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Journal Français d'Ophtalmologie
Volume 41, n° 1
pages e11-e21 (janvier 2018)
Doi : 10.1016/j.jfo.2017.11.003
Received : 1 September 2017 ;  accepted : 14 November 2017
Editor's choice

Anterior uveitis
 

J. Gueudry , M. Muraine
 Service d’ophtalmologie, hôpital Charles-Nicolle, CHU de Rouen, 1, rue de Germont, 76031 Rouen cedex, France 

Corresponding author.
Summary

Anterior Uveitis is the most common form of uveitis. There are several known and many possible etiologies for anterior uveitis. After examining the posterior segment and ruling out masquerade syndromes, the main step of etiologic diagnosis is clinical characterization. It is essential to establish the presence or absence of unilateral versus bilateral and granulomatous features. Subsequently, a directed work-up may be obtained which then helps to confirm diagnostic hypotheses based on the detailed history and clinical examination. The priority is to rule out an infection. Treatments are adapted according to etiology and disease severity. Finally, biologics have greatly changed the management and prevention of some forms of anterior uveitis, in particular uveitis associated with HLA-B27 and juvenile idiopathic arthritis-associated anterior uveitis.

The full text of this article is available in PDF format.

Keywords : Anterior uveitis, Iridocyclitis, Herpetic uveitis, HLA B27, Juvenile idiopathic arthritis


Introduction

Uveitides are relatively rare diseases of variable causes. They are potentially sight threatening, representing 10% of legal blindness in industrialized countries [1]. The uveitis may be just the tip of the iceberg and may be the presenting sign of a systemic disease. Anterior uveitis is the most frequent. Certain routine steps on the initial clinical examination along with simple ancillary testing allow a directed approach to further testing and treatment by avoiding certain pitfalls.

Definition of anterior uveitis

The current classification of uveitis is an anatomic classification, as set forth by the International Uveitis Study Group (IUSG) then confirmed by the Standardization of Uveitis Nomenclature (SUN) work group [2, 3]. This classification is based upon the concept of the “primary” or “initial” site of inflammation. It is thus based on the place where the inflammation predominates. It distinguishes between anterior uveitis with iris and ciliary body involvement, intermediate uveitis with peripheral chorioretinal involvement, posterior uveitis with choroidal and retinal involvement and panuveitis. The associated complications do not change the type of uveitis. For example, an HLA-B27 positive anterior uveitis complicated by macular edema remains classified as anterior uveitis. The SUN also allows for distinguishing uveitides as a function of their presentation, sudden-onset or insidious, as well as their progression; acute, in the case of a sudden, brief episode; recurrent, in the case of multiple episodes separated by quiet periods of 3 months or more without treatment; chronic, in the case of a persistent episode with relapses occurring less than 3 months after treatment is discontinued.

Epidemiology of anterior uveitis

In 2016, in over 4 million Americans, the prevalence of uveitis was found to be 133/100,000 inhabitants and 121/100,000 inhabitants just for non-infectious causes. Among these, 80% represented anterior uveitis [1]. The clinical entities found most frequently in series in western countries are HLA-B27 positive uveitis, Fuchs heterochromic iridocyclitis and herpetic uveitis [4].

Etiologic diagnosis
Clinical characterization of anterior uveitis

The key to etiologic diagnosis of uveitis is the clinical examination. The characterization of a case of uveitis allows the patient to be integrated into a clinical context, which points quickly toward certain etiologies (Table 1) [5]. The anatomic characterization of uveitis, its mode of progression and its unilaterality or bilaterality are thus necessary for a targeted diagnosis and appropriate treatment. Finally, it is necessary to define whether the involvement is granulomatous, which allows the number of possible etiologies to be filtered down, even if it is not always easy. Any uveitis may begin as non-granulomatous. Thus, it has been described that over half of patients with biopsy-proven sarcoidosis presented initially with non-granulomatous uveitis [6].

