The Large Hellenic Study of Uveitis: Diagnostic and Therapeutic Algorithms, Complications, and Final Outcome

Abstract

Purpose: 

The purpose of this study is to present the diagnostic and therapeutic algorithms, complications, and final outcome in the management of uveitic patients at a tertiary academic referral center.

Design: 

Observational study.

Methods: 

Analysis of the archives of 6191 uveitic patients at the Ocular Inflammation Service of the Department of Ophthalmology of the University Hospital of Ioannina in Greece from 1991 to 2020.

Results: 

During the 30 years of the study, the diagnostic ability climbed from 45.43% (1991–1995) to 73.4% (2016–2020). This improvement was linked to several factors including the increase in the number of diagnostic paracenteses for the analysis of intraocular fluids, the range and quality of laboratory blood tests, the multimodal ophthalmic imaging, the proper use of nonophthalmic imaging, and the multidisciplinary approach. The degree of uveitis-related complications was related to the severity and cause of inflammation, the recurrence rate, inappropriate treatment, and the prolonged or initially inactive inflammation. The 3 most common complications included cataract, macular edema, and glaucoma. Apart from the modern treatments and surgical techniques, the 3-month preoperative control of inflammation played a critical role in the surgical outcomes. The percentage of patients with a successful outcome increased from 72% (2001–2005) to 90.50% (2016–2020). The center’s experience, prompt referral, patient’s compliance, and regular follow-ups are associated with a better outcome. The analysis of the results allowed the development of diagnostic and therapeutic algorithms.

Conclusions: 

Developing diagnostic and therapeutic algorithms allows for the efficient management of uveitis, leading to better visual outcome and therefore a better quality of life.

INTRODUCTION

In 1991, the Ocular Inflammation Service was founded at the University Hospital of Ioannina, Greece to provide a specialist uveitis facility to the population of Ioannina and the wider region of Epirus and northwestern Greece. Immediately, a database was created to record each new patient attending the clinic. Over 6000 patients have been examined and the collected data provide critical information on this population. To the best of our knowledge, this is one of the largest studies on uveitis reported in the current literature. A paper detailing epidemiology and demographics has been submitted, recording the profile of uveitics, the geographical distribution and pattern of referrals, as well as the etiology and the classification of uveitis. This paper presents the diagnostic and therapeutic algorithms of uveitis, the complications, and the final outcome.

METHODS

This study was based on the results of a doctoral dissertation conducted in the Department of Ophthalmology at the University Hospital of Ioannina in Greece. Our analysis concerns a large observational period of 30 years from 1991 to 2020. The large archive of the Ocular Inflammation Service enabled the analysis of a large number of uveitic patients, allowing the extraction of valid and reliable data for this special category of patients. We included an overall of 6191 patients who were recorded until the end of 2020. The research protocol was approved by the Scientific Board of the Faculty of Medicine (School of Health Sciences) of the University of Ioannina (Greece) (846^α/27-3-2018) and followed the tenets of the Declaration of Helsinki.

Particular emphasis was placed on the assessment of the diagnostic contribution of laboratory tests (especially intraocular fluids), ophthalmic imaging [eg, fluorescein angiography (FA), indocyanine green angiography (ICGA), or ultrasound, electrophysiological examinations, photography of the anterior and posterior segment, and fundus autofluorescence (FAF)], as well as nonophthalmological imaging examinations [eg, x-rays and computed tomography (mainly high-resolution computed tomography), magnetic resonance imaging (MRI) of brain-orbit, as well as MRI and x-rays of the musculoskeletal system].

This study also evaluated the gradual development of therapeutic strategies, the contribution of other specialties in the treatment of uveitis, and the key role of ophthalmic examination in the diagnosis of underlying systemic diseases. In addition, we assessed the effect of the cause and/or severity of uveitis, the delay in diagnosis or implementation of appropriate treatment, the center’s experience, and the association of the patient’s compliance with the final outcome.

RESULTS

The patterns of uveitic patients and the evolution of diagnostic accuracy are described in Table 1 and Figure 1.

TABLE 1 - Evolution of the Diagnostic Capacity Every 5 Years

Years	Total no. patients	No. patients with definite diagnosis	No. patients with undetermined cause of uveitis
1991–1995	394	179 (45.43%) IU: 96 NIU: 80 MS: 3	215
1996–2000	575	301 (52.34%) IU: 142 NIU: 148 MS: 11	274
2001–2005	911	588 (64.54%) IU: 272 NIU: 296 MS: 20	323
2006–2010	1162	819 (70.48%) IU: 400 NIU: 388 MS: 31	343
2011–2015	1630	1160 (71.16%) I: 501 NI: 620 MS: 39	470
2016–2020	1519	1115 (73.4%) IU: 514 NIU: 564 MS: 37	404

IU indicates infectious uveitis; MS, masquerade syndromes; NIU, noninfectious uveitis.

FIGURE 1: This figure summarizes the landmarks that led to the improvement of the diagnostic accuracy and highlights the gradual reduction of uveitic patients with undetermined diagnosis. EDI-OCT indicates enhanced depth imaging optical coherence tomography; FAF, fundus autofluorescence; ICGA, indocyanine green angiography; OCTA, optical coherence tomography angiography; SD-OCT, spectral domain optical coherence tomography; UBM, ultrasound biomicroscopy; WFA, widefield angiography.

