The treatment of normal-tension glaucoma

C. Nucci et al. (Eds.) Progress in Brain Research, Vol. 173 ISSN 0079-6123 Copyright r 2008 Elsevier B.V. All rights reserved

CHAPTER 14

The treatment of normal-tension glaucoma Priya V. Desai and Joseph Caprioli Jules Stein Eye Institute, UCLA, 100 Stein Plaza, Suite 2-118, Los Angeles, CA 90095, USA

Abstract: Normal-tension glaucoma (NTG) is generally defined as visual field loss and optic nerve defects consistent with glaucoma and an intraocular pressure (IOP) that does not exceed 21 mmHg (Allingham, R.R., Damji, K., Freedman, S., Moroi, S., Shafranov, G., Shields, M.B. (2005). In: Pine J. and Murphy J. (Eds.), Shields’ Textbook of Glaucoma, 5th edn., Lippincott Williams & Wilkins, Philadelphia, PA, pp. 197–207, Chapter 11). If a patient has an atypical presentation (unilateral disease, decreased central visual acuity or visual field loss not consistent with optic disk appearance) then the clinician should rule out medical or neurologic etiologies. IOP-dependent and IOP-independent mechanisms play a role in NTG nerve damage. The exact mechanisms of IOP-independent damage are not currently known. Research has shown that vascular etiologies, such as vascular insufficiency and vasospasm, may be possible mechanisms for IOP-independent damage. The mainstay of glaucoma treatment remains robust IOP reduction. The chief goal of ongoing glaucoma research is to more clearly identify IOP-independent mechanisms of damage and to find neuroprotective treatment strategies to prevent retinal ganglion cell death and consequent visual loss. Keywords: normal-tension glaucoma; low-tension glaucoma; open-angle glaucoma; glaucoma; acquired pit of optic nerve; optic nerve pit; optic disk; focal ischemic glaucoma; senile sclerotic glaucoma; NTG; optic disk hemorrhage; visual field; central corneal thickness; intraocular pressure (IOP); vascular dysfunction; vasospasm; retinal ganglion cells; migraine; Raynaud’s phenomenon; collaborative normal-tension glaucoma study; calcium channel blockers; treatment; diagnosis; neuroprotection; noncompliance; genetics; gene been much controversy regarding the classification of NTG. Some physicians classify NTG as an entity distinct from primary open-angle glaucoma (POAG), citing studies showing different patterns of optic disk and visual field loss. Others view it as a variant of POAG with a disease course that is indistinguishable from POAG. In fact, this controversy dates back to von Graefe who retracted his description of this condition due to intense opposing peer opinions. The IOP criterion for diagnosis of NTG is called into question by some physicians. There is no distinct division between normal IOP and

Introduction The concept of normal-tension glaucoma (NTG) was first described by Graefe (1857). It is often defined as visual field loss and optic nerve abnormalities consistent with glaucoma and an intraocular pressure (IOP) that does not exceed 21 mmHg (Allingham et al., 2005). Though this definition may seem straightforward, there has

Corresponding author. Tel.: +1 310 825 0146; Fax: +1 310 825 1480; E-mail: [email protected]

DOI: 10.1016/S0079-6123(08)01114-X

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abnormal IOP. The traditionally used threshold of 21 mmHg as the line between normal and high IOP is an arbitrary distinction. It is based on an IOP level that is two standard deviations above the mean, for a Gaussian distribution of IOPs within a Caucasian population. Also, the exact mechanisms that cause POAG have not yet been clarified. Once these mechanisms become better elucidated, we may have some resolution to this debate. Regardless of how NTG is presently categorized, this debate underscores the likelihood that there are many unknown and variable factors that influence glaucomatous visual field loss.