The typical symptoms, which lead to consultation, are pain, redness, photophobia and decreased visual acuity. However, certain patients may remain asymptomatic, for example in the case of Fuchs heterochromic iridocyclitis or uveitis associated with juvenile idiopathic arthritis (JIA). One must also keep in mind that the contrast between the appearance of intraocular inflammation in a “white eye” is suggestive of masquerade syndromes, notably in neoplastic pseudo-uveitis, since cellular infiltrates actually simulate visible inflammatory elements.

A ciliary flush may be present. Slit lamp examination identifies and quantifies the cellular and/or protein Tyndall effect and looks for the presence or absence of keratic precipitates and iris nodules. They define the granulomatous nature of the uveitis. The appearance and location of the keratic precipitates are a large help toward a correct diagnosis (Figure 1).



Figure 1


Figure 1. 

Appearance of granulomatous keratic precipitates. “Mutton fat” precipitates (a); distribution in an inferiorly based triangle in sarcoidosis (b); stellate whitish appearance with diffuse, regular distribution to the top of the cornea, suggestive of Fuchs heterochromic iridocyclitis (c and d); few, central, clear precipitates in Posner–Schlossman syndrome (e and f); central or paracentral gray precipitates with paving-stone appearance, of herpetic uveitis (g and h).

Zoom

Granulomatous precipitates may be:

fine and spiculated, distributed over the entire posterior surface of the cornea (such as in Fuchs heterochromic iridocyclitis);
of medium size, more or less central, such as in herpes, often gray or brown, with a “leopard skin” distribution;
of large size, in a triangular distribution (such as in sarcoidosis or tuberculosis), sometimes referred to as “mutton fat”.

Iris nodules are referred to as Koeppe nodules, situated at the pupillary margin, or Busacca nodules, situated within the iris stroma (Figure 2). Their presence must be assessed prior to dilation.



Figure 2


Figure 2. 

Granulomatous anterior uveitis and iris nodules. Appearance of multiple iris nodules at the pupillary margin (Koeppe nodules) and iris stroma (Busacca nodules) (a); isolated Koeppe nodule in anterior uveitis associated with multiple sclerosis (b); angular iris nodule in sarcoidosis and its appearance on gonioscopy (c and d).

Zoom

On the other hand, fine, dust-like keratic precipitates and fibrin in the anterior chamber suggest non-granulomatous uveitis. This fibrin may organize within the anterior chamber in the form of a membrane and partially or completely occlude the pupil. A hypopyon is a mass of inflammatory cells, which settle inferiorly due to gravity (Figure 3). It is an indicator of the severity of uveitis more so than an element of the etiologic diagnosis. Classically, it is described in HLA-B27 positive uveitis, Behçet's disease, rifabutin uveitis, or in cases of infectious uveitis such as herpetic uveitis [7]; however, any severe uveitis may present with a hypopyon.



Figure 3


Figure 3. 

HLA-B27 positive non-granulomatous uveitis. Note the fibrin present on the anterior lens and the dust-like cellular deposit inferiorly (a); note the fibrin on the anterior lens, persistent posterior synechia, hypopyon and absence of keratic precipitates (b).

Zoom

Certain uveitides are typically bilateral, such as sarcoidosis. Unilaterality suggests infection and alternating laterality is characteristic of HLA-B27 positive uveitis.

An increase in intraocular pressure as the uveitis progresses may result from multiple causes such as a steroid response, clogging of the trabecular meshwork, extensive posterior synechiae resulting in iris bombé, or the progression of anterior synechiae. However, the intraocular pressure change may occur at the onset of the episode, suggesting an etiologic diagnosis. Hypotony is possible with episodes of anterior uveitis due to ciliary body shutdown, with a return to normal upon resolution of the inflammation. It is frequently observed with HLA-B27 positive uveitis. However, chronic inflammation may provoke permanent hypotony without recovery of the secretory function of the ciliary body. On the other hand, ocular hypertension suggests infectious uveitis such as viral uveitis, Posner–Schlossman syndrome and Fuchs heterochromic iridocyclitis in unilateral cases, but also sarcoidosis or tuberculosis in bilateral cases. Lens-induced uveitis also often raises the intraocular pressure.

Keratouveitis first suggests herpetic or zoster involvement, which may occur in the absence of concomitant skin involvement. Corneal hypesthesia or anesthesia is also suggestive. Also, corneal examination may reveal band keratopathy, which suggests chronic anterior segment inflammation.