The main factors that increased the diagnostic ability (ie, timely and accurate diagnosis) (Fig. 1) were chronologically the following:

1. The gradually increasing cooperation with other specialties.
2. The increase in the range of laboratory blood tests for serological tests to detect microorganisms responsible for uveitis and immunologic markers for the diagnosis of uveitis associated with possible underlying systemic disease.
3. Diagnostic aspirations of the anterior chamber or vitreous cavity (for obtaining aqueous humor and vitreous, respectively) increased after 2000 (Fig. 2) and were enriched with new techniques [polymerase chain reaction (PCR) and flow cytometry].
4. The role of optical coherence tomography (OCT) and ICGA was pivotal in the study of posterior uveitis.
5. Over the last 15 years, the ability to diagnose tuberculous uveitis (even with solely ocular localization) has been enhanced by Interferon-Gamma Release Assays (QuantiFERON-TB).
6. During the last decade, wide-angle angiography (up to 130 degrees) with the Heidelberg SPECTRALIS played a critical role in the imaging of peripheral choroidal retinal lesions and vasculitis, whereas FAF was extremely useful in the evaluation of the posterior segment for various forms of choroiditis.
7. From 2017 onward, the application of ultrasound biomicroscopy for the anterior segment (especially useful in anterior uveitis) and high-resolution OCT angiography for posterior uveitis.

FIGURE 2: Diagnostic aspirations of the anterior chamber or vitreous cavity (for obtaining aqueous humor and vitreous, respectively) increased after 2000 and were enriched with new techniques (polymerase chain reaction and flow cytometry).

ICGA has made a significant contribution to understanding the pathophysiology of many forms of choroiditis, distinguishing between choroid capillaries [eg, inflammatory choroid choriocapillaropathies, multiple evanescent white dot syndrome , acute posterior multifocal placoid pigment epitheliopathy (APMPPE), multifocal choroiditis, punctate inner choroidopathy, and serpiginous choroiditis], Vogt-Koyanagi-Harada (VKH), birdshot chorioretinopathy (BCR), sympathetic ophthalmia, sarcoidosis, tuberculosis (TB), and syphilis. The extent and location of the lesions, as demonstrated by ICGA, can orientate our therapeutic approach and also act as prognostic indicators.

FA evidence of optic disc edema provided the impetus for the differential diagnosis of causes of uveitis such as sarcoidosis, Adamantiades-Behcet disease (ABD), nodular polyarteritis, sympathetic ophthalmia, VKH, APMPPE, Leptospira spp, Bartonella spp, Toxoplasma gondii, and Mycobacterium tuberculosis (MTB).

FA also distinguishes, in terms of retinal vasculitis, arteritis [eg, systemic lupus erythematosus, nodular polyarteritis, syphilis, and acute retinal necrosis (ARN)] and phlebitis (eg, sarcoidosis, BCR, TB, and Eales disease). Some diseases may affect both retinal arteries and veins [ABD, multiple sclerosis (MS), and granulomatous polyangiitis].

A subanalysis of the impact of the various significant causes (infectious or noninfectious) every 5 years is presented in Figure 3A–C. Figure 3A and B shows the significant increase in the incidence of herpes viruses during the last 15 years, while there is a significant decrease in the percentage of TB-related uveitis compared with the previous 15 years. Figure 3C shows an increase in the incidence of white dot syndromes (and syndromes presenting with white dots) and reactive uveitis over the last 15 years, which is largely attributed to the improved diagnostic approach.

FIGURE 3: A subanalysis of the impact of the various significant causes (infectious or noninfectious) every 5 years is presented. A and B, Showing the significant increase in the incidence of herpes viruses during the last 15 years, while there is a significant decrease in the percentage of tuberculous uveitis compared with the previous 15 years. C, Showing an increase in the incidence of white dot syndromes (and syndromes presenting with white dots*) and reactive uveitis over the last 15 years, which is largely attributed to the improved diagnostic approach. *syndromes presenting with white dots. AS indicates ankylosing spondylitis; CMV, cytomegalovirus; HSV, herpes simplex virus, MTB, Mycobacterium tuberculosis; T. gondii, Toxoplasma gondii; VZV, varicella zoster virus; WDS, white dot syndromes.

The management of masquerade syndromes was substantially augmented by more than 1 other medical or surgical specialties in 57.44% of cases (81 patients out of an overall of 141 cases with masquerade syndromes).

The refinement of the diagnostic approach over time led to a critical reduction of misdiagnosed cases (Fig. 4A).

