Graefe's Archive for Clinical and Experimental Ophthalmology

, 247:289

Sympathetic ophthalmia

Authors

  • Claudia Patricia Castiblanco
    • Retina ServiceYale University Eye Center
    • Retina ServiceYale University Eye Center
Review Article

DOI: 10.1007/s00417-008-0939-8

Cite this article as:
Castiblanco, C.P. & Adelman, R.A. Graefes Arch Clin Exp Ophthalmol (2009) 247: 289. doi:10.1007/s00417-008-0939-8

Abstract

Background

Sympathetic ophthalmia (SO) is a rare, bilateral, non-necrotizing, granulomatous uveitis that occurs after ocular trauma or surgical procedures to one eye threatening sight in the fellow eye. The pathophysiology is not clearly understood, but it appears that the disrupted integrity of the inciting eye leads to an autoimmune hypersensitivity reaction against the exposed ocular antigens in the injured eye as well as in the sympathizing eye. More recently, vitreoretinal surgery has been noted to be a risk factor for the development of SO.

Methods

Medline search for case reports of sympathetic ophthalmia with links to full text in English yielded articles for review of patient demographics, clinical presentation and examination, therapies and final visual acuity.

Results

Eighty-six patients with SO were included in this review. Sixty-two patients were male and 24 were female with an average age of 46 years. Injuries accounted for 47% of patients while ocular surgery was reported in 44% of patients with pars plana vitrectomy occurring in 21%. Most patients reported reduced vision and presented with uveitis. Ninety-five percent of them received systemic corticosteroid therapy and 75% of patients also received immunomodulators. About 70% of patients had improved visual acuity in their sympathizing eye at their last reported evaluation.

Conclusions

Sympathetic ophthalmia warrants prompt evaluation and treatment to maintain a favorable visual outcome. Ocular surgeries including vitreoretinal surgery and cyclodestructive procedures have been noted to be risk factors for the development of sympathetic ophthalmia. With current medical management including corticosteroids and immunomodulators visual prognosis is relatively good.

Keywords

Sympathetic ophthalmiaGranulomatous uveitisOcular traumaDalen-Fuch’s nodulesImmunosuppressionEviscerationEnucleation

Introduction

Ancient Greeks were aware of this disease and referred to it in the teachings of Hippocrates [2]. William Mackenzie provided the clinical description and named the disease in the Middle Ages [42]. However, it was in 1905 when Fuchs published the classic description and described its histopathology. Sympathetic ophthalmia has been associated with ocular contusion, open globe trauma, glaucoma surgery, cyclodestructive procedures, cataract surgery, vitreoretinal surgery, resection of iridociliary melanoma and proton beam irradiation for choroidal melanoma [4, 24, 28, 37, 41]. The eye sustaining the injury or surgery is referred to as the inciting eye and the fellow eye is called sympathizing eye. The time between the ocular injury or surgery of the inciting eye to the development of SO is quite varied. The sympathizing eye usually presents with inflammation within 3 months after the injury but the range has been noted to be from 2 weeks to 50 years [4]. About 80% of cases occur within a 3-month time frame and 90% occur within 1 year [24, 41].

Epidemiology

The true incidence of sympathetic ophthalmia has been hard to establish due to its rare occurrence and its diagnosis based on clinical findings. In 1979, sympathetic ophthalmia following intraocular surgery was reported to have an incidence of 0.1%, while open globe injuries had an incidence of 0.2% to 0.5% [43]. A severely injured eye with a retained intraocular foreign body holds a real chance of developing SO. In patients who sustained open globe trauma, with a retained foreign object who developed SO, about 80% developed it within 3 months and 90% developed it within 1 year [47].

Recently, Kilmartin et al. [33] conducted a prospective study in England and Ireland with a surveillance of 59 million citizens, where 23 patients with a new diagnosis of SO were reported in a 15-month period. The resulting incidence was estimated to be 0.03 in 100,000. The study also demonstrated ocular surgeries as the most common cause of SO. Most of the newly diagnosed cases occurred in patients with multiple ocular trauma incidents, suggesting a possible additive risk [27]. Surgical interventions noted to be associated with sympathetic ophthalmia include glaucoma surgery, cataract extraction, scleral buckling, pars plana vitrectomy and cyclodestructive procedures that affect the integrity of uveo-retinal tissue [16]. In the year 2000, the calculated risk of SO was estimated to be 1 in 1152 retinal surgical procedures [34].

Historically, males and children were greatly affected due to higher incidence of ocular trauma. Currently, it appears there is no gender predilection and there is an increasing number of elderly patients affected. This is likely due to the efficacy of injury prevention programs and the increased need for ocular surgery in the aging population [34]. In a review of 32 patients with SO at the National Eye institute during a 10 year period, 1.4% of 2287 of patients who presented with uveitis had SO. The age range was from 3 to 80 years old, affecting all age groups with no racial predilection noted [11].

In terms of military conflict, where eye trauma is common, it seems that the rate of reported sympathetic ophthalmia has decreased. In 1989, Albert et al. [2] noted that few cases were reported during World War I and II and no reports of sympathetic ophthalmia were made in the Vietnam, Korean and Six Day wars. In 1997, Wong et al. [62] reviewed other military conflicts in the 20th century and no reports of SO were made.

It was in 2006, when Freidlin et al. [19] reported the first case of sympathetic ophthalmia during the Iraq War and the first war related SO since World War II. Despite eye trauma and open globe injuries being common during military conflict, SO appears to be rare. Its low incidence may be related to timely medical attention, improved surgical techniques and possible underreporting by private physicians who evaluate and treat patients but do not report their findings back to the military [19].