Examination of the iris prior to dilation sometimes also aids in the etiologic diagnosis. Sectoral iris atrophy visible on transillumination is very suggestive of herpetic or zoster uveitis (Figure 4). Iris heterochromia is also very suggestive of Fuchs heterochromic iridocyclitis due to iris stromal atrophy, as well as the loss of iris relief and disappearance of iris crypts. After dilation, the presence of posterior synechiae also directs the etiologic diagnosis.



Figure 4


Figure 4. 

Sectoral iris atrophy in herpetic uveitis. Sectoral transillumination (a and b); more diffuse involvement (c); sectoral iris atrophy causing corectopia, note the old pigmented keratic precipitates (d).

Zoom

A view of the ocular fundus is absolutely necessary. It allows one to know if the involvement is strictly anterior and if it is really unilateral or bilateral. When the fundus cannot be seen during the initial visit, a repeat examination after 24–48hours of treatment allows for identification of posterior involvement.

At the conclusion of the clinical examination, certain principles may however be applied. For example, HLA-B27 positive uveitis and Behçet's disease are never granulomatous. Posterior synechiae are always absent in Fuchs heterochromic iridocyclitis. Unilateral uveitis suggests above all an infectious process, especially when it is granulomatous and highly steroid dependent or steroid resistant.

History

The history is then directed based on the differential diagnosis arising from the clinical examination. Certain systematic questions are useful and will avoid errors. For example, asking the patient about oral ulcers is necessary due to the ophthalmologic morbidity associated with Behçet's disease, and this will not necessarily be reported spontaneously by the patient (Appendix A) [8].

Ancillary testing

At the conclusion of the clinical examination, the etiologic diagnosis may be purely ophthalmologic and not typically require additional testing, such as for a typical herpetic uveitis, sometimes confirmed by PCR analysis of the aqueous humor after anterior chamber paracentesis. However, in the majority of cases, diagnostic hypotheses require confirmation. A minimal etiologic work-up will be proposed upon initial evaluation of the uveitis (Appendix A) [8] and will be supplemented based on the differential diagnosis. Syphilis serology is systematic, given the polymorphism of the associated uveitis. Antinuclear antibodies are useful in children to document possible juvenile idiopathic arthritis. Rheumatoid factor levels are not systematically necessary in adults. Actually, rheumatoid arthritis causes scleritis much more frequently. An extensive systematic work-up has a role for severe chronic uveitis. Finally, numerous viruses may cause an anterior uveitis concomitantly or subsequently to the initial infection, such as Zika, Chinkungunya or even influenza [9].

Tests to detect production of interferon-γ aid in the diagnosis of tuberculosis. There are two main tests, QuantiFERON-TB gold® and T-Spot TB®. These test reproduce in vitro in a standardized fashion the first stage in the delayed-type hypersensitivity reaction to Mycobacterium tuberculosis . They are performed on a blood sample. In these tests, blood T lymphocytes are stimulated in vitro with tuberculosis antigen, and the production of interferon-γ is measured the next day. The particularity of these tests is to no longer use tuberculin antigen, but antigens not shared with the tuberculosis vaccine (BCG) or the majority of atypical mycobacteria. A positive test indicates the presence in the subject's blood of memory T cells specific for Mycobacterium tuberculosis . This test does not allow for differentiation between latent tuberculosis infection and active or treated tuberculous disease. These tests are not recommended in France for the diagnosis of active tuberculosis disease except in extrapulmonary forms where the diagnosis is difficult, such as presumed tuberculous uveitis. In the literature, two studies in non-endemic zones have demonstrated significance of the threshold of positivity of the QuantiFERON-TB gold® test, although the laboratory, which markets it, does not indicate this. Thus, a result above 1.5IU/mL [10] or 2IU/mL [11], increases the success rate of antituberculous treatment in the case of presumed tuberculous uveitis, most often extrapulmonary.

Anterior chamber paracentesis (ACP) is often helpful, notably for the diagnosis of presumed viral involvement, in order to perform aqueous humor analysis. It is performed, under local anesthesia with tetracaine, after placing a lid speculum most often in the operating room, by aspiration with a 30-gauge needle, which is then capped.