FIGURE 4: A, Another observation regarding the identification of the cause of uveitis concerns the time point when the final diagnosis was made after the first diagnostic examination of each patient. It describes the percentage of patients with a confirmed diagnosis at the first differential diagnostic approach (“time point 0*”), at 1, 3, and 5 years. This graph shows that regular and long-term follow-up of patients with uveitis over a 5-year period contributes significantly to finding the cause of uveitis. In the whole period from 1991 to 2020, during the first investigation, a diagnosis was made in 44% of patients, whereas in 1, 3, and 5 years, the rate of confirmed diagnosis gradually increased reaching ~81% in 5 years. Unexplained uveitis after a follow-up of 5 consecutive years were considered idiopathic. B, This graph illustrates the trends in the use of immunomodulatory drugs used for the treatment of noninfectious uveitis.

The profile of uveitic patients was completed by including cases from areas outside Greece. Interestingly, the causes of uveitis in patients from countries such as Albania and the Republic of Northern Macedonia, as well as countries in Latin America, Asia, and Africa, were mostly infectious.

The 3 most common complications of uveitis, with a significant difference from the others, were cataracts (30.14%), cystoid macular edema (14.26%), and glaucoma (10.53%). Other complications include hypotony, phthisis, band keratopathy, and disorders of the vitreous (eg, bleeding) or fundus (eg, retinal detachment or epiretinal membrane).

In some cases where uveitis coexists with anterior necrotic scleritis. This combination has been correlated to unfavorable prognosis, because of the presence of a usually aggressive underlying autoimmune disease in many of these cases.

Tables 2 and 3 separately describes the association of delayed diagnosis, as well as patient compliance with treatment with the final outcome.

TABLE 2 - Relationship Between Delay in Diagnosis and Final Outcome

	Early diagnosis	Delay in diagnosis*	Total
Successful outcome†	3548	1411	4959
Poor outcome	370	862	1232
Total	3918	2273	6191

χ²=731.9736, P-value <0.00001.

^*A delayed diagnosis is defined as a period of time without a definite diagnosis (mainly because of late referral to a uveitis specialist service) that led to various cumulative damages depending on the severity and/or chronicity (even in cases of low-grade inflammatory activity) of inflammation, and recurrences that occurred during this interval. This delay may fluctuate from weeks to years and is associated with the etiologic factor and the underlying disease (if any).

^†A successful (or favorable) outcome was considered Snellen visual acuity in both eyes of at least 3/10 and above, long-term remission of the disease for at least 5 years, control of inflammation [absence of inflammation or subclinical reaction (ie, aqueous cells: 0, 5+, flare: traces, and vitritis: traces)] and the long-term absence of inflammation after the end of treatment.

TABLE 3 - Relationship Between Patient Compliance and Final Outcome

	Compliance	Noncompliance	Total
Successful outcome	3976	983	4959
Poor outcome	574	658	1232
Total	4550	1641	6191

χ²=571.4475, P-value<0.00001.

Delay in diagnosis and noncompliance with treatments and regular monitoring generally lead to a worse prognostic outcome. The combination of patient’s compliance and early diagnosis play a crucial role in a successful outcome. The number of patients who combine these 2 parameters (a total of 619 patients) represent 50.2% of patients with poor outcome.

Regarding the treatment of noninfectious uveitis (Fig. 4B), the 5 years from 1991 to 1995 were dominated by corticosteroids (topical and systemic), as well as immunomodulatory drugs such as methotrexate and azathioprine. In the next 5 years, especially in the treatment of idiopathic uveitis, the use of cyclosporine-A increases, whereas in the last decade, with the peak of the last 5 years, the use of biological agents by ophthalmologists increased substantially (up to 20% of cases). The response to biological agents (with or without other immunomodulatory drugs) reached 93%.

Reforming the treatment protocols after 2000 and again after 2010 concerns both novel drugs and new combinations, as well as the optimal time of their administration. The same applies to the treatment of infectious uveitis.

Key points that need special attention are the following:

• Regimens of systemic treatment in infectious uveitis (eg, uveitis attributed to herpetic infection, toxoplasmosis, TB, Spirochetes, Bartonella spp, Brucella spp) have generally remained stable following the international guidelines.
• In the last 15 years, an increase in intravitreal injections with antimicrobial agents was noted [mainly clindamycin 1 mg/0.1 mL in toxoplasmic retinochoroiditis (1991–2000: 0% of patients; 2001–2005: 11.76% of patients; 2006–2010: 30.86% of patients; 2011–2015: 33.86% of patients; 2016–2020: 42.35% of patients), and ganciclovir 2 mg/0.1 mL in ARN (in the last 7 out of 11 ARN cases; 3 patients had 2–3 intravitreal ganciclovir injections, whereas 5–10 injections were conducted in the 4 most recent cases)].
• The use of dexamethasone intravitreal implants (0.7 mg) for the treatment of noninfectious intermediate, posterior uveitis, and panuveitis increased during the last 10 years.

Recurrence of uveitis due to herpes simplex virus-1 or herpes zoster virus/varicella zoster virus (HZV/VZV), which are the most common causes of infectious uveitis, was found to decrease with increasing duration of antiviral per os treatment (acyclovir) to 12 months. Further prolongation of treatment does not seem to reduce the recurrence rates.

In noninfectious uveitis, the reduction of relapses and the control of inflammation are positively correlated with the duration of systemic treatment (18% after 1 y, up to 80% and more after 5 y).

