Prevalence, Etiopathogenesis, differencial diagnosis, Basic work up, CNGTS and treatment of normal tension glaucoma.

1. NORMAL TENSION GLAUCOMA
PRESENTER – DR. EKNATH PAWAR.
(DNB Ophthalmology) SSN, Guwahati.

2. INTRODUCTION
 Normal tension glaucoma (NTG) is an optic neuropathy
associated with
 Glaucomatous optic nerve head damage,
 Progressive retinal nerve fiber layer thinning,
 Characteristic visual field defects,
 Open anterior chamber angles on gonioscopy and
 Maximum intraocular pressure (IOP) below 21 mmHg.

3.  In 1857, von Graefe first described a form of glaucoma manifesting optic
nerve head damage and an open anterior chamber angle, but with an
intraocular pressure (IOP) within the reference range; this is now known as
normal-tension glaucoma (NTG)
 NTG is a type of open-angle glaucoma.
 Nonetheless, NTG does have distinctive features compared with primary
open-angle glaucoma:IOP–independent risk factors including vascular factors,
systemic disease–associated factors, and myopia-related biomechanical
factors, and shows structural and functional clinical features distinguishing it
from POAG.

4. PREVALENCE
 Glaucoma affects more than 66 million people and is the second leading cause
of visual loss worldwide.
 POAG prevalence rates ranging from 0.5% to 8.8% including NTG.
 White and African population studies, the POAG prevalence is between 1.1%
and 8.8%, with NTG ranging from 30.0% to 57.1%.
 POAG Asian populations is between 1.0% and 3.9%, with NTG somewhere
between 46.9% and 92.3%.

5. Kim KE, MD, Park KH. Update on the Prevalence, Etiology, Diagnosis, and
Monitoring of Normal-Tension Glaucoma. Asia-Pacific Journal of Ophthalmology.
2016. 5(1):23-31.

6.  To date, the highest NTG proportion reported was 92.0%, from the Tajimi
Study conducted in Japan, and the lowest was 30%, from the Italian Egna-
Neumarkt Study.

7. ETIOPATHOGENESIS
 RISK FACTORS
 Old age.
 Females
 Central corneal thickness (CCT)
 Smoking and high body mass index.

8.  IOP-Dependent Mechanisms
 Glaucomatous eyes exhibit conjunctival change induced by high IOP –
impression cytology and laser scanning invivo confocal microscopy.
 Epithelial microcysts formed – Post Trab, POAG, OHT. [1]
 NTG patients shows similar changes, indicating that hyperbaric damage
also plays a role even in eyes within the IOP reference range. [2]
 NTG patients have IOP within the reference range but higher than those of
normal subject.
 Protective effect of IOP-lowering treatment.
 NTG pressures are not as high as POAG ones, IOP still plays an important
role in the pathogenesis of NTG.
1 Messmer EM, Zapp DM, Mackert MJ, et al. In vivo confocal microscopy of filtering blebs after
trabeculectomy. Arch Ophthalmol. 2006;124:1095–1103.
2. Ciancaglini M, Carpineto P, Agnifili L, et al. Conjunctival modifications in ocular hypertension and
primary open angle glaucoma: an in vivo confocal microscopy study. Invest Ophthalmol Vis Sci. 2008;49:
3042–3048.

9.  IOP-Independent Mechanisms
Structural-Biomechanical Factors
 Myopia - a notable risk factor for glaucoma.
 The structural thinning/stretching and inherent structural weakness from axial
elongation in myopic eyes can increase vulnerability to glaucomatous damage even
within the IOP reference range.
 However, glaucoma-like structural and functional damage can occur because of
myopia alone.
 Thinner laminar thickness compared with high-IOP POAG eyes.
 Limited number of studies are available on the characteristics of the lamina
cribrosa in NTG.

10. Systemic and Ocular Vascular Risk Factors
 Migraine and Raynaud’s phenomenon.
 More common in patients with with NTG.
 Vascular dysregulation – Underlying mechanism of migraine.
 Patients with migraine could have poor blood flow at the optic nerve head, leading
to an increase in the susceptibility to glaucomatous damage.
 Primary Vascular Dysregulation
 Ability to maintain sufficient blood flow is diminished despite the absence of
causative diseases or anatomical factors.
 NTG patients are reported to have decreased autoregulation capacity.
 Flammer syndrome.

