Intermediate uveitis (IU) is a chronic intraocular inflammatory disorder in which the vitreous, pars plana, and peripheral retina represent the major sites of inflammation.1 Intermediate uveitis was first described in the literature as chronic cyclitis by Fuchs2 in 1908. Different terms have been used to describe this disease.3 With the development of the binocular indirect ophthalmoscope, Brockhurst et al4 described changes in the pars plana and the peripheral retina. The disease was named peripheral uveitis. Welch et al5 used the term pars planitis to describe a subset of these patients who developed cellular exudation or membrane formation over the inferior pars plana.
In 1987, the International Uveitis Study Group6 adopted the term intermediate uveitis to classify patients who developed intraocular inflammation involving predominantly the vitreous and peripheral retina. Intermediate uveitis includes diseases of various causes and different clinical manifestations. Pars planitis is considered a subset of IU and is characterized by the presence of white exudates (snowbanks) over the pars plana and ora serrata or by aggregates of inflammatory cells in the vitreous (snowballs) in the absence of an infectious etiology or a systemic disease.1
The management of IU is tailored individually, based on specific causes of the disease and associated complications. Patients with mild disease are typically observed. Medical and surgical treatments are available for patients with more severe disease. The treatment options of IU are evolving, with the development of various immunosuppressants and biological agents.
Literature selection for this review was based on the PubMed database (National Library of Medicine) and OVID database (Wolters Kluwer). Articles published any date up to December 2012 were included. The search was limited to articles of the English language as well as foreign-language publications with English-language abstracts. Key words were used in single and combination including uveitis, IU, pars planitis, chronic cyclitis, vitritis, immunosuppressant, steroid, and surgery. All retrieved articles were cross-referenced, and citations in the bibliography were retrieved if deemed relevant. Articles displayed in the “related articles” link on PubMed were also utilized when relevant.
Intermediate uveitis was reported to account for 1.4% to 25% of all uveitis cases7–11 and around 10% to 20% of uveitis cases in children.12–14 It is the second most common form of uveitis in childhood.15 Intermediate uveitis was found in 3% to 17% of uveitis cases in Asia Pacific region.16–18 The exact prevalence is difficult to determine, because the clinical course can be indolent and patients are often asymptomatic.19 Although IU affects patients in all age groups, it is most commonly seen in the first 3 decades of life.8,20 Bilateral involvement is seen in 70% to 90% of cases.21,22 Intermediate uveitis does not show definitive predilection for gender or race.3
Symptoms and Signs
The most common presenting symptoms are blurry vision and floaters (Table 1).23 Sometimes, patients with IU may be asymptomatic.24 Pain and photophobia are not common. The symptoms are usually gradual in onset.23,25 The disease is bilateral in around 70% to 90% of cases. Approximately one third of unilateral cases will eventually become bilateral.26
Anterior chamber cells or flare are usually mild.25 However, children may occasionally present with more severe anterior segment inflammation.27 Occasionally, patients with multiple sclerosis (MS) develop granulomatous anterior uveitis with characteristic mutton keratic precipitates. The hallmark of IU is the presence of cellular aggregates in the vitreous.24 Aggregates of inflammatory cells may appear in the lower vitreous and are referred to as “snowballs” (Fig. 1). Grayish yellow exudation, called “snowbank,” is found along the inferior ora serrate (Fig. 2). In severe cases, this exudation may encircle the entire retinal periphery. The presence of a snowbank has been reported to be associated with more severe disease and increased incidence of cystoid macular edema (CME).28 Optic disc swelling can also be found (Fig. 3). Retinal changes in IU include tortuosity in arterioles and venules, sheathing of peripheral veins, neovascularizations, and retinal detachments.29,30
Intermediate uveitis is most often a benign form of uveitis. Complications are usually related to the chronicity of IU and if left untreated can lead to blindness (Table 2). Intermediate uveitis is frequently associated with peripheral retinal phlebitis and is characterized by a high prevalence of CME (Fig. 4). Incidence of CME varies from 12% to 51%.24,31 The incidence of macular edema increases with the duration and severity of the disease.3,32 Macular edema with cystoid changes and retinal thickening due to IU is associated with impaired visual acuity and visual field changes.33 Other less common causes of visual loss include cataracts, uveitic glaucoma and vitreous hemorrhage, epiretinal membrane and choroidal neovascularization, retinal detachment, and band keratopathy.23,25,34
Intermediate Uveitis in Children
Pediatric IU has several features different from adult-onset cases. Children tend to have worse visual acuity, higher risk of vitreous hemorrhage, higher incidence of anterior segment inflammation, and risk of amblyopia.35,36 Children presenting with IU have worse visual acuity at both initial diagnosis and follow-up than do adult patients. The reasons for this are not clear. Childhood IU may be a more aggressive disease process resulting in a worse prognosis.35 Besides, the relative inability of children to express their symptoms may lead to a delay in diagnosis and therefore more advanced disease at presentation.