As already mentioned, uveitic cataract was one of the most frequent complications. The success rate of uveitic cataract surgery in our center has gradually increased from 45% (1991–1995) to 87% (2016–2020). This observation was attributed to the more effective perioperative treatment (including control of inflammation) and development of more advanced surgical techniques.

OCT contributed significantly in the evaluation of macular edema, which may be cystoid or diffuse, extensive or limited, low or high (the latter category is defined as an increase in central retinal thickness in micrometer). An increase of retinal thickness >350 μm, especially above 400 μm, was associated with a higher risk of unsuccessful outcome because it may lead to other complications (eg, epiretinal membrane or macular hole). In the absence of typical macular edema, an increase in the thickness of the central retina was observed in some patients (usually not >330 μm), which usually subsided with treatment. This finding was observed in 8% of uveitics and of these in 95% did not develop macular edema.

Given the severity of macular edema, the effort to successfully treat this complication of uveitis is an important therapeutic parameter. The success rate of macular edema treatment has increased from 15% to 88% over time because of newer therapeutic approaches.

Uveitic glaucoma is the third most common complication of uveitis. Fifty-seven percent of glaucomatous eyes due to uveitis eventually underwent surgery [trabeculectomy (TRAB), glaucoma drainage device (GDD), or minimal glaucoma invasive surgery (MIGS)]. The majority of cases were operated on in the University Hospital of Ioannina. In most cases, the first surgical approach was TRAB with mitomycin-C (MMC) and involved 372 of the 410 eyes (90.73% of the first initial surgical approach, in case of drug failure, was TRAB + MMC). GDD (BAERVELDT Glaucoma Implant or Ahmed Glaucoma Valve) or MIGS (EX-PRESS Glaucoma Filtration Device Procedure) was used in cases where surgical treatment needed to be repeated. The success rate of TRAB as the first surgical approach to uveitic glaucoma has increased over the last 15 years, especially over the last 5 years (from 34% in 1991–1995 to 81% in 2016–2020). This observation has been linked with the improved treatment protocols, preoperative preparation, and postoperative follow-up, ensuring the absence of active inflammation.

In both uveitic glaucoma and uveitic cataract, the 3-month preoperative period with minor or no inflammation was a key parameter in a successful outcome. In almost all cases, the preoperative period was 3 months or more in the vast majority of cases with cataracts or glaucoma (96% of eyes). Prostaglandin analogues were avoided, not only during active inflammation, but also in cases of inactive herpetic uveitis.

During the studied period (1991–2020), a gradual improvement of the final outcome is observed. More specifically, comparing the results of the treatment every 5 years confirms the increase in the percentage of patients with a successful outcome. This percentage, increased from 50.50% (1991–1995) to 72% (2001–2005), finally escalading to 90.50% (2016–2020).

The increasing success rates in the management of uveitis have resulted in an increase (approximately from 5% to 29%) in the number of patients with uveitis coming from more distant areas (ie, from areas outside Epirus, Etoloakarnania, Corfu, and Lefkada). This fact has resulted in the gradual increase of the number of patients belonging to the urban population, mainly from Attica or the wider area of Thessaloniki, as well as other urban areas. There is a statistically significant (P<0.05) predominance of noninfectious causes (72.8%) versus the infectious causes in the urban population compared with the rural population (67.77%).

Briefly, based on the analysis of our data, the diagnostic approach required a detailed history (medical, social, geographical, and family history), after the ophthalmologist was oriented based on the clinical findings of the anterior and posterior segment. Moreover, the oriented laboratory and imaging investigation played a pivotal role in detecting the etiologic factor. Certain examinations, such as serological testing (eg, for Spirochete, Brucella spp, T. gondii, Toxocara canis, Bartonella spp, herpesviruses) x-rays, chest CT, brain MRI, serum angiotensin-converting enzyme, purified protein derivative skin test and interferon-gamma release assays for TB, immunology test (including antinuclear antibodies, c-antineutrophil cytoplasmic antibody, p-antineutrophil cytoplasmic antibody), human leukocyte antigens (HLA) typing (mainly HLA-B51 for ABD, HLA-B27 for ankylosing spondylitis (AS) and Crohn disease and HLA-A29 for BCR), as well as investigations of intraocular fluids (PCR, flow cytometry, cytology, and cultures), were some of the most important and useful exams for the diagnostic exploration of the uveitic patient. Depending on the clinical findings and symptoms, each patient was also referred to other medical specialties (eg, rheumatologists, dermatologists, gastroenterologists, neurologists, and pediatricians) for further investigations and assessment, when required. In the event that no diagnosis was made regarding the cause of uveitis, the follow-up allowed the reevaluation of the clinical picture (ocular and systemic findings) and further laboratory investigation, optimizing the diagnostic potentials.

Our analysis led to the development of diagnostic (Fig. 5A–F) and therapeutic (Fig. 6A–F) algorithms that provide guidelines on the holistic approach of a patient with uveitis that will allow the clinician to initiate appropriate treatment early, reducing the severity and frequency of cumulative damages.