Epidemiology Population-based studies have shown NTG to be more common than originally expected, with a prevalence of 40–75% of individuals with newly diagnosed chronic open-angle glaucoma (Allingham et al., 2005). The prevalence varies with race and ethnicity, with the Japanese having a higher prevalence of NTG as a proportion of POAG (Shiose et al., 1991). When compared with high-pressure POAG, NTG occurs at an older age. Geijssen reported a mean age of 66.5 years for NTG patients in contrast to a younger mean age of 51.7 years for high-pressure POAG patients (Geijssen, 1991). Also, the mean age of NTG patients in the Low-Pressure Glaucoma Treatment Study was 64.9 years (Krupin et al., 2005).

more diffuse and peripheral in POAG (Woo et al., 2003). This is in accordance with a previous report which showed that inferotemporal notching of the optic disk occurred more often in NTG in contrast to generalized cupping of the disk, which was associated with POAG (Caprioli and Spaeth, 1985). Some experts further divide NTG into two groups based on optic disk appearance: (1) focal ischemic glaucoma and (2) senile sclerotic glaucoma. The focal ischemic group has deep focal notching in the neural rim, while the senile sclerotic group has shallow pale sloping of the neuroretinal rim and is usually found in older patients with vascular disease (Simmons et al., 2004) (Figs. 1–4). It is important for the clinical ophthalmologist to realize, however, that any pattern of glaucomatous optic disk and nerve fiber layer damage can be seen with NTG. Optic disk hemorrhage has been associated with NTG in several studies (Allingham et al., 2005; Krupin et al., 2005) and has also been shown to be a predictive factor for progression (Martus et al., 2005), pointing to vascular disease as a possible mechanism for this pathology (Fig. 5). One study found that in NTG an inferior area of peripapillary atrophy correlated with superior hemifield visual field damage, but a corresponding relationship was not found with superior peripapillary atrophy (Kawano et al., 2006) (Fig. 6). A clinician who sees either of these findings (disk hemorrhage or inferior peripapillary atrophy) in an NTG patient can expect to see visual field damage and should consider more aggressive treatment.

Clinical features

Visual field

Optic disk

There is some evidence that the visual field defects that are associated with NTG are more focal, deeper and occur earlier in the disease course when compared with POAG with higher IOP (Simmons et al., 2004; Allingham et al., 2005) (Figs. 1–7). While some studies have shown that the visual field defects are closer to fixation in NTG (Caprioli and Spaeth, 1984), there have been conflicting reports. This discrepancy may be due to different testing methods. Often the initial defect seen in NTG is a dense paracentral scotoma possibly encroaching on fixation (Simmons et al., 2004). This may be

There are several studies that demonstrate a difference in patterns of optic disk damage in NTG compared with POAG associated with high IOP. The neuroretinal rim has been shown to be thinner in NTG, especially inferiorly and infratemporally, when compared to POAG patients matched for total visual field loss (Simmons et al., 2004; Allingham et al., 2005). In addition, the retinal nerve fiber layer defects are more localized and central in NTG, while these defects tend to be

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Fig. 1. Disk photos and corresponding visual field of an NTG patient. (A) Normal right eye. (B) Inferior notch (arrow) on the left optic nerve with corresponding superior visual field defect encroaching on fixation.

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Fig. 2. The progression of both a superior and inferior acquired pit of the optic nerve (APON) in an NTG patient. (See Colour Plate 14.2 in the colour plate section.)

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Fig. 3. Disk photo of acquired pit of the optic nerve (APON) and corresponding visual field of the right eye from an NTG patient.

Fig. 4. Example of shallow pale sloping of neuroretinal rim seen with senile sclerotic changes of optic nerve head in NTG.

due to a selection bias as patients are more likely to notice a central visual field defect than a peripheral visual field defect. Therefore, it is not unusual for patients with NTG to present with a complaint of central visual field loss.

implication of this study is that thinner CCT may lead to falsely low measurements of IOP and misdiagnosis of POAG patients as NTG. Alternatively, thinner CCT may intrinsically be related to an increased optic nerve susceptibility, for as yet unknown reasons.