Specific entities
HLA-B27 positive uveitis

HLA-B27 positive uveitis is common. It is associated with spondyloarthritis (ankylosing spondylitis, arthritis associated with inflammatory bowel disease, psoriatic arthritis, reactive arthritis, undifferentiated spondyloarthropathy), but may be isolated without arthritic symptomatology. The frequency of the uveitis is variable, depending on the duration of the disease and the type of spondyloarthritis, rising to 30% of patients [12]. The prevalence of the uveitis is greater in the case of ankylosing spondylitis (20–30%), than in arthritis associated with inflammatory bowel disease (2–9%) or psoriatic arthritis (7–16%).

Among those with recurrent anterior uveitis, about half are associated with HLA-B27 or a spondyloarthropathy, and up to 60% in a recent study of 798 patients with at least 2 episodes of anterior uveitis [13]. Anterior uveitis is thus a frequent presenting condition of patients with the diagnosis of spondyloarthritis, while the rheumatologic complaints are more easily ignored by the patient. The uveitis occurs in a delayed fashion relative to the rheumatologic manifestations; Monnet et al. have reported a delay of 8 years on average. Recurrence is frequent, said to be alternating in laterality, although it appears that the first eye involved is more often affected and that the recurrences are spaced accordingly with the progression of the disease [14].

The typical clinical presentation of HLA-B27 positive uveitis is an acute unilateral uveitis of sudden onset, occurring most often in a young subject between 20 and 40 years, and non-granulomatous. It is sometimes difficult to differentiate this uveitis from endogenous endophthalmitis when the fundus cannot be visualized. Posterior synechiae are frequent. It is common to observe a few cells in the anterior vitreous, or more rarely a true diffuse vitritis. The most frequent complications are posterior synechiae, cataract, glaucoma and development of chronic uveitis. Macular edema is a complication in 10 to 30% of patients [15]. A recent study showed that secondary glaucoma was the most frequent cause of irreversible loss of visual acuity in this type of uveitis [16]. Each episode lasts between 4 and 6 weeks, typically with complete remission between episodes.

Anterior uveitis associated with herpes viruses

Herpes viruses are enveloped DNA viruses, which are able to persist in a latent state within the host after the primary infection. Reactivations and primary infections may be symptomatic. Herpes simplex virus (HSV) uveitis is classically unilateral, recurring, granulomatous or non-granulomatous and most often associated with ocular hypertension. A slight hyphema is sometimes present. It causes relatively few synechiae. The iris examination is very suggestive in the case of associated sectoral iris atrophy. Anterior segment manifestations associated with the HSV virus and varicella-zoster virus (VZV) have been previously described (further reading). We will discuss here anterior uveitis suspected to be associated with cytomegalovirus (CMV).

CMV anterior uveitis occurs in the immunocompetent patient as opposed to CMV retinitis, which is reserved for the profoundly immunocompromised. The diagnosis can only be made by PCR analysis of the aqueous humor after ACP. The role of CMV in Posner–Schlossman syndrome was suggested the first time in 1987, by identification of local synthesis of anti-CMV antibodies in the aqueous humor by Bloch-Michel et al. [17]. In 2002, this hypothesis was confirmed by PCR in 2 patients [18]. Other teams have since been able to find CMV by PCR in immunocompetent patients with anterior uveitis and no other etiologies found [19, 20, 21].

CMV anterior uveitis manifests itself as a uveitis similar to the anterior uveitis of HSV and VZV; with brown inferior keratic precipitates, marked ocular hypertension and marked iris atrophy, associated or not with endotheliitis, but refractory to typical medical treatment [22]; or as the clinical picture of Posner–Schlossman syndrome. Also note that the CMV genome has been isolated in cases of uveitis identified as Fuchs heterochromic iridocyclitis [23].