A, Infectious uveitis must be ruled out as early as possible to avoid incorrect treatment. In masquerade syndromes, the delay in revealing the underlying disorder can be fatal, not only for the eye, but also for the patient’s life. B, The choice of aqueous or vitreous, as well as the type of laboratory examination depends on the anatomic location of the uveitis and the specific clinical picture on a case-by-case basis. C. D, *Choosing the appropriate examination depends on the posterior segment findings. **See anterior uveitis. E, *Choosing the appropriate examination depends on the posterior segment findings. Ocular tissue biopsy is important and necessary in the differential diagnosis, such as in the sympathetic ophthalmia (Dalen-Fuchs nodules), granulomatous polyangiitis (presenting with choroidal granulomas), and generally in cases of mass-like lesions, where other tests do not show a specific cause, vision function is either endangered or no longer exists and there is a suspicion of a life-threatening disease (eg, malignancy mimicking a choroidal granuloma). F, Fundus photography is mandatory in all cases. ABD indicates Adamantiades-Behcet disease; AS, ankylosing spondylitis; CD, cluster of differentiation; ERM epiretinal membrane; ICGA, indocyanine green angiography; FA, fluorescein angiography; FAF, fundus autofluorescence; OCT, optical coherence tomography; PCR, polymerase chain reaction; VKH, Vogt-Koyanagi-Harada disease; VMT, vitreomacular traction; VRA, vitreoretinal adhesion; VRT, vitreoretinal traction.

A, Please note that septic infections are classified as masquerade syndromes. The initiation of treatment in infectious uveitis should be immediate or at least without significant delay. In many of these cases, the initiation of treatment can only be based on clinical diagnosis or suspicion, even before laboratory confirmation to prevent potentially catastrophic effects on vision. The same is true for serious septic infections, such as endogenous endophthalmitis in masquerade syndromes. On the other hand, with regard to noninfectious uveitis, the therapeutic algorithms that emerge as a final result of the analysis of the treatment protocols in these 30 years, offer the possibility to be used as guidelines. B, Addition or change of biological agent. In patients with juvenile idiopathic arthritis adalimumab can be considered. C, *Cyclosporine-Α, Methotrexate, Azathioprine. This figure summarizes the therapeutic algorithms of noninfectious uveitis without known systematic correlation, it is worth noting that in case of deterioration despite the start of treatment, the investigation for infectious diseases should be repeated immediately. In addition, in case of systemic disease during follow-up, the treatment is formulated according to the systemic disease. Taking into account the guidelines for the therapeutic approach of patients with noninfectious uveitis with known systematic association or those with distinct uveitic clinical entities, it is emphasized that the dexamethasone intravitreal implant is selected in patients with the implementation of appropriate treatment protocols. D, Apart from the patients’ age, the association with an underlying systemic disease play a significant role in defining each step of the therapeutic algorithm. E, Initially, in relation to diagnostic algorithms, it is important to confirm or rule out the infectious cause and masquerade syndrome (especially in cases that may be associated with malignancy or persistent septic infection). The aspiration for obtaining both aqueous (mainly) aqueous and vitreous for laboratory tests, are of primary importance for the confirmation or exclusion of a diagnosis or at least for the differential diagnostic orientation. Because ocular fluids and especially aqueous humor cannot be taken in large quantities, it is important, based on the history and clinical picture, to prioritize the requested examinations. Also, imaging tests are of particular importance in terms of data analysis with the aim of categorizing, assessing the severity of uveitis and drawing conclusions about biomarkers and prognostic factors. Utilization of all necessary imaging examinations should be done depending on the anatomic location of the uveitis, the history and the diagnostic suspicion not only before the start of the treatment but also during the monitoring of the patient. F. The development of diagnostic and therapeutic algorithms that provide guidelines for the holistic approach of a patient with uveitis that will allow the clinician to initiate appropriate treatment early, reducing the severity and frequency of cumulative damages. ABD indicates Adamantiades-Behcet disease; ARN, acute retinal necrosis; MS, multiple sclerosis, MTX, methotrexate; PVRL, primary vitreoretinal lymphoma; TB, tuberculosis; T. pallidum; Treponema pallidum; VKH, Vogt-Koyanagi-Harada; WDS, white dot syndromes.

DISCUSSION

The epidemiological data on uveitis provide valuable information that can be considered during the diagnostic and therapeutic approach of the uveitic patient. A relatively recent study underlined the contribution of complementary testing to the diagnosis of ocular sarcoidosis in a selected patient population.¹ The Uveitis: Medico-economical and Clinical Evaluation of a Standardized Strategy for an Etiological Diagnosis study² was the first prospective study to evaluate the effectiveness of a standardized strategy for etiologic diagnosis of uveitis. The first stage of this study consisted of the least possible laboratory investigation with examinations that were oriented based on clinical findings. In the absence of data that could guide the differential diagnosis or the diagnosis after the first stage, further investigation was performed depending on the anatomic type of inflammation. This standard strategy is based on the diagnostic strategy proposed by Harper et al³ in 2002, taking into account the findings of recent studies and expert advice,⁴ which, in the absence of a diagnosis, may require a wider range of tests.

