Normal Tension Glaucoma

 

Author: Helen Flohr

Abstract
Normal tension glaucoma is a type of primary open angle glaucoma with intraocular pressure (IOP) in the statistically normal range.  Its pathogenesis involves IOP-dependent factors as well as IOP-independent factors including dysregulation of blood flow to the optic nerve head and an increased susceptibility of the optic nerve head to glaucomatous damage.  Current treatment methods target IOP reduction but there is ongoing research into treatments which address the IOP-independent pathogenic factors.  A typical case of normal tension glaucoma and its management options is presented.

Glaucoma
Introduction 
Primary open angle glaucoma (POAG) is a chronic optic neuropathy in which raised intraocular pressure (IOP) results in damage at the optic nerve head, reduced retinal nerve fibre layer thickness and subsequent death of retinal ganglion cells.  Normal tension glaucoma (NTG) represents a subgroup of POAG with measured, untreated IOP in the statistically normal range.   Its definition is evolving as a better understanding of the underlying mechanisms is gained, but it is generally defined as an optic neuropathy associated with:
  • optic disc cupping
  • corresponding visual field defects
  • open drainage angles on gonioscopy
  • IOP within a statistically normal range  (<21mm Hg)1
Between 20 and 40% of those with primary open angle glaucoma have normal tension glaucoma, with an even higher incidence amongst Latino-Americans of Mexican Origin and Japanese ethnic groups2.  
In the absence of raised IOP, it is thought that other factors are also involved in NTG that increase the optic nerve head's susceptibility to glaucomatous damage, including:
  • Dysregulation of blood flow to the optic nerve head  and ocular perfusion pressure, evidenced by the increased association of NTG with systemic vascular factors such as:
  • Vascular occlusive disease (diabetes mellitus, prior stroke)3
  • Vasospastic diseases (migraine, Raynaud's phenomenon) 4
  • Nocturnal hypotension 5
  • Morphological and structural optic nerve weakness, as evidenced by the following signs that occur more commonly in NTG:
  • Peripapillary atrophy: a crescent of absent retinal pigment epithelium at the disc border, often in the region of worst cupping
  • Focal notching of the optic cup, often associated with nerve fibre layer defects and/or a highly localised, dense, arcuate field defect
  • Drance (splinter) haemorrhages at the disc 6
Diagnosis of NTG and the decision to treat is made by compiling a clinical picture which may include the following findings: 
  • optic disc changes, including increased cup-disc ratio (CDR), with or without notching;  peripapillary atrophy; Drance haemorrhages; and nerve fibre layer defects
  • progressive visual field loss characteristic of glaucoma, such as arcuate scotomas or hemifield defects that respect the horizontal midline; nasal steps; and steep, paracentral defects within 5 degrees of fixation that are more common in NTG than in 'high-pressure' open angle glaucoma 7 
  • progressive thinning of the retinal nerve fibre layer (RNFL) and Ganglion Cell Complex (GCC) focal loss on Optical Coherence Tomography (OCT)8 
  • family history of glaucoma in first degree relative
  • systemic risk factors for progression, particularly female gender, history of migraines,  Raynaud's phenomenon or hypotension 4

Case Study 
NP, an eighty-six year old female, had been attending the practice for six years for annual diabetic eye exams.  Medications included those for diabetes (Metformin) and for cardiovascular disease and blood pressure control (Caduet, a combination calcium channel blocker and statin; Aspirin; and Karvezide, a combination of angiotensin II receptor antagonist and thiazide diuretic).   Recent HbA1c was 7.4%.  She was allergic to amoxicillin.  She had no history of migraine or Raynaud's syndrome.
She had a low degree of hypermetropia with best corrected visual acuity of R 6/6=, L 6/7.5=.  Pupil reactions were normal and there was no relative afferent pupil defect.  Slit lamp examination showed mild nuclear cataracts bilaterally and the anterior chambers were deep by Van Herrick estimation.  Fundus examination showed disc asymmetry, with CDRs of R 0.6, L 0.4.  The right optic cup was notched inferiorly with a Drance haemorrhage at the inferior margin (see Figure 1a & 1b).  Intraocular pressures were R 16, L 15 at 1:30pm, measured with Perkins applanation tonometer.  Pachymetry showed average central corneal thickness of R 564 microns, L 552 microns.
 
Glaucoma-retina

 

 
At previous visits, intraocular pressures had been consistently between 15 and 16mm Hg.  CDRs were R 0.4, L 0.3 until two years previously when they were estimated at R 0.5, L 0.4, with a Drance haemorrhage at the inferior margin of the right optic cup.  Scanning laser polarimetry screening using a Zeiss GDx VCC was passed and the haemorrhage was assumed to be related to her cardiovascular disease.   Twelve months later there had been no further change to her optic discs.  
Today, computerised visual fields (Humphrey Central 24-2 threshold) showed a right superior arcuate defect and nasal step and left inferior nasal step (see Figure 2a &2b).  OCT showed RNFL thickness values of R 78, L 83 with a right infero-temporal nerve fibre layer defect; ganglion cell layer analysis of the right macular cube showed an infero-temporal step, respecting the horizontal raphe (see Figures 3a & 3b).
 
