Intermediate Uveitis 

Updated: Jan 15, 2019
Author: Robert H Janigian, Jr, MD; Chief Editor: Hampton Roy, Sr, MD 

Overview

Background

Intermediate uveitis refers to inflammation localized to the vitreous and peripheral retina. Intermediate uveitis was first described in the literature as chronic cyclitis by Fuchs in 1908. According to the Standardization of Uveitis Nomenclature Working Group, the primary site of inflammation is the vitreous and such entities as pars planitis, posterior cyclitis, and hyalitis are encompassed. Intermediate uveitis may be initially associated with the development of a systemic disease, such as multiple sclerosis (MS) or sarcoidosis. As such, intermediate uveitis may be the first expression of autoimmunity in these patients.

Pars planitis is considered a subset of intermediate uveitis 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 (eg, Lyme disease) or a systemic disease (eg, sarcoidosis). Some authorities believe that patients with pars planitis have worse vitritis, more severe macular edema, and a guarded prognosis compared to other patients with intermediate uveitis. This primary form accounts for over 50% of patients with intermediate uveitis.

Pathophysiology

There may be an immunogenetic predisposition for the disorder in some cases (see Causes), accounting for family clustering that is seen on occasion, indicating environmental or hereditary associations. The available evidence would suggest an autoimmune mechanism; however, the antigenic stimulus remains elusive.

Epidemiology

Frequency

United States

Traditionally, the proportion of patients with intermediate uveitis is estimated to be 4-8% of uveitis cases in referral centers. The National Institutes of Health (NIH) reports a higher percentage (15%), which may indicate improved awareness or the nature of the uveitis referral clinic. In the pediatric population, intermediate uveitis can account for up to 25% of uveitis cases.

Mortality/Morbidity

Permanent loss of vision is most commonly seen in patients with chronic cystoid macular edema (CME). Every effort must be made to eradicate CME when present. Other less common causes of visual loss include rhegmatogenous retinal detachment, glaucoma, band keratopathy, cataracts, vitreous hemorrhage, epiretinal membrane, and choroidal neovascularization.

Race

No racial predilection exists for this disease.

Sex

The incidence of intermediate uveitis is equal in men and women.

Age

Although intermediate uveitis can develop at any age, it primarily afflicts children and young adults. There is a bimodal distribution with one peak in the second decade and another peak in the third or fourth decade.

In the pediatric age group, intermediate uveitis is associated with a worse presenting visual acuity. Poorer outcomes may be related to delayed presentation/diagnosis, the inherent difficulties of immunosuppression in children, or a more aggressive disease.

 

Presentation

History

The most common symptoms of intermediate uveitis are blurry vision and floaters.

Pain and photophobia are the exception.

Bilateral involvement at initial presentation approaches 80%, although it is frequently asymmetric. Eventually, approximately one third of unilateral cases will become bilateral.

Later in the disease course, more severe visual loss may occur secondary to chronic CME (28-50%), uveitic glaucoma (15%), rhegmatogenous retinal detachment (3-22%), vitreous hemorrhage (6-28%), cataracts (15-20%), or cyclitic membrane development.

Physical

See the list below:

  • On ocular examination, the ophthalmologist encounters vitritis that ranges in severity. The absence of cellular activity in the vitreous precludes the diagnosis of active intermediate uveitis.

  • The presenting visual acuity is often reduced to 20/40 (mild visual loss) due to mild vitritis and CME.

  • Anterior segment inflammation is infrequent and more commonly associated with pediatric intermediate uveitis. On occasion, patients with MS develop granulomatous anterior uveitis with characteristic mutton keratic precipitates.

  • Aggregates of inflammatory cells may appear in the inferior vitreous as white or yellow tufts termed vitreous snowballs. A snowbank, the requisite finding in pars planitis, may be seen as a grayish yellow exudate along the inferior ora serrata, frequently extending over the pars plana. Not all patients with intermediate uveitis manifest snowbanks.

    • In severe cases, the exudates may coalesce across the entire periphery for 360°, albeit rarely.

    • Scleral depression is usually required to appreciate snowbanks, but, sometimes, they can be seen with the eye infraducted using an indirect ophthalmoscope without the 20 D-lens.