Defining the anatomic location of uveitis is vital for the diagnostic approach. Our results demonstrated that anterior uveitis is either idiopathic (higher percentage) or herpetic (herpes simplex virus-1 and VZV/HZV), followed by other etiologies. A considerable number of cases with intermediate uveitis are also idiopathic, followed by other causes such as MS and some of the major imitators that should never be overlooked (MTB, sarcoidosis and Bartonella spp). The most common cause of posterior uveitis is T. gondii, with white dot syndromes, followed by other infectious and noninfectious causes. Finally, in panuveitis, idiopathic uveitis affects more than one third of cases, and followed in smaller percentages by multifocal choroiditis and panuveitis (typically in young and middle-aged women), sarcoidosis, ABD, phacoanaphylactic uveitis, whereas the most common infectious causes are MTB and Brucella spp.

Choosing the appropriate laboratory examinations for the diagnostic workup of uveitis is a “tailored” process for each patient (based on the patient’s history and clinical assessment). Our study underlines that the development of novel diagnostic tools⁵ increased the diagnostic accuracy. Moreover, the characterization of novel clinical forms in different types of uveitis⁶ has affected their incidence and led to the description of new subsets of each disease. Similarly, in syphilis⁷ or other types of infectious uveitis,⁸ PCR enhanced the ability of setting an early and accurate diagnosis.⁹

A significant number of clinical findings (ocular or systemic), laboratory values, and ophthalmic and systemic imaging findings constitute biomarkers that are useful not only for the differential diagnosis but also for assessing the severity of uveitis and response to treatment. A typical example is active sarcoidosis-associated vasculitis (as can be seen in FA) persistent to treatment, despite the remission of respiratory symptoms and findings. In cases of severe retinal involvement, electrophysiological examinations, in particular the electroretinogram (ERG) including multifocal ERG, contribute significantly to the differential diagnosis, for example, in cases of difficult distinction between sarcoidosis and BCR or VKH and APMPPE). ERG results are currently useful biomarkers for the severity of inflammation and the assessment of response to treatment.¹⁰

Multimodal imaging provides valuable information,¹¹ allowing the display of a wide range of abnormalities associated with uveitis, such as retinal and choroidal lesions, vasculitis, optic nerve disorders, retinal ischemia, and macular edema. Imaging is useful not only in diagnosing the cause of uveitis, but also in monitoring the response to treatment.¹² Cunningham et al¹³ emphasized the usefulness of ultra-widefield imaging, providing a wider imaging of the posterior segment so as to reveal more peripheral lesions. Ultra-widefield imaging may be particularly useful in pathologies such as syphilis, APMPPE, multiple evanescent white dot syndrome, and primary intraocular lymphoma (PIOL), as a large proportion of their findings are likely to be located in the mid-periphery and distal periphery.

Our results highlight the significance of intraocular fluid (aqueous and vitreous humor) analysis. Flow cytometry has been instrumental in the differential diagnosis of uveitis, especially in masquerade syndromes associated with malignancies, such as PIOL.¹⁴ Furthermore, the abundance of polymorphonuclear leukocytes confirms the suspicion of septic endophthalmitis, in cases of negative cultures. Finally, the cytologic examination¹⁵ identifies specific elements such as lenticular masses (in phacoanaphylactic reaction), amyloid (in cases of amyloidosis), precipitation of microbial material (in septic endophthalmitis), and morphology of cells (especially lymphocytes in PIOL). However, the clinician should carefully choose among the available diagnostic modalities (flow cytometry, PCR, cytologic examination and culture), as the aspiration of intraocular fluids can only provide a small amount of sample.

In some cases, biopsy of both ocular and other tissues may be required to provide a definite diagnosis.¹⁶ Intraocular biopsy is a histopathologic or cytologic evaluation of surgically obtained specimens, such as the aqueous or vitreous humor, retinal fluid, and tissues such as the iris, retina, and choroid. Current biopsy techniques have contributed significantly to the decision-making. These methods include anterior chamber aspiration, iris and ciliary body biopsy, fine needle aspiration biopsy, vitreous, and retinal biopsy. The most common indications include nonresponsive uveitis, iris or ciliary mass, and laboratory and clinical findings that do not lead to a clear diagnosis or masquerade syndromes.

A better understanding of the pathogenetic mechanisms together with a detailed description of the clinical, imaging, and laboratory findings is essential for the diagnostic approach, especially in pathologies such as TB, syphilis, sarcoidosis, and PIOL, which constitute the so-called “great-imitators.”¹⁷ On the basis of our results, Bartonella spp can be also considered an imitator, as it can cause a great variety of clinical manifestations.^18,19 Another major imitator of systemic manifestations is systemic lupus erythematosus, which causes primarily retinal vasculitis (ie, arteritis).²⁰

The eye can be the first or even the only target organ in systemic disorders.^21–24 Various systemic diseases, such as AS, sarcoidosis, MS, ABD, inflammatory bowel disease (IBD), and juvenile idiopathic arthritis, are associated with uveitis, which can occur as the first manifestation of these systemic diseases. The appropriate utilization of standard diagnostic tools (eg, lumbar x-rays in AS)^25,26 or newer techniques complements the holistic approach (eg, the high-resolution computed tomography chest in the diagnosis of sarcoidosis).²⁷

The gradual improvement of the diagnostic accuracy is attributed to the increase of clinical experience, the development of diagnostic techniques, and the establishment of effective and thorough cooperation with other specialties.²⁸

A well-organized follow-up plan seems to contribute substantially to setting a definite diagnosis of uveitis. As described in our results, the percentage of our patients with a confirmed diagnosis of the cause of uveitis (1991–2020) reached up to 80.5% in 5 years of follow-up.