Central corneal thickness Disease course One small study has shown that the central corneal thickness (CCT) is significantly lower in NTG when it is compared to POAG and to age matched healthy subjects (Morad et al., 1998). The possible

The disease course of NTG is highly variable, and ranges from long-term stability to slowly progressive to rapidly progressive. In addition, some NTG

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2007 2005 Fig. 5. Disk photos document recurrent disk hemorrhage in an NTG patient. The visual fields show new focal nasal step defect after the first disk hemorrhage in 2002 and then progression of this defect to encroach on fixation after second disk hemorrhage. (See Colour Plate 14.5 in the colour plate section.)

patients show episodic progression. The Collaborative Normal-Tension Glaucoma Study (CNTGS) demonstrates this variability well. In this study, 65% of NTG patients did not show any progression

despite not receiving any treatment. Conversely, 12% of NTG patients showed progression in spite of aggressive reduction of IOP by 30% (CNTGS, 1998a, b). There is, however, no reliable method for

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Fig. 6. Disk photos of an NTG patient that show tilted disks with inferior and temporal peripapillary atrophy and corresponding visual fields. (A) Note the inferior notch on the right nerve. (B) Note the superior notch on the left nerve. (See Colour Plate 14.6 in the colour plate section.)

determining which patients will progress rapidly and hence appropriate follow-up and treatment must be given to all NTG patients. Risk factors Intraocular pressure The relationship between NTG and IOP has been examined and debated by many researchers and

clinicians. Two studies have demonstrated that NTG patients with asymmetric IOPs have worse visual field loss in the eye with higher IOP (Cartwright and Anderson, 1988; Crichton et al., 1989). The LowPressure Glaucoma Treatment Study, however, did not find such a relationship between IOP asymmetry and visual field asymmetry (Greenfield et al., 2007). Another small study found the IOP to rise in a subset of NTG patients after initial diagnosis and demonstrated that the rising IOP correlated with a

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Fig. 7. (A) Disk photo showing the infratemporal thinning of neuroretinal rim of the right nerve in an NTG patient. The corresponding visual field shows a focal nasal defect. (B) Disk photo and visual field of the patient’s left eye. (C) HRT also shows the larger cup and thinner neruoretinal rim of the right nerve head. (D) Both OCT and GDx show thinning in the nerve fiber layer inferiorly in the right eye.

higher maximum IOP over 24 h and development of disk hemorrhage (Oguri et al., 1998). The most influential of studies regarding the relationship between IOP and NTG is the CNTGS. The CNTGS showed that IOP reduction of 30% resulted in lowering the rate of visual field progression from 35 to 12%. This demonstrated a definite role of IOP as a risk factor for progressive visual field loss in NTG. Some patients (12%), however, had progression in spite of aggressive IOP reduction, illustrating, as in POAG, that other factors may also be important in

disease progression. Within NTG, therefore, there may exist IOP-independent and IOP-dependent mechanisms of damage (Fig. 8). Further research is needed to identify potential IOP-independent mechanisms in order to develop more effective therapies to protect the optic nerve. Though it is now widely accepted that IOP reduction has a direct effect on the progression of NTG, the extent of the influence of IOP on disease progression versus IOPindependent mechanisms is variable, and unpredictable, among patients.

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Fig. 7. (Continued)

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Fig. 7. (Continued)

Fig. 8. A hypothetical scheme of the relative roles of pressure-dependent and pressure-independent mechanisms of optic nerve damage in glaucoma. In patients who develop optic nerve damage only at high IOPs, pressure-dependent mechanisms likely predominate. In patients who develop optic nerve damage at relatively low IOPs, pressure-independent mechanisms may be relatively more important. In this scheme, pressure-independent factors are operative across the range of IOPs, and pressure-dependent factors may still be operative to some extent at low pressures. The latter hypothesis is supported by the CNTGS at least in some people. Adapted with permission from Caprioli (1998).