Children with IU experience a higher rate of vitreous hemorrhage. In a study by Lauer and coworkers,37 28% of children with pars planitis had vitreous hemorrhage, compared with 6% of adult patients. Besides, children with IU are more likely to experience anterior segment inflammation.38 Some may present only with anterior uveitis and develop features of IU later in the course of disease. In contrast, most adults with IU have minimal anterior segment inflammation. Furthermore, there is a potential for amblyopia when IU or its complications occur during childhood.27 As treatment of IU alone may not be sufficient to restore vision, amblyopia therapy should be begun in a timely manner.
The understanding of the pathogenesis of IU is still limited. A genetic predisposition and involvement of autoimmune processes have been suggested.39,40 Several familial cases have been reported.41–43 The presence of human leukocyte antigen DR15 (HLA-DR15; a subtype of HLA-DR2, which is also associated with MS) and HLA-A28 has been demonstrated in patients with IU.44,45 Other associations include HLA-B8 and HLA-B51.46 Human leukocyte antigen association identifies individuals at risk, but it is not a diagnostic marker.47
Although the exact cause of IU is unknown, several conditions are associated with the syndrome, including MS,48 idiopathic optic neuritis,49 autoimmune corneal endotheliopathy,50 sarcoidosis,49 thyroid diseases, inflammatory bowel diseases,49 and large cell lymphoma.51 These associations suggest that an autoimmune process plays a role in pathogenesis. Intermediate uveitis may be the first expression of autoimmune diseases in these patients. Furthermore, IU has been associated with a number of infectious agents including Borrelia burgdorferi (Lyme disease), Toxocara canis (toxocariasis), syphilis,52 tuberculosis,53 Whipple bacilli (Whipple disease), Epstein-Barr virus, human T-cell lymphotrophic virus type 1, and HIV.25 Antecedent or subclinical infection has been suggested to initiate disease through the process of molecular mimicry.54 T-helper lymphocytes in conjunction with HLAs are likely to be involved in the development of uveitis.55
In pathologic specimens of IU, a prominent perivascular lymphocytic cuffing (perivasculitis) and wall infiltration of the retinal vessels (vasculitis), primarily involving the venous system (phlebitis), have been observed. The uveal tract is typically devoid of inflammation.54,56.
Histologic studies of the peripheral retina and ciliary body demonstrate condensed vitreous, fibroblasts, spindle cells, hyperplastic nonpigmented pars plana epithelium, lymphocytes, and blood vessels.56,57 Peripheral snowbanks are composed mainly of glial elements, Müller cells, and organized collagen and may be associated with new vessels.58,59 Vitreous biopsy at the time of active disease demonstrates lymphocytes, epithelioid cells, macrophages, and giant cells. Vitreous lymphocytes are mostly T cells with variable numbers of macrophages and few B cells.57,60 A preponderance of CD4+ T lymphocytes has been found in the pars plana and snowbank, and these outnumber CD8+ T lymphocytes by 10:1. CD4+ T cells expressing the activation marker CD69 in either peripheral blood or the aqueous humor of patients with idiopathic uveitis support the hypothesis that T-helper cells are involved in inducing and sustaining the inflammatory process.61 Increased frequency of effector-memory CD57+ T cells was also shown to be associated with pars planitis.62
Circulating T lymphocytes, which recognize several retinal antigens, have been identified but are not specific to IU.63 Patients with MS, with or without IU, may have increased circulating T lymphocytes, particularly CD54+64 and antibodies that recognize a series of glial proteins. Significantly elevated concentrations of multiple intraocular cytokines were found in IU patients, especially interleukin 6 (IL-6) and IL-8 in those with CME and active disease.65,66 Serum IL-1 receptors, which down-regulate the immune response, become elevated with successful treatment.67 Elevated serum levels of tumor necrosis factor α (TNF-α), independent of the presence of associated systemic disease, were found in IU patients, but the serum TNF-α level would decrease under immunosuppressive treatment. However, intraocular TNF-α levels of IU patients were not increased, and the levels of diverse cytokines and chemokines in their intraocular fluids did not correlate with their serum levels.66 The identification of proinflammatory molecules involved in the IU could contribute to the development and implementation of new therapies.
The polymorphism of interferon γ and IL-10 genes were shown to be associated with a worse visual acuity at 5 years from presentation of IU.68 Complement factor H-rs800292 and KIAA1109-rs4505848 genes are associated with noninfectious intermediate and posterior uveitis. Besides, gender susceptibility for uveitis might be involved in the KIAA1109 gene.69 It demonstrated that outcome in IU may be partly determined by a complex interplay among genes of cytokine and complement system. This observation may have implications for future treatment with biological agents that target these cytokines or complement systems.