    • In fact, snowbanks may be fibroglial masses and not a true protein exudate (see Histologic Findings).

  • Peripheral retinal vascular abnormalities are not uncommon but may become obscured by the dense vitritis.

    • Sheathing or obliteration of small venules may be noted. This finding may appear months or years after initial presentation.

    • Less often, a periarteritis or a combined perivasculitis is present with exudates.

    • Peripheral retinal neovascularization can occur as a result of ischemia, causing vitreous hemorrhages; this occurs more commonly in children.

    • The neovascularization can evolve into a vascular cyclitic membrane in the rare patient, exercising traction on the ciliary body and leading to hypotony and phthisis bulbi.

  • CME may be seen. Severe macular edema can be appreciated clinically. Angiographic study or optical coherence tomography is often necessary for a definitive diagnosis, especially if the edema is subtle or if the media are hazy. Some patients with angiographic CME may present with 20/20 acuity.

    • Estimates of the incidence of macular edema vary.

    • Most early reports have noted this complication in 28-50% of cases.

  • Optic nerve edema is not uncommon, especially in pediatric cases where the disk is edematous at least half of the time. In a retrospective study, optic disk edema was found in 71% of patients with onset of the disease before age 16 years.

  • In the anterior segment, late findings include anterior and posterior synechiae, band keratopathy, cataracts, and glaucoma.

    • The glaucoma may be related to both the uveitis and/or corticosteroid use.

    • The incidence of cataract formation, most often a posterior subcapsular opacity, has been reported in approximately 15-20% of cases and may not be independent to the use of steroids for treatment.

  • The late complications of intermediate uveitis are important to recognize early.

    • A combination of vitreous hemorrhage and vitreous fibrosis can cause traction on the peripheral retina and lead to retinal detachment. Studies vary widely in the frequency of this late complication, ranging from 3-22%. Some detachments may become complete, leading to a phthisical eye.

    • Chronic CME may cause moderate-to-severe vision loss. Treating CME, regardless of how good the vision may be, is therefore imperative.

    • Peripheral retinal neovascularization can occur as a result of ischemia, causing vitreous hemorrhages, as discussed above.

    • A vascular cyclitic membrane can exercise traction on the ciliary body and lead to hypotony and phthisis bulbi.

Causes

The cause of intermediate uveitis or pars planitis has not been elucidated. Intermediate uveitis is a category of uveitis based on an anatomical classification system that can include diseases of various etiology and clinical manifestations. Associations of the disease with such entities as MS, sarcoidosis, or inflammatory bowel disease suggest an autoimmune component in at least a subset of patients. The clustering of familial cases has led to the investigation of human leukocyte antigen (HLA) associations. The inciting event appears to be peripheral retinal perivasculitis and vascular occlusion, leading to ocular inflammation, vitritis, and snowbank formation. The etiology of the antigenic stimulus is not clear and may be either vitreal or perivascular in nature.

  • In 1963, Kimura and Hogan first noted several members of one family to be afflicted with chronic cyclitis.[1] Since then, there have been multiple case reports of intermediate uveitis in families, including a case report in identical twins.

    • Several studies show that the HLA-DR2 histocompatibility complex gene is associated with intermediate uveitis, suggesting an immunogenetic predisposition for the disorder in some cases.

    • In a prospective study of 53 patients with pars planitis by Raja et al, an association was found with the HLA-DR15, a subtype of HLA-DR2.[2] In addition, there was a suggestion that the association was stronger for patients with both pars planitis and MS. This supports previous studies showing a similar relationship.

    • Other associations include HLA-A28, HLA-B8, and HLA-B51.

    • It is evident that genetics plays some role in the pathophysiology of intermediate uveitis, but the importance remains unclear.

    • In addition, cytokine gene polymorphism may be associated with disease development and visual prognosis in patients with intermediate uveitis. In particular, TT homozygotes for the interferon-gamma (INF-gamma) gene may be at a higher risk of disease development and may also run a more severe course.