Posner–Schlossman syndrome (PSS)

This is a unilateral uveitis typically affecting men aged 20–50 years. Patients typically present for blurred vision related to corneal edema due to a very significant elevation of the intraocular pressure to between 40 and 60mmHg. The anterior chamber reaction is minimal and a few central gray keratic precipitates are visible. The attacks may lead to severe glaucomatous involvement, although this syndrome has long been considered benign and self-limited [24]. In PSS, it now appears useful to screen for the CMV viral genome in the aqueous humor. Studies of the largest numbers of patients appear to indicate that CMV is found in approximately half of cases of PSS [23, 25]. Visual field analysis appears useful for evaluating optic nerve function, which may be increasingly affected by the repeated attacks. Note that it appears that CMV positive PSS has a poorer prognosis than CMV negative cases. In these cases, it has been shown recently that endothelial cell loss was more severe and filtering surgery was more frequently required [25]. In CMV positive PSS, specific local or systemic treatment may be instituted. Classic anti-herpetic drugs such as acyclovir and valacyclovir are ineffective. Thus, intravenous ganciclovir or more frequently its prodrug valganciclovir, available orally, must be utilized. There is no established protocol for the management of these uveitides. The use of 2% ganciclovir eye drops appears effective for treatment induction and maintenance to limit recurrence [25]. Topical therapy has the advantage of avoiding the toxicity (notably hematologic) of ganciclovir and valganciclovir. In France, 0.15% ganciclovir gel is available; it might also have a certain efficacy in combination with topical steroid therapy [26]. In CMV negative forms, treatment rests on a short course of topical steroids and topical glaucoma medications. However, its recurrent nature requires repeating the search for a viral cause, which may be identified after several attempts.

Fuchs heterochromic iridocyclitis (FHI)

This is a chronic anterior uveitis of insidious onset. It most often affects young subjects and is most often unilateral, although 15% of cases are actually bilateral [27]. Typically, considered benign, the management of the secondary glaucoma may in reality be very complex and it must not lead to a maladapted use of steroids, which may bring about their own complications. Typically, FHI does not cause the usual symptoms of anterior uveitis, with redness and pain absent. The anterior segment inflammation is characterized by a moderate Tyndall effect and fine white stellate keratic precipitates distributed fairly characteristically over the entire corneal endothelium. The other type of uveitis, which may result in diffuse keratic precipitates, is herpetic or zoster uveitis. A vitritis with large floaters, leading the patient to seek consultation, is very frequent. However, the subtlety of the various clinical signs may delay the diagnosis of FHI until the time when a visually incapacitating cataract appears. The heterochromia is seen on examination of both irides in bright ambient light prior to dilation. It represents progressive diffuse atrophy of the iris stroma. It is generally the lighter colored eye that is affected by the inflammation, except for very light blue eyes, for which the appearance of the iris pigment epithelium on the posterior surface of the iris may make the iris appear darker than is really is. In the bilateral case, heterochromia is difficult to identify. In this case, certain clinical signs of iris atrophy may help, such as diffuse and discrete zones of iris transillumination or a smoother appearance of the iris stroma with less marked relief. The iris vessels become more apparent. The fragility of the vessel walls may probably provoke the classic hyphema upon anterior chamber paracentesis, or Amsler's sign [28]. Importantly and relatively pathognomonically, posterior synechiae and ciliary flush are absent, as well as macular edema in the unoperated cataract patient, despite the chronic inflammation. Iris nodules are relatively frequent in over 30% of cases [29].

Long-term use of anti-inflammatories in ineffective and sometimes harmful in FHI. Management rests on screening for and treating cataract, ocular hypertension and glaucoma. The secondary glaucoma may become rapidly refractory to medical treatment. Glaucomatous involvement is present in 15 to 59% of cases [30]. The prognosis is usually good, with visual acuity of 5/10 or greater after cataract surgery [31, 32]. In the postoperative period, posterior synechiae may form, as well as intraocular lens deposits. Thus, use of high-frequency steroids would appear useful during this period to prevent these complications.

While FHI is felt to be idiopathic, there are now some reasons to associate it with rubella. The presence of ocular rubella infection has been identified by measuring the Goldmann–Witmer coefficient in several studies [33, 34, 35]. In addition, its incidence seems to be less since the widespread rubella vaccination compared to an older or foreign population [36]. Although the diagnosis is clinical, a work-up for other etiologies as well as ACP for molecular analysis of the aqueous humor may be considered. One particular form is FHI associated with ocular toxoplasmosis, for which a scar or active focus must be systematically sought [37].

