Sympathetic Ophthalmia

What is sympathetic ophthalmia?

Sympathetic Ophthalmia is a bilateral, granulomatous uveitis that occurs after trauma to the eye.
The disease is vision-threatening, and many patients still end up with significant vision loss especially
if treatment is not instituted quickly. The onset can be insidious and slow or acute. Patients usually
present with blurry vision, a red eye, and decreased vision. The clinical exam is significant for mutton
fat keratic precipitates, serous retinal detachments and pinpoint hyper fluorescence seen on
fluorescein angiography. Prevention is limited to urgent closure of the traumatized eye and
enucleation within 10 days to 2 weeks after the traumatic event. Treatment is limited to
corticosteroids and immunomodulators. The aetiology is thought to be autoimmune, but many
questions remained unanswered.

Etiology
The etiology is not well understood but is thought to be secondary to the development of an
autoimmune reaction to ocular antigens that are exposed during the traumatic or surgical event. The
primary mediators are thought to be T cells. Studies have shown that the initial wave of infiltrative
cells is composed of CD4+ helper T cells and the later wave of infiltrative cells are CD8+ cytotoxic T
cells. In vitro testing has shown proliferative T cell responses to uveal melanocytes in the peripheral
blood of patients with sympathetic ophthalmia.

Risk Factors
Prior ocular trauma with delayed closure of the wound or prior ocular surgery is the major risk factor
for onset of sympathetic ophthalmia. The interval between the time of injury and the onset of
symptoms is variable and has been reported to be from 5 days to 66 years although the vast majority
of cases occur within the first year.

Pathology
The injured eye is the exciting eye and the fellow eye is known as the sympathizing eye. Clinically
both eyes appear the same and it is only by history that one can identify which eye is the exciting
eye. Inflammation is usually granulomatous in nature. Often, the sympathizing eye (the non-
traumatized eye) has worse vision than the exciting eye. The choroid is diffusely thickened with
lympocytes, nests of epithelioid cells and multinucleated giant cells. The epithelioid cells and giant
cells often contain melanin pigment. The inflammatory process does not usually involve the
choriocapillaris or the retina and is limited to the choroid. Dalen-Fuchs nodules, which are clusters of
epithelioid cells containing pigment lying between the RPE and Bruch’s membrane, are also seen.
The iris can also appear thickened with nodular infiltrations.

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Antigen exposure and tissue injury
Ocular antigens are normally sequestered within the eye behind the blood-retinal barrier, thus
preventing exposure of these antigens and their detection by the systemic immune system.
However, in the event of a penetrating injury or surgical procedure this barrier is breached and
ocular antigens leak into the systemic environment. The tissue damage alerts and recruits antigen
presenting cells, such dendritic cells, to the site where they phagocytose and process the free ocular
antigens into peptide fragments. CD4+ helper T cells recognize the peptides presented by class II .

HLA is Human Leukocyte Antigen which is part of the Major Histocompatibility Complex (MHC) which
are a set of genes that, in part, direct T cell mediated immunity. There are two classes of MHC that
are involved with directing T cell immunity: class I present peptides to CD8+ T cells and class II
present peptides to CD4+ T cells. The peptides presented by either classes of MHC are derived from
either “self” (own proteins) or from invading pathogens. HLA are one of the most polymorphic
genes, meaning that many variants exist, and the pairs of inherited genes create a unique set of
immune responses in each person. HLA are known to be associated with different diseases and with
transplantation compatibility/ incompatibility.

Under normal circumstances, where ocular antigens remain in the eye, CD4+ helper T cells do not
recognise ocular proteins because autoreactive T cells are deleted in the thymus during T cell
development. However, there are rare instances when an autoreactive T cell develops because there
is cross-reactivity between the ocular peptide and a previously encountered peptide, which may
have occurred in response to previous immune responses to other infections. This cross-reactivity
with a peptide seen previously in an infection is known as molecular mimicry. When this occurs T
cells that respond to the ocular antigen undergo clonal expansion and migrate to the site of
inflammation.

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Activated T cells up-regulate surface receptors that allow them to extravasate from the blood
circulation into inflamed tissue. Vascular endothelial cells also up-regulate receptors to facilitate
this process when stimulated by inflammatory cytokines such as Interleukin 1(IL-1) has many
functions on many
different cells and is
secreted by a number of
cells including
macrophages, monocytes
and dendritic cells. It also
helps to activate T helper
cells by acting as a co-
stimulator with the
antigen presenting cell
receptors and it helps
promote the maturation
and clonal expansion of B
cells.

