White dot syndromes are inflammatory diseases characterized by the presence
of white dots on the fundus, the interior surface of the eye. The
majority of individuals affected with white dot syndromes are younger than
fifty years of age. Some symptoms include blurred vision and visual field
loss. There are many theories for the etiology of white dot syndromes
including infectious, viral, genetics and autoimmune.
Classically recognized white dot syndromes include:
Acute posterior multifocal placoid pigment epitheliopathy
Birdshot chorioretinopathy Multiple evanescent white dot syndrome
Acute zonal occult outer retinopathy Multifocal choroiditis and panuveitis
Punctate inner choroiditis Serpiginous choroiditis
Specific white dot syndromes Specific characteristics regarding the
white dots and predicted etiology are presented of selected diseases.
= Acute Posterior Multifocal Placoid Pigment Epitheliopathy =
Acute posterior multifocal placoid pigment epitheliopathy primarily occurs
in adults. Symptoms include blurred vision in both eyes, but the onset may
occur at a different time in each eye. There are yellow-white placoid lesions
in the posterior pole at the level of the RPE. Some suggest a genetic
predisposition to the disease, while others postulate an abnormal immune
response to a virus. = Birdshot choroidopathy =
= Multiple evanescent white dot syndrome Multiple evanescent white dot syndrome
occurs mostly in females. Symptoms include a sudden loss of central vision,
but patients eventually regain normal vision. The white dots are small and
located in the posterior pole at the level of the retinal pigment epithelium.
The white dots may disappear after the first few weeks of the disease. The
cause is generally unknown, but a viral illness has been reported prior to MEWDS
in one-third of cases. Since the disease occurs primarily in females, “hormonal
status” might be a contributing factor. = Acute zonal occult outer retinopathy =
Some discrepancy exists as to whether acute zonal occult outer retinopathy is
actually considered a white dot syndrome. However, AZOOR may definitely
be related to other diseases included in the white dot syndrome group. AZOOR
occurs in young to middle age adults and may eventually progress to retinal cell
death. Symptoms include acute visual field loss and photopsias. Suspected
causes for AZOOR include autoimmune, viral, and fungal.
= Multifocal choroiditis and panuveitis Multifocal Choroiditis occurs mainly in
myopic females. The fundus presents with yellow or gray lesions at the level of
the choroid and RPE. The size of the white dots are between 50 to 500
micrometres and localized in the macula. MPC is characterized by vitritis and
anterior chamber inflammation. Decreased vision due to vitreous inflammation may
occur. Unlike MEWDS, MPC is a chronic disorder and macular scarring
contributes to severe visual loss. Theories regarding the cause include an
exogenous pathogen sensitizing an individual to antigens within
photoreceptors, RPE, or choroid. = Punctate inner choroiditis =
Punctate inner choroiditis is an inflammatory choroiditis which occurs
mainly in young females. Symptoms include blurred vision and scotomas. .
Gray-white or yellow lesions are mainly present in the posterior pole and are
between 100 to 300 micrometres in size. PIC is one of the so-called White dot
syndromes which come under the heading posterior uveitis.The appearance of
punctate areas is at the level of the inner choroid. These lesions are
typically located centrally at the back of the eye.
= Serpiginous choroiditis = Serpiginous choroiditis, also known as
geographic or helicoid choroidopathy, is an uncommon chronic progressive
inflammatory condition affecting adult men and women equally in the second to
seventh decades of life. Nature of white dots
The white dots of the white dot syndromes are lesions that vary in their
location in the fundus and in most cases tend to disappear. White dots appear
early in the disease stages of PIC and MEWDS. In this case, the white dot is
localized in the posterior pole, small, and do not clump together. In contrast,
white dots appear later in the disease stages of birdshot choroidopathy,
serpiginous choroiditis, and APMPPE. The white dots in these diseases may be
present throughout the entire fundus, larger, and tend to clump together.
