Meeting the Challenge of Normal-Tension Glaucoma

Diagnosing this disease requires significant detective work.

By Andrew Rabinowitz, MD

Shallow optic nerve cups and inferior neuroretinal rim thinning in each eye are indicative of normal-tension glaucoma in a 65-year-old woman, and the right optic nerve showed a disc hemorrhage inferotemporally before treatment was initiated.

Most studies that have attempted to quantify the incidence of normal-tension glaucoma (NTG) in the United States have estimated that 15% to 30% of all glaucoma patients will not show the classic symptom of elevated IOP. But even the landmark Baltimore Eye Survey, published in 1991 by researchers from the Wilmer Eye Institute at Johns Hopkins University, conceded that any definition of NTG is somewhat arbitrary and that changing the high-end limit of NTG from 20 mm Hg to 21 mm Hg greatly increased the percentage of NTG diagnoses.¹

Though definitions of NTG are not exact, without the compelling “red flag” of high IOP to rely on we are challenged to find other ways to make an accurate diagnosis of NTG, which has also been called low-tension, normotensive or normal-pressure glaucoma.

Paths to an NTG Diagnosis

Glaucoma specialists tend to differ somewhat in how they go about arriving at a diagnosis of NTG. I place the highest priority on making a detailed analysis of the patient’s complete medical history. Others may put more emphasis on quantitative tests, such as corneal hysteresis, which uses the Ocular Response Analyzer (Reichert Technology, Depew, N.Y.) to provide a corneal-compensated IOP reading that can translate to a much higher IOP than traditional Goldmann applanation.² Still others may order greater frequency of IOP measurements to ensure they are not missing some elevated IOP readings indicative of classic glaucoma.³

Whatever diagnostic methods we use, we must understand the basic factors that differentiate NTG from typical primary open-angle glaucoma. As clinicians, we must know what physical conditions or events can cause NTG. We must know what methods we can use to accurately diagnose the disease, and we must have therapeutic approaches that enable us to treat and manage the disease. (Although elevated IOP is not the primary cause of NTG, it is clear that IOP reduction still remains crucial to its treatment.) This article will deal with the three basic challenges of this tricky and somewhat mysterious disease.

Why Glaucomas Are Different

Glaucomatous neuropathy is, in most cases, the consequence of elevated IOP. In the classic type of pressure-related glaucoma, the mechanisms of glaucomatous neuropathy have long been identified as both mechanical and vascular. The mechanical etiology is a consequence of elevated IOP causing a physical “crushing” of neurons at the level of the lamina cribrosa. The vascular etiology arises as elevated IOP causes the arteries to the optic nerve head to constrict, causing a reduction in blood flow to the optic nerve. Neuronal ischemia and consequently neuronal cell death ensues.

Conversely, we view the more elusive NTG as a cerebrovascular condition that results when either the quantity or quality of oxygenated blood reaching the optic nerve is compromised. The causes of vascular compromise in NTG are largely independent of elevated IOP.

The optic nerve is comprised of neuronal cells that originate at the retinal ganglion cell layer and traverse to the lateral geniculate body. The neuronal cells synapse at the level of the lateral geniculate body and traverse to the occipital cortex. The neurons of the optic nerve require adequate oxygen and nutrients to maintain ideal function. The oxygen and nutrients reach the neuronal cells via cardiovascular and cerebrovascular circulation. Abnormalities of the circulatory system can compromise the volume of oxygenated blood reaching the optic nerve.

Clues Start at the Heart

Conditions that compromise the quantity of oxygenated blood that reach optic nerves usually begin at the heart. Any cardiologic condition that compromises the flow of oxygenated blood exiting the left ventricle can cause low-tension glaucoma. Decreased ventricular function results in a decreased ejection fraction. The consequence of a decreased ejection fraction is a chronic compromise in the amount of oxygenated blood reaching the optic nerve and perhaps other neural tissues. Examples of cardiac disease that can contribute to or cause NTG include dilated viral cardiomyopathy, ischemic cardiomyopathy and cardiac arrhythmias as well as cardiac valve disease.