  • Despite a high prevalence of intermediate uveitis and pars planitis in uveitis clinics, the causative factors are still unknown. Apart from idiopathic forms of the disease, there are known associations with such entities as MS, sarcoidosis, and inflammatory bowel disease. Evidence of a systemic disorder can be found in up to one third of patients with intermediate uveitis. Infectious etiologies include Epstein-Barr virus (EBV) infection, Lyme disease, human T-cell lymphotrophic virus type1 (HTLV-1) infection, cat scratch disease, and hepatitis C.

    • The association between MS and intermediate uveitis is well documented. Raja et al reported a 16.2% prevalence rate of MS in a small population with pars planitis, which agrees with the findings of Malinowski and his colleagues.[2, 3]

    • Retinal phlebitis, vitreous cells or snowball opacities, posterior synechiae, iritis, iridocyclitis, and retinal neovascularization are common manifestations of ocular sarcoidosis, which emphasizes the overlap of ophthalmologic signs between idiopathic intermediate uveitis and ocular sarcoidosis.

 

DDx

 

Workup

Laboratory Studies

See the list below:

  • The diagnostic approach to intermediate uveitis should center on the history and clinical examination.

  • As demonstrated by Henderly et al and also by Rodriguez et al, approximately two thirds of patients will have idiopathic intermediate uveitis.[4, 5]

  • Since intermediate uveitis 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.

  • A minimum workup should include a serum ACE level, chest x-ray, Venereal Disease Research Laboratory (VDRL) test, fluorescent treponemal antibody absorption (FTA-ABS) test, and CBC. The laboratory workup can be expanded, depending upon the clinical history and physical findings.

    • Focus on excluding sarcoidosis and MS with a thorough review of systems. Patients with intermediate uveitis due to MS are usually older than 25 years, and they may require an MRI. In general, order an ACE level and chest x-ray on all patients to rule out subclinical sarcoidosis.

    • If the above are inconclusive or negative in a setting of a strong clinical suspicion, a Gallium scan or pulmonary function tests can be obtained as well.

    • Patients from endemic areas for Lyme disease with a history of a rash typical of erythema migrans, chronic arthritis, or cranial nerve palsies should undergo testing for antibodies to Borrelia burgdorferi.

    • Seek consultation with a gastroenterologist in patients with symptoms suggestive of inflammatory bowel disease or Whipple disease, if the diagnosis has not already been established.

    • 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. Intraocular lymphoma may respond to steroids to some extent.

    • The white lesion in toxocariasis, if affecting the peripheral retina, can be confused with a snowbank, especially when associated with the usual vitritis. The patients are usually younger, and the disease tends to be unilateral.

    • Other diseases associated with intermediate uveitis include HTLV-1 infection and syphilis.

    • In one case report, a patient with cat scratch disease presented with pars planitis. There is usually a retinitis with optic nerve and/or choroidal involvement.

    • Irvine-Gass syndrome, a postoperative intraocular inflammation associated with CME, is in the differential. It should generally not present much confusion since most patients will have recently undergone cataract surgery.

Imaging Studies

Fluorescein angiography

Fluorescein angiography is useful in determining the presence and extent of CME.

Knowing if CME exists helps in choosing the appropriate treatment plan.

The angiogram provides information about the integrity of the retinal vasculature. Staining of the vessel walls and/or leakage indicates a perivasculitis.

Retinal neovascularization and optic nerve edema can be recognized easily.

B-scan ultrasonography

When media are obscured by vitreous hemorrhage, inflammatory debris, cyclitic membrane, or cataract, B-scan ultrasonography can be useful.

Obtain B-scan ultrasonography to document the extent of vitreous debris, retinal detachment, and cyclitic membranes.

Ultrasound biomicroscopy may show features that are not clinically obvious, such as uveal thickening, the exact nature of inflammatory condensations in the vitreous, and vitreoretinal adhesions with traction.

Both 50 MHz and 20 MHz ultrasound imaging in patients with intermediate uveitis readily demonstrated inferior pars plana exudates and cyclitic bands, which are of extreme value in preoperative planning in patients with dense media and/or a secluded pupil due to posterior synechiae.

Optical coherence tomography (OCT)

OCT has replaced traditional fluorescein angiography as the imaging modality of choice in establishing a diagnosis of CME.