A significant proportion of patients with IU maintain a good visual function.32,70 Malinowski et al34 found that long-term visual acuity (20/44) in patients followed up for an average of 90 months was not statistically different from the presenting visual acuity (20/46). Rothova et al71 found that 72% of patients with IU did not experience visual impairment. The most common cause of visual loss in these patients is CME.38 In addition, formation of epiretinal membrane, cataract, macular ischemia, detachment of the macula, and vitreous hemorrhage from retinal neovascularization are other causes of visual loss.24
A number of schemes have been used to classify IU,4,72,73 but none can predict the overall prognosis of the disease accurately. The disease is typically chronically active or follows a course of intermittent exacerbation punctuated by periods of quiescence.38 A permanent resolution of the disease is uncommon.24,38 The SUN Working Group has defined remission as inactive disease at least 3 months after discontinuing all treatment.1 In a retrospective cohort study of 29 IU patients with follow-up of at least 10 years,38 one third them achieved a remission of their intraocular inflammation for longer than 1 year and had a mean time to remission of 8.6 years. When properly treated, around two thirds of IU patients can maintain a visual acuity of 20/40 or better.24,70
In the pediatric group, the majority of IU was bilateral and chronic74,75 and it is associated with a worse presenting visual acuity.36 Poorer outcomes may be related to delayed presentation/diagnosis, the inherent difficulties of immunosuppression in children, or a more aggressive disease.35 A remission of disease for at least 1 year could be found in 47% of pediatric patients.74 A case series of 35 patients suggested that children diagnosed before age 7 years have poorer visual outcomes than those who are diagnosed at an older age.35 Patients who were younger at onset of IU were less likely to achieve remission than those who were older at onset.
The diagnostic approach to IU should center on the history and clinical examination. Approximately two thirds of patients would have idiopathic IU.11 Since IU has been described in association with several systemic disorders, the initial diagnostic evaluation should serve to exclude masquerade syndromes and infectious diseases in which immunosuppression may be ineffective or contraindicated. There is no specific laboratory test for diagnosis of IU. Investigations are performed to rule out underlying causes of vitreous inflammation, to evaluate extent of inflammation, to define the cause of decreased vision, and to guide treatment (Table 1).
The patient’s history should concentrate on the duration of symptoms, the number of recurrences, and findings that might be associated with systemic disorders. Fever, fatigue, or night sweats are typical signs of sarcoidosis and tuberculosis. Paresthesias of the hands, arms, or legs raise the suspicion of MS. Signs of dermatitis may point to Lyme disease, syphilis, or tuberculosis. Arthritis of the knee may be related to Lyme disease, and contact with cats may suggest possibility of Bartonella infection.
The initial laboratory investigation may include complete blood count with differential, erythrocyte sedimentation rate, venereal disease research laboratory, and fluorescent treponemal antibody absorption test. Serum and urinary calcium as well as serum angiotensin-converting enzyme can be checked if sarcoidosis is suspected. Chest radiography is used to look for tuberculosis and sarcoidosis. The laboratory workup can be expanded, depending on the clinical history and physical findings.
Patients from endemic areas for Lyme disease with a history of a rash typical of erythema migrans, chronic arthritis, or cranial nerve palsies should be checked for antibodies to B. burgdorferi (Lyme disease). If patients develop neurologic symptoms or have a history of optic neuritis, a magnetic resonance imaging of the brain and subsequent consultation with a neurologist should be considered to rule out MS. A computed tomography of the chest or a gallium scan can be considered when there is a high clinical suspicion of sarcoidosis. Consultation with a gastroenterologist may be required in patients with symptoms suggestive of inflammatory bowel disease or Whipple disease. Older patients presenting with vitreous cells should raise the suspicion for intraocular lymphoma. Diagnostic vitrectomy, cytological evaluation of cerebrospinal fluid, and neuroimaging may be necessary.
Fluorescein angiography is useful in documenting macular (Fig. 5) and disc edema, retinal vasculitis, ischemia, and neovascularization. Characteristic fluorescein angiography findings include large vein staining, peripheral venous leakage, and optic disc hyperfluorescence76 (Fig. 6).
Optical coherence tomography (OCT) is a noninvasive technique that provides detailed information about macular edema (Fig. 7), subretinal and epiretinal membranes, and macular hole,77 even in the presence of moderate vitreous opacities or small pupils. Sequential OCT scans are also useful on follow-up.