Etiology

The etiology of SO has not been completely understood. Historically, it was hypothesized that the inflammatory process spread via the optic nerve and optic chiasm from one eye to the other [55]. A more recent hypothesis proposes that SO results from an autoimmune, inflammatory response against ocular antigens exposed to the lymphatic system in the conjunctiva or orbit. The location of such antigens remains controversial and may be located in the uveal tissue, retina or choroidal melanocytes [34]. The possible immunosuppressive function of aqueous humor, retinal secretions of anti-inflammatory molecules and genetic predisposition due to association with HLA subtypes may also play a role in the development of SO [40]. Immunologic studies have shown CD4 helper and inducer T cells during the early phase of inflammation compared to infiltration by CD8 suppressor and cytotoxic T cells in the later stages. B-lymphocytes were also found to predominate in some patients in a study by Shah et al. [54]. Cytokine gene polymorphisms may be markers of the severity of disease, recurrence and the necessary level of immunosuppression to control the ocular inflammation [3]. Genetic factors may be implicated since association with MHC haplotypes have been identified including HLA-DR4/DQw3, HLA-DR4/DRw53, HLA-A11, HLA-B40, HLA DRB1*04 and HLA-DQB1*04 [35].

Infectious agents have also been proposed as part of the etiology, but have not been isolated [31]. Buller et al. [10] recently reported a case of sympathetic ophthalmia after fungal keratitis and hypothesized that infection permitted the diffusion of inflammatory mediators and fungal antigens leading to a disturbed blood-retinal barrier exposing retinal antigens. Previously, it had been hypothesized that a purulent infection within the eye would destroy the uveal tissue in such a way that SO would not develop [63]. However, 3 cases have been reported where SO developed in the setting of endophthalmitis indicating that the infection may not offer prevention against SO. This finding suggests that the antigen is not affected by the infection and the infection may even facilitate the development of SO [53]. Incidence of SO and endophthalmitis has been reported by Lubin and Trowbridge to be in the range from 1% to 9% [41, 59]. In 2006, Rathinam et al. [53] report an incidence of 11% in their series of 32 patients.

Clinical presentation

Patients can present with bilateral intraocular inflammation after injuries including contusions, open globe trauma and surgical interventions. Symptoms have been reported to occur from 1 week to 66 years after initial injury. Patients experience flare-ups and recurrent inflammation. Clinical symptoms include gradual onset of blurry vision, mild visual disturbance to significant visual loss, pain, photophobia, photopsia, and floaters [60]. Near vision may be compromised due to change in accommodation. In examination, bilateral acute anterior uveitis with mutton-fat keratic precipitates on the corneal endothelium may be observed [17, 21]. Lymphocytic infiltration of the iris can lead to thickening and synechiae while change in the intraocular pressure may be due to ciliary body shutdown or blockage of trabecular meshwork [17]. In the posterior segment, SO can manifest itself in the form of moderate to severe vitritis, inflammation of the ciliary body, choroiditis, peripapillary choroidal atrophy and optic nerve edema [17, 21, 45]. Serous retinal detachment and macular edema may also be present [34]. Chang et al. [13] reported bilateral exudative retinal detachment in a patient with Turner syndrome as a rare and initial presentation of sympathetic ophthalmia. Yellow-white lesions at the level of retinal pigment epithelium correspond to Dalen-Fuchs nodules, which are composed of epitheloid cells and histiocytes [9, 51]. These nodules were initially described in patients with SO, but are not specific to SO and they may not be seen in 30 to 50% of the cases [34]. Associated extra-ocular findings include headache, meningismus, deafness, poliosis, vitiligo, and CSF pleocytosis [34]. The presence of SO and hearing loss is rare, but a possible link is that the uvea and auditory labyrinth may share antigens since both structures are derived from the neural crest [15]. Complications of SO include cataract, glaucoma, subretinal fibrosis, atrophy of the optic nerve, choroid and retina, and phthisis bulbi [17]. Few reports have noted choroidal neovascularization to be a complication of sympathetic ophthalmia. Kinge et al. [36] reported the use of photodynamic therapy as a treatment modality for juxtafoveal CNV in the sympathizing eye resulting in stable VA and “angiographic closure” of the CNV in a 12-month follow-up period. Surgical excision, argon laser photocoagulation and cyclosporine therapy have been also used for CNV associated with SO [8, 9, 32].

Histopathology

A diffuse granulomatous, non-necrotizing inflammatory reaction may be found in the inciting and sympathizing eye. Infiltration of epitheloid cells and monocytes can lead to posterior choroidal thickening. Lymphocytes can infiltrate the uveal tract and epitheloid cells can phagocytose pigment [50]. The retina and choriocapillaris are usually but not always spared. Mechanisms of such choriocapillaris preservation have highlighted the presence of anti-inflammatory products released by the RPE, such as transforming growth factor beta and retinal pigment epithelial protective protein that inhibit the release of superoxides from phagocytes, thereby suppressing inflammation [51]. However, it is worth noting that the extent of choriocapillaris involvement may be dependent on the progression of the disease and be more affected in the advanced stages. In the study by Croxatto et al, about 40% of patients had involvement of the choriocapillaris. Atypical cases may also feature retinitis and perivasculitis. In enucleated eyes, about half demonstrate retinal detachment, in which serous retinal detachment can occur from choroidal inflammation [16].

Differential diagnosis

Before diagnosing a patient with sympathetic ophthalmia, it is necessary to rule out other causes of granulomatous uveitis. Most cases are diagnosed based on history and presentation, and 20% are confirmed by the histology [56]. If the patient has sustained previous trauma, one must rule out uveal effusion syndrome, lens induced uveitis, and post-traumatic iridocyclitis. Infections such as syphilis, tuberculosis, and endophthalmitis usually do not involve both eyes. Autoimmune illnesses including Vogt-Koyanagi-Harada syndrome (VKH), sarcoidosis, multifocal choroiditis can be very similar to SO. Dalen-Fuch nodules, choroiditis and papillitis can be found in SO and sarcoidosis. Infiltration by T lymphocytes can occur in VKH, SO and sarcoidosis and antibodies to retinal antigens can be identified in both SO and VKH [47]. Intraocular lymphoma and bilateral phacoanaphylaxis can also have a similar presentation to SO. Phacoanaphylaxis will reveal granulomatous inflammation around the lens, a disrupted capsule, adherence of the iris to the lens capsule, and lymphocytic infiltration [53]. Landolfi et al. [39] reported a case where sympathetic ophthalmia presented like multiple evanescent white dot syndrome. In patients with ocular trauma who received high-dose steroids and experience loss of vision in the contralateral eye, it is important to rule out central serous chorioretinopathy. CSR can occur after stress and administration of steroids and should be distinguished from SO since continuing steroids could worsen the condition [57]. Atypical presentations have also been reported and include progressive subretinal fibrosis with multifocal granulomatous chorioretinitis with the patient having antiretinal antibodies [61].