IL-1 and TNF-a. In this way ocular antigen-specific CD4+ helper T cells are able to penetrate the
usually impervious blood-retinal barrier in the damaged eye and respond to the same ocular
antigens. The inflammatory response continues to recruit more immune cells overwhelming the
immune privilege status of the eye and causing further damage. This continues if unchecked,
resulting in the swelling observed in our case, unless immunosuppressive drug therapy is initiated.

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Inflammation in the sympathising eye
This is most likely due to systemic cytokine effects, with CD4+ helper T cells specific for the ocular
antigen originally from the damaged left eye, which can now penetrate the blood-retinal barrier of
the undamaged right eye (sympathizing eye). This initiates an immune response to the same antigen.
Penetration of the right eye is likely due to upregulation of receptors on vascular endothelial cells in
the sympathising eye by the action of IL-1 and TNF-a. The activated T cells secrete cytokines that
recruit further T cells and antigen presenting cells that can continue to process ocular antigens. This
cycle of events leads to inflammation and subsequent damage to the sympathising eye that can
cause visual loss unless the damaged eye is removed early enough or immunosuppressive drugs are
initiated in time.

Let’s look at the pathophysiology of sympathetic ophthalmia in closer detail, as this is an example of
how immune tolerance is broken which causes disruption to an immune privileged organ.
The eye is an essential organ of survival because it provides vision. For this reason, it is one of the
body’s immune privileged sites and mechanisms of immune tolerance operate to protect ocular
tissues from immune-mediated damage. Other areas of the body which display similar immune
tolerance include the brain, placenta and testis.

Ocular tissues have minimal ability to regenerate if damaged and therefore regulatory systems are in
place to limit excessive pro-inflammatory immune responses. These include simple barrier systems
to restrict antigen and cellular traffic as well as soluble and cell-bound factors that suppress immune
cell activation. Six such mechanisms are discussed here in more detail: a) blood-retinal barrier; b)
immune evasion; c) apoptosis; d) inhibitory factors; e) soluble immunosuppressive factors and f)
immune deviation.

The Blood-retinal Barrier

Segregation of antigens from immune cells in the periphery is partially achieved by the blood-retinal
barrier. Vascular endothelial cells are connected by impermeable tight-junctions and there is a
basement membrane (Bruch’s membrane) that prevents soluble molecules from diffusing out of the
eye. The retinal pigment epithelium is also an impermeable cell layer connected by tight junctions to
protect the photoreceptor cells. The eye also lacks a lymphatic system, which serves as a drainage
for inflammatory agents, and so the effects of inflammation are highly constrained. However, the
important point to note, is that ocular antigens can prime new T cell responses at lymph nodes distal
to the eye.

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Immune Evasion
The primary goal of immunosuppressive mechanisms in the eye is to circumvent damage to cells
required to maintain vision. Mechanisms known to operate in the protection of ocular tissues from
attack by cytotoxic immune cells such as natural killer cells and CD8+ cytotoxic T cells involve lack of
expression of the classical class I HLA is Human Leukocyte Antigen which is part of the Major
Histocompatibility Complex (MHC) which are a set of genes that, in part, direct T cell mediated
immunity. There are two classes of MHC that are involved with directing T cell immunity: class I
present peptides to CD8+ T cells and class II present peptides to CD4+ T cells. The peptides
presented by either classes of MHC are derived from either self (own proteins) or from invading
pathogens. HLA are one of the most polymorphic genes, meaning that many variants exist, and the

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pairs of inherited genes create a unique set of immune responses in each person. HLA are known to
be associated with different diseases and with transplantation compatibility/ incompatibility.

Lack of expression of classical HLA A, B and C molecules and the upregulation of expression of non-
classical class I HLA E and G receptors. Specifically, it has been shown that the absence of HLA A, B
and C receptors prevents CD8+ cytotoxic T cells from responding to foreign peptides while the
expression of HLA E and G receptors interacts with CD94/NKG2 receptors inhibiting the action of
natural killer cells.

Apoptotic Factors and Inhibitory Factors

The cells of certain ocular tissues express membrane receptors that induce apoptosis or inhibition of
activated immune cells as well as cellular enzymes that deplete tryptophan, any organic acid
containing one or more amino groups (NH2) and a carboxyl group (CO2H) forming the essential
components of proteins.

