Ian Conner, MD, PhD; Kimberly V. Miller, MD; Joel S. Schuman, MD, FACS; and David L. Epstein, MD, MMM
DEFINITION
Normal-tension glaucoma (NTG) has long been poorly understood in terms of diagnosis, pathophysiological mechanisms, and therapy. This confusion is nefarious because NTG is not uncommon, is easily missed in its earliest stages, can affect central visual field early, and is difficult to treat. NTG is surprisingly common in Japan,1 but we have likely underappreciated its frequency in the United States.
It is conceptually useful to first reconsider optic nerve cupping in response to elevated intraocular pressure (IOP). As previously discussed, there appears to be an individual susceptibility of the optic nerve to cupping in response to a given IOP. For example, one patient may have progressive damage with IOPs in the low 20s, while another patient with similar IOPs may never develop damage. What explains the increased susceptibility of the optic nerve to IOP in the first patient? There has been much discussion of possible mechanical or vascular factors2–5 that may predispose to cupping.
This text deals with the practical clinical care of the glaucoma patient and builds on long-term clinical experience with such patients. Our clinical experience strongly indicates that almost all patients with NTG have an IOP-sensitive component, and that adequately lowering the IOP improves the course of the disease. Further, the Collaborative Normal-Tension Glaucoma Study demonstrated that lowering IOP by 30% or more reduces visual field progression in NTG patients.6 Unfortunately, IOP alone does not appear to explain the exceptional susceptibility of the optic nerve to cupping in NTG.
Nonprogressive forms7 of NTG appear to be rare, so the treating ophthalmologist is advised to either treat the IOP or consider an alternative diagnosis if considering nonprogressive disease. The “curse” of long-term follow-up makes apparent that NTG is a progressive, potentially blinding disease for many patients. Thus, it is critical in NTG to lower the IOP aggressively and follow the optic nerve appearance and the visual field closely.
SYMPTOMS
Most patients with NTG are asymptomatic and are detected by the ophthalmologist on a routine examination based on the optic nerve appearance. Occasionally, patients present with a subjective scotoma near fixation. Sometimes, there does appear to be a credible history of sudden onset, although this commonly represents a discovery phenomenon when one eye is inadvertently covered.
Patients should be asked about neurological symptoms, such as weakness in extremities, dizziness, headaches, loss of consciousness, diplopia, etc. If a patient has any such symptoms, except for typical migraine headaches, a neuro-ophthalmological evaluation is indicated. Migraine has been associated with NTG,8,9 suggesting the possibility of vascular factors involved in pathogenesis, although the connection is controversial.10,11
TABLE 20-1. DIFFERENTIAL DIAGNOSIS OF NORMAL-TENSION GLAUCOMA
| Disorder | Comment |
| Temporal arteritis | Usually acute severe unilateral vision loss, optic disc swelling, increased disc cupping occurs after acute event, systemic symptoms (myalgias, headache), elevated erythrocyte sedimentation rate |
| Anterior ischemic optic neuropathy | Usually acute unilateral vision loss, disc swollen initially then pale, increase in disc cupping unusual, altitudinal visual field loss may mimic glaucoma |
| Pituitary or intracranial tumors | Visual field usually bilateral, visual field loss rarely appears glaucomatous, early loss of visual acuity and color vision, optic nerve pallor without abnormal disc cupping |
| Methanol intoxication | History of drinking moonshine, acute severe bilateral vision loss, early disc swelling followed by optic nerve pallor and disc cupping |
| Kjer’s hereditary optic neuropathy | Positive family history, usually bilateral with pallor and excavation affecting temporal disc in a young patient |
| Congenital optic pit or coloboma | Deeply excavated optic nerve, often unilateral, visual fields stable in absence of serous retinal detachment |
| Syphilitic (tertiary) optic neuropathy | Optic pallor with abnormal cupping, positive serology (fluorescent treponemal antibody and rapid plasma regain), other evidence of tertiary syphilis |
| History of past elevated IOP | Resolved steroid-induced, uveitic, or trauma-induced glaucoma in the past can mimic normal-tension glaucoma |
Raynaud’s phenomenon has been associated with NTG, and there is some evidence that immunological disease may also be associated with NTG.12,13
Systemic factors may be involved in the pathogenesis of NTG, helping to explain the special susceptibility of the optic nerve. Systemic nocturnal hypotension appears to be related to glaucoma progression in some patients, perhaps related to microangiopathy and decreased ocular blood flow. However, studies so far have been inconclusive.14
The presence of any neurological symptom indicates the need for a neuro-ophthalmological evaluation to rule out neurological disease that might masquerade as NTG. The suggestion of accompanying systemic disease, with the exception of migraine, in a patient with NTG would indicate the need for a medical evaluation as part of the global care of the whole patient.