OCT can help demonstrate the presence of cysts in the fovea and measure macular thickness. OCT is a highly sensitive, noninvasive method to help diagnose CME and provides the best method to monitor the therapeutic response of patients to treatment as macular thickness appears to correlate with visual acuity to some degree.

OCT can also help demonstrate the presence of epiretinal membranes, a known late complication of ocular inflammation.

The presence of neurologic symptoms or a history of optic neuritis should prompt the clinician to obtain an MRI of the brain and subsequent consultation with a neurologist to rule out MS.

If there is a high clinical suspicion of sarcoidosis as the cause of intermediate uveitis, a chest X-ray or a Gallium scan should be obtained as indicated. Older women with a negative chest X-ray and ACE may have hilar adenopathy identified on chest CT.

Histologic Findings

Histologic examination of the pars plana snowbank shows that it is not a true protein exudate. The snowbanks are predominantly a combination of collapsed vitreous, blood vessels, inflammatory cells (mainly lymphocytes), fibroblasts, and glial elements. Histologic studies also failed to identify cells positive for GFAP, an important glial cell marker, within the snowbanks. Peripheral veins may manifest lymphocytic infiltration and cuffing. The vascular component of the snowbanks has been shown to be continuous with retinal vessels. Vitreous snowballs are composed of epithelioid cells and multinucleated giant cells.

 

Treatment

Medical Care

See the list below:

  • Treatment of intermediate uveitis is undertaken to prevent permanent structural damage to vital ocular tissue, and, as a consequence, the method outlined by Kaplan is outdated.[6]

  • While mild asymptomatic vitreous cell may not require immediate treatment, any evidence of CME, neovascularization of the peripheral retina, extensive vasculitis, or significant vitreous cell requires treatment.

  • Treatment is no longer based on an arbitrary level of vision. As with most forms of uveitis, corticosteroids are the mainstay of therapy.

    • Topical therapy with prednisolone acetate 1% or prednisolone sodium phosphate 1% is only helpful in the treatment of the anterior segment inflammation. The intravitreal concentration of administered topically is too low to be efficacious in the face of moderate-to-severe vitritis, especially in the phakic patient.

    • Periocular injections of corticosteroids are preferentially given in unilateral cases and occasionally in bilateral cases. Triamcinolone acetonide can be administered superotemporally into the sub-Tenon space or through the inferior eyelid into the retroseptal space. If the disease is not controlled after 2-3 injections given over an 8-week period, systemic prednisone should be considered. Some authorities advocate the use of a combination of betamethasone and depot methylprednisolone in an effort to achieve early onset and prolonged duration of action.

    • Oral prednisone may be the preferred treatment in patients with bilateral intermediate uveitis or in cases resistant to topical or periocular steroids. A purified protein derivative (PPD) test is imperative prior to starting any patient on systemic corticosteroids if there are any risk factors for TB. Once the inflammation stabilizes, the oral dose is tapered according to disease activity. An H2 blocker (Tagamet or Zantac) or a proton pump inhibitor (Prilosec or Prevacid) can be prescribed adjunctively to oral steroids.

    • Intravitreal triamcinolone acetonide injections have been used to treat CME. In a case series by Hogewind et al, of 33 eyes with intermediate or posterior uveitis and refractory CME, 50% improved greater than 2 lines at 3 months; but, by 12 months, the proportion of improved eyes declined to 40%.[7]

    • Several small case series have explored the use of somatostatin analogues (Octreotide) IM and intravitreal bevacizumab (Avastin) in patients with refractory uveitic CME.

    • For recalcitrant cases with high corticosteroid requirements to control the inflammation, the surgical implantation of a device releasing fluocinolone acetonide in the vitreous can be considered (see Surgical Care).

  • In the event that corticosteroids cannot control the intermediate uveitis or in those whose disease invariably flares when steroids are discontinued, immunosuppressive therapy often is attempted. Immunosuppression or immune-modulation is also used as part of the concept of steroid-sparing therapy in an effort to reduce the patient's requirement for systemic corticosteroids and, therefore, to diminish the adverse effects of systemic corticosteroid therapy.