Ultrasonography can be useful when there are media opacities that prevent visualization of the retina, including vitreous hemorrhage, inflammatory debris, cyclitic membrane, or cataract. It helps to determine degree of vitreous involvement and retinal anatomic status such as tractional or rhegmatogenous retinal detachment. Ultrasound biomicroscopy is indicated in cases when posterior synechiae, cataract, or vitreous opacities do not allow a good exploration of pars plana and peripheral retina.
In a retrospective cohort of 51 patients with IU, 8 cases were found to have new associated diagnoses after at least 5 years of follow-up.78 Therefore, initial workup of the patient with IU is not sufficiently sensitive. A careful follow-up of these patients considerably improves the diagnosis of associated disease.
Management Approach of Intermediate Uveitis
Intermediate uveitis due to infectious or systemic causes should be treated for the underlying illnesses. A significant proportion of patients with IU maintain a good visual function.32,70 Rothova et al71 found that 72% of patients with IU did not experience visual impairment.
Therefore, not all cases of IU require treatment. Kaplan’s79 algorithm is the most popular treatment strategy for IU. The indications of treatment include (1) visual acuity worse than 20/40, (2) cystoid macula edema, (3) secondary retinal vasculitis or neovascularization, and (4) patients bothered by visual floaters (Fig. 8). Smoking cessation should be strongly encouraged as Thorne et al22 found a 4-fold increased risk of uveitic CME in smokers with IU. Intermediate uveitis patients should be followed up every 1 to 4 weeks during the active phase of the disease, more frequently if cystoid macula edema or severe inflammation is present. Because IU is a long-term and recurrent disease, patients should be educated to recognize symptoms of a flare-up (eg, floaters, blurred vision, eye redness, discomfort) and seek medical advice appropriately.
Although the number of prospective studies in the treatment of noninfectious uveitis has increased in recent years, the vast majority of published studies in IU are case series or nonrandomized trials. There remains a lack of level 1 evidence to guide the choice and duration of therapy.80 Nevertheless, corticosteroids remain the mainstay of therapy,3,81 based on their established advantages over alternative approaches that was affirmed by an expert panel review conducted in 2000.82 Choice of treatment modalities can be determined by the severity of inflammation, response to treatment, presence of complications, and bilateral involvement of the disease (Table 3).
Anterior segment inflammation can be managed with topical corticosteroid (prednisolone acetate 1% or prednisolone sodium phosphate 1%). Because of limited intraocular penetration, topical corticosteroids are useful only to control anterior segment inflammation.83 In patients with unilateral or asymmetric bilateral disease or in whom systemic administration of corticosteroid is less desirable, for example, during pregnancy or in patients with a history of gastric ulceration,25,84 periocular injections of corticosteroids are preferentially given. Depot preparation of either a long-acting methylprednisolone (40 mg) or triamcinolone acetonide (20 mg) can be administered superotemporally into the sub-Tenon space or through the inferior eyelid into the retroseptal space. The precise mechanisms by which locally injected corticosteroids enter the eye are not known,85 but systemic drug levels remain low, and corticosteroids can be found in all layers of the eye, even at 30 days after a single sub-Tenon injection of triamcinolone acetate.86 Helm and Holland87 showed that 67% of patients experienced improvement in Snellen visual acuity, improving by at least 2 lines. Adverse effects are similar to topical corticosteroids, with approximately 30% of patients having a rise in intraocular pressure as well as cataract and very rarely inadvertent ocular penetration. The median time to improvement was 3 weeks.87 If the disease is not controlled after 2 to 3 injections given over an 8-week period, systemic prednisone can be considered.88
Systemic corticosteroids are generally advocated for IU that is bilateral, resistant to periocular steroids, or associated with systemic disease.25,84 Before starting systemic corticosteroids, screening for tuberculosis and viral hepatitis should be performed to prevent flare-up of these diseases during the treatment. Oral prednisolone is started at 1 mg/kg per day. Adverse effects of oral corticosteroids include gastric ulcers, weight gain, psychological disturbances, osteoporosis, diabetes, hypertension, and suppression of growth in children.84 A histamine H2 receptor antagonist or a proton pump inhibitor can be prescribed adjunctively to help prevent peptic ulcer. Patients should have intraocular pressure monitored to look for any steroid responsive glaucoma. Oral prednisolone can be tapered according to disease activity when the inflammation stabilizes. The aim is for good control of inflammation at a dose of 7.5 mg or less, and if this cannot be achieved, the use of an adjunct second-line agent should be considered.84 Tapering can be initiated as soon as 2 weeks after treatment was started, according to the clinical response of the patient. The minimal effective dose controlling the inflammation should be maintained for at least 4 months.88