DIFFERENTIAL DIAGNOSIS
Certain nonglaucomatous conditions can present with contour changes in the optic nerve head that might be misinterpreted as NTG (Table 20-1).
Contour changes of the disc rim occur in one-third or more of patients with a history of giant cell arteritis. There is usually severe visual field and acuity loss in these cases,15 and the disc contour changes are typically first detected a few weeks after the event, after the initial disc swelling has subsided. The characteristic history of sudden vision loss and reduction in central visual acuity are helpful differentiating features. Other forms of ischemic optic neuropathy can rarely produce focal contour changes as well.
Visible disc cupping is rarely present with pituitary and other intracranial tumors, but thinning of the retinal nerve fiber layer (RNFL) frequently occurs in these diagnoses. The RNFL damage is often detectable by optical coherence tomography (OCT), confocal scanning laser ophthalmoscopy, or scanning laser polarimetry. The presence of non glaucomatous visual field loss, substantial asymmetry of the optic nerves, thin RNFL that corresponds to non glaucomatous visual field defects, or any unexpected neurological symptoms indicates the need for neuro-ophthalmological evaluation. If in doubt, it is best to refer such a patient for neurological evaluation. It is advisable not to miss an intracranial tumor, even though this is a rare masquerade.
Methanol intoxication is usually detectable by history if one remembers to ask about consumption of noncommercial moonshine. There should be a history of acute vision loss accompanied by bilateral disc edema, followed later by atrophy of the optic nerves with occasional disc contour changes. The typical rapid loss of vision and bilateral sustained reduction in central visual acuity can be helpful in differentiation.
Family history should assist with the diagnosis of Kjer’s and other hereditary optic neuropathies, which classically present in the first 2 decades.
Tertiary syphilis (the great masquerader) has been reported to cause a pseudoglaucomatous disc appearance, but the authors have never observed this occurrence and believe the presentation as a NTG masquerade must be rare.
Colobomas and pits can sometimes create confusion, but usually the deep focal excavation on careful examination helps establish the diagnosis. Field defects should be nonprogressive, unless serous macular detachment occurs. The widespread use of OCT can be especially helpful in establishing these diagnoses.
TABLE 20-2. WHEN TO PURSUE NEUROLOGICAL WORK-UP IN A PATIENT WITH SUSPECTED NORMAL-TENSION GLAUCOMA
| Monocular optic nerve involvement or marked asymmetry |
| Unexplained reduction in visual acuity |
| Color vision loss without advanced visual field loss |
| Visual field loss out of proportion to optic nerve damage |
| Nonglaucomatous or atypical neurological symptoms |
| Optic nerve pallor instead of cupping |
Remember that the severe vision loss or atypical visual field loss suggests a diagnosis other than NTG. When the other conditions mentioned cause contour changes on the disc, there is usually some atypical character to the cupping. Most commonly, the atypical finding is the color of the rim tissue not involved in the contour change. This is usually pale (ie, demonstrating optic atrophy) in these pseudoglaucomatous conditions, unlike typical cases of glaucoma in which the unaffected disc tissue maintains its normal color.
