Clinical association and visual morbidity in uveitis with systemic diseases: An analysis from a tertiary ophthalmic center

Abstract

AIM:

The aim of this study was to identify the incidence, etiology, most common presentations, complications, and the causes of visual loss in posterior uveitis (PU).

MATERIALS AND METHODS:

A retrospective study was conducted on a cohort of 125 patients with PU with a minimum follow-up of 6 months. Ocular evaluation consisted of slit-lamp examination, indirect ophthalmoscopy, tonometry, and refraction. Ancillary ophthalmic investigations such as fundus fluorescein angiography, optical coherence tomography, and B-scan ultrasonography were done. Laboratory tests were performed on blood on all patients and in aqueous humor samples obtained by anterior chamber paracentesis in cases of diagnostic dilemmas. All the data were analyzed using SPSS program.

RESULTS:

PU occurred in 61%. Infections were noted in 34% and autoimmune diseases in 27%. The most frequent presentation was choroiditis. The most common etiologies were tubercular uveitis in 50%, Toxoplasma retinochoroiditis in 23%, and autoimmune category of serpiginous choroiditis in 56% of patients. Complications occurred in 27% and were most commonly cystoid macular edema and macular scarring. Polymerase chain reaction (PCR), nested PCR, and real-time PCR on ocular fluids were required for diagnosis in 30%. A combination of laboratory investigations on blood and aqueous humor samples were confirmation in 88%.

CONCLUSION:

PU and its sequelae are known to be sight threatening and are associated with systemic diseases. They have diverse etiologies and presentations. Identification of etiology is important as management is diametrically opposite in infections and autoimmune diseases.

Introduction

Inflammation in the uveal tract can cause defective vision both during the active and healed stages. It can be anterior uveitis, intermediate, posterior, or panuveitis. Posterior uveitis (PU) is a frequently encountered type of inflammation with speculations regarding its progress, prognosis, and the etiology (infection, autoimmune, or idiopathic).[1] The choroid is the primary site of inflammation resulting in choroiditis but can comprise a multitude of presentations due to the spread and involvement of adjacent structures such as the retina, vitreous, blood vessels, and optic nerve or may cause spillover and anterior uveitis. Systemic diseases have a profound association with PU and may be the first presenting feature.[2] The association of uveitis with systemic diseases often goes unrecognized due to varied presentations, differences in epidemiology, and spectrum of clinical features. It is of paramount importance to identify the possible etiology as PU can be infective or noninfective and treatment is diametrically opposite in both. Clinical overlap and heterogeneous presentations such as choroiditis, retinochoroiditis, vasculitis, and vitritis could further complicate our diagnosis. This heterogeneous presentation may be because of the varied etiology and underlying disease. Examination can narrow down the cause, but a confirmation requires ocular ancillary investigations and laboratory tests[3] which may be done using blood or intraocular fluids.[4] PU is vision threatening during both the active stages or due to complications of the inflammation and aggressive treatment is required.

Symptoms are usually blurred vision, scotomas, photopsia, flashes, and floaters. The course may be acute, limited, or chronic. A support of comprehensive medical history of skin, neurological, respiratory, gastrointestinal, and sexually transmitted diseases can provide insights about a likely etiology. Some tumors and retinal degenerations can masquerade as uveitis.[5] A correct and tailored set of investigations will help to narrow down and identify the etiology of both ocular and underlying systemic conditions.

The aim was to perform a retrospective analysis of patients with PU attending the outpatient department. This is an observational study of PU done over a 3-year period in a multispecialty hospital to identify the frequency of etiology, most common presentations, complications, and the causes of visual loss.

Materials and Methods

Records of 125 patients diagnosed with PU over a 3-year period with a minimum follow-up for 6 months were included after ethics committee approval, and informed consent was obtained (RR/177­PT/1/2009). This is a retrospective, interventional cohort study performed in concurrence with the departments of infectious diseases, internal medicine, dermatology, and rheumatology. A detailed history and physician's opinion was obtained for patients.

Examination and grouping of patients

The standardized uveitis classification[6] was adopted and a diagnosis of PU was made if the patient satisfied the criteria (A was mandatory along with B or C):

1. Clinical features of any of the following are present (choroiditis, chorioretinitis, retinal vasculitis, or granuloma with or without anterior uveitis/vitritis/optic nerve head involvement)

2. More than one positive investigation (blood or ocular fluid) with supportive evidence from ancillary ophthalmic investigations such as angiography.