    • Cyclosporine, tacrolimus, azathioprine, and methotrexate are the most commonly used agents with documented efficacy in many uveitic conditions. Chlorambucil can be considered for intractable cases. They can be used concurrently with corticosteroids as steroid sparing agents or alone.

    • Murphy et al prospectively evaluated the efficacy and the safety of cyclosporine and tacrolimus in patients with posterior and intermediate uveitis.[8] The 2 agents did show a similar response rate (approximately 67%), but cyclosporine was associated with a higher incidence of adverse effects.

    • Two phase 3 studies (VISUAL 1 and VISUAL 2) showed that adults with active and inactive noninfectious intermediate uveitis, panuveitis, and posterior uveitis treated with adalimumab had a significantly lower risk of treatment failure as compared to placebo. In July 2016, the FDA approved adalimumab as a second-line treatment for patients who do not respond appropriately to steroids, making adalimumab the first noncorticosteroid medication approved for uveitis. Adalimumab is an important addition to the treatment armamentarium in the management of patients with noninfectious uveitis.[9, 10]

    • The use of infliximab, an anti-tumor necrosis factor (anti-TNF) monoclonal antibody, has been shown to be effective in improving macular thickness and visual acuity in patients with uveitic refractory CME due to intermediate uveitis or other noninfectious uveitis. Initial successful reports by Markomichelakis et al were duplicated by Rajaraman et al in a pediatric population in which infliximab achieved reduction in intraocular inflammation with concurrent elimination or decrease in steroid requirements.[11, 12]

    • Finally, interferon-beta (INF-beta), 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 intermediate uveitis associated with MS.

Surgical Care

See the list below:

  • Cryotherapy has been shown to be effective in treatment of intermediate uveitis. 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.

    • By ablating the peripheral retina with a transconjunctival approach, compromised vasculature can be destroyed, eliminating both the source for inflammatory mediators and the stimulus for neovascularization.

    • The effect is noted after several weeks but may need to be repeated after 3-6 months.

    • Devenyi et al reported that 90% of steroid-resistant eyes no longer required corticosteroid treatment after cryotherapy, and, in 78%, vitritis was eliminated.[13]

    • This surgical approach is not without complications including transient worsening of vitreous inflammation, decreased accommodative potential, cataract, hyphema, epiretinal membranes, and retinal detachment.

    • Therefore, some authors advocate the use of cryotherapy only for patients with peripheral retinal neovascularization and a history of vitreous hemorrhage.

  • Park and colleagues evaluated the use of peripheral scatter photocoagulation in 10 eyes with steroid-resistant pars planitis.[14] Photocoagulation appeared to be as effective as cryotherapy in controlling intraocular inflammation and neovascularization of the vitreous base.

  • Another surgical option for treating intermediate uveitis is pars plana vitrectomy.

    • This modality is gaining popularity, because it theoretically reduces the antigen load and inflammatory mediators in the vitreous.

    • Pars plana vitrectomy has been shown to decrease the intensity of the intraocular inflammation and reduce CME, but controlled clinical trials are lacking.

    • In a published review of 44 interventional case series of pars plana vitrectomy for uveitis, the most common indication of pars plana vitrectomy was intermediate uveitis. This review by Becker et al grades pars plana vitrectomy as possibly relevant to the outcomes of improving vision and reducing inflammation and CME.[15]

    • Another small prospective study found that eyes randomized to pars plana vitrectomy/immunomodulatory therapy had improved uveitis compared with those given immunomodulatory therapy alone.[16]

    • Retinal detachment, cataract, and recurrent vitreous hemorrhage are known complications. Several authorities reserve the use of vitrectomy for patients with either dense vitreous debris with known complications of intermediate uveitis such as nonclearing vitreous hemorrhage or epiretinal membrane.

    • Vitrectomy also may be indicated in patients who are steroid responders or those who cannot use/tolerate immunosuppressive therapy.

    • In a retrospective analysis, pars plana vitrectomy was combined with cataract surgery in 22 of 43 eyes with intermediate uveitis; 40 of 43 eyes achieved a similar or better visual acuity after an average follow-up period of 45 months. In a small subset, immunosuppression could also be discontinued.