Of course, some patients with nonglaucomatous optic neuropathy will develop glaucoma as a separate clinical disease. In addition to other considerations, these patients can be challenging to manage because of their preexisting optic nerve damage.
In the differential diagnosis of NTG, one must finally include causes of prior elevation of IOP that have now resolved. Examples include previous steroid usage, uveitis, or trauma-related glaucoma. Such secondary glaucomas may not have been appreciated at the time of occurrence.
WHEN TO OBTAIN NEUROLOGICAL TESTING IN A PATIENT WITH NORMAL-TENSION GLAUCOMA
Unfortunately, NTG is now recognized as a common disease. Routine neuroimaging is not performed, but the treating ophthalmologist must maintain a high index of suspicion for atypical presentation and disease course. A full neuro-ophthalmological evaluation is recommended in these cases (Table 20-2). There is no such entity as unilateral NTG, and substantial asymmetry is very uncommon. All such patients need neurological evaluation.
NORMAL-TENSION GLAUCOMA AND THE GENERAL OPHTHALMOLOGIST
David L. Epstein, MD, MMM
INCORRECT DIAGNOSIS
The general ophthalmologist is an unsung but true hero in the detection of patients with NTG. Consider in a busy general practice a patient whose IOP is normal, where in the absence of any visual field data the general ophthalmologist is suspicious about NTG on the basis of his or her evaluation of the optic nerve. This ophthalmologist is a true disc sleuth. Recall the previously described techniques of evaluation of the optic nerve in glaucoma by assessing disc contour (see Chapter 8), as well as optic nerve and nerve fiber layer imaging (see Chapter 9). The goal is to detect NTG before there is clinically significant optic nerve damage, and especially before the patient notices the presence of subjective scotomata, which notoriously can involve points close to central fixation in NTG. Because this disease may be increasing in prevalence in our aging population, the disc sleuthing general ophthalmologist truly deserves our praise.
THERAPY
Although there must be some systemic influence in NTG, there is no proven systemic therapy for this condition. There have been conflicting data16,17 about calcium channel blockers, even with regard to mechanism of action in NTG patients, so we do not routinely recommend calcium channel blocker therapy.
It is clear that there is an IOP-sensitive component18–20 in most patients with NTG. Documentation of the patient’s baseline IOP is critically important. One should aim to decrease IOP by at least 20% to 25% as a first step. Special attention should be pain to managing patients with scotomata close to central fixation, and central 10-degree visual field measurement should be performed in addition to the usual 24-degree fields. Patients with such advanced field loss should be monitored closely (eg, at least 3 times per year). Treatment for NTG follows the same protocol as for POAG.
Typically, one begins with a prostaglandin analog and then progresses to a secondary agent, which is selected based on the individual patient’s other comorbid conditions. Laser trabeculoplasty should also be considered as a first-line treatment in patients where compliance or convenience merit. Filtering surgery may become necessary when the maximum tolerated medical or laser therapy fails to control the IOP at a level sufficent to prevent progressive damage. Surprisingly, laser trabeculoplasty with or without concomitant medical therapy can be often be effective21 to achieve an IOP around 10 mm Hg.
As with POAG, it is important to establish a target pressure to guide your management. Baseline stereo disc photographs and 24-degree visual fields are important for baseline documentation and need to be reevaluated as frequently as every 4 to 6 months. Structural imaging of the optic nerve and RNFL is helpful as well.