Following the circulatory system distal to the heart, the next possible cause of NTG is carotid artery stenosis. Unilateral or bilateral carotid stenosis can also compromise the amount of oxygenated blood reaching one or both optic nerves. The ischemia can be more pronounced either ipsilateral or contralateral to the stenotic carotid artery. Distal to the carotid arteries, the next sites that can contribute to normal-tension glaucoma are the ophthalmic arteries. Like carotid artery stenosis, ophthalmic artery tortuosity or stenosis can reduce the amount of oxygenated blood reaching the optic nerves leading to vascular glaucoma.

Finally, some patients have what is considered “small vessel arterial disease.” These patients do not have any known cardiac, carotid or ophthalmic artery abnormalities, yet appear to be prone to episodes of vasospasm. The exact triggers of vasospastic disease are unclear. For this reason, the vasostabilizing properties of calcium channel blockers have been indicated for NTG.

Blood Quality as a Factor

Conditions that compromise the quality of oxygenated blood reaching the optic nerves can also cause NTG. Red blood cell anemias and hemoglobenopathies can reduce the oxygen-carrying capacity of blood. In these scenarios, the amount of oxygen that reaches the optic nerve can be chronically compromised in spite of “normal” hemodynamics.

Any anatomic or physiologic condition that compromises the quality or quantity of oxygenated blood that reaches the optic nerve can cause NTG.

Why NTG Can Go Undiagnosed

Despite the many disease states that can cause or contribute to the development of NTG, it is often a diagnosis of exclusion.

In the absence of elevated IOP, NTG patients often go undiagnosed for years. NTG typically does not get diagnosed until an astute clinician notices optic nerve head abnormalities or visual field clues, or both. NTG patients often are unaware of any visual disturbance.

When attempting to make a diagnosis of NTG, the clinician must start with the patient history. This is the crucial, detailed detective work that separates a great diagnostician from an average one. In patients with primary open-angle glaucoma, the medical history is not always crucial. In NTG, it is vital to have a good understanding of the patient’s history as key to the diagnosis and management of the disease.

A Medical History Is Critical

When evaluating a patient who appears to have glaucomatous optic nerves or glaucomatous visual field loss, or both, in the absence of elevated IOP, I pay particular attention to the medical history. This encompasses disease states past and present, previous surgeries, prior traumas and all drug use.

Occasionally, a patient who presents with what appears to be glaucomatous optic nerve damage may in fact be manifesting evidence of a previous systemic hypovolemic event as opposed to a progressive disease such as NTG. A trauma that resulted in significant blood loss can provoke hypovolemic shock. A motor vehicle accident or inadvertent surgical trauma requiring blood transfusions are examples of vascular hypovolemia.

Hypovolemic events can cause a one-time ischemic state leading to optic nerve damage that may be indistinguishable from glaucomatous neuropathy. Because these hypovolemic events can be temporally remote, we must compel patients to dig deep into their memories to try to avoid overlooking these events. If the patient can recall an antecedent trauma that required blood transfusions, this must be placed high in the differential diagnosis.

Play Sherlock Holmes

Study the patient’s medical history meticulously for any cardiac abnormalities such as cardiomyopathy, arrhythmias, cardiac valve disease, and coronary artery disease. Additionally, diabetes and systemic migraines have also been associated with NTG.

In patients age 70 or older, take care to rule out giant cell arteritis (GCA) anytime a patient has optic neuropathy absent of elevated IOP. GCA can be ruled out initially with an erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) testing. If these tests are equivocal, temporal artery biopsy may be necessary for definitive diagnosis.

Beta-blockers and NTG

In my practice, the most commonly documented cause of NTG is the concomitant use of oral beta-blockers. These drugs can exacerbate nocturnal hypotension and bradycardia. The reduction in systemic blood pressure and heart rate can compromise retrobulbar hemodynamics and lead to optic nerve head ischemia and NTG.

