Glaucoma is often a complicating factor for patients suffering with uveitis. The relationship between uveitis and glaucoma is quite complex and often multifactorial, which makes management challenging. In acute uveitis, IOP can be decreased from ciliary body shutdown. However, several mechanisms can lead to uveitic glaucoma over the course of the disease, such as open-angle mechanisms, secondary angle closure and steroid response.

In this article, I will discuss those mechanisms further along with evaluation, management and other bridging interventions.

MECHANISMS THAT LEAD TO UVEITIC GLAUCOMA

Open-angle glaucoma

Open-angle glaucoma is the most common cause of elevated IOP in uveitis. Inflammatory cells, fibrin and debris obstruct the trabecular meshwork. In addition, cytokine-induced inflammation of the trabecular meshwork can disrupt aqueous outflow as well. Chronic inflammation leads to fibrovascular proliferation and scarring of the outflow pathways.

Closed-angle glaucoma

Chronic inflammation may induce peripheral anterior synechiae (PAS) or posterior synechiae (PS) formation. In the angle, broad-based PAS can cause total closure of the angle. At the pupil margin, PS can block the flow of aqueous fluid from the posterior to anterior chamber, which results in iris bombé and acute angle closure. Less commonly, chronic angle closure can result from anterior rotation of the ciliary body as a result of inflammation and edema.

Steroid-induced glaucoma

Steroids are the mainstay of treatment of uveitis. Often, patients can develop a steroid response. Corticosteroid-induced IOP elevation is primarily due to increased outflow resistance and is thought to result from suppression of phagocytic activity, which leads to increased deposition of glycosaminoglycans and a decrease in prostaglandin synthesis. Steroid response can be unpredictable. Often it is seen within a few weeks of starting therapy. However, patients who have been on chronic steroids with previously normal IOP can also exhibit steroid response.¹

EVALUATION

Just as the severity of uveitis varies widely, so does the severity of glaucoma. A significant percentage of patients with uveitis will develop glaucoma. One key pearl in managing patients with both uveitis and glaucoma is to discuss glaucoma early in the course of uveitis before they develop glaucoma. Set expectations for the risk and need for management of glaucoma. Make a point to share the eye pressure with the patient whether it is of concern or not. On your initial exam, gonioscopy is very helpful to determine the extent of current and/or past inflammation. As you follow the patient, serial gonioscopy provides an idea of whether the patient has had flares in between visits, even if they may be symptomatic, especially in children.

Gonioscopy should be performed at baseline, with each flare, and yearly at minimum. If significant PAS are present, the patient’s risk for developing chronic angle closure is higher. Documenting a baseline disc photo and optic nerve optical coherence tomography are also helpful as you follow patients with uveitis over time.²

MEDICAL MANAGEMENT

Glaucoma medications

If a patient’s eye pressure is elevated — it varies for different people but typically above 22 mm Hg — good first-line options are a beta blocker or carbonic anhydrase inhibitors. I prefer a beta blocker if there is no contraindication of quick onset and option for once daily dosing. Once the IOP is at a point where I am treating it with a topical drop, I get a baseline visual field as soon as the patient is over the acute flare.

My second-line choice for uveitic glaucoma is a combination drop with a beta blocker like dorzolamide hydrochloride-timolol maleate ophthalmic solution (Cosopt, Akorn) or brimonidine tartrate-timolol maleate ophthalmic solution 0.2%/0.5% (Combigan, Allergan). If a third agent is required, I add brimonidine or a carbonic anhydrase inhibitor.

At this point, I typically begin collaborating with a glaucoma colleague. If the patient already has advanced cupping, I refer to a glaucoma specialist even sooner. Early collaboration is important to relieve patient anxiety in times of flare as well as prepare for surgical options if needed.

Often, if the patient has to take high-frequency topical steroids — cycloplegic and glaucoma drops — I look into preservative-free options (eg, PF-Cosopt [Akorn]) and/or compounded drops (from ImprimisRx or OSRX, for example). The surface irregularity and discomfort are challenging for patients and their drop compliance. I recommend preservative-free artificial tears if the patient is on two drops and has any signs of surface keratopathy. It is important to monitor and stress compliance with medications. I routinely inquire about side effects and tolerance. If intolerance is affecting compliance, intervene early.