Amino acids essential for T cell survival. Several of these mechanisms are now well understood. For
simplicity, our graphic has been divided into two: one part which describes the factors involved in
apoptosis and the second part which describes the inhibitory factors. Although depicted separately
these are processes which occur simultaneously. FasL and PD-L1 engagement promotes apoptosis in
activated T cells following interaction with respective Fas and PD-1 receptors. While another ligand,
TRAIL (TNF-related apoptosis ligand), engages with receptors on macrophages and neutrophils to
induce apoptosis. Activated neutrophils also express Fas that interacts with FasL to promote
apoptosis. CD86 receptors engage with the inhibitory receptor CTLA-4 on T cells. In addition, some
ocular cells inhibit T cell proliferation by mediating depletion of tryptophan with IDO (indolamine
2,3-dioxygenase).

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Soluble Immunosuppressive Factors

Other immunosuppressive mechanisms in the eye include secretion of soluble factors into the
aqueous and vitreous humor. Some of these factors are seen in the other immune privilege sites.

 TGF-beta is a potent suppressor of activation of T cells, natural killer cells and

macrophages. It also primes antigen presenting cells to preferentially generate regulatory T
cells in response to antigen presentation.

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  CGRP and a-MSH prevent activated macrophages from secreting pro-inflammatory
cytokines.
 VIP suppresses T cell activation
 SOM prevents activated T cells from secreting IFN-gamma.
 Neutrophils do not become activated under the action of sFasL.
 MIF inhibits natural killer cell cytotoxic function.
 CRP prevents activation of the complement cascade.

Immune Deviation
This process is a mechanism that protects the eye from collateral damage to an immune-mediated
damaging response after infection. In a normal situation, when foreign antigens are deposited in the
anterior chamber, due to infection, pro-inflammatory immune responses fail to be elicited due to
anterior chamber-associated immune deviation (ACAID). Although this has only been described in
experimental models, it is thought that ocular antigen presenting cells can preferentially select and
activate regulatory T cells through the action of TGF-b. In mice it has been shown that ocular F4/80+
macrophages phagocytose foreign antigens in the anterior chamber of the eye and then migrate to
the thymus and spleen. In the thymus they stimulate the generation of NK-T cells, while in the
spleen antigen-specific CD8+ and CD4+ T cells are primed leading to the generation of regulatory T
cells. These migrate back to the anterior chamber of the eye and suppress pro-inflammatory
immune responses. It is unlikely that ACAID operates to this degree when the eye is physically
disrupted.

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Prevention
There has been debate regarding the only known means of prevention of sympathetic ophthalmia,
i.e. removal of the injured eye (enucleation) within a week after the traumatizing incident. There
have been arguments made that the exciting eye should be enucleated immediately after trauma [9]
as well as arguments that steroid use after the onset allows for continued good vision in the
contralateral eye. Occasionally, the exciting eye is the eye with better vision after the onset of
sympathetic ophthalmia, but it remains to be seen whether this continues to be the case as with the
changing treatments available, these patients are seen sooner and treated with corticosteroids and
immunomodulators sooner. There is no known benefit to enucleation of the exciting eye after the
onset of sympathetic ophthalmia.

Diagnosis
 History
The history plays an important role in the diagnosis of sympathetic ophthalmia. Usually,
the patient has a history of major trauma or surgery to one eye, either recently or in the
past. This diagnosis can sometimes be made after multiple surgeries in an eye, but the
vast majority of patients have a history of trauma.

 Symptoms
Patients usually present with non-specific symptoms of ocular inflammation: blurred
vision or decreased vision, ocular discomfort, conjunctival injection, etc.

 Clinical evaluation
Patients will have bilateral uveitis with mutton fat keratic precipitates along with variable
inflammation of the choroid manifesting as vitritis, optic nerve swelling (papillitis), and
multifocal choroiditis ( Dalen Fuchs nodules) [10]. Patients classically have multiple
exudative retinal detachments that are visible on dilated fundus exam and can be
captured on optical coherence tomography (OCT). These areas of serous retinal
detachments correspond to pinpoint hyper fluorescence and leakage on fluorescein
angiogram.

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  Ancillary procedures
Optical Coherence Tomography has been shown to be a reliable method of following serous
retinal detachments [11]. Fluorescein angiography shows multiple areas of pinpoint hyper
fluorescence which leak on later phases in areas that correspond to the serous retinal
detachments seen clinically.