Timely referral to a uveitis specialist also seems to play a crucial role in the effective management of uveitis. A nonspecialist may not always be prepared for the holistic approach of a patient with uveitis. In countries such as the United Kingdom, the manner and frequency of referrals to specialized centers has improved, with the number of referrals showing a gradual increase over the last 2–3 decades.²⁹

The role of early administration of antimicrobial therapy is significant for the treatment of infectious uveitis. In cases with severe inflammation threatening the vision and the anatomic integrity of the eye, empirical treatment can be started if there is a strong clinical suspicion of a particular microbial agent (eg, in ARN and toxoplasmosis).^30,31 The duration of treatment plays a pivotal role in the final outcome, especially in pathologies such as tuberculous³² and herpetic uveitis.³³ Intravitreal injection of antimicrobial agents can be also considered in pathologies such as ARN or toxoplasmic retinochoroiditis. Other intraocular inflammatory disorders, such as septic endophthalmitis (masquerade syndrome that can imitate uveitis either as a late onset of postoperative endophthalmitis or as endogenous endophthalmitis), may also require surgical treatment (ie, vitrectomy). A classic example of endogenous endophthalmitis is that associated with resistant Candida of the urinary tract.²²

For many years, the treatment of noninfectious uveitis relied on corticosteroids, which are administered in 3 forms: topically as drops, topically as subconjunctival or intravitreal injections, and systemically. Each of these treatment options has advantages and disadvantages and should be used as part of an individualized treatment plan. Immunosuppressive drugs (methotrexate, azathioprine, cyclosporine, etc) can be used in the treatment regimen reducing the need for high doses of corticosteroids (“steroid-sparing agents”), especially in clinical entities where there may be chronic inflammation, such as ABD.^34,35

Much of the improvement in the treatment of noninfectious uveitis is attributed to the gradual increase in the use of biological agents.³⁶ “Biological response modifiers,” commonly referred to as biological agents, are a term used to describe therapeutic proteins designed to inhibit the activity of bioactive mediators of the immune response. Biological agents are mainly recombinant antibodies and proteins derived from antibodies. Conventional treatment with corticosteroids and immunomodulatory agents, such as methotrexate, azathioprine, mycophenolate mofetil, and cyclosporine, may not be sufficient to control ocular inflammation or prevent nonocular complications in patients with refractory disease. The addition of biological agents is very useful when conventional immunomodulatory therapy has failed or has not been tolerated by the patient, offering significant benefits in the treatment of both ocular and systemic inflammation. Treatment with biological agents, mainly infliximab and adalimumab, has been shown to be rapidly effective in treating various subtypes of uveitis and retinal obstructive vasculitis, especially in patients with ABD or uveitis associated with juvenile idiopathic arthritis. In the future, other agents are expected to have positive effects in treating noninfectious uveitis. With proper monitoring, biological therapy can significantly improve the quality of life in patients with uveitis. These agents should be used with caution by experienced clinicians in specialized centers.^35–37 In Greece, the first study on the use of biological agents in ophthalmology was published 20 years ago³⁸ and since then the view has been strengthened that biological agents can be a particularly useful treatment in the treatment of noninfectious uveitis and retinitis. For the last 5 years, adalimumab has been an approved drug in Greece for the treatment of noninfectious intermediate and posterior uveitis and panuveitis,³⁹ whereas it has been 3 years since the official use of adalimumab in Greece for noninfectious anterior uveitis children older than 2 years,^40,41 with very satisfactory results in combination or not with methotrexate. In addition, the contribution of interferon in the treatment of noninfectious uveitis should be noted, although it shows significant side effects. In our material, the newest therapies concern the biological agents with the main representative being adalimumab,⁴² whereas interferon was not used in any of our cases. The possibility of infectious disease must be ruled out before initiating any immunomodulatory therapy.

Patient compliance with treatment and follow-up appointments is associated with better results.^43,44 Identifying factors that limit compliance are essential to optimize treatment and develop strategies that will enhance compliance with treatment and regular monitoring.⁴⁵

The patient’s immune profile is a substantial parameter for the management of uveitis. Very often, intraocular inflammation in immunocompromised patients can lead to irreversible blindness.⁴⁶

The complications of uveitis are mainly related to the severity of inflammation (acute anterior uveitis with ≥3+ reaction and vitreous haze ≥3+ were found to be more frequently associated with complications), etiologic factor (eg, ARN, serpiginous choroiditis, BCR, ABD), recurrence rate, inappropriate treatment, and prolonged (even low-grade) inflammation. Usually, vision effects do not result from a single episode, but from recurrent episodes or chronic inflammation, leading to so-called “cumulative damages,” a term coined in 2006 by Quan Dong Nguyen.⁴⁷ Early referral to a specialist clinic, the overall duration of the disease, the anatomic location of the inflammation (anterior, intermediate, posterior, or panuveitis) and the number of episodes of uveitis play a decisive role in the final outcome of the disease.^48,49