OCULAR EFFECTS OF CALCIUM CHANNEL BLOCKERS: PAST PROMISE
Peter A. Netland, MD, PhD
Calcium channel antagonists block cell membrane–bound calcium channels and inhibit calcium influx, which can have a profound effect on cellular metabolism and function. In blood vessels, these drugs cause relaxation of smooth muscle cells in vascular walls, decrease vascular resistance, and improve blood flow. The ocular effects of calcium channel blockers were once thought to be of great interest in relation to glaucoma, but much of the previous expectations have not been realized.1
Historical studies revealed that the vascular effects of calcium channel blockers could inhibit vasospasm or enhance ocular blood flow,2,3 which could then theoretically prove beneficial in glaucoma patients. In “vasospastic” patients and patients with low-tension glaucoma (LTG), systemic administration of calcium channel blockers was shown to be associated with improvements in visual field testing.4,5 Some clinicians believed that improvement or stabilization of visual fields in LTG patients could be significant after treatment with systemic calcium channel blockers. In the past, we evaluated serial stereoscopic optic nerve photographs and visual fields for evidence of glaucomatous progression in LTG patients who were concurrently taking calcium channel blockers compared with controls.6 In this retrospective study, the use of systemic calcium channel blockers was associated with a slowed progression of LTG. We have postulated that this apparent beneficial effect may be related to the inhibition of vasospasm or enhancement of optic nerve blood flow caused by these drugs.
The effect of calcium channel blockers on IOP may also be of significance. Systemic administration of verapamil or nifedipine in rabbits sometimes caused a decrease in IOP.7,8 In humans, either no effect or sometimes a decrease in IOP after systemic administration of verapamil, nifedipine, nitrendipine, or diltiazem has been observed.9–12 However, a more pronounced effect was observed in ocular hypertensives or established glaucoma patients, who demonstrated elevated IOP at baseline.9
Topical administration of verapamil causes a significant reduction of IOP in ocular hypertensive human participants.13 This effect was sustained after topical administration of verapamil 3 times daily for 2 weeks.14 Significant reduction of IOP has also been observed in normal human participants after treatment with topical verapamil.2 Experimental studies in rabbits have shown either no effect8 or a reduction15 of IOP after treatment with topical calcium channel blockers. Topical administration of higher doses of calcium channel blockers (1.5% to 5%) resulted in transient elevation of IOP,16 suggesting a dose-dependent, biphasic response at higher doses of these drugs, perhaps due to other nonspecific effects besides calcium channel blockade.1 Topical treatment with the calcium ionophores A23187 and X573A have been observed to increase IOP in rabbits.17 These agents would be expected to demonstrate an opposite action to calcium channel blockers.
Topical administration of the calcium channel blocker verapamil, therefore, usually causes a moderate reduction of IOP. The more consistent effect on IOP of topical compared with systemic treatment may be due to higher drug levels reached after topical instillation of verapamil.18 The mechanism of action may be due to enhancement of outflow facility.19,20 Topical calcium channel blockers were found to lower episcleral venous pressure.21 These studies suggested a future possible role for topical therapy in the management of glaucoma. However, translation of this treatment modality to clinical practice from the preclinical setting and early rudimentary human studies was unsuccessful, and the previous hope for this class of therapy was not realized. Case reports of an association with systemic adverse events with systemic calcium channel blockers were a concern in glaucoma patients22,23; however, comparative retrospective and randomized prospective trials found evidence of benefits of calcium channel blockers in LTG patients.24,25 Topical calcium channel blockers were not developed for commercial use due to the relatively small market of LTG patients and, at that time, the lack of a regulatory pathway for non-IOP effects in patients with glaucoma.
Much of what has been presented in this section is of historical relevance but is still of value to those developing new therapies for glaucoma. Early promise does not always translate into wide clinical use. However, we learn from every experience, and even failures can lead to bigger breakthroughs that will allow us to better treat our patients.
REFERENCES
1. Netland PA, Erickson KA. Calcium channel blockers in glaucoma management. Ophthalmol Clin North Am. 1995;8:327-334.
2. Netland PA, Grosskreutz CL, Feke GT, et al. Color Doppler ultrasound analysis of ocular circulation after topical calcium channel blocker. Am J Ophthalmol. 1995;119:694-700.
3. Harino S, Riva CE, Petrig BL. Intravenous nicardipine in cats in creases optic nerve head but not retinal blood flow. Invest Ophthalmol Vis Sci. 1992;33:2885.