Prostaglandin analogues and cholinergic agents are a relative contraindication, because they can exacerbate inflammation through further breakdown of the blood-aqueous barrier. However, a prostaglandin analog can be added with close monitoring if a patient’s IOP requires it.

Rho kinase inhibitors — which act on the trabecular meshwork cells and endothelial cells in Schlemm’s canal to enhance outflow facility — may be of value. Typically, these are used as third- or fourth-line agents in my uveitis algorithm because of the side effect of hyperemia potentially clouding the uveitis picture.

Oral carbonic anhydrase inhibitors are a good option, especially while working to reduce the inflammation in advance of surgery. Caution must be exercised due to their side-effect profile, including impaired renal absorption of bicarbonate, leading to a diuretic response that ultimately lowers IOP. Adverse effects such as hypokalemia, kidney stones, metabolic acidosis, agranulocytosis and renal/hepatic failure, have been associated with this class of medication.

Cycloplegics

Mydriatic agents such as atropine, cyclopentolate or homatropine are often added to the uveitis regimen to prevent PS formation and to relieve discomfort. Tropicamide can be used as well in times of coverage and availability challenges.

Avoiding anti-inflammatory medications

Nonsteroidal anti-inflammatory drugs may counteract the hypotensive effect of some glaucoma medications, such as brimonidine. Educate patients of the risk of steroid response and glaucoma as well as cataract at each visit.

Development of steroid response can be unpredictable. Patients who have been on chronic steroids without IOP elevation can still develop steroid response later in their course. Periodic monitoring of IOP in all patients on steroids is essential even without a history of IOP elevation and/or inactive disease. If the patient is on any steroid, the eye pressure should be monitored at a minimum of every 6 months even if the pressure has been well controlled.

If the patient is unable to be tapered off topical steroids and continues to have uncontrolled IOP or the patient is found to have concern for underlying systemic autoimmune disease, I refer the patient to a rheumatologist for consideration of systemic immunosuppression. This is done early to provide the collaborating rheumatologist time to get routine labs and conduct a full evaluation. When the patient needs systemic immunosuppression, the rheumatologist can be ready to go with the drug and prior authorizations. Keep in mind that uncontrolled glaucoma is more likely to cause blindness than uncontrolled uveitis.

Systemic immunosuppression

Oral corticosteroids may be considered when topical corticosteroids fail to control intraocular inflammation or in the perioperative period. Education regarding side effects of elevated glucose and blood pressure, gastritis, mood swings, difficulty sleeping, etc., is key, especially for patients with diabetes and hypertension. Oral steroids are typically used as temporizing agents and not for long-term immunosuppression because of the side-effect profile.

Immunomodulatory agents have a significant role in the treatment of chronic noninfectious uveitis. They are often used to wean patients off oral steroids and to reduce risks of systemic complications of corticosteroids. They also help to improve long-term control of uveitis and thereby glaucoma. The conventional steroid-sparing agents include antimetabolites (eg, methotrexate, mycophenolate mofetil and azathioprine) and T-cell inhibitors (eg, cyclosporine and tacrolimus); however, these medications may fail to control uveitis in up to 40% of cases.³

Newer classes of biologics, namely the TNF-α inhibitors, have shown significant success in the treatment of chronic, noninfectious uveitis. Regular communication with the rheumatologist is essential to monitor systemic side effects.

SURGICAL MANAGEMENT

When it’s required

Surgical intervention may be required for glaucoma when medical management fails to control IOP.

The success of surgery depends significantly on the suppression of inflammation during the perioperative period. In general, uveitic glaucoma patients have lower success rates with glaucoma surgical interventions. Uveitic glaucoma patients also have higher rates of hypotony postoperatively.

The goal is to not have to perform a glaucoma surgery while the patient is actively inflamed. Oral glaucoma medications can be used to help get patients through their active uveitis phase until surgery.