Ocular investigations

Ophthalmic evaluation consisted of slit-lamp examination, indirect ophthalmoscopy, applanation tonometry, and refraction. Ancillary investigations such as fundus photography, fundus fluorescein angiography (FFA), indocyanine green angiography, optical coherence tomography (OCT), and B-scan ultrasonography were performed during the first visit and subsequently during follow-up for detection of complications and to monitor response to treatment.[7] The clinical features, recurrences, final visual acuity, and description of healed lesions were documented.

Aqueous humor samples were collected using anterior chamber (AC) tap done under aseptic precautions, topical anesthesia, and a sterile 26-gauge needle mounted on a tuberculin syringe. Aqueous aspirate of 0.1 mL was sent for microbiological analysis.

Systemic investigations

Laboratory tests employed consisted of complete blood count, erythrocyte sedimentation rate (ESR), purified protein derivative skin test, chest X-ray, VDRL, antinuclear antibody, and if required, QuantiFERON TB Gold and polymerase chain reaction. Specific investigations such as high-resolution computed tomography (HRCT), immunoglobulin (Ig) G, IgM, lysozyme assay, serum angiotensin-converting enzyme (ACE), serum calcium, blood culture, and enzyme-linked immunosorbent assay (ELISA) were performed based on clinical suspicion. Polymerase chain reaction (PCR), nested PCR, and real-time PCR (RT-PCR) were done on aqueous samples.

The outcome of the study was measured using the following signs and criteria:

Clinical resolution

• A two-step decrease in AC reaction (cells/haze), vitreous haze

• Better definition borders of the lesion suggestive of resolving edema

• Pigmentation within the lesion

• Improvement of visual recovery.

Antibiotics and antimicrobials were used to treat infection. In those with autoimmune PU, corticosteroids and immunosuppressives such as methotrexate, mycophenolate mofetil, cyclosporine, and adalimumab were used depending on the age and type of PU. The visual outcome in these patients was assessed and graded based on the Snellen's chart as improvement, no improvement, and deterioration.

The results of clinical examination, investigations, and outcome were tabulated and statistical analysis was performed using SPSS, Version 20.0. (Armonk, NY: IBM Corp.). Descriptive statistics was calculated for background variables. Chi-square test was done as a test of significance to test the association between categorical variables. In order to perform a correlation of clinical signs with systemic manifestations, subgroup analysis was performed and P < 0.05 was considered statistically significant.

Results

PU was analyzed in 125 patients. The incidence of PU in systemic disease was 61%. The median age of presentation was 35–45 years. Seventy (56%) males and 55 (44%) females were affected. It was unilateral in 72 (57%) and bilateral in 53 (42%). Anterior uveitis was observed in association with PU in 28 patients. The most common presentation was choroiditis followed by retinochoroiditis.

In our study, PU was due to an infectious etiology in 52 (42%), autoimmune disease in 34 (27%), and idiopathic in 39 (31%) patients [Table 1].

Table 1.

Etiology of Posterior Uveitis

Etiology	No. of patients (Percentage)
Infection	52 (42)
Autoimmune diseases	34 (27)
Idiopathic	39 (31)

Among infections, tubercular PU was the most common cause and occurred in 26 (50%) in the form of multifocal lesions of serpiginous-like choroiditis (SLC), focal choroiditis, vasculitis, and choroidal abscess [Figure 1]. Other etiologies were Toxoplasma retinochoroiditis in 12 (23%), viral retinitis in 8 (15%) (acute retinal necrosis, HIV, and cytomegalovirus [CMV]), fungal endophthalmitis in 3 (5%), Toxocara granuloma in 2 (3%), and cysticercosis in 1 (2%) [Table 2]. Among patients with non-infectious etiology, serpiginous choroiditis occurred in 19 (56%), Vogt–Koyanagi–Harada (VKH) in 9 (26%), sarcoidosis in 2 (5%) [Figure 2], acute posterior multifocal placoid pigment epitheliopathy (APMPPE) in 2 (5%) and Behcet's disease in 2 (5%) patients [Table 3].

Figure 1.

Tubercular choroiditis with positive Mantoux reaction and positive polymerase chain reaction performed on aqueous humour sample

Table 2.