  • 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 fluocinolone acetonide (Retisert, Yutiq) or dexamethasone (Ozurdex) implant can be considered. In a cohort of patients with recurrent posterior noninfectious uveitis, where the more severely affected eye was selected to receive a fluocinolone implant, the selected eyes showed a significant decrease in disease recurrences, from 51.4% to 6.1%, after 34 weeks of follow-up, with a moderate benefit in visual acuity as well.[17] In addition, in a randomized trial, the 0.7-mg dexamethasone implant effectively reduced intraocular inflammation and improved visual acuity over a 6-month period.[18]

  • Many patients with intermediate uveitis develop cataract, either secondary to the disease process or due to corticosteroid treatment.

    • Management of cataract in these patients is controversial.

    • It is well established that maximal preoperative suppression of inflammation is imperative before cataract surgery. Younger patients should be cell free for 6 months prior to surgery, and older patients for at least 3 months, depending upon the judgment of the experienced operating surgeon.

    • The controversy lies in whether these patients would benefit more from aphakic correction or intraocular lens (IOL) placement.

    • Some authors report a poor visual outcome secondary to a postoperative escalation of inflammation and/or adherent debris onto the IOL, requiring multiple YAG laser procedures.

    • Other investigators have found that select patients can enjoy a relatively uncomplicated postoperative course and improved visual acuity with pseudophakia.

    • Although it was speculated that heparin surface-modified intraocular lenses would reduce postoperative debris collection and posterior synechiae, small prospective case series suggest that there is no statistical difference between heparin-coated IOLs and polymethyl methacrylate (PMMA) IOLs in terms of final visual acuity, lens deposits, posterior capsular opacities, or anterior/posterior synechiae.

    • In a retrospective series of 86 patients (100 eyes) with pars planitis who underwent phacoemulsification, 91% had better visual acuity postoperatively and only 10% had a decrease in visual acuity as a result of reactivation of pars planitis or progression of CME. This study determined that acrylic IOL had a statistically significant lower incidence of posterior capsular opacification compared to PMMA IOLs.

Consultations

A cost-effective, directed, patient-specific laboratory diagnostic evaluation is best directed by the informed ophthalmologist. This approach incorporates the demographics, history, and examination findings into a comprehensive, practical diagnostic approach to the patient with uveitis.

For any patient with uveitis, seek an internist for a general medical evaluation.

Input from a gastroenterologist, neurologist, or infectious disease specialist may be necessary, depending on physical findings or pertinent elements of the review of systems.

Consultation with an experienced chemotherapist is mandatory when using alkylating and cytotoxic agents.

 

Medication

Medication Summary

The goal is to suppress intraocular inflammation, which usually is accomplished with systemic corticosteroids. In some cases, this treatment is inadequate, and immunosuppressive or immune-modulating agents are required to control the disease. These agents can be used adjunctively with steroids or alone.

Corticosteroids

Class Summary

Have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Prednisone (Deltasone, Meticorten, Orasone)

Readily absorbed through the GI tract and inhibits phospholipase A2 (an enzyme that liberates arachidonic acid from phospholipids in the production of inflammatory mediators).

Triamcinolone (Amcort)

A long-acting depo-steroid. For inflammatory dermatosis responsive to steroids; decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing capillary permeability. Observe for ptosis or anterior dissection. Generic preparations appear to be equally efficacious compared to proprietary Kenalog.

Prednisolone 1% (Pred Forte)

Has 3-5 times the anti-inflammatory action as hydrocortisone. Glucocorticoids inhibit the edema, fibrin deposition, capillary dilation and phagocytic migration of the acute inflammatory response. Steroids are also potent inhibitors of the inflammatory enzyme cascade, angiogenesis, and mast-cell degranulation. Steroids stabilize cell membranes.

Loteprednol etabonate binds to anti-inflammatory receptors 4.3 times more avidly than dexamethasone. Possible reduced risk of glaucoma due to ester substitution for ketone moiety at the 20 position on the steroid cholesterol ring. Shake well for susp (acetate).