Imaging

Flourescein angiography is used commonly to confirm and assess the extent of SO. Characteristic findings include multiple fluorescing spots in the pigment epithelium during the venous phase of the study corresponding to areas of flourescein leak [51]. In the presence of retinal vasculitis or Dalen-Fuchs nodules, the flourescein leaks will correspond to these regions. Staining of optic nerve can also be observed [14]. In indocyanine green angiography (ICGA) active choroidal lesions will manifest themselves as areas of hypoflourescence during the intermediate phase [14]. Moshfeghi et al. [46] report Dalen-Fuchs nodules that correspond to areas of hypoflourescence in a pre-treatment mid-phase ICGA. Following therapy, mid-phase ICGA reveals normal choroidal appearance with no hypoflourescent spots. However, as the study progresses, multiple hypoflourescent spots reappear in the later phases. These findings suggest that ICGA is a useful tool in confirming the diagnosis and monitoring response to therapy [5, 54]. OCT can be used to evaluate retinal elevation, and serous retinal detachment as well as to monitor retinal status in response to therapy [36]. B-Scan ultrasonography is used to evaluate choroidal thickening.

Medical treatment

Early treatment with high doses of steroids and immunosuppressive agents should be instituted since it has been linked with good visual outcome in the retrospective study by the National Eye institute in 1995 [11]. Vote et al. [60] have reported an algorithm for treatment starting with topical steroids and oral steroids (50–75 mg/day). Others have suggested starting prednisone doses ranging from 0.5 mg/kg/day to 2 mg/kg/day [23]. In severe cases, IV pulse steroid therapy has been used with methylprednisolone at 1g/day for 3 days. Three months is a reasonable time period to assess the effectiveness of therapy [47]. The steroid tapering should be gradual and dependant on the patient’s clinical response. Slow tapering over a 2–3 month period is recommended in order to reduce steroids to a dose of 10 mg/day [60]. Nussenblatt suggests that inflammation control can be achieved at doses of 15–20 mg and if long-term treatment is required, alternate-day dosing can also be used [47]. Once the maintenance dose has been achieved the patient should continue on this dose for about 3 to 6 months followed by cessation trials and monitoring for flare-ups of inflammation. Stopping therapy can be considered only when the patient has been free from signs of inflammation for a considerable period such as 6 to 12 months [4]. If the patient needs to undergo further surgical procedures, adequate immunosuppresion is necessary [30]. Therapy can last for months to years depending on the clinical response and exacerbations. Steroid side effects include diabetes mellitus, adrenal insufficiency, arterial hypertension, obesity, irritability, susceptibility to infections, aseptic necrosis of hip, and osteoporosis [30].

Immunomodulators have been shown to control the inflammation in SO [50]. These agents should be considered in patients who have a contraindication for steroids, have experienced significant steroid induced side effects, have demonstrated flare-ups on tapering or cessation trials or do not respond to steroid therapy [60]. Combination therapy with steroids and immunomodulators should be instituted before reducing the steroid doses. Using more than one immunomodulator may be warranted for those patients with refractory uveitis. Cyclosporine, cyclophosphamide, azathioprine and chlorambucil have been successfully used. The recommended dose for cyclosporine is 5 mg/kg/day and can be slowly tapered over 1–2 month period, stopping therapy only after the inflammation has been well controlled for at least three months [60]. Close monitoring is necessary since these agents have significant toxicities and consultation with a rheumatologist may be warranted [17].

Intravitreal injections facilitate the delivery of high concentrations at the site of illness. This type of steroid administration allows for the reduction of systemic immunosuppressants and alleviates some of the steroid induced side effects [49]. Triamcinolone acetonide has been used effectively to manage chronic uveitis, diabetic macular edema and pseudophakic cystoid macular edema [12]. Intravitreal triamcinolone acetonide (IVTA) is useful during the initial stages of sympathetic ophthalmia [12]. It has been shown to reduce intraocular inflammation, improve visual field, visual acuity and decrease the doses of systemic therapy [29]. Jonas et al. reported IVTA injections of 20 mg every 2 to 4 months as effective therapy in a patient with chronic SO. The patient tolerated 8 IVTA injections in period of 2.5 years while experiencing resolution of steroid induced weight gain, diabetes and hypertension. However, it is still unclear how long IVTA lasts and what is its optimum dose [29]. Complications include cataract formation, steroid-induced increased IOP, retinal detachment, retinal tears, and endophthalmitis [17, 49]. Administering intravitreal steroids poses significant risk. These complications would be particularly devastating for those patients who remain monocular after trauma to the inciting eye and must undergo injections to their sympathizing and only functioning eye.

Surgical treatment

Evisceration or enucleation are surgical options indicated in situations where the inciting eye is blind or severely traumatized. However, there is controversy about which procedure is the most appropriate and when the procedure should be done. It has been suggested that if the surgery is performed within 10 days following the injury, the chances of developing sympathetic ophthalmia are very low. However, if sympathetic ophthalmia has occurred, these procedures may not be effective and the patient must have medical management with immunosuppressants [26].