Posterior Uveitis due to Infections

Ocular manifestation	Percentage of patients
Tubercular uveitis	50%
TB focal choroiditis	3%
TB focal multifocal choroiditis	14%
TB vasculitis	6%
TB granuloma	3%
Toxoplasma retinochoroiditis	23%
Acute retinal necrosis	12%
CMV retinitis and HIV retinopathy	3%
Fungal endophthalmitis	5%
Toxocariasis	3%
Cysticercosis	2%

Figure 2.

Sarcoid posterior uveitis with anterior spillover of inflammation

Table 3.

Posterior Uveitis due to Autoimmune diseases

Ocular manifestation	No. of patients	Percentage
Serpiginous choroiditis	19	56%
VKH syndrome	9	26%
Sarcoid posterior uveitis	2	5%
Vasculitis due to Behcet's disease	2	5%
APMPPE	2	5%

Visual loss due to macular involvement occurred in 28 (22%) patients. Etiology in these patients was VKH, macular serpiginous choroiditis, APMPPE, and Toxoplasma retinochoroiditis and TB choroiditis. Recurrences occurred in 9 (7%) patients, of whom 3 patients had serpiginous choroiditis, 4 had tubercular PU, and 1 had Toxoplasma retinochoroiditis [Table 4].

Table 4.

Causes of macular involvement and visual loss

Type of posterior uveitis	Percentage
Macular serpiginous choroiditis	12%
VKH syndrome	5%
Toxoplasma retinochoroiditis	7%
APMPPE	2%
TB choroiditis	2%

Chest X-ray in 12%, Mantoux test in 66%, PCR in 45%, and QFT-G in 33% confirmed TB. Collectively, systemic investigations inclusive of complete blood count, ESR, serum ACE, lysozyme, calcium assay, human leukocyte antigen B5, Toxoplasma IgG and IgM, and ELISA for Toxocara antigen were positive in 72% of patients. In inconclusive patients, nested PCR and/or RT-PCR were done on aqueous humor samples and were diagnostic in 21%.

Oral corticosteroids in the form of tablet prednisolone 1 mg/kg body weight once a day after breakfast with supplements of calcium and antacid were given in isolation or with immunosuppressives. Significant improvement of vision was seen in 15 (2%) patients and deterioration in 13 (17%) patients. Improvement was seen in 3 months in 22% and 6 months in 74%. Tubercular PU had the best visual outcome following treatment and the best prognosis with nine patients showing improved acuity. Those with macular involvement were administered intravenous (IV) methylprednisolone in the dose of 1 g daily for 3 days followed by oral steroids.

Complications were seen in 24 (32%) patients. Irreversible complications caused blindness in 6%, and reversible complications with improvement in vision were seen in 31%. Macular scarring occurred in seven patients, cystoid macular edema in seven patients, choroidal neovascular membranes (CNVMs) in three patients, tractional retinal detachment in one patient, and vitreous hemorrhage in one patient. Macular scarring occurred in tubercular PU, serpiginous choroiditis, and toxoplasmic retinochoroiditis. Cystoid macular edema was seen in VKH syndrome and CNVM in macular serpiginous choroiditis and Toxoplasma retinochoroiditis. Tractional bands and epiretinal membranes occurred with Eales disease and Toxoplasma retinochoroiditis.

Discussion

The causes of posterior uveitis may occur due to an infection, an autoimmune disease or could be idiopathic. Evaluation is done by estimation of visual acuity, ophthalmic examination, and analysis to detect the presence and severity of inflammatory foci in the choroid. The presence of spillover of inflammation into the AC and contiguous inflammation in the retina, vitreous, vessels, and optic nerve can contribute to progression and visual loss.

Ancillary ophthalmic investigations are useful to confirm the diagnosis. Ciardella et al. have reported the usefulness of angiography for retinal or choroidal nonperfusion, ischemia, vascular involvement, and OCT to detect macular edema.[8] Laboratory investigations are confirmatory, but invasive investigations such as AC tap, vitreous, or chorioretinal biopsy are required in diagnostic dilemmas.[9] The ocular sample is analyzed by microbiological and histopathological methods. In our study, some patients who had been diagnosed as idiopathic PU were found to have latent tuberculosis by QuantiFERON TB Gold test when investigated further.[10] Pulmonary and extrapulmonary TB can cause PU.