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Intraocular pressure–independent mechanisms Local vascular factors Optic disk hemorrhage is a significant predictor of disease progression for POAG and NTG (Allingham et al., 2005; Krupin et al., 2005; Martus et al., 2005). These hemorrhages are gross clinical signs of vascular abnormalities, though cause and effect relationships cannot be proven. Animal models of glaucoma have shown that retinal ganglion cells die by the process of apoptosis (Quigley et al., 1995), which is a form of cell death in which a programmed sequence of events leads to the destruction of cells without releasing inflammatory substances into the surrounding area. Vascular dysfunction (decreased perfusion, vasospasm or autoregulation deficit) may result in apoptosis of retinal ganglion cells via glutamate-mediated toxicity and neurotrophin withdrawal (Harris et al., 2005) (Fig. 9). As shown in the figure, both increased IOP and vascular factors can induce pathologic changes in glaucoma. Accordingly, several studies have shown a correlation between reduced ocular blood flow and optic disk filling defects to glaucomatous visual field loss (Harrington, 1969; Melamed et al., 1998). Increased IOP

Excitotoxicity

In patients with asymmetric glaucoma, hemodynamic abnormalities were found to correlate with the extent of glaucomatous damage (Nicolela et al., 1996). Additionally, interocular differences in glaucoma progression have been associated with interocular differences in blood flow independent of IOP (Schumann et al., 2000). Studies have also shown that patients with NTG have lower retrobulbar flow velocity and higher vessel resistance than healthy subjects (Rojanapongpun et al., 1993; Butt et al., 1995). It is important to note that these are simply relationships, and do not necessarily represent cause and effect. Chronic vascular insufficiency of the optic nerve may be caused by systemic abnormalities. Many studies have documented nonocular conditions with vasospasm, such as migraine and Raynaud’s phenomenon, to occur at higher frequencies in NTG (Phelps and Corbett, 1985; Cursiefen et al., 2000; Drance et al., 2001; Allingham et al., 2005). Cardiovascular conditions such as asymptomatic myocardial ischemia were much more common in NTG (45%) than in normal subjects (5%) (Waldmann et al., 1996). Also, a greater nocturnal drop in blood pressure has been reported in NTG than in the healthy population (Meyer et al., 1996). Hayreh et al. (1994) performed 24-h blood Ischemia

Abnormal glial-neuronal interactions

Neurotrophin starvation

Vascular Insufficiency

Defective endogenous protection

Autoimmune mechanisms

glutamate p53 activation [Ca++]

proteases nucleases

Necrosis

NO

TNF-α

He at Sh ock Protei n Bax / Bcl-X

Apoptosis

Fig. 9. A scheme of potential IOP-dependent and IOP-independent factors leading to ganglion cell death.

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pressure monitoring of patients with NTG, POAG and anterior ischemic optic neuropathy and found significantly lower nocturnal diastolic blood pressure and a significantly greater mean decrease in nocturnal diastolic blood pressure in NTG. In fact, they found an interesting relationship between systemic hypertension, visual field deterioration, and nocturnal hypotension: among patients taking medications for systemic hypertension, those who had progression of visual field defects had significantly greater drops in nocturnal blood pressure than those considered clinically stable. Another study by Hayreh et al. (1999) showed that patients who were using topical b-blockers had significantly greater dips in nocturnal diastolic blood pressure and patients with NTG receiving topical b-blockers had significant visual field progression more often than those not receiving b-blockers. In addition to vascular insufficiency, hematologic abnormalities, such as increased blood viscosity and hypercoagulability, have been associated with NTG. Magnetic resonance imaging studies in patients with NTG have shown an increased incidence of diffuse cerebral ischemia which is also consistent with a vascular etiology (Ong et al., 1995; Stroman et al., 1995). Immune mechanisms Other IOP-independent mechanisms of glaucomatous optic neuropathy are immunogenic etiologies. Several studies have shown that immune-related diseases occur at higher frequencies in patients with NTG (Cartwright et al., 1992; Wax et al., 1994; Romano et al., 1995). One study found that 30% of NTG patients had immune-related diseases compared to 8% of an ocular hypertension control group (Cartwright et al., 1992). Despite some evidence linking ischemia and immunogenic mechanisms to glaucomatous optic neuropathy, current diagnostic and therapeutic procedures do not take these into consideration. Currently, the only proven modality for treatment of glaucoma is IOP reduction. Only with continued research will mechanisms of optic nerve damage in NTG be identified and the above factors more clearly elucidated. A better understanding of the various mechanisms causing

glaucomatous nerve damage will allow for better and more targeted therapies.

