory site (supportive)
Presence of rice-shaped depigmented ‘birdshot lesions’ (BRC fundus lesions) (strongly
supportive but not required)
BRC, birdshot retinochoroiditis; ICGA, indocyanine green angiography.
HLA-A29 uveitis, a more appropriate name for BRC?
In case of fulfilment of the above-listed clinical and investigational (especially
angiographic) characteristics, birdshot cases can be expected to be associated with
HLA-A29 positivity almost 100% of the time as long as PCR methodology is used; this
rate is by far the highest known HLA association with a disease. Furthermore, if the
diagnostic criteria cited here are used together with HLA-A29 determination, early
diagnosis before the pathognomonic BFLs are seen, becomes possible. It would therefore
be justified and even advisable to rename the disease after the most frequent characteristic
element associated with it, the HLA-A29 antigen, which must be elevated to a disease-defining
criterion. Indeed, in the early stage of disease, birdshot lesions are not disease
defining, and classically relying on their presence leads to diagnostic delay when
early diagnosis and treatment are so important.35
In practice, cases devoid of fundus lesions that were referred to us with vitritis
and FA signs compatible with BRC usually were sent with the a diagnosis of retinal
vasculitis (figure 3). When performing ICGA, which is absolutely necessary with such
a constellation, the presence of bilateral ICGA angiographic signs including HDDs
and fuzziness of vessels invariably led to HLA testing. HLA-A29 positivity confirmed
the diagnosis in the absence of any BFLs, making HLA-A29 antigen rather than BFLs
the hallmark of the disease.
Figure 3
Case of birdshot retinochoroiditis without birdshot fundus lesions at presentation.
The patient was referred for retinal vasculitis and also complained of floaters bilaterally.
Posterior segment showed numerous vitreous opacities but no fundus lesions (top).
Middle: diffuse retinal vasculitis in both eyes. Bottom: typical indocyanine green
angiography signs of stromal choroiditis with numerous HDDs and non-recognizable pattern
of choroidal vessels. The patient was immediately tested for the presence of HLA-A29
antigen, which was indeed positive.
Perspective and concluding remarks
BRC has been characterised by a strong clinical phenotype since its initial description.
Subsequently, additional and even stronger investigational disease-defining criteria
have become available. HLA-A29 histocompatibility antigen was first estimated to be
present in up to 95% of BRC cases, but was finally found to be present in almost 100%
of cases when PCR methodology was used.12 Long-neglected ICGA showed a stromal choroiditis
in 100% of cases. Together, these two strong disease-defining criteria have opened
the way to early diagnosis of the disease, no longer requiring the presence of BFLs,
representing a diagnostic delay until BFLs appear. Recent data have even shown that
in case of early and sustained treatment, birdshot lesions are prevented altogether,
changing the phenotype of BRC.23 In this context of a disease without BFL, the traditional
name no longer corresponds to the new reality of this clinical entity. To retain it
could even have a deleterious effect on disease management by delaying therapeutic
intervention during the wait for birdshot lesions to arise. ‘HLA-A29 uveitis’ more
adequately reflects the current, updated clinical context. This name change would
have the same implications as HLA-B27 uveitis because both terms reference diseases
for which the etiopathogenicity is unknown but the exact course of the disease is
well-established.