Among all these syndromes, there exists some retinal vessel inflammation. The
differences in the dots are usually in the size, position, and depth of the
lesion within the choroid. The way in which the dots form in some
of the white dot syndromes has been reported. The dot appears as a small
granuloma which is composed of lymphocytes and macrophages. The lesion
may occur within the choroid, between Bruch’s membrane and RPE, or between the
RPE and photoreceptors. Despite the differences in location, the white dots
all are of similar composition. The center of the lesion consists of
macrophages and epithelioid cells. CD4+ T cells are on the periphery of the
granuloma. Benezra has theorized that a large amount of CD8+ T suppressor cells
are observed in the later stages of the disease in order to down regulate the
inflammatory immune reaction. The formation of a granuloma occurs when
activated antigen presenting cells, specifically dendritic cells, “bind to T
cells and induce…the release of pro-inflammatory cytokines and
chemokines.” This response attracts additional antigen presenting cells and
will eventually become a granuloma. Choroidal dendritic cells span several
levels within the choroid and also associate with the RPE. Usually, the
dendritic cells disappear after removing the antigen. If removal did not occur,
the formation of a granuloma would result. The white color of the dots when
illuminated may be due to the granulomas composed only of “white cells”. Each
granuloma will disappear leaving no trace of its presence but in some cases
it may leave a ‘punched out’ scar. It is important to note that the formation of
white dots may occur more frequently but is undetected. In normal cases,
inflammation of the retina or choroid does not occur. Muller and RPE cells
normally release immunosuppressive factors, but certain combinations of
cytokines may stimulate RPE cells to release factors encouraging
inflammation. Generally, mild intraocular inflammation
results in a small, discrete, evanescent lesions. Larger dots, having less
discrete borders, are the result of high intensity intraocular inflammation. In
essence, an immune response with the normal amount and appropriate cytokine
release will result in small white dots and a misregulated response eventually
will produce scarring of the retinal tissue. Treatment is required in the
latter case to combat loss of vision. The white dots usually disappear
naturally. Corticosteroids have been shown to speed up this process. The
differences in the immune response of each patient may contribute to the
differences seen between the white dot syndromes.
= Distinct diseases = Due to the number of common features
among the multiple syndromes, many suggest that the white dot syndromes are
not distinct and represent a spectrum of one disease. Gass described the ‘AZOOR
complex’ which consists of MEWDS, MPC, PIC, acute idiopathic blind spot
enlargement, acute macular neuroretinopathy, acute annular outer
retinopathy, and AZOOR. He suggested these diseases represent one disease due
to common factors such as a high occurrence in females, unexplained
visual field loss, and reduced electroretinographic amplitudes. Reddy
et al. conducted a study on the blind spots in MPC, PIC, MEWDS, and diffuse
subretinal fibrosis syndrome. Clinical and electroretinographic evidence
suggested the diseases are distinct. However, numerous differences do occur
in fundus appearance, the clinical course of the diseases, and
electrophysiology. = Suspected etiology =
One cause of the White Dot Syndromes as suggested by Gass involves viral or
infectious agents. Specifically pertaining to the ‘AZOOR complex,’ Gass
has postulated that a virus may enter the retina at the optic head and the
infection may spread from one photoreceptor to another. Some
unexplained features include the development of more than one disease in
the same patient and the majority of cases occurring in females.
According to Becker’s common genetic hypothesis, “unlike mendelian genetic
disorders, common autoimmune and inflammatory diseases arise from
combinatorial interactions of common non-disease specific loci, disease
specific loci, and specific environmental triggers.” An important
aspect of this hypothesis pertains to the existence of common non-disease
genes that predispose patients to autoimmune diseases. Jampol and Becker
insinuate that ‘common susceptibility genes’ are present in patients affected
by white dot syndromes. The presence of environmental triggers, such as viral
infections, immunizations, and stress, and interactions with other genes
contribute to the development of the white dot syndromes. Additionally,
Jampol and Becker hypothesize that the predisposing genetic loci can be
identified. Gass points to a lack of evidence in
support of the Becker theory. Instead, Gass highlights that although evidence
indicates that patients with AZOOR have a greater chance of developing
autoimmune diseases, this does not mean that the AZOOR complex of disorders are
themselves autoimmune diseases. This is supported by the difficulty in detecting
“retinal autoantibodies” in AZOOR patients.
Two other diseases which also present with white dots on the fundus are
retinitis punctata albescens and fundus albipunctatus. These diseases are not
white dot syndromes, but have much more defined etiology. Retinitis punctata
albescens is caused by mutations in RLBP1, the gene for retinaldehyde
binding protein 1. In comparison, fundus albipunctatus is caused by mutations in
RDH5 gene for an 11-cis-RDH in RPE cells.
See also Ophthalmology
Retina Retinal pigment epithelium
References External links
PIC Society, a UK based support group and discussion forum for people with a
diagnosis of PIC or Punctate Inner Choroidopathy
Birdshot Uveitis Society, a UK based support group and discussion forum for
people with a diagnosis of Birdshot Chorioretinopathy