To manage CME not responsive to sub-Tenon or systemic corticosteroid, intravitreal triamcinolone acetonide injections have been used. The dose most commonly used is 4 mg, and the typical duration of the effect is 4 to 5 months, with the maximum effect on visual acuity occurring at 1 to 6 months after injection.89 Kok et al90 studied the outcome of intravitreal triamcinolone (4 mg/0.1 mL) in 65 cases of uveitis-related CME inadequately responsive to treatment combinations of oral corticosteroids, periocular orbital floor corticosteroid injections, and second-line immunosuppressive agents. They reported a mean improvement of visual acuity of logMAR (logarithm of the minimum angle of resolution) 0.26, after a mean period of 4 weeks.90 The improvement in visual acuity was more significant if the duration of CME before intravitreal triamcinolone was less than 12 months and if patients were younger than 60 years. Forty-three percent experienced an intraocular pressure increase of greater than 10 mm Hg. The dosage of oral corticosteroids and/or second-line immunosuppressive medication was reduced or stopped altogether in 55% cases. In a case series by Hogewind et al,91 of 33 eyes with intermediate or posterior uveitis and refractory CME, 50% improved greater than 2 lines at 3 months after intravitreal injection of 10 mg triamcinolone acetonide. On the other hand, Sallam et al92 reported a mean improvement of visual acuity of logMAR 0.6 a mean of 3 weeks after intravitreal injection of triamcinolone, in 8 cases of childhood CME from IU. Resolution of CME was achieved in all of the treated eyes, but 3 cases (38%) had recurrent CME after a median period of 7 months.92
Several small case series have explored the use of intramuscular somatostatin analogs (octreotide) and intravitreal bevacizumab (Avastin) in patients with refractory uveitic CME.93,94 Missotten et al95 studied 20 patients with recurrent CME during otherwise quiescent uveitis. Intramuscular octreotide reduced CME in 70% of cases, after a mean of 3 months of treatment. In 36% of successfully treated episodes, CME was absent for more than 1 year. In a recent randomized trial comparing the effects of intravitreal injections of bevacizumab and triamcinolone acetonide for the treatment of persistent macular edema in noninfectious uveitis, improvement in visual acuity at 6 months was achieved in 96% of eyes in triamcinolone group and in 83% eyes in bevacizumab group. Although there was no significant difference in improvement of visual acuity, triamcinolone could achieve a greater reduction in central macular thickness.96 In a series of 7 patients with refractory uveitic macular edema, intravitreal ranibizumab (Lucentis) was also shown to reduce the central retinal thickness and improve the visual acuity at 3 and 6 months.97 For patients not suitable for intravitreal triamcinolone, these drugs provide an alternative to manage refractory CME.
For cases that require a high dose of systemic corticosteroids or frequent periocular injections to control flare-ups of the disease, the surgical implantation of a device releasing corticosteroid in the vitreous can be considered.98,99 Steroid implants offer the benefit of sustained corticosteroid delivery to the eye while avoiding systemic complications of other therapies.
The fluocinolone acetonide implant (Retisert; Baush and Lomb, Rochester, NY) was developed to deliver corticosteroids for up to 30 months and is currently approved in the United States as a 0.59-mg fluocinolone acetonic implant for chronic noninfectious posterior uveitis. In the Multicenter Uveitis Steroid Treatment Trial, the effect of fluocinolone acetonide implant was comparable to systemic anti-inflammatory therapy in controlling IU.100 The implant and systemic therapy groups had an improvement in visual acuity of 6.0 and 3.2 letters after 24 months’ follow-up. Over the 24-month period, implant-assigned eyes had a higher risk of cataract surgery (80%) and glaucoma (17%). On the other hand, patients assigned to systemic therapy had more prescription-requiring infections than patients assigned to implant therapy (0.60 vs 0.36/person-years). They concluded that the choice between fluocinolone acetonide implant and systemic therapy should be judged on the individual basis.
Besides, dexamethasone implant (DEX implant Ozurdex; Allergan, Inc, Irvine, Calif) has recently been studied for its benefit in IU. It has been shown to improve intraocular inflammation and visual acuity persisting for 6 months.99 The efficacy of Ozurdex for noninfectious intermediate or posterior uveitis was assessed in a 26-week, multicenter, double-masked, randomized clinical trial. Forty-seven percent of treated patients achieved a vitreous haze score of 0 (no inflammation) at 8 weeks, and 43% of treated patients achieved a 3-line improvement in best corrected vision. The most common ocular complications included intraocular pressure elevation (25%) and conjunctival hemorrhage (22%). Cataract occurred in 5% cases.