Immunosuppressives

Class Summary

Inhibit cell-mediated and (to a lesser degree) humoral immunity by arresting T-lymphocyte activity. The ultimate goal is to suppress inflammation.

Cyclosporine (Sandimmune, Neoral)

A cyclic polypeptide produced as a fungus metabolite, capable of reversibly arresting the T-lymphocyte cell cycle in the G0 and G1 phases. Potent down-regulator of interleukin 2 production and receptor expression. Newer Neoral preparation is better absorbed and may require marked dosage reductions.

Azathioprine (Imuran)

Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity.

Methotrexate (Folex PFS, Rheumatrex)

Antimetabolite that inhibits dihydrofolate reductase, thereby inhibiting DNA synthesis in rapidly replicating cells. Immunosuppressive actions may be related to reduction in cytokines. Available as 2.5-mg pills.

Histamine H2-receptor antagonist

Class Summary

Reduces postprandial daytime and nighttime gastric acid secretion by about 50-80%. May increase gastromucosal defense and healing in acid-related disorders (ie, stress-induced ulcers) by increasing production of gastric mucus, increasing mucosal secretion of bicarbonate and gastric mucosal blood flow as well as increasing endogenous mucosal synthesis of prostaglandins. Histamine H2-receptor antagonists can be used prophylactically to prevent gastritis and ulcer disease in patients taking oral or intravenous corticosteroids.

Cimetidine (Tagamet)

Used as prophylaxis against corticosteroid induced gastric and duodenal ulcer.

Consult with internist if patient has preexisting symptoms of GERD or peptic ulcer disease prior to beginning corticosteroid therapy.

Ranitidine (Zantac)

Used as prophylaxis against corticosteroid-induced gastric and duodenal ulcer.

Gastric pump inhibitors

Class Summary

Thought to be a gastric pump inhibitor in that it blocks the final step of acid production by inhibiting the H+/K+ -ATPase system at the secretory surface of the gastric parietal cell. Both basal and stimulated acid secretions are inhibited. Short-term (4-8 wk) treatment of active duodenal ulcer, active benign gastric ulcer, erosive esophagitis (all grades), and heartburn and other symptoms associated with GERD.

Omeprazole (Prilosec)

Decreases gastric acid secretion by inhibiting the parietal cell H+/K+ -ATP pump.

Lansoprazole (Prevacid)

Inhibits gastric acid secretion.

Esomeprazole magnesium (Nexium)

S-isomer of omeprazole. Inhibits gastric acid secretion by inhibiting H+/K+ -ATPase enzyme system at secretory surface of gastric parietal cells.

DMARDs, TNF Inhibitors

Adalimumab (Adalimumab-atto, Amjevita, Humira)

A fully humanized anti-TNF alpha antibody FDA-approved for the treatment of intermediate uveitis, posterior uveitis, and panuveitis.

Corticosteroid Ophthalmic Implants

Fluocinolone intravitreal implant (Retisert, Yutiq)

The implants are surgically inserted by the ophthalmologist and indicated for chronic, noninfectious uveitis of posterior segment of eye. Retisert releases 0.6 mcg/day initially; amount released decreases after the first month to 0.3-0.4 mcg/day over ~30 months. Yutiq releases at a rate of 0.25 mcg/day over ~36 months.

Dexamethasone intravitreal implant (Ozurdex)

The implant is surgically inserted by the ophthalmologist and indicated for chronic, noninfectious uveitis of posterior segment of eye.

 

Follow-up

Further Outpatient Care

Observe patients every 1-4 weeks during the active phase of the disease, more frequently if CME or severe inflammation is present.

Since corticosteroids can cause glaucoma at anytime, it is imperative that patients return for intraocular pressure monitoring at 4-week intervals while using corticosteroids or after periocular injections. Periocular triamcinolone can cause steroid responsive glaucoma many months after an injection.

Consider fluorescein angiography and/or OCT whenever CME is suspected.

Consider reordering any relevant laboratory tests if the clinical situation changes. For example, a patient who initially presents with routine intermediate uveitis and negative findings on workup is found to have multiple choroidal granulomata 14 months later. In this case, unless proven otherwise, consider sarcoidosis (or other granulomatous disease).