Multifocal choroiditis and subretinal abscess due to liquefactive necrosis within a tuberculoma can occur in miliary TB. Eales disease is retinal vasculitis due to TB and presents in young individuals with sudden diminution of vision in one eye due to vitreous hemorrhage. Rao et al. have reported that lesions in TB can occur due to active infection or due to hypersensitivity to the DNA of the TB bacilli.[11]

Bansal et al. have reported that multifocal tubercular PU can resemble serpiginous choroiditis and is called SLC.[12] In our study, three patients had presented with tubercular SLC and the diagnosis was confirmed using RT-PCR on aqueous humor though all other systemic investigations for TB were negative. RT-PCR has the advantage of providing evidence and quantification.

Toxoplasma retinochoroiditis can occur due to both congenital and acquired toxoplasmosis. It is a unilateral focal necrotizing retinitis at the macula with profuse vitritis and usually presents as satellite lesions adjacent to scars due to reactivation. Macular involvement occurs in more than 50% of patients causing significant visual loss.[13]

Viral retinitis usually causes rapid progression and visual loss due to retinal detachment and proliferative vitreoretinopathy. Herpes group of viruses are the most common causes of infectious viral uveitis.[14] Healthy and immunosuppressed hosts can be affected, but clinical presentation varies based on the immune status of the individual. Viral retinitis can be isolated or a part of systemic disease. Acute retinal necrosis is the classical presentation of herpes virus and the triad of arteritis, retinitis, and vitritis with peripheral involvement and rapid spread is typical. Good visual recovery has been reported after high dose IV acyclovir. HIV retinopathy and CMV retinitis was seen in 3 patients (5%). Among those with CMV retinitis, both the granular and fulminant form were noted.^[15] An initial high dose of intravitreal ganciclovir followed by regular doses can decrease the load of CMV and is recognized as an important treatment modality of viral retinitis.

Tang et al. reported that Candida and Aspergillus are the most common causes of endogenous fungal endophthalmitis. Uncontrolled diabetes, indwelling catheters, IV alimentation, and IV drug abusers are at risk.[16] Chorioretinitis and vitritis can coexist in these patients. In vision-threatening macular involvement, intravitreal amphotericin B or voriconazole is required to achieve high therapeutic concentrations as adequate penetration of the ocular coats does not occur with the oral route. In our study, Candida retinochoroiditis had negative blood cultures, but due to strong clinical suspicion, intraocular assay was performed and diagnosis was confirmed by PCR on aqueous humor sample [Figure 3].

Figure 3.

Candida retinochoroiditis with positive blood culture

In our study, serpiginous choroiditis was the most common cause in the autoimmune group. We saw all three types of morphological presentations which included peripapillary, macular, or ampiginous types.[17]

Ocular features in VKH syndrome have bilateral presentation with multifocal exudative detachment and panuveitis with or without disc edema.[18] The majority of our patients had probable VKH which is an isolated ocular disease where neurological and integumentary signs are absent. FFA showed patchy hyperfluorescence with pinpoint leaks at the level of RPE which was confirmed by OCT. Treatment with immunosuppressives is required for resolution during the active stage and to prevent recurrences.

In the Indian population where infections are abundant PU is most commonly due to TB, viral infections such as the herpes, HIV or CMV and protozoa such as toxoplasma gondii. However, involvement of the macula with visual loss is more frequent with autoimmune diseases such as VKH and macular serpiginous choroidopathy. Toxoplasma retinochoroiditis was the predominant infection which caused early macular involvement and visual loss. Signs in PU do not respect any set criteria, and variations in clinical presentation can occur even with the same infection. Scarring and CNVM were noted as the most frequent cause of defective vision. In those with CNVM, FFA was performed to identify the type and location of the membrane. They were treated with laser photocoagulation or anti-VEGF agents.

Conclusion

PU and its sequelae are known to be sight threatening. They have diverse etiologies and presentations. Both infections and autoimmune diseases may present first with ocular inflammation and PU before becoming apparent as a systemic disease. Differentiation between infections and autoimmune type is very important as treatment is diametrically opposite. Aqueous humor analysis is an effective way of establishing the diagnosis. Follow-up is important to look for recurrence and complications. We recommend that all patients with systemic disease need to undergo regular ophthalmic screening to prevent ocular morbidity.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.