In June 2005, a 60-year-old black female was referred to our clinic by a local optometrist for suspected glaucoma. The practitioner was concerned about the appearance of the patient's optic nerve and her apparent visual field loss with frequency doubling perimetry. In addition, the IOPs in both of the patient's eyes had fluctuated in the midteens over the course of a number of visits, and she had a family history of glaucoma.
The patient's past medical history was significant for hypertension and thyroid dysfunction, and her previous surgical procedures included hysterectomy and thyroidectomy. She was taking lisinopril and hydrochlorothiazide for her hypertension.
At our initial evaluation, the patient had a BCVA of 20/20 OD and 20/50 OS, and her IOPs measured 14 mm Hg bilaterally with Goldmann applanation tonometry. These measurements were obtained at 1:44 PM. The anterior segment examination was remarkable for mild nuclear sclerotic cataracts bilaterally, but we did not note afferent pupillary defects. Gonioscopy with a four-mirror gonioprism revealed angles that were open to the ciliary body band bilaterally with mild pigmentation throughout the entire circumference of the trabecular meshwork. Pachymetry measured 563 µm OD and 564 µm OS. Ninety-diopter stereoscopic ophthalmoscopy showed enlarged cup-to-disc ratios bilaterally and deep cupping inferiorly that was greater on the left than on the right (Figure 1).
Figure 1. Photographs of the patient's right and left optic discs taken 6 months after her initial evaluation showed thinning of the inferior rim that was greater on the left than on the right.
We also noted significant pallor of the neuroretinal rims bilaterally. A SITA-Standard 24-2 Humphrey visual field test (Carl Zeiss Meditec, Inc., Dublin, CA) revealed an early superior arcuate scotoma in the patient's right eye and a dense superior arcuate scotoma in her left eye (Figure 2A and B).
How Would You Proceed?
1. Would you diagnose this patient with a normal-
tension variant of primary open-angle glaucoma (POAG) versus nonglaucomatous cupping?
2. Would you perform additional diagnostic tests such as neuroimaging? What other tests would you perform?
3. Would you initiate topical medical therapy immediately? If so, which agents would you prescribe?
Figure 2. Results of the SITA-Standard 24-2 Humphrey visual field testing taken in May 2005 revealed scattered missed superior points for the patient's right eye and a superior arcuate defect for her left eye.
Clinical Course
We strongly suspected the patient had POAG of the normal-tension variant due to her previous IOP measurements, the pallid appearance of her optic nerves, and the changes in her visual fields that correlated with her optic nerves' inferior cupping. She also had several risk factors for POAG, including race, hypertension, and family history.1 In addition, normal-tension glaucoma (NTG) is more common in women than in men.2
According to the Collaborative Normal-Tension Glaucoma Study,3 patients at risk for this type of glaucoma benefit from treatment that lowers their IOP by 30% from baseline. Because NTG is a diagnosis of exclusion, however, we ordered ancillary tests that included magnetic resonance imaging (MRI) of the brain, a bilateral carotid ultrasound, complete blood count, and erythrocyte sedimentation rate. While we waited for the results of the studies, we started the patient on a 1-month trial of latanoprost ophthalmic solution (Xalatan; Pfizer Inc., New York, NY) at bedtime in her left eye only. We were also concerned that the patient's symptoms might be caused by a nonglaucomatous neuropathy.
The cranial MRI revealed bilateral subacute subdural hematomas in the patient's frontotemporal regions. The lesion on the left, which was larger than the one on the right, mildly effaced the body of the left hemisphere and the left lateral ventricle without an apparent midline shift. The carotid ultrasound revealed insignificant stenosis bilaterally, and the blood tests were unremarkable. The patient was referred to neurosurgery for the serendipitous intracranial findings, and she underwent evacuation of the subdural hematomas in September 2005.