Evisceration is a simpler surgery with less damage to orbital tissues, faster recovery time, better movement of the eye and better cosmetic appearance [48]. In 2003, a survey showed that 92% of interviewed clinicians preferred evisceration as the treatment of choice for eye removal [58]. However, in SO enucleation procedures still outnumber eviscerations. Griepentrog et al. report the onset of SO after evisceration and highlight whether the procedure could have been the inciting insult or if the surgery disrupted the immunosuppressive mechanism that had been established after the patient’s injury 66 years before [25]. Gurdal et al. [26] propose that evisceration may be the best choice for patients who have panophthalmitis or who could not have primary repair.

It has been believed that if enucleation of the non-viable inciting eye is done within 2 weeks after initial injury it may prevent the risk of developing SO [6]. Lubin et al. [41] reported that 74% of their patients had a visual acuity of 20/70 or better if enucleation took place within 2 weeks of SO onset. However, only 50% of patients had a visual acuity of 20/70 or better if the enucleation was done after 6 months of onset. Other studies suggest that once SO has been diagnosed, secondary enucleation performed to decrease inflammation in the sympathizing eye may not assure good visual outcome. Reports by Marak and Kuo suggest that early enucleation does not impact visual outcome [38, 44]. Kuo further suggests that enucleation could decrease the number of flare-ups. Enucleation may be considered in patients who sustained such an extensive injury that thorough removal of uveal tissue would be challenging [19]. Primary enucleation may also be considered in patients presenting with penetrating injuries in previously injured blind eyes as a way to prevent the development of SO [27]. The decision to enucleate or not needs to be made very carefully since in the long term the vision in the inciting eye may be better than the vision in the sympathetic eye [14].

Sympathetic ophthalmia case report review

A Medline search for case reports of sympathetic ophthalmia with links to full text in English was done yielding 29 case reports from 1970 to 2007. Case reports with no full text were excluded. Articles were also retrieved and reviewed via cross-referencing. Articles were reviewed for demographics, symptoms, signs and treatment modalities. A total of 86 patients were included. The individual case reports amounted to 34 patients while studies by Rathinam et al., Kilmartin et al., Pollack et al. had 26, 18, 8 patients respectively. Table 1 contains all of the patients’ demographic information, examination findings, therapies, follow-up and final reported visual acuity.
Table 1

Characteristics of patients with sympathetic ophthalmia

Author/ Year

Pts (n)

Age (y)/Sex

Injury/ Surgery

Time of Onset

Clinical Presentation

Findings on exam

Imaging

Treatment

Follow-Up & Final VA

VA

Slit Lamp

Funduscopy

Systemic

Injections

Enuc /Evis

Ahmad et al. [1] 2007

1

41/F

Malignant ciliary body melanoma s/p Ru plaque insertion/removal

6 mos s/p surgery

Reduced Vision Photophobia Redness OU

6/24 OD 6/36 OS

Anterior uveitis, MFKP OS

RD, Sub retinal spots

FA: HypoF spots, RD OCT: ERD

CST taper

None

No

6 mos 6/5 OU

Chang et al. [13] 2006

1

34/F

Corneoscleral rupture, uveal prolapse OS s/p immediate repair

1 mo s/p injury

Reduced vision OU, HA

CF OU

Mild Iritis OU

Multifocal ERD, yellow choroidal infiltrates OU, Trace vitritis OS

FA: HyperF OU, Exudative retinitis

IV MPred 125 mg, Q8H, 5 doses Prednisone 50,70, 17.5 mg/d

None

No

12 mos 20/30 SE CF IE

Jonas et al. [30] 2006

1

47/M

CRVO/cryocoag/GDDI/ Enuc. OD ICCE/PPV/ Phakectomy OS

1 yr s/p CRVO

Reduced Vision Hypotonia OS

6/20 SE

N/R

N/R

N/A

Prednisolone 30 to 2.5 mg/d Cyclosporin A, Methotrexate, TNF

Steroid, IVTA 20 mg, q3-4 mos for 2.5 yrs.

Enuc. OD

17 yrs 6-10/20 OS

Buller et al. [10] 2006

1

16/M

Injury w/ fungal keratitis OS s/p evis.

18 days s/p evis.

Blurred Vision Photophobia Pain

6/12 SE

Anterior uveitis

Peripheral white retinal nodules, mild retinal vasculitis

N/A

CST 7.5 mg/d for 6 mos.

None

Evis. OS

6 mos 6/4 OD

Subedi et al. [55] 2005

1

25/M

Injury/Globe Rupture OS

9 wks s/p injury

Blurred Vision, Photophobia Watering OD

NLP IE 6/6 SE

AC cells/flare, KP, posterior synechiae

ODE, Vitritis

OCT: ERD

CST 2 mg/kg Azathiorprine 50 mg/BID for 2 mos

Mydricain 0.5 ml PS -TA 20

No

11 mos 6/6 OD

Freidlin et al. [19] 2006

1

21/M

Injury s/p evis. OS

3 wks s/p injury

Conj. redness, floaters, paracentral scotoma

20/20 SE

AC cells, AV cells

Hyperemic Optic Disc, White choroidal lesions

N/A

Prednisone 40 mg/d taper

None

Evis. OS

6 mos 20/20 OD

Garcia-Arumi et al. [22] 2006

1

49/M

Malignant iriodociliary melanoma s/p iridocyclectomy

5 wks s/p surgery

Acute vision loss OU HA, Meningismus, tinnitus, deafness

HM OU

Granulomatous uveitis

Papillitis, vitritis, choroiditis, DFN

FA: HyperF dots, ERD

IV MPred 1 g/d for 3 days, Prednisone 1 mg/kg for 18 mos. Cyclosporine, Azathiorpine

IVTA

No

24 mos 20/200 IE 20/25 SE

Rathinam et al. [52] 2006

26

59 20/M 6/F

16 injuries 10 surgeries

N/R

Acute/ Gradual vision loss, Redness, photophobia, HA, neck pain, tinnitus

IE NLP-6/18 SE FCF-20/20

KP, flare/cells

RD

FA: Disk leakage RPE leaks, RD B-Scan: Thickened Choroid, RD

CST (26) for 1–24 mos. Methotrexate 10–15 mg/d (17)

S-TA (26) for range of 2 days- 24 mos duration

Enuc (8)

1–24 mos FCF- 6/60 in IE FCF- 20/20 SE

Chan et al. [12] 2006

1

29/M

Injury OD s/p enuc.