Corticosteroid-sparing agents are indicated when inflammation requires high-dose steroids for control of ocular inflammation for more than 1 month (>60 mg or <60 mg based on the weight of individual dose 1 mg/kg), chronic doses greater than 7.5 mg, or adverse effects requiring discontinuation of steroids.82 Patients are typically transitioned to steroid-sparing therapy, and the steroid is slowly tapered once the ocular inflammation is quiet. Standard initial treatment for steroid-resistant disease is to add a single immunosuppressant to the regimen, with additional agents being substituted or added as required. Combination of 2 immunosuppressants in addition to steroids may be indicated especially in chronic inflammation. There are several classes of agents including antimetabolites, T-cell inhibitors, alkylating agents, and biologic agents.
Methotrexate, azathioprine, and mycophenolate mofetil are the most commonly used agents with documented efficacy.80,81 They are antimetabolites interfering with the production of nucleotides required for DNA replication, hence inhibiting rapidly dividing cells including lymphocytes. Methotrexate has gained its popularity for its good record of safety and tolerability.81 The initial dose is 7.5 to 12.5 mg/wk. The maximum dose is 25 mg/wk. Samson et al101 reported a control rate of 89% in patients with IU. In the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study, 47% IU had complete suppression of inflammation sustained for 28 days or more within 6 months after addition of methotrexate to an anti-inflammatory regimen; 71.5% patients required 17.5 mg/wk or less. Corticosteroid-sparing success (sustained suppression of inflammation with prednisone 10 mg/d) was achieved in 41.3% of cases within 6 months.102 Methotrexate has also been used safely in children with IU.103 The dose of oral steroid could be decreased from a mean of 18 mg/d to 2.85 mg/d.
Azathioprine (initial dose, 1 mg/kg per day) and mycophenolate mofetil (initial dose, 500 mg twice a day) have a similar immunosuppressive effect on T and B lymphocytes, but mycophenolate mofetil may have a better adverse effect profile.104,105 Ninety percent of patients taking azathioprine could achieve complete control of inflammation sustained for at least 28 days, and 68% patients could obtain a corticosteroid-sparing benefit.106 On the other hand, 83% and 39% patients using mycophenolate mofetil could obtain control of inflammation and obtain steroid-sparing benefit, respectively, in 6 months.107 Adverse effects of this group of immunosuppressants include gastrointestinal upset, hepatotoxicity, nephrotoxicity, and myelosuppression.
Cyclosporine (initial dose, 2.5-5.0 mg/kg per day) and tacrolimus (initial dose, 0.15-0.30 mg/kg per day) both inhibit calcineurin-dependent transcription of IL-2 by activated T lymphocytes.108 Murphy et al109 prospectively evaluated the efficacy and the safety of cyclosporine and tacrolimus in patients with posterior and IU. Sixty-eight percent of patients taking tacrolimus and 67% of patients taking cyclosporine responded to treatment. The median durations of response to cyclosporine and tacrolimus were 7 and 6 months, respectively. Kacmaz et al108 also reported that 74% of IU patients using cyclosporine had controlled inflammation, with no activity or slight activity within 6 months of treatment. The 2 drugs showed a similar response rate, but cyclosporine was associated with a higher incidence of adverse effects, including headache, gingival hyperplasia, fatigue, and palpitations. The adverse effects of cyclosporine and tacrolimus include renal impairment, systemic hypertension, and metabolic abnormalities.
Alkylating agents (cyclophosphamide and chlorambucil) cause cross-linking of DNA, which prevents RNA transcription and DNA replication. Cyclophosphamide can be administered both orally (1–2 mg/kg daily) and intravenously (750–1000 mg/m2 body surface area every 3–4 weeks), whereas chlorambucil can be administered orally at 0.1 mg/kg per day.110,111 They profoundly suppress the function of both T and B cells, broadly inhibiting the immune system. Severe adverse effects include bone marrow suppression, infertility, teratogenicity, and increased risk of malignancy. In view of their potential toxicity, cyclophosphamide and chlorambucil are usually reserved for cases of uveitis resistant to other forms of second-line immunosuppression.80 For cyclophosphamide, a complete control of inflammation for at least 28 days was observed in 50% of patients with noninfectious uveitis, whereas 31% of patients obtained a steroid-sparing benefit.110 A response rate of 68% has been reported for treatment-resistant noninfectious uveitis treated with chlorambucil.112
Interferon β, which has an established value in the treatment of MS, appears to have a positive effect in terms of visual acuity, CME, and aqueous and vitreous inflammation in IU associated with MS. There has been a report of the use of interferon β in the treatment of IU related to MS. In this pilot study of 13 patients, aqueous and vitreous inflammation improved in 100% and CME improved in 82% of those affected.113 Seventy-one percent of cases obtained improved visual acuity. Interferon α has also been shown to be effective in controlling CME.114 Interferon α was also introduced to treat severe, sight-threatening refractory uveitis.115 Interferon α was shown to be effective to achieve complete resolution of CME within 3 months in 63% of noninfectious uveitis, including IU. Common adverse effects include flulike symptoms, fatigue, or increased liver enzymes.