 
 Perimetry RE
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Perimetry LE
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OCT-glaucomaThe diagnosis of early normal tension glaucoma was made by the presence of optic nerve head changes and a Drance haemorrhage, characteristic visual field defects and OCT findings.  NP was prescribed 1gt Xalatan nocte to be instilled in both eyes, followed by one minute of punctal occlusion with closed eyes.  Review was scheduled for five weeks to check the efficacy of treatment.
At review, intraocular pressures were R11, L 12, achieving the target of 30% reduction in IOP.  She reported good compliance with the drop regime and was not experiencing any stinging on instillation.  The next review of IOP and optic discs was scheduled for three months, and review of visual fields and OCT was scheduled for six months.

Differential Diagnosis 
It is necessary to determine the correct aetiology of the optic neuropathy and likelihood of progression before initiating appropriate treatment.  Other conditions that should be considered in the diagnosis of NTG include:

1.High-pressure glaucoma with normal pressure at time of measurement due to
  • Falsely low IOP measurements by tonometry due to thin corneas
  • Large diurnal IOP variation
  • Past elevation of IOP by steroid use, uveitis, intermittent angle closure or burnt-out pigmentary glaucoma
  • Systemic medications such as beta-blockers
2.Congenital disc abnormalities
  • Physiologically large cups with no field loss
  • Congenital disc anomalies with field loss such as coloboma or optic disc drusen
3.Non-glaucomatous optic neuropathies due to 
  • Non-arteritic anterior ischaemic optic neuropathy (NAION)
  • Giant cell arteritis
  • Hypovolemic shock
4.Other causes of field loss
  • Branch retinal artery or vein occlusion, resulting in an arcuate nerve fibre layer defect and corresponding, non-progressive visual field defect
  • Orbital or intracranial tumour producing a prechiasmal type of visual field defect6.
A detailed history can help to exclude non-glaucomatous optic neuropathies; while the visual field loss in NTG tends to be slow, chronic and often asymptomatic, ischaemic vascular insults to the optic nerve are more often acute and visually symptomatic.   Additionally, optic disc pallor is the predominant sign over disc cupping; whenever pallor outweighs cupping, ischemic optic neuropathies should be considered as  a differential diagnosis.   Greenfield et al recommends that neuroimaging be performed to evaluate for non-glaucomatous processes if: age less than 50; visual acuity less than 6/12; vertically aligned visual field defects; or neuroretinal rim pallor in excess of cupping9.  

Discussion 
The goal of glaucoma management is to maintain functional vision for the duration of the patient's life, at a sustainable cost, while minimizing side effects that could affect the patient's quality of life.
Current management of NTG is based on the findings of the Collaborative Normal Tension Glaucoma Study (CNTGS), a large study which investigated the role of IOP in NTG pathogenesis.  The study's major conclusions were:
  • IOP is a factor in NTG
  • Reduction of IOP by 30%, whether by medical or surgical means, slowed visual field loss compared with untreated eyes10
  • Some cases progress despite 30% reduction in IOP and require downward adjustment of the target IOP.  Risk factors for progression include:
  • Female gender
  • Migraine sufferers
  • Drance haemorrhage 
  • The disease is often slow or non-progressive; 50% of untreated eyes did not progress over 5 years; two visual fields showing progression are recommended for confirmation before treatment is initiated11
Because of the wide variability in progression rate, management should be individualised.  If a case seems likely to be non-progressive, it would be reasonable to monitor the patient at regular intervals.  However, if a case seems typical and likely to progress, initiation of treatment would be prudent in order to prevent functional vision loss.   In the case presented here, changes in the optic disc, visual fields and OCT were typical of glaucoma and correlated with each other.  Additionally, progression of the optic nerve cupping had been documented, and there were risk factors for further progression, the patient being female and with Drance haemorrhages seen on two occasions.  
When treatment is initiated, the target IOP and treatment modality used to achieve it (medical or surgical) also need to be tailored to the individual.  An initial target of 30% reduction is recommended, but those patients with risk factors for progression may be found to require still lower IOPs to prevent visual field loss.  In these cases, the target IOP should be adjusted downward by a further 20% 12.  
The general principles of medication choice are the same as when managing other types of POAG.  Medication is selected to lower the IOP to below the level that results in optic nerve damage, while avoiding harmful side effects.  Medical treatment options include those drugs which increase aqueous outflow (prostaglandin analogues, alpha-2-agonists and cholinergics) and those which decrease aqueous production (beta-blockers and carbonic anhydrase inhibitors).  Combination products are also available.  
The order of treatment choices, as recommended by the NHMRC guidelines, is firstly prostaglandin analogues or beta-blockers; secondly alpha-2-agonists, carbonic anhydrase inhibitors or proprietary-fixed combination products; and thirdly cholinergics13.  As in the case presented, prostaglandin analogues such as Xalatan or Lumigan are typically the first to be trialled due to their good safety profile and high efficacy, typically achieving 25-30% reduction in IOP as monotherapy.  If the first prostaglandin analogue is not effective, another  can be substituted before moving onto other medication families.  
If the target IOP cannot be achieved with monotherapy, or if the patient shows progression despite achieving the initial target IOP, it may be necessary to add another medication.  The preferred choice is one which has a different mechanism of action from the first, ie. adding an agent that decreases aqueous production to one which increases aqueous outflow.  Beta-blockers are contraindicated for the elderly patient in the case study, who has diabetes, cardiac disease, and several blood pressure lowering medications, as beta-blockers can result in poor blood sugar level control, bradycardia, hypotension and increased risk of falls.  Alpha-2-agonists are also contraindicated because of her cardiovascular disease.  For this patient, a carbonic anhydrase inhibitor such as Azopt twice a day would be considered a better second treatment arm if a prostaglandin alone was not sufficient to retard progression.  
If medications are not sufficient, or if intolerable side effects preclude their use, laser trabeculoplasty  or surgical interventions such as trabeculectomy or glaucoma drainage devices can be considered.  This may lower IOP to the required level on its own, or medications may continue to be required.   
While the current mainstay of treatment for NTG is IOP reduction, there is potential for development of new treatment agents in the area of neuroprotection and prevention of premature retinal ganglion cell death.  This is perhaps particularly relevant to normal tension glaucoma in which there are other factors involved that make the optic nerve head more susceptible to glaucomatous damage.  Potential agents include antiexcitotoxic agents that slow retinal ganglion cell apoptosis, and neurotrophins which, in addition to slowing apoptosis, also activate cell survival signals.  A large number of studies are ongoing but as yet have not discovered clinically effective agents.  They have, however, shown that some currently used glaucoma medications, in addition to their IOP lowering effects, also have neuroprotective benefits: betaxolol is a calcium channel blocker which may slow apoptosis of retinal ganglion cells14; brimonidine has also been shown to have neuroprotective benefits, though its mechanism of action is uncertain 15.
Management of normal tension glaucoma requires ongoing monitoring to ensure that the chosen treatment modality prevents further progression, with regular review of intraocular pressures, visual fields, optic nerve head imaging and, if available, OCT, to compile the full clinical picture and make the best management decisions to maintain functional vision for the lifetime of the patient.  