Differential diagnosis The differential diagnosis for NTG can be divided into two main categories, undetected high-tension glaucoma and nonglaucomatous optic nerve disease (Table 1). Diagnostic evaluation A medical history consisting of previous ocular diagnoses and treatments, family history, impact of visual function on daily living, and use of ocular and systemic medications should be obtained for each patient (Gaasterland et al., 2005). A history of previous hypotensive crises, such as myocardial infraction, shock, and hemorrhage, should also be elicited as this can cause visual field loss consistent with glaucoma but may be nonprogressive. A thorough medical history not only allows the clinician to effectively formulate a differential diagnosis but also brings to highlight any possible factors for noncompliance that may affect prognosis. A complete ophthalmic physical examination should be performed on all new patients (Gaasterland et al., 2005). This includes pupil examination, slit-lamp anterior segment examination, IOP measurement, central corneal thickness, gonioscopy, optic nerve head and retinal nerve fiber layer evaluation, and visual field examination. The IOP should be measured with applanation tonometry before gonioscopy. If the patient is being dilated then IOP should be measured before and after dilation. If the disk damage does not correlate with the single IOP measurement then determining diurnal IOP fluctuations may be helpful. The optic nerve head and retinal nerve fiber layer evaluation should be performed with magnified stereoscopic visualization (slit-lamp biomicroscope) and preferably through a dilated pupil. IOP should be remeasured after dilation. Each time the optic nerve and retinal nerve fiber layer are examined it should be documented with photos or a detailed drawing. Automated static threshold perimetry is the recommended technique for evaluating the visual field.

206 Table 1. Differential diagnosis of normal-tension glaucoma Undetected high-tension glaucoma  POAG with wide diurnal IOP fluctuation  Intermittent IOP elevation J Angle-closure glaucoma J Glaucomatocyclitic crisis  Previous history of high IOP that has since normalized  ‘‘Burnt-out’’ secondary glaucoma J Past history of steroid use J Uveitic glaucoma J Pigmentary glaucoma J Past history of surgery or trauma  Use of medications that decrease IOP (masked IOP)  Tonometric error Nonglaucomatous optic nerve disease  Compressive optic neuropathy J Vascular lesions J Trauma J Tumors – Pituitary tumors – Optic nerve sheath meningioma – Optic glioma J Graves ophthalmopathy  Congenital anomalies  Hemodynamic shock optic neuropathy  Arteritic and nonarteritic ischemic optic neuropathy  Retinal disorders  Optic nerve drusen  Optic neuritis  Trauma  Methyl alcohol poisoning  Leber’s hereditary optic neuropathy

According to the Preferred Practice Patterns from the American Academy of Ophthalmology (Gaasterland et al., 2005), all follow-up glaucoma status evaluations should include a history and focused physical examination including visual acuity, slit-lamp biomicroscopy, and IOP with time of day measurement. Optic nerve head evaluation and documentation and visual field evaluation should be performed at the recommended intervals shown in Tables 2 and 3. Also gonioscopy should be performed periodically (every 1–5 years) if there is suspicion of an angleclosure component, shallowing of anterior chamber, or an unexplained rise in IOP. Three common ancillary diagnostic tests for glaucoma are optical coherence tomography (OCT), nerve fiber layer polarimetry (GDx NFA), and confocal laser scanning tomography

Table 2. Recommended frequency of optic nerve head evaluation Target IOP Progression achieved of damage

Duration of Follow-up control (months) interval (months)

Yes Yes Yes No

p6 W6 n/a n/a

No No Yes Yes or no

6–12 6–18 2–12 2–12

Modified from Gaasterland et al. (2005).

Table 3. Recommended frequency of visual field evaluation Target IOP Progression achieved of damage

Duration of Follow-up control (months) interval (months)

Yes Yes Yes No

p6 W6 n/a n/a

No No Yes Yes or no

6–18 6–24 1–6 1–6

Modified from Gaasterland et al. (2005).