4 wks + 2 days s/p injury

Reduced Vision, Photophobia

NLP IE 20/50 SE

AC cells/flare

Macular edema, DFN

FA: Punctate hyperF. in sub-retina OCT: SRD

Prednisone 0.7 to 0.2 mg/kg/d Cell cept 500 mg/d

IVTA 4 mg

Enuc. 4 wks

10 mos 20/20 SE

Griepentrog et al. [25] 2005

1

75/M

Injury, s/p evis. for neovascular glaucoma in OD

14 wks s/p evis.

Decreased vision

20/200 SE

Ciliary injection

Trace vitreous cells, SRF, mottling RPE

FA: Punctate hyperF, late hyperF OCT: SRD

Prednisone 100 to 7.5 mg/d for 9 mos

None

Evis. OD

9 mos 20/25 SE

Blum-Haraeuveni et al. [7] 2006

1

12/M

Corneal perf./ endopthalmitis s/p PPV, lensectomy, SOI OD

1 mo s/p surgery

Decreased vision

NLP IE 20/60 SE

AC & PC cells/flare, KP

DFN

N/A

CST, Imuran

None

No

12 mos 20/20 SE

Kinge et al. [36] 2005

1

24/M

Injury s/p PPV, Lensectomy, endophotocoagulation OS

1 yr s/p injury

Uveitis

Variable 20/80 IE 20/40 SE

AC cells/flare

DFN OU, perivasculitis, macular edema

N/A

Prednisone 120 to 30 mg/d for >1 yr, Cyclosporine

None

No

7 yrs 20/50 IE 20/200 SE

Bakri et al. [4] 2005

1

18/M

Non-penetrating injury OD

4 wks since injury

Blurry vision OU Redness

20/20 OU

AC cells, KP

Vitritis OD, DFN OU

N/A

Prednisone with taper, Cyclosporine Mycophenolate mofetil

None

No

2 yrs 20/50 IE 20/20 SE

Moshfeghi et al. [46] 2005

1

78/F

RD s/p multiple PPV, SB

2 yrs s/p last surgery

N/R

N/R

N/R

DFN

FA: Multifocal hypoF spots ICGA: Areas of hypoF/hyperF

CST

Steroid

No

N/R

Ozdemir et al. [49] 2005

1

29/F

Injury s/p immediate surgery OS

10 yrs s/p injury

Blurred vision OD

NLP IE 20/63 SE

AC cells

ERD

FA: HyperF, leakage at RPE ICGA: Confluent areas of hypoF OCT: SRD

IV Mpred 1 g/d for 3 days Prednisone 2 to 1 mg/kg/d

IVTA 4 mg

No

8 mos NLP IE 20/20 SE

Vote et al. [59] 2004

3

72/M

5 RD s/p surgical repair OD

9 mos s/p last surgery

Blurred vision Photopsia, Floaters

LP IE 6/9 SE

Non-Granulamoatous uveitis

ODE OU, DFN

N/A

Prednisone 70 to 10 mg/d

None

No

N/R FU 6/6 SE

48/M

E & RD s/p 2 vitreoretinal surgeries.

36 mos s/p last surgery

Photophobia, Photopsia, Floaters OS

LP IE 6/12 SE

Anterior uveitis

Vitritis, chorioretinal infiltrates

N/A

Prednisone 60 mg/d, Cyclosporin A

None

No

6/6 SE

50/F

Glaucoma s/p YAG & RD surgeries OD

3 yrs s/p last surgery

Decreased vision OS

6/15 OU

Panuveitis OU

Mild vitritis, mild macular edema

FA: Macular edema, retinal vasculitis, choroidal hyperF

Prednisone 50 mg/d for 9 mos

None

No

3 yrs 6/7.5 IE 6/6 SE

Saatci et al. [53] 2004

1

21/M

Blind/Severe irritation OS

2 wks s/p irritation

Blurred vision OD

20/200 SE

AC cells, perf. staphyloma OS

Mild Vitritis Multifocal SRD

FA: Sub-retinal pooling ICGA: HypoF dots in posterior pole

IV MPred 250 mg/d for 3 days Prednisone 80 mg/d

None

Enuc OS

N/R FU 20/30 SE

Landolfi et al. [39] 2004

1

17/F

Ruptured Globe s/p PPV, SB, SOI in OD

8 wks s/p injury

Decreased vision OS

LP IE 20/25 SE

AC cells

Vitreous cells, ODE, grey-white discoloration at level of RPE

FA: hyperF, optic nerve leakage B-Scan: Choroidal thickening

Prednisone 60 mg/d with taper Methotrexate

None

Enuc OD

18 mos 20/20 OS

Kumar et al. [37] 2004

1

60/M

Laser Diode cyclo-photocoagulation OD

9 mos s/p last tx.