If surgery must be performed in an actively inflamed eye, perioperative steroids are essential to moderate postoperative inflammatory response. Even in cases of quiesced eye, perioperative immunosuppression is key to moderating any postoperative inflammatory response. This can be in the form of periocular steroids or oral steroids. In urgent or emergent cases, where we do not have the time to fully quiet the eye, higher doses of steroids may be required with a slower postoperative taper.

Undesirable interventions

Other more common bridging interventions between medical therapy and surgery, such as selective laser trabeculoplasty and cyclophotocoagulation, are pro-inflammatory and not preferred for uveitic glaucoma. They include:

• Nd:YAG laser peripheral iridotomy. This may be indicated for acute angle closure secondary to extensive PS and iris bombé. Multiple and large iridotomies may be required due to closure from inflammation.
• Cycloablative procedures. Either transscleral or intraocular, these procedures can exacerbate inflammation, cause hypotony and lead to phthisis bulbi. Thus, they should be used only as a last resort for refractory uveitic glaucoma, and treatment must be carefully titrated.
• Laser trabeculoplasty. This is not recommended in uveitic glaucoma because of angle alteration. This modality, especially with use of argon-based lasers, has the potential to induce inflammation and damage the trabecular meshwork.

Minimally invasive glaucoma surgery (MIGS)

The use of MIGS is becoming popular in the treatment of POAG and is under evaluation for uveitic glaucoma patients with open angles. Ab interno trabeculotomy increases trabecular outflow by removing part of the trabecular meshwork. These procedures may have an advantage over small-lumen devices that may become obstructed from inflammatory debris.

Canaloplasty may be of special interest in these cases, because this procedure dilates and maintains a patent canal of Schlemm, expanding the intertrabecular spaces that are compromised as a result of glucocorticoids.

More investigation is necessary in regard to efficacy in patients with uveitic glaucoma.¹

Glaucoma drainage devices

Glaucoma drainage devices are the preferred first-line surgery in uveitic glaucoma, especially in cases with active inflammation. The Ahmed Glaucoma Valve (AGV) is often favored because of its immediate action and its unidirectional valve mechanism, which lowers the risk of postoperative hypotony. If an eye can tolerate high IOP for 4-6 weeks, a Baerveldt tube can be considered because it has a lower rate of reoperation and possible lower long-term IOP. Although no investigations have formally compared AGV to Baerveldt in uveitic glaucoma, studies have shown positive outcomes for both.¹

Trabeculectomy

Trabeculectomy should be avoided in eyes with active inflammation. However, in eyes with well-controlled uveitis, standard trabeculectomy or the Ex-Press glaucoma filtration device (Alcon) with anti-metabolite agents such as 5-fluorouracil and mitomycin C, which help minimize excessive scarring and decrease failure rates, can be considered.

CONCLUSION

Glaucoma, secondary to ocular inflammation, is potentially blinding and requires aggressive multifaceted management. Early education and counseling are key for compliance and expectation setting. Collaboration is often required with uveitis, glaucoma and rheumatology specialists. Increased medical and surgical interventions are also creating new opportunities for vision preservation. OM

REFERENCES

1. Kesav N, Palestine AG, Kahook MY, Pantcheva MB. Current management of uveitis-associated ocular hypertension and glaucoma. Surv Ophthalmol. 2020;65:397-407.
2. Gedde SJ, Vinod K, Wright MM, et al. Primary open-angle glaucoma: Preferred Practice pattern. Ophthalmology. 2021;128:P71-P150.
3. Sharma SM, Damato E, Hinchcliffe AE, et al. Long-term efficacy and tolerability of TNFα inhibitors in the treatment of non-infectious ocular inflammation: an 8-year prospective surveillance study. Br J Ophthalmol. Published Online First: March 12, 2019.

Purnima S. Patel, MD, is the CEO and founder of Ophthalmology and Retina Associates of Georgia. Dr. Patel has built a clinical and surgical practice at Emory University and the Atlanta VA Medical Center and was promoted to associate professor.
Find her on Twitter and Instagram @pspateleyeMD.
Dr. Patel reports no relevant financial disclosures.