Outcome
Due to the patient's brain surgery, we did not see her again for 6 months. Upon examination, her IOPs measured 12 mm Hg bilaterally (at 5:30 PM). Because her IOPs were within the range for NTG, we decided to continue treating her for this condition. To lower her IOP, we instituted a monocular trial of brimonidine 0.15% (Alphagan P; Allergan, Inc., Irvine, CA) twice daily in her left eye for its potentially neuroprotective effects.4
Following the guidelines set by the Collaborative Normal-Tension Glaucoma Study, we set the patient's target IOP at 10 mm Hg or lower to achieve a 30% reduction from her baseline IOP of 14 mm Hg. The patient initially responded well to the brimonidine, with her IOP measuring 8 mm Hg OS versus 11 mm Hg OD. She has since undergone selective laser trabeculoplasty for her left eye and has switched to bimatoprost ophthalmic solution 0.03% (Lumigan; Allergan, Inc.) to potentially improve treatment efficacy and compliance.
The patient has maintained IOPs between 8 and 10 mm Hg OU (by Goldmann applanation tonometry) on this regimen. Two consecutive Humphrey visual fields obtained since her initial visit revealed stable, nonprogressive superior arcuate defects (Figure 2C and D).
Figure 2. One year later, the same test showed similar results, indicating that the patient's visual fields were stable (right, C; left, D).
Discussion
Diagnosing NTG in a patient who has cupping of the optic nerve and intraocular pressures within the normal range can be challenging, because other diseases can cause similar changes. Neuroimaging of the orbits and the brain can rule out other diseases, but these tests are expensive and can unnecessarily alarm the patient. How, then, does one decide which patients with suspected NTG should get an MRI?
Initially, a thorough medical, surgical, and ocular history can efficiently condense the differential diagnosis and provide a more directed workup. A careful examination that includes gonioscopy may reveal that the patient has another form of glaucoma, such as pigmentary or chronic angle closure glaucoma. Burned-out POAG can present with normal tensions as well. Furthermore, findings such as a significant diurnal IOP spike and thin central corneas can unmask POAG. Other disease processes that can result in an optic neuropathy and visual field loss with normal IOPs include:
• Vasculopathies and vasospastic disorders: Raynaud's phenomenon, migraines, autoimmune disorders, significant carotid atherosclerosis, nocturnal hypotension;
• Blood abnormalities: hyperviscosity states, acute blood loss, anemia;
• Systemic diseases: hypothyroidism, syphilis, tuberculosis, multiple sclerosis, autoimmune neuropathy (heat shock proteins)5;
• Orbital and prechiasmal intracranial lesions;
• Optic nerve disorders: drusen, ischemic optic neuropathy, old optic neuritis or papilledema; and
• Iatrogenic factors: medications such as isoniazid, ethambutol, sidenafil, beta-blockers, and nocturnal hypoperfusion.
The following factors should help clinicians differentiate between glaucomatous cupping and nonglaucomatous cupping from a compressive lesion:
The Beaver Dam Study demonstrated that NTG was more common with advancing age.2 The disease's incidence increased from 0.2% among patients 43- to 54-years old to 1.6% among patients older than 75 years. Moreover, Greenfield et al3 showed that optic nerve cupping in patients younger than 50 years was 93% specific for nonglaucomatous etiologies.
Optic disc cupping is more suggestive of NTG when it is associated with visual acuities of 20/50 or better. In Greenfield's study,3 76.9% of the NTG subjects had visual acuities of 20/50 or greater versus 47.7% of patients who had compressive intracranial lesions. In addition, NTG is more common among females than males.
Although previous studies have indicated an association between family history and optic disc cupping due to POAG,3 no published data demonstrate a similar association between family history and nonglaucomatous cupping.
Overall, disc hemorrhages are relatively rare and were seen in only 14% of glaucomatous optic nerves studied by Greenfield et al.3 Several studies, however, have found a convincing correlation between disc hemorrhages and NTG.4 Tanna and Jampel6 noted this defect in 10.4% to 21.7% of eyes with NTG. The presence of disc hemorrhages in flat, cupped optic nerves is likely due to glaucoma. Greenfield et al3 reported that disc hemorrhages were not seen in any patient with cupping due to a nonglaucomatous entity.
The presence of optic disc hemorrhages in glaucomatous eyes is also important because it often signifies faster disease progression and visual field loss.7 Such a finding may warrant closer follow-up and call for more aggressive IOP-lowering therapy.