References 
1.Lee BL, Bathikja R, Weinreb RN. The definition of normal-tension glaucoma. J Glaucoma. 1998; 7: p. 366-371.
2.Mudumbai RC. Clinical update on normal tension glaucoma. Seminars in Ophthalmology. 2013; 28: p. 173-179.
3.Kim C, Kim T. Comparison of risk factors for bilateral and unilateral eye involvement in normal-tension glaucoma. Invest Ophthalmol Vis Sci. 2009; 50: p. 1215-1220.
4.Anderson DR, Drance SM, Schulzer M. Factors that predict the benefit of lowering intraocular pressure in normal tension glaucoma. Am J Ophthalmol. 2003; 136: p. 820-829.
5.Hayreh SS, Podhajsky P, Zimmerman MB. Role of nocturnal arterial hypotension in optic nerve head ischemic disorders. Ophthalmologica. 1999; 213: p. 76-96.
6.Anderson DR. Normal-tension glaucoma (low-tension glaucoma). Indian J Ophthalmol. 2011; 59: p. S97-101.
7.Gutteridge IF. Normal tension glaucoma: diagnostic features and comparisons with primary open angle glaucoma. Clin Exp Optom. 2000; 83: p. 161-172.
8.Kim NR, Hong S, Kim JH, Rho SS, Seong GJ, Kim CY. Comparison of macular ganglion cell complex thickness by fourier-domain OCT in normal tension glaucoma and primary open-angle glaucoma. J Glaucoma. 2013; 2: p. 133-139.
9.Greenfield DS, Siatkowski RM, Glaser JS, Schatz NJ, Parrish RK. The cupped disc: who needs neuroimaging? Ophthalmology. 1998; 105: p. 1866-1874.
10.Collaborative normal-tension glaucoma study group. Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Am J Ophthalmol. 1998; 126: p. 487-497.
11.Collaborative normal-tension glaucoma study group. Risk factors for progression of visual field abnormalities in normal tension glaucoma. Am J Ophthalmol. 2001; 131: p. 699-708.
12.Canadian Glaucoma Study Group. Canadian glaucoma study: 1. Study design, baseline characteristics and prelimary analyses. Can J Ophthalmol. 2006; 41: p. 566-575.

13.National Health and Medical Research Council. Guidelines for the screening, prognosis, diagnosis, management and prevention of glaucoma 2010: Commonwealth of Australia.
14.Danesh-Meyer  HV.  Neuroprotection in glaucoma: recent and future directions. Curr Opin Ophthalmol. 2011; 22: p. 78-86.
15.Krupin T, Liebmann JM, Greenfield DS, Ritch R, Gardiner S. A randomized trial of brimonidine versus timolol in preserving visual function: results from the low-pressure glaucoma treatment study. Am J Ophthalmol. 2011; 151: p. 671-681.