Sarcoid anterior uveitis

Sarcoid uveitis is usually bilateral. Anterior uveitis is the most frequent presentation, in 41 to 75% of cases. It is chronic and granulomatous or not [38]. The diagnosis of sarcoidosis is histologic, but this confirmed diagnosis is difficult to obtain. In 2009, diagnostic criteria for ocular sarcoidosis were published to define on clinical, laboratory and radiologic criteria, the diagnosis of certain, presumed, probable or possible ocular sarcoidosis [39].

Anterior uveitis associated with Behçet's disease

Uveitis is one of the diagnostic criteria for Behçet's disease. The anterior uveitis is rarely isolated, but the posterior segment involvement may be absent or in the initial stage. The clinical picture is most often stormy, progressing episodically. The involvement is non-granulomatous, accompanied rather frequently by a hypopyon. This anterior involvement rarely affects the prognosis.

Anterior uveitis associated with multiple sclerosis

The prevalence of uveitis is patients with multiple sclerosis is about 1% and the prevalence of multiple sclerosis is cases of uveitis is also about 1%, based on large studies. Although intermediate uveitis is the most frequent, the occurrence of anterior uveitis is possible, between 14.3 and 28.6% [40]. Granulomatous uveitis appears to be the most frequent [41].

Uveitis and medications

Immunotherapies used in the management of metastatic cutaneous melanoma are responsible for intraocular inflammatory side effects. Anterior uveitis has been reported with BRAF inhibitors, notably vemurafenib [42], and with ipilimumab, which is designed to stimulate the existing T-cell immune response [43]. Whether anti-TNFα may cause de novo occurrences of uveitis remains debated. Lim et al. report, however, 26 cases of uveitis possibly associated with the use of anti-TNFα for whom no existing disease predisposing to uveitis was known [44]. However, side effects paradoxically causing uveitis are possible, such as the development of sarcoidosis.

More classically, biphosphonates (treatment for the prevention of osteoporosis, treatment of bone metastases) and rifabutin (treatment for atypical mycobacteria) may engender anterior uveitis complicated or not by a hypopyon. Treatment of the anterior uveitis rests on local steroids. Discontinuation of the causative medication is to be weighed against its benefits. Brimonidine may also provoke a picture masquerading as granulomatous anterior uveitis, paradoxically associated with ocular hypertension, after at least 12 months of instillation. This uveitis may be associated with allergic conjunctivitis, which appears to precede the uveitis [45]. Moxifloxacin has also been incriminated in the occurrence of pseudo-uveitis in association with pigment dispersion and diffuse iris atrophy [46].

Anterior uveitis in children

Uveitis in children represents 5 to 10% of all intraocular inflammation. The majority of pediatric uveitis is bilateral and non-infectious [47]. All the etiologies of adult anterior uveitis may affect children, but JIA associated uveitis is the most frequent and is specific to an onset in childhood. The subgroups of JIA complicated by uveitis are essentially the pauciarticular forms with positive antinuclear antibodies. The frequency of JIA associated uveitis is estimated between 4 and 38% [48]. This uveitis has the particularity of being asymptomatic with a white eye and non-painful until complications arise. Typically, it is a chronic anterior uveitis, granulomatous or not, and bilateral. In about 5% of cases, the uveitis precedes the onset of the arthritis.

Differential diagnosis: masquerade syndromes

Certain non-inflammatory pathologies may mimic a large number of diagnostic elements of anterior uveitis and divert the etiologic diagnosis toward uveitis when there is not any. Thus, when faced with an anterior uveitis resistant to the usual treatment, one must re-evaluate the diagnosis before escalating therapy [49].

Primary infiltration of the anterior segment (extension of a retinoblastoma or vitreoretinal lymphoma into the anterior segment) or secondary infiltration (metastases from leukemia, systemic lymphoma, solid tumor) may give the appearance of anterior uveitis. Thus, acute lymphoblastic leukemia is the primary cause of hypopyon in children [50].