 Differential diagnosis

The most common alternate diagnosis entertained when evaluating a patient with
sympathetic ophthalmia is Vogt-Koyanagi-Harada syndrome. However, alternate diagnoses
include tuberculosis, syphilis and other causes of infectious granulomatous uveitis, however,
sarcoidosis, phacoanaphylactic uveitis, posterior scleritis, and infiltrative conditions must be
considered. The infectious causes of uveitis must be ruled out prior to initiating treatment for

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 sympathetic ophthalmia due to the risk of worsening the underlying infection with steroid
use. 

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Management
Corticosteroids are the mainstay of treatment. Steroids should be initiated as soon as the
diagnosis is made in the absence of other contraindications and once infectious testing is
negative. Along with corticosteroids, immunomodulators such as cyclosporine or azathioprine
can be used. Patients should be followed closely and may need to be admitted if they cannot
follow up or take the medications as prescribed. Patients should be seen often until they begin to
stabilize and improve at which point visits can be spread out. 

Prognosis
Sympathetic Ophthalmia is a serious vision-threatening disease. Half of all patients will have
20/40 or worse vision and one third of all patients will end up legally blind [12]. Complications
include macular oedema, choroidal neovascularization, and recurrent anterior segment
inflammation [13].

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 References
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writing (author's transl)]. Klinische Monatsblatter fur Augenheilkunde 170 (1): 154–8.
2. Jump up↑ Chan CC, Benezra D, Rodrigues MM, Palestine AG, Hsu SM, Murphree AL,
Nussenblatt RB. Immunohistochemistry and electron microscopy of choroidal infiltrates and
Dalen-Fuchs nodules in sympathetic ophthalmia. Ophthalmology 1985; 92:580–90.
3. Jump up↑ Jakobiec FA, Marboe CC, Knowles DM, Iwamoto T, Harrison W, Chang S, Coleman
DJ. Human sympathetic ophthalmia. An analysis of the inflammatory infiltrate by
hybridomamonoclonal antibodies, immunochemistry, and correlative electron microscopy.
Ophthalmology 1983; 90:76–95.
4. Jump up↑ Damico F, Kiss S, Young LH. Sympathetic Ophthalmia. Semin Ophthalmol
2005;20:191–197.
5. Jump up↑ Lubin JR, Albert DM, Weisntein M. Sixty-five years of sympathetic ophthalmia. A
clinicopathologic review of 105 cases (1913–1978). Ophthalmology 1980;87:109–112.
6. Jump up↑ Chan CC, Roberge RG, Whitcup SM, Nussenblatt RB. Thirty two cases of sympathetic
ophthalmia. A retrospective study at the National Eye Institute Bethesda, MD from 1982–1992.
Arch Ophthalmol 1995;113:597–601.
7. Jump up↑ Goto H, Rao NA. Sympathetic Ophthalmia and Vogt-Koyanagi-Harada syndrome. Int
Ophthalmol Clin 1990;30:279–28541.
8. Jump up↑ Goto and Rao. Sympathetic ophthalmia and Vogt-Koyanagi-Harada syndrome. Int
Ophthalmol Clin (1990) vol. 30 (4) pp. 279-85
9. Jump up↑ Lubin JR, Albert DM, Weisntein M. Sixty-five years of sympathetic ophthalmia. A
clinicopathologic review of 105 cases (1913–1978). Ophthalmology 1980;87:109–112.
10. Jump up↑ Gupta V, Gupta A, Dogra MR. Posterior sympathetic ophthalmia: a single centre long-
term study of 40 patients from North India. Eye. 2008;3(12):1459–1464.
11. Jump up↑ Chan RV, Seiff BD, Lincoff HA, Coleman DJ. Rapid recovery of sympathetic
ophthalmia with treatment augmented by intravitreal steroids. Retina. 2006;3(2):243–247.
12. Jump up↑ Chan CC, Roberge RG, Whitcup SM, Nussenblatt RB. Thirty two cases of sympathetic
ophthalmia. A retrospective study at the National Eye Institute Bethesda, MD from 1982–1992.
Arch Ophthalmol 1995;113:597–601.
13. Jump up↑ Damico F, Kiss S, Young LH. Sympathetic Ophthalmia. Semin Ophthalmol
2005;20:191–197.

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