4. Gasser P, Flammer J. Influence of vasospasm on visual function. Doc Ophthalmol. 1987;66:3.
5. Kitazawa Y, Shirai H, Go FJ. The effect of Ca2+-antagonist on visual field in low-tension glaucoma. Graefes Arch Clin Exp Ophthalmol. 1989;227:408.
6. Netland PA, Chaturvedi N, Dreyer EB. Calcium channel blockers in the management of low-tension and open-angle glaucoma. Am J Ophthalmol. 1993;115:608.
7. Green K, Kim K. Papaverine and verapamil interaction with prostaglandin E2 and 9-tetrahydrocannabinol in the eye. Exp Eye Res. 1977;24:207.
8. Payne LJ, Slagle TM, Cheeks LT, et al. Effect of calcium channel blockers on intraocular pressure. Ophthalmic Res. 1990;22:337.
9. Schnell D. Response of intraocular pressure in normal subjects and glaucoma patients to single and repeated doses of the coronary drug adalat In: Lochner W, Engel HJ, Lichtlen PR, eds. Second International Adalat Symposium. Berlin, Germany: Springer Verlag; 1975:290.
10. Monica ML, Hesse RJ, Messerli FH. The effect of a calcium-channel blocking agent on intraocular pressure. Am J Ophthalmol. 1983;96:814.
11. Kelly SP, Walley TJ. Effect of the calcium antagonist nifedipine on intraocular pressure in normal subjects. Br J Ophthalmol. 1988;72:216.
12. Suzuki R, Hanada M, Fujii H, et al. Effects of orally administered alpha-2-adrenergic blockers and calcium-channel blockers on the intra ocular pressure of patients with treated hypertension. Ann Ophthalmol. 1992;24:220.
13. Abelson MB, Gilbert CM, Smith LM. Sustained reduction of intraocular pressure in humans with the calcium channel blocker verapamil. Am J Ophthalmol. 1988;105:155.
14. Goyal JK, Khilnani G, Sharma DP, et al. The hypotensive effect of verapamil eye drops on ocular hypertension. Ind J Ophthalmol. 1989:37:176.
15. Segarra J, Santafe J, Garrido M, et al. The topical application of verapamil and nifedipine lowers intraocular pressure in conscious rabbits. Gen Pharmacol. 1993;24:1163.
16. Beatty JF, Krupin T, Nichols PF, et al. Elevation of intraocular pressure by calcium channel blockers. Arch Ophthalmol. 1984;102:1072.
17. Podos SM. The effect of cation ionophores on intraocular pressure. Invest Ophthalmol. 1976;15:851.
18. Ettl A, Daxer A, Hofmann U. Calcium channel blockers in the management of low-tension and open-angle glaucoma. Am J Ophthalmol. 1993;116:778.
19. Erickson KA, Schroeder A, Netland PA. Verapamil increases outflow facility in the human eye. Exp Eye Res. 1995;61:565-567.
20. Schuman JS, Beaton MA, Erickson KA, Schroeder A. Effects of topical verapamil on intraocular pressure, aqueous flow, and outflow facility in humans. Invest Ophthalmol Vis Sci. 1994;35(suppl):1483.
21. Abreu MM, Kim YY, Shin DH, Netland PA. Topical verapamil and episcleral venous pressure. Ophthalmology. 1998;105:2251-2255.
22. Sinclair NL, Benzie JL. Timolol eye drops and verapamil—a dangerous combination. Med J Australia. 1983;1:548.
23. Pringle SD, MacEwen CJ. Severe bradycardia due to interaction of timolol eye drops and verapamil. Br Med J. 1987;294:155.
24. Kanellopoulos AJ, Erickson KA, Netland PA. Systemic calcium channel blockers and glaucoma. J Glaucoma. 1996;5:357-362.
25. Netland PA. Calcium channel blockers in glaucoma therapy. Ophthalmol Clin North Am. 1997;10:357-364.
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