Further Inpatient Care

Patients generally are treated on an outpatient basis.

Inpatient & Outpatient Medications

Topical steroids (prednisolone acetate 1%, loteprednol etabonate 0.5%) are used for anterior segment inflammation. Frequency of use depends on severity of inflammation. Possible discrepancy in potency between proprietary Pred Forte 1%, and generic prednisolone acetate 1%, wherein the generic preparation is less potent due to markedly higher suspension particle diameter and resultantly decreased surface exposure and intraocular absorption.

Triamcinolone is given as a periocular injection in the office setting to suppress intraocular inflammation and CME. The most commonly used dose of triamcinolone acetonide is 20 mg. If no response occurs, it can be repeated as soon as 2 weeks after the initial injection. If no improvement occurs after 3 consecutive injections, a different treatment modality must be considered.

Use oral prednisone (0.5-1 mg/kg) in the presence of moderate-to-severe inflammation, especially when it is bilateral. Tapering can be initiated as soon as 2 weeks after treatment was started, according to the clinical response of the patient, and the minimum effective dose controlling the inflammation should be maintained for at least 4 months.

Immunosuppressive agents (ie, methotrexate, cyclosporine, tacrolimus, azathioprine) generally are used as steroid-sparing agents or for severe inflammation that is unresponsive to steroids. Immune-modulating agents (ie, infliximab) can be considered to treat persistent macular edema or to decrease the steroid requirements of selective patients. Consult with a specialist who is familiar with these drugs.

Deterrence/Prevention

Smoking cessation should be strongly encouraged. Thorne et al found a 4-fold increased risk of uveitic CME in smokers with intermediate uveitis.[19]

Complications

See the list below:

  • Cataract

  • Glaucoma

  • CME

  • Vitreous hemorrhage

  • Retinal detachment

  • Epiretinal membrane

Prognosis

See the list below:

  • Approximately one half of patients with intermediate uveitis present with a visual acuity of 20/30 or better.

    • When properly treated, at least two thirds of patients can maintain a visual acuity of 20/40 or better.

    • According to an early review, greater than one third of patients develop significant vision loss.

  • There are many possible levels of chronicity for this form of uveitis; the proportions of patients with each potential end point vary from facility to facility. Early aggressive treatment generally portends a more benign course in appropriately selected patients.

    • Some patients have mild inflammation that may not lead to significant visual loss or macular edema even without treatment. Despite long-term follow-up care, permanent remission rates are reportedly low. Most cases are long term and loosely classified as mild, moderate, or severe; each has variable and unpredictable responses to treatment, although the severe form tends to be more recalcitrant.

    • Regardless of the severity of a patient's inflammation, use caution when encouraging patients that their disease will likely "burn out" with time. The disease is typically chronically active or follows a course of intermittent exacerbation punctuated by periods of quiescence. Permanent spontaneous resolution of the disease is uncommon.

  • Whether the presence of a pars plana snowbank predicts a worse prognosis is unknown.

    • Henderly and colleagues found that a snowbank is associated with more severe vitreous inflammation and more frequent and extensive CME.[4]

    • Patients without this finding tended to have a milder inflammation, less macular edema, better visual acuity, less phlebitis, and fewer snowballs.

    • These differences were not statistically significant, which may have been in part due to the small sample size.

    • Some patients with a snowbank had good vision without CME.

    • Nevertheless, the trends are intriguing and could suggest that a snowbank is a sign of progression along the same disease continuum.

  • The prognosis of pediatric patients with intermediate uveitis was considered unfavorable secondary to late presentation in the course of the disease and the inherent difficulties in treating such patients with immunosuppressive agents.

    • In a cohort of 32 consecutive patients with onset of the disease before age 16 years, an incidence of legal blindness of 12-13% was found after 8 years of follow-up.

    • According to the same study, 3 of 16 patients showed a complete remission after 3 years of follow-up. The proportion of patients showing complete remission increased to 47% after a follow-up of 5 years.

    • Another 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.[20]

Patient Education

Since this disease is long term and recurrent, patients must recognize symptoms of a flare-up (ie, floaters, blurred vision, redness, discomfort) early and seek medical attention appropriately.