The appearance of the optic nerve may provide clues about the underlying cause of glaucomatous changes. Characteristic patterns of cupping seen in POAG, such as a vertical elongation of the cup and peripapillary atrophy, are also commonly seen with NTG, but they may occur less frequently with compressive optic neuropathies. Vessel nasalization is an equivocal finding and may be seen frequently with glaucomatous and nonglaucomatous cupping of the optic nerve.3 Optic nerve pallor in excess of cupping most often points to a compressive lesion.
Although NTG and compressive prechiasmal lesions can produce visual field defects that are similar to those caused by POAG, controversy remains over whether NTG produces characteristic field changes. One study suggests that NTG produces visual field defects that are often deeper, steeper, and closer to fixation.8 Conversely, visual fields that strictly respect the vertical midline are more specific for intracranial pathology.
Our patient's risk factors for POAG and NTG included female gender, race, and a positive family history. Her Humphrey visual fields revealed superior defects that respected the horizontal meridian bilaterally, but she also had associated temporal neuroretinal pallor with disc cupping and a mildly depressed visual acuity of 20/40 in her left eye. Moreover, at 60 years of age, she was at the younger end of the high-risk range for POAG and NTG. Accordingly, we felt this patient should have an MRI.
Although the patient's MRI revealed bilateral subdural hematomas, these lesions were probably unrelated to her optic nerve cupping. Previously, clinically silent intracranial lesions were identified in 3.8%2 to 6.9%5 of neuroimaging studies obtained for suspected NTG. Such intervention is rarely needed to confirm a diagnosis of NTG, but we feel it may be necessary when disc pallor is out of proportion to disc cupping. In most cases, observation over time will obviate the need for neuroimaging in these patients.
Steven V. L. Brown, MD, is Associate Professor of Ophthalmology at Rush University Medical College, Rush-Presbyterian-St. Luke's Medical Center in Chicago, and he is Senior Attending Clinical Instructor at Northwestern Medical School, Evanston Northwestern Hospital in Evanston, Illinois. Dr. Brown is in private practice with the Chicago Glaucoma Consultants in Chicago and Evanston, Illinois. He acknowledged no financial interest in the products or companies mentioned herein. Dr. Brown may be reached at (847) 492-3250; drsvlb@aol.com.
Seanna Grob is a Research Fellow at the Chicago Glaucoma Consultants in Chicago and Evanston, Illinois. She acknowledged no financial interest in the products or companies mentioned herein. Ms. Grob may be reached at (847) 492-3250; seannagrob@gmail.com.
Elizabeth Yeu, MD, is a Chief Resident in Ophthalmology at the Rush University Medical Center in Chicago. She will begin a clinical fellowship in Cornea and Anterior Segment Diseases at the Baylor College of Medicine in Houston in July 2007. She acknowledged no financial interest in the products or companies mentioned herein. Dr. Yeu may be reached at (312) 942-5315; elizabeth_yeu@rush.edu.
1. Chumbley LC, Brubaker RF. Low-tension glaucoma. Am J Ophthalmol.1976;81:761-767.
2. Klein BEK, Klein R, Sponsel WE, et al. Prevalence of glaucoma. The Beaver Dam Study. Ophthalmology. 1992;99:1499-1504.
3. Greenfield DS, Saitkowski RM, Glaser JS, et al. The cupped disc: who needs neuroimaging? Ophthalmology. 1998;105:1866-1874.
4. Siegner SW, Netland PA. Optic disc hemorrhages and progression of glaucoma. Ophthalmology. 1997;104:566-567.
5. Stewart WC, Reid KK. Incidence of systemic and ocular disease that may mimic low-tension glaucoma. J Glaucoma. 1992;1:27-31.
6. Tanna AP, Jampel HD. Glaucoma diagnosis and management: normal-tension glaucoma. Ophthalmol Clin North Am.
2000;13:455-464.
7. Rasker MT, van den Enden A, Bakker D, Hoyng PF. Deterioration of visual fields in patients with glaucoma and without optic disc hemorrhages. Arch Ophthalmol. 1997;115:1257-1262.
8. Greve EL, Geijssen HC. Comparison of glaucomatous visual field defects in patients with high and with low intraocular pressures. Doc Ophthalmol Proc Ser. 1983;35:101-105.