During the last few years, there have been reports on the role of TNF-α and other interleukins in the pathogenesis of ocular inflammation.116 These have been used as targets for treating uveitis. Daclizumab (Zenapax; Hoffman-La Roche, Nutley, NJ), infliximab (Remicade; Centocor, Horsham, Pa), and adalimumab (Humira; Abbott, North Chicago, Ill) are the major biologic agents that have been used to treat uveitis.117
Daclizumab, a humanized IL-2 receptor–blocking antibody, is administered as 1 to 2 mg/kg infusions every 2 to 4 weeks. Subcutaneous administration is also used. Adverse effects include rash, edema, granulomatous reactions, viral respiratory infections, elevated liver enzymes, and leukopenia.118 In a multicenter nonrandomized interventional case series, it allowed control of ocular inflammation with stability in visual acuity with reduction of concomitant immunosuppression by at least 50% in 67% of patients with noninfectious IU, posterior uveitis, or panuveitis receiving subcutaneous daclizumab treatment.119 Yeh et al120 reported the use of high-dose daclizumab in 5 patients with noninfectious intermediate or posterior uveitis and demonstrated an improvement in vitreous haze in 4 of 5 patients by the fourth week of follow-up. It was well tolerated, but there might be a potential increased risk of infection associated with immunosuppression.120 Despite the success of daclizumab in treating uveitis, it was recently pulled from the market because of diminishing market demand and availability of alternative agents (based on a September 2009 Hoffmann-La Roche Inc drug announcement).
Tumor necrosis factor α inhibitors include infliximab and adalimumab, which are monoclonal antibodies against TNF-α. Infliximab (Remicade; Centocor Ortho Biotech, Malvern, Pa) is a 149-kd chimeric immunoglobulin G1 monoclonal antibody composed of human constant and murine variable regions. It is given intravenously. The use of infliximab has been shown to be effective in improving macular thickness and visual acuity in patients with uveitic refractory CME due to IU or other noninfectious uveitis.121 Markomichelakis et al122 and Rajaraman et al123 found that infliximab achieved reduction in intraocular inflammation with concurrent decrease in steroid requirements in both adult and pediatric populations. Adverse effects include development of an infusion reaction, opportunistic infections including latent tuberculosis, malignancies, lupus-like reactions, and elevations of autoantibodies and transaminases. Patients must be screened for hepatitis B and C as well as tuberculosis with chest radiography and tuberculin skin test.124
The experience with the use of adalimumab (a fully human monoclonal antibody) in the treatment of uveitis is limited, but the preliminary results show its promising role in the management of uveitis. Recently, a prospective case series on the efficacy on the use of adalimumab for the treatment of refractory uveitis was performed. A total of 131 patients, including 16 pars planitis patients, who are intolerant or failed to respond to prednisone and at least 1 other systemic immunosuppressive drug, were included. Diaz-Llopis et al125 showed that all patients had good response with adalimumab, as demonstrated by decrease in anterior chamber and vitreous cavity inflammation, overall gain in visual acuity, reduction of macular thickness, or decrease of the immunosuppression load after 6 months of treatment with 40-mg subcutaneous injections of adalimumab. Eighty-five percent of patients were able to reduce at least 50% of their baseline immunosuppression load.125 Long-term data on the effectiveness of adalimumab therapy in patients with noninfectious refractory uveitis, including IU, are warranted. Adalimumab has so far demonstrated some preliminary advantages over infliximab, including its subcutaneous route of administration, no need for hospitalization, being less immunogenic and less expensive, and having a more protracted therapeutic response in uveitis.126 However, adalimumab is substantially more expensive than many other immunosuppressive drugs, and it is suitable for only selected patients.
For IU patients who fail corticosteroid treatment or have contraindications to corticosteroids and immunomodulatory therapy, peripheral ablation with cryotherapy or indirect laser photocoagulation to the peripheral retina can be considered. Cryotherapy has been shown to be effective in treatment of IU.127 It may be used after periocular or systemic corticosteroid therapy failure and is often combined with a periocular steroid injection. Peribulbar anesthesia is required for this procedure. Destruction and elimination of the neovascularization and ischemic tissue seem to be the mechanism behind the success of this treatment.19 The effect is noted after several weeks but may need to be repeated after 3 to 6 months. Devenyi et al128 reported that 90% of steroid-resistant eyes can be managed without corticosteroid treatment after cryotherapy, and in 78% of cases, vitritis was eliminated. Patients with smaller snowbank may have better visual improvement.127 Complications included transient worsening of vitreous inflammation, decreased accommodative potential, cataract, hyphema, epiretinal membranes, and retinal detachment.25
A retrospective review of 22 eyes with pars planitis that had undergone peripheral retinal laser photocoagulation was conducted by Pulido et al.129 Although there was no significant improvement in visual acuity, laser photocoagulation could decrease need of corticosteroids in 60% cases. Moreover, vitritis, neovascularization of the vitreous base, and CME were significantly reduced after the laser treatment. An increase in epiretinal membranes had been reported after laser.129 Park et al130 also evaluated the use of peripheral scatter photocoagulation in 10 eyes with steroid-resistant pars planitis. All cases obtained the regression of neovascularization regressed, stabilized inflammation, and improvement in CME, without complications of the treatment.