Decreased Vision, HA

6/45 SE NLP IE

AC cells/flare MFKP hyphema

Vitreous cells Subretinal infiltrate

FA: ODE, SRD, RPE elevation ICGA: Areas of hypoF/ hyperF

Prednisone 200 to 7.5 mg/d, Cyclophosphamide 100 mg

None

No

18 mos 6/6 OD

Ganesh et al. [21] 2003

3

8/M

Injury OD

3 yrs s/p injury

Decreased vision OS, Pain, Redness, watering

NLP IE 1/60 SE

Anterior uveitis,

Vitreous cells Vitreous haze, ODE, DFN

B-Scan: Choroidal thickening

IV MPred 15 mg/kg for 3 days Prednisone 1 mg/kg Azathioprine 1 mg/kg Cyclosporine 5 mg/kg

None

Enuc. OS

18 mos LP SE

27/M

Blind/ recent choroiditis OD

8 mos s/p choroiditis

Decreased vision OS

NLP IE, CF SE

Normal OS

ODE, choroidal elevation, DFN, ERD

N/A

IV MPred 1 g/d for 3 days Prednisone 1 mg/kg Azathioprine 1 mg/kg Cyclosporine 5 mg/kg

None

No

Lost to F/U

41/M

Vitrectomy, SOI OD

2 yrs s/p surgery

Pain, Floaters OS

NLP IE 6/6 SE

Anterior uveitis,

Vitreous cells, ODE, choroidal elevation, DFN

N/A

IV MPred Prednisone 1 mg/kg Azathioprine 1 mg/kg Cyclosporine 5 mg/kg

None

No

24 mos 6/6 SE

Wang et al. [60] 2002

1

72/M

RD s/p retinopexy/SB in OS, PPV/lensectomy OD

5 mos s/p last surgery

Decreased vision OU

3/200 SE LP IE

AC cells/flare OU, KP OU,

Vitreous haze OS, ODE OD, Ret./Sub-reti.RPE deposits

FA: Multiple hypoF/ hyperF areas B-Scan: Elevated Retina

N/R

N/R

Enuc. OS

N/R FU NLP SE

Bom et al. [8] 2002

1

60/M

Injury s/p enuc. OS

1 yr s/p enuc.

Decreased vision

6/24 SE

Anterior uveitis

Vitritis, DFN

FA: Subfoveal CNV

Prednisolone 10 mg/d, Azathioprine 50 mg/TID

None

Enuc. OS

5 yrs 6/36 SE

Borkowski et al. [9] 2001

1

41/M

Injury s/p enuc. OD

3.5 mos s/p enuc.

Metamorphopsia OS

20/60 SE

Clear AC

Vitreous cells Pigmentary atrophy/ clumping, SRH

FA: CNV near fovea

Prednisone 80 to 3 mg/d, Cyclophosphamide

Periocular TA 40 mg

Enuc. OD

4 yrs, 20/25 SE

Comer et al. [15] 2001

1

72/F

Trabeculectomy/ trauma w/ choroidal detachment OS

25 days s/p trauma

Blurred vision Pain OD

LP IE 6/12 SE

Uveitis

Vitritis, Choriodal thickening, DFN

N/A

IV Mpred 1 g/infusion Prednisone 20 to 12.5 mg/d Cyclosporin A

None

No

N/R FU 6/9 OU

Kilmartin et al. [33] 2000

18

56.1 9 /M 9 /F

10 surgeries, 6 injuries, 2 combined inj./surg.

12 mos s/p initial injury

N/R

6/5- CF SE

Mod/Severe Panuveitis AC Inflamation

DFN, CNV

 

CST 0.15 mg/kg Azathioprine 1.8 mg/kg/d Cyclosporine 3 mg/kg/d Mycophenolate 2 g/d

 

Enuc (5)

1 yr F/U for 16 pts.

Pollack et al. [50] 2001

8

55 6 /M 2/ F

S/P PPV

7 mos s/p surgery

Decreased vision, Metamorphopsia

NLP-20/400 IE CF- 20/30 SE

Anterior uveitis, KP, vitritis

ODE, Sub-RPE deposits, SR-CNV, choroiditis,

 

Prednisone 60–100 tapered to 20–40 mg/kg Cholarambucil 5–8 mg/kg Cyclosporine 2.5 mg/kg

ST-kenalog

Enuc (4)

1–70 mos CF- 20/15 IE

Bernasconi et al. [5] 1998

2

83/M

Injury, s/p cyclodiathermy & CE OD

6 mos s/p CE

Decreased vision OS

FC SE

Anterior uveitis

Vitritis, Yellow retinal lesions, Neovascular membrane

FA: Neovascular membrane ICGA: HypoF areas, ill defined choroidal vessels

Prednisone 1 mg/kg

None

Enuc OD

N/R FU, 20/200 SE

40/M

Injury s/p 3 vitreoretinal surgeries OD

8 yrs s/p injury

Decreased vision inflammation OS

20/33 SE

AC cells, conj. injection

Vitritis, SRD, yellow retinal lesions

FA: Papillitis, SRD ICGA: HypoF areas, ill defined choroidal vessels

Prednisone 1 mg/kg for 6 mos.

None

Enuc OD

6 mos 20/200 SE

Kilmartin et al. [32] 1998

1

3/M

Injury s/p repair OD

4 mos s/p injury

Decreased vision

FC OU

 

Vitritis, Yellow macular lesion, CNV

N/A

Prednisone 1 mg/kg Cyclosporine 5 mg/kg

None

No

25 mos 20/100 IE 20/60 SE

DeVoe et al. [18] 1970

4

12/M

Injury s/p linear extraction OD

8 mos s/p injury

Redness OS

FC IE 10/200 SE

AC flare

Vitreous haze

N/A

Cortisone 100 mg/d, IV Corticotropin, Dexamethasone

Steroids, IM Typhoid, IM Corticotropin gel

Enuc. OD

15 yrs 20/15 SE

39/M

Injury s/p repair OD

6 wks s/p surgery

N/R

 

Anterior uveitis

N/R

N/A

CST

None

Enuc. OD

19 yrs 20/25 SE

18/M

Injury s/p repair OD

16 days s/p surgery

N/R

 

AC cells

N/R

N/A

CST

None

Enuc. OD

18 yrs 20/60 SE

5/M

Injury s/p repair OS

4 mos s/p injury

N/R

 

AC cells, KP, Koeppe nodules on iris

Normal Optic disc

N/A

 

IM diphteria toxin 15,000 units

No

1 yr 20/200 IE 20/20 SE

LEGEND: N/R, not reported; N/A, not applicable Injury/Surgery section: s/p, status post; CRVO, central retinal vein occlusion; CE, cataract extraction, ICCE, intracapsular cataract extraction; RD, retinal detachment; PPV, pars plana vitrectomy; SOI, silicone oil injection; SB, scleral buckle; Evis., evisceration; Enuc., enucleation, Perf., perforation; GDDI, glaucoma drainage device insertion, Inj., injury, Surg., surgery. VA Section: IE, inciting eye; SE, sympathetic eye; NLP, no light perception; LP, light perception; HM, hand motion; CF, counting fingers; FCF, fingers close to face.