If I identify a patient with NTG who is taking an oral beta-blocker, I will communicate with the prescribing physician and inquire as to whether the patient can be placed on another class of drug to help achieve the desired cardiovascular effect without compromising retrobulbar hemodynamics. Although I have seen many cases of NTG in which oral beta-blockers were contributory, the true prevalence of NTG among patients using oral beta-blockers has not been clearly elucidated.

Conduct a Complete Work-up

The work-up for NTG requires participation of the patient’s primary-care physician (PCP), who may wish to involve cardiology and neurology. I will communicate with the PCP and allow him or her to determine how to go about the cardiovascular and neurovascular work-up. If the PCP is not comfortable performing the cardiovascular and neurologic work-up, I leave it to his or her discretion to make the appropriate referrals.

The cardiovascular work-up should include EKG, high-resolution echo-cardiography, Holter monitoring, cardiac stress test and carotid Doppler imaging. Blood work should include CBC, ESR, CRP, coagulation studies and ACA (anti-cardiolipin antibody) testing.

The neurologic work-up for NTG should involve baseline neuroimaging, including an MRI and possibly MRA. I do not order the neuroimaging studies on my own. I ask the PCP or neurologist to order them. I proceed in this manner so that if the test results are abnormal, the patient will be in contact with the appropriate physician to help address the implications of the test results.

Arriving at a Diagnosis

Once the non-ocular studies have been completed, we may have a better understanding of the presence of any concomitant disease states that can hasten the progression of NTG. If the studies identify any cardiovascular abnormalities, they must be addressed and treated to the highest degree possible. The same goes for the patient’s neurologic status. The role of the ophthalmologist in the treatment of NTG is to reduce IOP using topical medications while avoiding the use of non-selective beta-blockers.

NTG Treatment and Management

The pharmacologic treatment of NTG is similar to that of pressure-related glaucomas, with the exception of the role of topical non-selective beta-blockers. Prostaglandins are often the first-line drug for managing NTG. If prostaglandin monotherapy fails to lower IOP to the target range, then alpha-agonists or topical carbonic anhydrase inhibitors can be added in whatever order the treating physician prefers. If a combination of topical hypotensive agents fails to reduce IOP to the target range, one can use SLT adjunctively.

For the future, clinical trials with Rho Kinase (ROCK) inhibitor drugs are showing promise in being able to lower IOP from even normal levels (see “Glaucoma as a Neurodegenerative Disease,” page 47). This quality could have positive implications in the treatment of NTG. OM

REFERENCES

1. Sommer A, Tielsch JM, Katz J, et al. Relationship between intraocular pressure and primary open-angle glaucoma among black and white Americans. The Baltimore Eye Survey. Arch Ophthalmol. 1991;109:1090-95

2. Morita T, Shoji N, Kamiya K, Hagishima M, Fujimura F, Shimizu K. Intraocular pressure measured by dynamic contour tonometer and ocular response analyzer in normal-tension glaucoma. Graefes Arch Clin Exp Ophthalmol. 2010; 248:73-77.

3. WuDunn D. The unique challenges of normal-tension glaucoma. Ophthalmology Management, November 2010; 14:36-39

4. Crish S, Calkins D, Neurodegeneration in glaucoma: progression of calcium-dependent intracellular mechanisms. Neuroscience. 2011; 176:1-11.

5. Schumer R, Podos S. The nerve of glaucoma. Arch Ophthal. 1994;112:37-44.

6. Samples J. Prospects for neuroprotection in glaucoma. Ophthalmology Management. February 2011;15:34-37

7. Cantor LB. Brimonidine in the treatment of glaucoma and ocular hypertension. Ther Clin Risk Manag. 2006;2:337-46.

Andrew Rabinowitz, MD, is the principal glaucoma specialist for Barnet, Dulaney Perkins Eye Centers, a multi-location practice based in Phoenix. He can be reached via e-mail at andrewrabinowitz@aol.com. He has no financial interest in any product mentioned in this article.