Chronic ocular ischemic syndrome of atheromatous or arteritic origin is secondary to chronic hypoperfusion of the globe due to involvement of the carotid arterial system. It may present a clinical picture similar to anterior uveitis by breakdown of the blood-aqueous barrier, which may induce a Tyndall effect and more rarely keratic precipitates. However, there is frequently rubeosis iridis with little or no elevation of the intraocular pressure, due to ciliary body ischemia. The anterior segment signs may be isolated; however, posterior segment involvement is most frequent and leads to diagnosis most often due to tortuous arteries, cotton-wool spots and blot hemorrhages in the mid-periphery. Carotid Dopplers are necessary and fluorescein angiography aids in the diagnosis [51].

Pigmentary glaucoma is frequently mistaken for refractory anterior uveitis. The diagnosis is clinical, emphasizing the pigmented nature of the Tyndall effect, the presence of a Krukenberg spindle (vertical pigmented keratic precipitates), as well as engorgement of the anterior chamber angle with pigment on gonioscopy.

Iridocorneal-endothelial or ICE syndromes have no recognized etiology (Figure 5). They may, due to the induced ocular hypertension, iris atrophy and unilaterality, mimic a herpetic uveitis. However, there is no anterior chamber inflammation nor keratic precipitates. Specular microscopic analysis with an inverted appearance of the endothelial mosaic confirms the diagnosis.



Figure 5


Figure 5. 

Differential diagnosis of anterior uveitis. Appearance of ICE syndrome, which may mimic herpetic uveitis (a); inverted appearance of the endothelial mosaic confirms the diagnosis on specular microscopy (b) compared to the healthy eye (c).

Zoom

Neovascular glaucoma and unrecognized intraocular foreign body are also causes of masquerade syndromes.

Therapeutic strategy

The treatment of anterior uveitis has as its primary goal the treatment of the acute inflammatory episode, which will then be adapted if the condition becomes chronic or if required to prevent recurrences.

In the case of non-infectious uveitis, after having eliminated a masquerade syndrome, especially in a child, the cornerstone of treatment rests on steroid eye drops. Only the inflammation associated with FHI should be untreated. The frequency of installation must at first be sustained and adapted according to the suspected etiology and the clinical severity. Initially, hourly instillation of dexamethasone drops is prescribed during the day; an antibiotic-steroid ointment may be added at bedtime in the acute phase, as well as mydriatic drops for pain relief and to break posterior synechiae. After 48hours, the frequency of instillation is reduced progressively over several weeks. In the case of severe or refractory inflammation, subconjunctival dexamethasone injections are used, typically for 3 to 5 consecutive days. Resorting to systemic steroids is exceptional. In the case of systemic involvement associated with anterior uveitis requiring systemic treatment, this most often results in resolution of the anterior uveitis. A therapeutic strategy for unilateral or bilateral non-infectious anterior uveitis is proposed (Figure 6) [52]. In the case of ocular hypertension, prostaglandins should be avoided even though their potential harm has not been demonstrated [53]. In the case of posterior segment complications, notably macular edema, peri or intraocular depot steroids may be utilized [54]. Patients with chronic anterior uveitis not requiring systemic steroids most often benefit from long-term reduced-dose steroid drops. The side effects of long-term topical steroid therapy must of course be kept in mind. More recently, therapeutic advances based on several biologic agents, notably anti-TNF α, allow better long-term control of uveitis. Recommendations published in 2014 advocate the use of infliximab or adalimumab for steroid sparing in cases of refractory chronic uveitis associated with spondyloarthropathies or HLA-B27 [55]. However, anti-TNF α agents do not have market approval for the management or prevention of anterior uveitis, as opposed to treatment of refractory intermediate or posterior uveitis, for which they are already approved in Europe [56]. Their use in the setting of uveitis takes place in France in collaboration with internists, and adult or pediatric rheumatologists.



Figure 6


Figure 6. 

Therapeutic management of non-infectious anterior uveitis adapted from LeHoang, P. The gold standard of noninfectious uveitis: corticosteroids. Dev Ophthalmol 2012.