[Heidelberg Retinal Tomograph (HRT)]. Both OCT and GDx NFA analyze the thickness of the retinal nerve fiber layer. It is a known fact that reductions in retinal nerve fiber layer thickness precede visual field loss. In NTG patients with unilateral visual field defects, studies have shown that RNFL thinning is already present in fellow eyes (Kim et al., 2005). The HRT is a confocal laser scanning system that gives a quantitative assessment of the topography of the optic nerve head. Change in the topography of the optic nerve head, such as cupping and thinning of the neuroretinal rim, can precede measurable visual field defects in glaucoma. Since these tests are noninvasive and relatively comfortable for the patient, clinicians should consider adding the OCT, GDx, or HRT to their glaucoma evaluations as these ancillary tests may aid in detecting and following glaucomatous changes (Fig. 7). If the clinical presentation is atypical, for example, unilateral or very asymmetric disease, decreased central visual acuity, or visual field loss not consistent with optic disk appearance, then further medical or neurological evaluation should be considered. Medical evaluation may consist of workup for anemia, cardiovascular disease, syphilis, and temporal arteritis. Routine neuroradiologic

207 Table 4. Indications to perform neuroimaging evaluation in normal-tension glaucoma General  Young age (less than 50 years)  New onset or increased severity of headaches  Localizing neurologic symptoms other than migraine  Neurologic visual abnormalities Ocular  Color vision abnormalities  Pallor of the remaining neuroretinal rim  Highly asymmetric cupping  Unilateral or highly asymmetric abnormalities  Lack of disc and visual field correlation  Visual field defect respecting vertical midline

evaluation is not performed in NTG diagnosis. Studies have shown that anterior visual pathway compression is a rare finding in neuroimaging of patients with a presumptive diagnosis of NTG (Greenfield et al., 1998). Relative indications to perform neuroimaging include younger age, decreased visual acuity, vertically aligned visual field defects that respect the midline, significant asymmetry, and neuroretinal rim pallor that exceeds the amount of cupping (Table 4). Therapy IOP reduction The mainstay of treatment for glaucoma remains IOP reduction. The CNTGS recommendation is to reduce IOP by at least 30% to reduce the incidence of visual field progression. The modalities for IOP reduction include glaucoma medications, laser trabeculopasty, and glaucoma surgery. Glaucoma medications are the usual initial therapy for treatment. Glaucoma filtering surgery with antifibrotic agents (5-fluorouracil or mitomycin C) is the preferred surgery for NTG as it can achieve a very low postoperative IOP. The rate of cataract formation is higher after glaucoma surgery as shown in the CNTGS and other studies (AGIS Investigators, 2001). In fact, the protective effect of IOP reduction on visual field was masked by the progression of cataract in the treated group. Only by removing the data affected by cataract, the protective effect of IOP lowering on preservation of

visual field was made evident (CNTGS, 1998a, b). It is important to point out that cataracts are reversible through a highly successful surgical procedure whereas visual field loss from glaucoma is not. Consequently, both the stage of glaucoma and the longevity of the patient need to be considered before embarking on surgical treatment that may accelerate cataract formation. Systemic medications New glaucoma therapies target IOP-independent mechanisms. Calcium channel blockers may protect visual field by increasing the capillary perfusion of the optic nerve head by relieving the effect of vasospasm in susceptible individuals, although results are conflicting and nonpersuasive. Various studies have suggested some benefits of nifedipine, verapamil, and nimodipine in protecting against glaucoma progression (Kitazawa et al., 1989; Bose et al., 1995; Netland et al., 1995), while other studies have shown no beneficial effect. Experts in the field of glaucoma do not commonly use calcium channel blockers because of a lack of clear evidence of efficacy and potential harmful side effects such as postural hypotension. If ophthalmologists wish to use calcium channel blocker therapy, they should coordinate treatment with a primary care physician because of potentially dangerous side effects such as systemic hypotension (Lumme et al., 1991). Another new but still experimental treatment is the use of angiotensin-converting enzyme (ACE) inhibitors. One small retrospective study found ACE inhibitors may have a favorable effect on visual field in NTG (Hirooka et al., 2006). The clinical significance of this study remains uncertain. A randomized controlled study is needed to evaluate the effect of ACE inhibitors in the prevention of visual field progression in NTG. Existing cardiovascular abnormalities (i.e., anemia, congestive heart failure, transient ischemic attack, arrhythmias) should be treated to ensure maximum perfusion of the optic nerve head. Neuroprotection IOP-independent mechanisms of glaucomatous optic nerve damage may play an important role in