On the basis of our results, the frequent recurrences of inflammation and prolonged active uveitis (especially when it exceeds 6 months), as well as the increased thickness of the retina in cases of macular edema [central retinal thickness (CRT) >400 μm] are crucial prognostic indicators. The duration of such macular edema plays an important role, especially in eyes with cystoid edema, as it may lead to a macular hole.⁵⁰ Finally, even in acute conditions, the severe anterior chamber reaction and/or the vitreous haze, as well as the prolonged duration of flare, are unfavorable prognostic indicators for the final outcome and must be considered in treatment protocols.⁵¹

Regarding the surgical management of complications attributed to uveitis, various factors have contributed significantly to the improvement of surgical outcomes. These factors include surgical techniques, smaller incisions, improved therapies and better perioperative treatment, increased experience, and of course the design of new types of intraocular lenses (acrylic hydrophobes are considered to be the most testable).⁵² A thorough clinical examination is pivotal for the preoperative surgical planning. It is emphasized that the eye should be at rest for at least 3 months before cataract surgery. Preoperative prophylaxis with corticosteroids is important to reduce the risk of macular edema and recurrence of uveitis. Antimicrobial prophylaxis can also reduce the risk of reactivation in the eyes with infectious uveitis. In patients <2 years of age and in eyes where inflammation is not well controlled, intraocular lens implantation should be postponed. Patients should be closely monitored for recurrence of the disease, inflammation, increased intraocular pressure, hypotension, and other complications. With proper patient selection, improved surgical techniques, and optimization of perioperative and postoperative care, good visual outcomes can be achieved in patients with uveitis.^53,54

The causes of ocular hypertension and glaucoma in patients with uveitis are multifactorial. The therapeutic approach to uveitic glaucoma is individualized and inextricably linked to the underlying etiology. Uveitis and glaucoma can be controlled with anti-inflammatory and antiglaucoma agents, respectively. It has been speculated that prostaglandin receptor agonists tend to increase inflammatory activity in a small percentage of patients.⁵⁵ For this reason, prostaglandin analogues, taking into account our own experience, should be avoided in patients with herpetic uveitis or cystoid macular edema.⁵⁵ The use of β-blockers and/or carbonic anhydrase inhibitors is suggested, while there are conflicting views on brimonidine. In cases where the intraocular pressure is not regulated by combining the last 2 factors, the surgical treatment begins to gain ground. In many cases, the suppression of the inflammatory process itself helps control the intraocular pressure. Patients receiving immediate and aggressive anti-inflammatory medication tend to have a significantly better clinical course of uveitic glaucoma. In cases where antiglaucoma drugs are insufficient (~25%–30%), invasive and surgical procedures are recommended (eg, TRAB, GDD, and MIGS).⁵⁵ As all of these parameters vary between specialist clinics in ways that are difficult to quantify, attempts at direct comparison between studies should always be made with caution. However, steroid-induced secondary glaucoma or ocular hypertension/glaucoma is recognized as a common and significant complication in patients with uveitis.^29,56

Pars plana vitrectomy (PPV) in eyes with uveitis has various diagnostic and therapeutic indications. With the advent of microincision vitrectomy surgery (MIVS), the use of PPV in uveitis has increased and gained a wider range of indications due to shorter surgery time, less patient discomfort, fewer conjunctival scars, and reduced complications compared with classic 20G vitrectomy.⁵⁷ Because of the faster postoperative recovery in terms of visual improvement and reduction of inflammation and reduced duration of systemic corticosteroids, MIVS has gained popularity in uveitis. The safety and effectiveness of MIVS is related to emerging vitrectomy techniques with better and newer cutters, lighting, and auxiliary instruments/tools. Because of the tools and fluids of MIVS, PPV seems as a safe and useful alternative to the diagnostic challenges of uveitis,⁵⁸ helping in the early diagnosis and better outcome of inflammatory disease, even in the presence of severe and active inflammation, which was once considered a relative contraindication to vitreous surgery. However, for surgeries on therapeutic indications and complications of uveitis, it is advisable to achieve optimal control of inflammation for better results. The growing reports of the use of MIVS in uveitis have led to its wider acceptance by clinicians specializing in uveitis.

CONCLUSIONS

Both diagnostic and therapeutic algorithms contribute significantly to the optimization of the treatment of uveitis. The protocols for the management of uveitis in a referral center must be frequently updated, taking into consideration a wide spectrum of parameters. The results of our analysis led to the formulation of diagnostic and therapeutic algorithms for the holistic approach of patients with uveitis. Their validity derives from the analysis of a large number of patients over a long period of time. Gaining substantial experience at our center has made it possible to avoid inappropriate and uncertain therapeutic approaches. The effective management of the uveitic patient is associated with reduced cumulative damages, and consequently improved anatomic and functional outcomes, as well as a better quality of life.