Clinical presentation/Findings Section: HA, headache; AC, anterior chamber; PC, posterior chamber; KP- keratic precipitates; MFKP, mutton fat keratic precipitates, DFN, Dalen-Fuch Nodules; CNV, choroidal neovascularization; SR- CNV- subretinal choridal neovascularizat on, ODE, optic disc edema, ERD, exudative retinal detachment; SRD, serous retinal detachement; RD, retinal detachment; SRH, subretinal hemorrhage; SRF, subretinal fluid; RPE, retinal pigment epithelium

Treatment: CST-corticosteroids; IV Mpred, intravenous methylprednisolone, TA, triamcinolone, acetate; IVTA, intravitreous triamcinolone acetate; S-TA, subtenons triamcinolone; IM, intramuscular; Enuc., enucleation; Evis.,evisceration

Imaging: FA, flourescein angiography; ICGA, Indocyanine green angiography; OCT, optical coherence tomography; hypoF, hypoflourescence; hyperF, hyperflourescence; ERD, exudative retinal detachment; SRD, serous retinal detachment; RPE, retinal pigment epithelium; CNV, choroidal neovascularization

Out of the 86 patients, 62 were males and 24 were females. The average age was 46 years, the median age was 47 years and the range was from 3 to 83 years. Only 5% of patients were less than 10 years old. Figure 1 demonstrates the age of the patients. Injuries occurred in about 40 patients, accounting for 47% of cases reported. Ocular surgery was the initial sole cause of eye disruption in about (38) 44% of patients. Eight (9.3%) patients had combined injury and surgical procedures that could have led to SO. The injuries reported include contusion and open globe trauma. Surgeries done on patients reported with sympathetic ophthalmia include pars plana vitrectomy, scleral buckle, glaucoma procedures, and cataract extraction among others shown in Table 2. Vitrectomy was reported in about 21% of patients and cataract extraction in 21% of patients accounting for the majority of reports of SO in patients with surgical interventions.
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Fig. 1

Age distribution of patients with SO

Table 2

Surgeries in patients with sympathetic ophthalmia

Surgeries reported in Patients with SO (n=46 pts)

Total

Pars Plana Vitrectomy

18

Cataract Surgery

18

Scleral Buckle & Retinal detachment Repair

13

Anterior vitrectomy

3

Laser retinopexy

3

Cyclodiodetherapy

3

Trabeculectomy

2

Tectonic Penetrating Keratoplasty

1

Radiotherapy

2

Glaucoma drainage device placement

1

Iridocyclectomy

1

In terms of onset of symptoms of sympathetic ophthalmia, the timing varied widely between weeks to years after the initial injury or initial surgical intervention. For those cases, where non-surgical injury to the exciting eye was the primary insult, the onset of symptoms ranged from 2 weeks to 10 years after injury. Most of the patients (83%) experienced their symptoms in less than a year. Patients with surgical interventions had their onset of their symptoms appear from 5 weeks to 3 years after the last surgery with 50% of them becoming symptomatic in less than a year. In patients who had combined ocular injury and surgery, their onset ranged from 25 days to 8 years from their injury or surgery with 50% of them manifesting their SO in less than a year.

The most common clinical complaint of patients with sympathetic ophthalmia found in this review was decreased vision in the sympathetic eye in 26 patients out of the 34 patients who had their clinical symptoms reported. This was followed by redness or inflammation or photophobia. Four patients reported floaters and painful eyes. Photopsia and watering of eyes was also noted by 2 patients respectively. Extra-ocular complaints included headache, meningismus, and hearing complaints including tinnitus, hypoaccusis and neurosensory deafness. Patients in the studies by Kilmartin, Rathinam and Pollack were not included in this categorization since the symptoms of these patients were not individually reported. Figure 2 shows the distribution of these symptoms among the 34 patients in the individual case reports.
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Fig. 2

Clinical symptoms at presentation

Upon presentation, most patients received slit-lamp and fundoscopic examination. All case reports except for the article by Rathinam et al. included their findings upon slit-lamp and fundus examination. Clinical findings are therefore reported for only 60 patients out of the total 86 patients diagnosed with sympathetic ophthalmia. Uveitis was present in 50 patients (83%). Inflammation in the anterior chamber manifested by anterior chamber cells and flare was noted in 33 patients (55%). Vitritis was noted in 29 patients (48%). Ten of the sixty (16.6%) patients presented with keratic precipitates, including the mutton fat keratic precipitates. The characteristic Dalen-Fuch nodules of sympathetic ophthalmia were found in 20 patients (33%). However, there was a myriad of reported sub-retinal deposits, nodules, choroidal infiltrates and macular lesions that were not categorized as Dalen-Fuchs nodules by the authors. Swelling of the optic nerve was seen in 12 patients (20%). Serous retinal detachment was present in 7 patients (12%). Choroidal involvement was manifested by choroiditis in 5 patients and choroidal neovascularization in 3 patients. Other clinical features can be found in Table 3.
Table 3

Clinical features of patients with SO upon presentation

Clinical Features at Presentation

No. of Patients (n = 60)