Zoom

In children, uveitis, although less frequent than in adults, is responsible for significant morbidity with potentially blinding long-term complications, constituting a veritable therapeutic challenge. Regarding the management of JIA associated uveitis, systemic steroid treatment is limited due to its side effects, notably on growth. It may be necessary for short periods in cases of poor control of uveitis by local treatment while waiting for the effect of other drugs. Regarding local steroid therapy, it is estimated that a threshold of steroid dependence over 3 drops per day of dexamethasone is detrimental. Above this dose, the risk of cataract over a mean period of 4 years is clearly elevated [57]. Thus, it is preferable to begin systemic immunosuppressive therapy, not necessarily with systemic steroid therapy. As first-line therapy, methotrexate is used. Its efficacy in the treatment of JIA is well known. Approximately 75% of patients may achieve improvement in the intraocular inflammation on methotrexate [58]. Anti-TNFα agents, infliximab (Remicade®) and adalimumab (Humira®) have revolutionized the management of severe pediatric uveitis [59, 60]. However, etanercept (Enbrel®) is effective in the control of the arthritis, without, however, appearing to be effective for uveitis [61].

In cases of infectious uveitis, systemic treatment adapted to the identified etiology is combined with local steroid treatment. Multidisciplinary management is necessary in cases of bacterial uveitis, especially since there is no defined therapeutic protocol, particularly in the case of tuberculous uveitis, which most often remains a presumptive diagnosis, and because of the possible side effects of certain drugs used. A therapeutic strategy is proposed in Table 2 [62, 63, 64, 65].

The value of anti-TNFα, particularly infliximab and adalimumab, in the prevention of HLA-B27 positive uveitis has been demonstrated [66].

Complications

Each episode of anterior uveitis or development of chronic uveitis sets the stage for potentially blinding complications. Posterior segment complications are possible, notably the occurrence of optic disc or macular edema. The occurrence of chronic ocular hypertension and then secondary glaucoma is a major complication of anterior uveitis. Cataract, encouraged by local or systemic steroid treatment, frequently complicates anterior uveitis due to the chronicity of the inflammation and the presence of posterior synechiae. It is most often a posterior subcapsular cataract. Its surgical management requires certain precautions so as to avoid rebound inflammation extremely deleterious to the visual prognosis.

Conclusion

Anterior uveitis is the most frequent and has multiple causes. The key step in etiologic diagnosis is the clinical characterization of the anterior uveitis, notably its characterization as granulomatous or not. Progress in molecular biology has allowed identification of certain viruses at the origin of uveitides, which were thought to be idiopathic. Biologic therapies, after multidisciplinary conferences, have greatly changed the management and prevention of certain uveitides, notably severe HLA-B27 positive uveitis, but have above all revolutionized the management of JIA associated pediatric uveitis [67].

Disclosure of interest

J.G.: consultant or clinical investigator or speaker for AbbVie, UCB, Allergan, Théa laboratories.

M.M.: consultant or clinical investigator or speaker for Théa, Horus, Dompé, Alcon laboratories.


Appendix A. Supplementary data

(184 Ko)
  
(191 Ko)
  

 See this article unabridged, illustrated and detailed, with electronic enhancements in EMC-Ophtalmologie: Gueudry J. Uvéites antérieures. EMC – Ophtalmologie 2017:1–13 [Article 21-220-A-40].

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Gueudry J. Uvéites antérieures EMC - Ophtalmol 2017 ; 1-13[Article 21-220-A-40].

Further reading

See this article, unabridged, illustrated and detailed, with electronic enhancements, in EMC-Ophtalmologie: Gueudry J. Uvéites antérieures. EMC - Ophtalmologie 2017:1-13 [Article 21-220-A-40].

Labetoulle M, Rousseau A, Bourcier T. Atteintes herpétiques du segment antérieur de l’œil : aspects épidémiologiques, cliniques et diagnostiques. EMC–Ophtalmologie 2014;11(1):1–10 [Article 21-200-D-20].

Labetoulle M, Rousseau A, Bourcier T. Atteintes herpétiques du segment antérieur de l’œil : aspects thérapeutiques. EMC–Ophtalmologie 2014;11(1):1–8 [Article 21-200-D-21].



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