When it’s not primary glaucoma

Systemic diseases and medications can increase intraocular pressure.

By Chandrasekharan Krishnan, MD

As an ophthalmologist in a busy practice, you might think of glaucoma solely in terms of its impact on eye health. However, for some subsets of patients, you should look at them holistically, and not just at their eyes. These subsets fall into several categories:

• systemic diseases that can lead to glaucoma

• glaucoma induced by systemic medications

• systemic implications of an “ocular” disease

• “masqueraders,” or systemic conditions that, while capable of causing optic neuropathies that look like glaucoma, do not.

Here, I will address the key points to keep in mind and provide select references for those interested in exploring a particular topic further.

Systemic diseases leading to glaucoma

Of all glaucomas, inflammatory glaucoma is the one most likely to garner systemic consideration by the ophthalmologist. Many entities can cause intraocular inflammation — some of these are limited to the eye (such as Fuchs heterochromic iridocyclitis), while others are systemic conditions with ocular manifestations. The vast majority of systemic diseases leading to inflammatory glaucoma are either infectious or autoimmune in nature.

Intraocular inflammation leads to elevated intraocular pressure (IOP) via one of three mechanisms: open-angle glaucoma (trabeculitis), acute-angle closure (formation of iridolenticular adhesions causing iris bombe; ciliary body swelling) or chronic-angle closure (development of iridotrabecular adhesions). The clinical picture of the patient should direct work-up.¹

Some of the systemic entities to consider (common tests in parentheses) include:

• Autoimmune. Sarcoidosis (ACE, lysozyme); juvenile rheumatoid arthritis (medical history, ANA, ESR/CRP); HLA-B27+ anterior uveitis

• Infectious. Tuberculosis (PPD, chest x-ray); syphilis (VDRL, FTA-ABS)

Many developmental diseases are associated with glaucoma.² Some diseases that should garner systemic considerations include:

• Axenfeld-Rieger. This syndrome is characterized by abnormal iris appearance, an anteriorly displaced Schwalbe’s line (posterior embryotoxon) and iris strands to Schwalbe’s line (Figures 1 and 2). These patients can have craniofacial and dental abnormalities. Occasionally, these patients have pituitary abnormalities and cardiac anomalies.



Figure 1. Anterior segment photo of an anterior displaced Schwalbe’s line (arrows) in a patient with Axenfeld-Rieger Syndrome.



Figure 2. A gonioscopic photo depicting iris adhesion to Schwalbe’s line (arrow) in a patient with Axenfeld-Rieger Syndrome.

• Aniridia. Caused by an abnormality in the PAX6 gene, patients with aniridia can develop glaucoma in a variety of ways, both via open-angle and angle-closure mechanisms. Systemically, one should consider WAGR syndrome (Wilms tumor (nephroblastoma), aniridia, genitourinary abnormalities and mental retardation) in patients with autosomal dominant inheritance patterns. Systemic issues in autosomal recessive inheritance patterns include cerebellar ataxia and developmental delay.

• Sturge-Weber syndrome (SWS). One of the phacomatoses, SWS can cause glaucoma due to increased episcleral venous pressure. It is typically unilateral and can be difficult to control. Systemic concerns include ipsilateral leptomeningioma (imaging is recommended) and seizure.

• Neovascular glaucoma. Neovascular glaucoma is caused by proliferation of new blood vessels over the trabecular meshwork, eventually leading to synechial angle closure glaucoma if untreated (Figure 3). These vessels grow because of lack of retinal oxygenation, causing the release of vascular growth factors.³ Some of the more common systemic issues leading to neovascular glaucoma include ocular ischemic syndrome (carotid disease), vein occlusion (hyperviscosity syndrome) or artery occlusion (valvular or carotid embolus) and proliferative diabetic retinopathy (poorly controlled diabetes).

Figure 3. Gonioscopy shows new blood vessel growth along the trabecular meshwork along with broad iridotrabecular synechiae in a patient with neovascular glaucoma.

Glaucoma induced by systemic medications

Many medications that are used to treat systemic disease can also cause glaucoma. For example, patients started on prednisone should be monitored closely, as IOP elevation can occur days to years after starting treatment.

Many nonsteroidal medications can cause glaucoma as well.⁴ The mechanism of action of these medications is varied — most act via an angle closure mechanism. This is especially a concern in patients who are already predisposed to angle closure by anatomically narrow angles. Common medications of concern include antihistamines and decongestants sold over the counter. Peripheral iridotomy is often required to break the attack.

Special consideration of medications should be given to patients presenting with bilateral angle-closure glaucoma. Bilateral acute (or subacute) angle-closure glaucoma is often induced by sulfonamide-containing medications due to ciliary body swelling (topiramate being most notorious for this). The treatment of patients with angle-closure glaucoma due to ciliary body swelling differs from treatment of primary angle-closure glaucoma, and includes discontinuing the oral agent, cycloplegia and medical treatment.

In situations where you believe that a systemic medication is causing glaucoma, it’s worth having a discussion with the prescribing physician to determine whether other options exist (i.e., steroid-sparing agents instead of prednisone for autoimmune conditions).

Systemic implications of an “ocular” disease

At times, glaucoma may be considered limited to the eye but have systemic implications. Pseudoexfoliation (PXF) results from a polymorphism in the LOXL1 gene, which produces an enzyme involved in crosslinking of elastin and collagen in the extracellular matrix. As ophthalmologists, we often think of PXF in terms of increased risk of glaucoma and cataract (Figure 4). However, emerging evidence shows that PXF is a systemic disease that affects multiple organs. For example, a meta-analysis performed in 2014 showed increased risk of vascular disease (including coronary heart disease and cerebrovascular disease) in patients with PXF.⁵

Figure 4. Anterior segment retroillumination photo demonstrating the typical dispersion of pseudoexfoliative material on the lens surface.

Further studies are needed to understand the full impact of systemic PXF, and what interventions (for example, anticoagulation) could help prevent the systemic complications of PXF.

Masqueraders

Systemic entities that have been associated with normal tension glaucoma (NTG) seem to have a vasospasmic link (Raynaud’s phenomena, Prinzmetal angina, migraine). The more common concern with NTG is determining whether the observed optic neuropathy is due to glaucoma or to another systemic etiology. Extraocular entities that can cause optic neuropathy similar in appearance to normal tension glaucoma include:

• old optic neuritis (due to systemic inflammatory diseases)

• anterior ischemic optic neuropathy (especially nonarteritic)

• sleep apnea

• low nocturnal blood pressure

• optic nerve tumor

• prior steroid use

• toxic/metabolic deficiencies

• prior blood loss or trauma.

A detailed history can help sort out many of these issues. Determine whether to image these patients (i.e., orbital MRI) and obtain additional lab work based on clinical history and suspicion.⁶

Conclusion

Ophthalmologists treating glaucoma will always be primarily concerned with the local impact of the disease. However, systemic consideration in select patients will help contribute to their overall health. OM

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