Being compared with cryotherapy, laser photocoagulation is easier to administer and produces less pain and possibly fewer complications.
Since 1978, numerous authors, beginning with Diamond and Kaplan,134 have documented the beneficial effect of pars plana vitrectomy (PPV) on visual acuity in patients with intermediate uveitis. Reductions in clinically significant CME, uveitis relapses, and systemic therapy use were additional benefits.131–137
Retinal detachment, cataract, and recurrent vitreous hemorrhage are known complications. A review about the role of PPV in treatment of IU was conducted by Becker and Davis.131 In 282 cases of IU from 9 studies with a mean percentage of IU cases of more than 59%, PPV could achieve improvement of vision in a mean 66% of cases and could reduce the CME from a median 42.1% to 12.5%.131 Trittibach et al138 established the positive effects of PPV on the course and complications of pediatric and juvenile chronic uveitis. A significant reduction in postoperative CME and improvement in visual acuity were found after the PPV.138 Their findings revealed that a low preoperative visual acuity and the presence of CME had a negative influence on the final visual acuity. Early treatment of IU in children and adolescents has been recommended if regional corticosteroid treatment and cryoretinopexy fail to control disease; 22 of 25 patients had visual improvement, and 7 patients with chronic macular edema had complete regression after the vitrectomy.139 Quinones et al140 have recently conducted a prospective randomized study to compare the benefit of PPV with immunomodulatory therapy for patients with recalcitrant IU. They showed that 82% (9/11 eyes) of those treated with PPV showed resolution of inflammation at follow-up at 5.93 years, whereas 57% (4 of 7 eyes) had persistent inflammation requiring subsequent PPV. Three PPV patients had CME initially; all resolved postoperatively. Cystoid macular edema improved in 2 of 3 eyes using immunosuppressive therapy. Patients with PPV showed greater improvement in visual acuity, intraocular pressure, and vitreous cell reduction.
A large proportion of patients with IU develop cataract, either secondary to the disease process or corticosteroid treatment.38 Preoperative suppression of inflammation is important before cataract surgery.141 Phacoemulsification and intraocular lens implantation are safe in patients with IU.142 Ninety-one percent of patients could achieve visual improvement after the cataract surgery, but CME or reactivation of pars planitis was observed in around 50% of cases. Fogla et al143 studied 54 cases of cataract surgery in IU patients. Visual acuity improved following surgery in 94.2% of eyes, and 71.2% of eyes achieved a final visual acuity better than or equal to 20/60. They concluded that absolute control of inflammation, atraumatic surgery, and regular postoperative follow-up could improve the results of the cataract surgery.143
Future Research Areas
Although the pathogenesis of IU is not fully understood, identification of proinflammatory molecules involved in the IU has contributed to the development and implementation of new therapies. Tumor necrosis factor α inhibitors, such as infliximab121 and adalimumab,125 have been shown to be effectively treating IU. Significantly elevated concentrations of multiple intraocular cytokines were found in IU patients, especially IL-6 and IL-8 in those with CME and active disease.65,66 These observations may have implications for future treatment with biological agents that target these cytokine or complement systems. Moreover, there is still a paucity of long-term results of these biological agents, which will provide more evidences about the efficacy and safety of these treatments.
Genetic polymorphisms have been shown to be associated with the outcomes of IU.68 It demonstrated that outcome in IU may be partly determined by a complex interplay among genes of cytokine and complement system. The prevalence of IU among different ethnic populations as well as the treatment response to those new biological agents is going to be an interesting area for further research in the future.
Intermediate uveitis is most often a benign form of uveitis. The management of IU is tailored individually, based on specific causes of the disease and associated complications. Choice of treatment modalities can be determined by the severity of inflammation, response to treatment, presence of complications, and bilateral involvement of the disease. The treatment options of IU are evolving, with the development of various immunosuppressants and biological agents. Nevertheless, corticosteroids remain the mainstay of treatment.
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