Uveitis

83.3%

*Anterior Chamber Cells/Flare

55%

*Vitritis

47%

*Keratic Precipitates

17%

Synechiae

1.6%

Dalen-Fuchs Nodules

33.3%

Optic Disc Swelling

20%

Serous Retinal Detachment

11.7%

Macular Edema

5%

Choroidal neovascularization

5%

Choroiditis

8.3%

Subretinal Hemorrhage

1.6%

Vasculitis

1.6%

Pigmentary Atrophy

1.6%

Flourescein angiography is a common imaging modality used among patients with sympathetic ophthalmia. Characteristic findings of hypoflourescent areas in the choroid that become hyperflourescent as the study progresses have been reported as well as pinpoint leaks in the RPE and retinal detachments [50]. Patients in this review had areas of hypoflourescence and hyperflourescence. Disc leakage and RPE leakage were also found as well as serous retinal detachments, macular edema, and neovascular membranes. Indocyanine green angiography was utilized in 7 patients and areas of hypoflourescence and hyperflourescence and ill-defined vessels were reported. Rathinam et al. used ultrasonography in the sympathizing eye as part of the initial evaluation of their 26 patients. Choroidal thickening was noted in 23 patients, serous retinal detachment was found in 5 patients and 2 patients had normal choroidal thickness. In the individual case reports, ultrasonography only revealed choroidal thickening in 2 patients and exudative retinal detachment in 1 patient. Optical coherence tomography was only used in 4 patients revealing serous retinal detachments in all patients. OCT was also employed to track the resolution of the serous retinal detachments.

Systemic anti-inflammatory therapy is the mainstay of treatment for sympathetic ophthalmia. Systemic corticosteroid therapy is the first line of therapy. For refractory and recurrent cases or intolerable steroid-induced side effects, immunomodulators have offered an alternative. In this review, systemic corticosteroid therapy was employed in 82 out of 86 patients (95%) with a wide range of starting doses demonstrated in Table 1. IV Methylprednisolone was used as initial therapy in 8 patients with the starting doses ranging from 125 mg/day to 1 g/day and eventually being replaced by oral prednisone. Other administrations that were noted in the case reports, but appeared to be more variable in regards to their use and benefits include topical steroid drops received by 16 patients, intraocular injections used in 36 patients and intravitreous, sub-tenons and peri-bulbar triamcinolone injections. Devoe et al. reported intra-muscular injections of steroids, diphtheria antitoxin and corticotropin, however, these types of injections are not longer part of the current treatment regimen for sympathetic ophthalmia. In regards to the use of immunomodulators 65 patients (76%) received immunomodulators with methotrexate and cyclosporine being most commonly used. In several cases, these medications were used in conjunction with systemic corticosteroids. Many patients were using more than one of these agents at a time during the course of their treatment. Table 4 shows the various immunomodulators used.
Table 4

Immunomodulator agents used to treat sympathetic ophthalmia

Immunomodulators

No. of Patients (n = 65)

Methotrexate

19 (29%)

Cyclosporine

18 (27.6%)

Azathioprine

8 (12.3%)

Cyclophosphamide

2 (3.1%)

Chlorambucil

2 (3.1%)

Mycophenolate

3 (4.6%)

TNF

1 (1.5%)

In terms of surgical approaches, 30 patients (35%) had enucleation of their inciting eye and only 3 patients (3%) underwent evisceration. This finding is consistent with the reports by Levine et al. that showed evisceration still lagged behind enucleation [40]. In the study by Pollack et al., 4 patients underwent enucleation and their vision either stabilized or improved. Figure 3 highlights the various therapies used by patients and the number of patients who received such treatments.
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Fig. 3

Management of sympathetic ophthalmia

Visual acuity (VA) of the sympathizing eye was evaluated at the initial presentation and at the last follow-up in 79 out of the total of 86 patients. The remaining 7 patients were either lost to follow up or their initial and final VA was not reported. Fifty-five of these 79 (70%) patients had improved visual acuity in the sympathizing eye. Out of these patients, 46 (58.2%) had a VA of equal or better than 20/40. Of the remaining patients, 15 had stable visual acuity and 9 experienced visual deterioration. In the prospective study by Kilmartin et al., 75% of the patients had a visual acuity of 6/12 or better at the 1-year follow up emphasizing the connection between favorable visual prognosis and timely administration of immunosuppresion. Figure 4 demonstrates the percentages of patients who experienced improvement, deterioration or stable visual acuity at their last reported follow-up visit. The follow-up period for the 86 patients varied from no follow-up at all to up to 19 years after the onset of sympathetic ophthalmia.
https://static-content.springer.com/image/art%3A10.1007%2Fs00417-008-0939-8/MediaObjects/417_2008_939_Fig4_HTML.gif
Fig. 4

Visual acuity outcomes

In conclusion sympathetic ophthalmia is a rare, but a visually significant complication of ocular trauma. Prevention of ocular trauma is an important measure in reducing the incidence of sympathetic ophthalmia. In recent years ocular surgery, especially vitrectomy has become a risk factor for SO. It may be reasonable that patients undergoing ocular surgeries be counseled about the possibility of sympathetic ophthalmia, its relapsing nature and the need for close and long-term medical follow-up. In addition to systemic and intravitreal corticosteroid therapy, immunomodulators play a significant role in the medical management of SO. Immunomodulators are especially useful for those patients who are refractory to steroids or who develop steroid induced side effects. Therapy needs to be carefully monitored and tailored to the patient’s response and adverse effect profile. Although definitive prevention of SO once required enucleation within the first 7 to 10 days and enucleation procedures predominated in this review, evisceration still offers an alternative. The current advances in intraocular surgical techniques offers eyes that were previously unviable a fair chance of regaining some visual function. As a result, an eye that has no light perception acutely after an injury is not a definite indication for enucleation. With prompt medical attention and treatment, most patients with sympathetic ophthalmia can expect to have relatively good visual acuity.

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© Springer-Verlag 2008