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NTG as a component of damage, or in a subset of susceptible patients. A goal of current glaucoma research is to develop neuroprotective treatment strategies to prevent retinal ganglion cell death (Kuehn et al., 2005). Memantine is a promising new drug that is currently being investigated for treatment of POAG. Memantine is thought to protect the optic nerve from the toxic glutamate levels that may lead to apoptosis of retinal ganglion cells in glaucoma. Any new treatment regime should have a rational scientific basis, be delivered safely to the site of damage, and show both efficacy and safety through randomized prospective clinical trials. Since glaucoma is a slowly progressive disease, it can take many years to detect a significant benefit of new treatments, particularly when added to robust IOP-lowering treatments.

the American Glaucoma Society is attempting to identify both the barriers to compliance and tools to overcome these obstacles (American Glaucoma Society). This project has suggested that tools such as memory aids and tracking tools for medications, appointment reminders, and a new bottle design that would alert patients that it is time to refill medications may prove to be helpful. Also, social programs that empower the patient like support groups and accessible patient education classes would be helpful. As the glaucoma population grows, it will become very important that we address the problem of noncompliance. This significant issue will become an even larger burden on society as it takes people out of the work force and makes them dependent on social programs.

Noncompliance Genetics of NTG Noncompliance may be an important reason that some glaucoma suspects or glaucoma patients under ‘‘treatment’’ go on to develop severe deterioration of vision. Many of these individuals may have retained meaningful vision if appropriate therapy had been effectively applied. Several studies have evaluated factors that predispose glaucoma patients to noncompliance. Low socioeconomic status, language barrier, and aspects of treatment regime (i.e., dose frequency, number of medications, number of clinic visits) have all been linked to noncompliance. Few studies have been conducted to look at factors for noncompliance in the NTG population specifically. One study showed that approximately 50% of patients classified as NTG suspects lacked appropriate follow-up care. The lack of health insurance was a significant barrier for these patients in this study (Ngan et al., 2007). Another study showed that even within a single comprehensive insurance plan patients thought to require treatment for glaucoma were not being monitored at recommended intervals set by medical guidelines (Friedman et al., 2005). The Glaucoma Adherence and Persistency Study has shown that patient adherence to glaucoma medications is poor and comparable to other chronic diseases (Friedman et al., 2007). More research is needed to better identify individuals at greatest risk for noncompliance. The Patient Care Improvement Project conducted by

A great deal of ongoing research is dedicated to identifying a genetic basis for NTG. An OPA1 gene polymorphism (OPA1 IVS 8+32 T/C) has been associated with NTG, and one study showed that it may be used as a marker for this disease association (Mabuchi et al., 2007). Little is known, however, about the function of the OPA1 protein and how this polymorphism may cause glaucomatous neuropathy. An optineurin sequence variation, Glu50Lys OPTN, has been associated with familial NTG (Alward et al., 2003). This change, however, is responsible for less than 0.1% of open-angle glaucomas. It is unclear exactly what the function of this novel gene is. It is thought to protect the optic nerve from TNF-a-mediated apoptosis, and consequently a loss of function of this protein may decrease the threshold for ganglion cell apoptosis. Also, studies of lymphocytes in NTG have shown altered expression of the p53 gene, which is a known regulator of apoptosis (Wiggs, 2005). These results indicate that abnormal regulation of retinal ganglion cell apoptosis may be one of the IOPindependent mechanisms of optic nerve damage in glaucoma. It is unlikely that a single gene or even a small set of genes will be accountable for the clinical disease. It is likely that downstream effects, including but not limited to proteonomics, play a significant role in mechanisms of damage.

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These require further intensive investigation to unravel and are likely to be quite complex.

Abbreviations ACE CCT CNTGS IOP NTG POAG

angiotensin-converting enzyme central corneal thickness Collaborative Normal-Tension Glaucoma Study intraocular pressure normal-tension glaucoma primary open-angle glaucoma

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