11.  Blood Pressure
 Increased or decreased blood pressure ????? Unsolved. [1]
 Diastolic perfusion pressure – (diastolic blood pressure – IOP),
 Normal – 50-70 mmHg.
 Excessive blood pressure lowering with antihypertensive medication or nocturnal
hypotension - decreased ocular perfusion pressure - insufficient oxygen and
nutritional support to the optic nerve head and subsequent ischemic injury – NTG
1. Zhao D, Cho J, Kim MH, et al. The association of blood pressure and primary open-angle glaucoma: a
meta-analysis. Am J Ophthalmol. 2014; 158:615.e9–627

12.  Ocular Perfusion Pressure
 Defined as two-thirds of the mean blood pressure – IOP.
 Decreased ocular perfusion pressure in glaucomatous eyes is important
pathomechanism, particularly in NTG eyes.
 In a study by Plange et al Prolonged arteriovenous passage time, reflecting
impaired autoregulation was found in NTG. [1]
 Correlating with low mean arterial blood pressure and low ocular perfusion
pressure.
 Large fluctuation of ocular perfusion pressure is a risk factor for NTG
development.
1. Okumura Y, Yuki K, Tsubota K. Low diastolic blood pressure is associated with the progression of
normal-tension glaucoma. Ophthalmologica. 2012;228:36–41.

13.  Baltimore Eye Survey
 Lower diastolic perfusion pressure (< 50 mmHg) was associated with an increased
prevalence of POAG.
 The Egna-Neumarkt Study
 Reduced diastolic perfusion pressure (< 70 mmHg) is an important risk factor for
primary open-angle glaucoma.
 Barbados Eye Study
 Lower PP at baseline increased risk of POAG
 Lower ocular perfusion pressures, doubled the risk of glaucoma.
 The Rotterdam study
 Low diastolic perfusion pressure (< 50 mmHg) was inversely associated with ntOAG

14.  Systemic Diseases
 Positive association is seen in Hypertension and DM.
 Obstructive sleep apnea (OSA) –
 Mechanical factors - increased IOP at night related to the supine position,
obesity and elevated intracranial pressure.
 Vascular factors - recurrent hypoxia with increased vascular resistance or
dysregulation and subsequent reperfusion injury, leading to increased
levels of oxidative stress and inflammation, decreased perfusion pressure,
and prolonged ischemia, ultimately damaging the optic nerve.

15.  Translaminar Pressure Difference
 Potential risk factor in glaucoma pathogenesis.
 Intracranial pressure is lower in patients with NTG than in those with POAG or
normal subjects.
 Low intracranial pressure in the context of normal IOP levels might in fact lead to
an abnormally large translaminar cribrosa pressure difference, thereby increasing
the probability of glaucomatous damage.

16.  Autoimmunity
 Increased titres of serum antibodies against retinal or optic nerve
proteins.
 Indicating that RGC degeneration can be accelerated by an imbalance
of immune regulation between the proapoptotic and antiapoptotic
pathways. [1]
 Patients with NTG also showed increased antiphosphatidylserine
antibodies compared with POAG patients and control subjects [2]
 Other hypotheses are - release of proinflammatory and vasoactive
substances, platelet activation and aggregation, production of
reactive oxygen species, or antibodies against H. pylori cross-reacting
with RGC, thus inducing their degeneration.[3]
1. Mastropasqua R, Fasanella V, Agnifili L, et al. Advance in the pathogenesis and treatment of
normal-tension glaucoma. Prog Brain Res. 2015;221:213–232
2. Kremmer S, Kreuzfelder E, Klein R, et al. Antiphosphatidylserine antibodies are elevated in
normal tension glaucoma. Clin Exp Immunol. 2001;125:211–215.
3. Kim JM, KimSH, ParkKH, et al. Investigation of the association between Helicobacter pylori
infection and normal tension glaucoma. Invest Ophthalmol Vis Sci. 2011;52:665–668.

17.  Genetic/Hereditary Factors
 Number of genes –
 Optineurin (OPTN),
 Myocilin (MYOC), [1]
 WD repeat-containing protein 36 (WDR36),
 optic atrophy 1 (OPA), [2]
 Toll-like receptor4 (TLR4) genes] [3]
 Other Caueses
 Hypercoagulability and increased blood viscosity
 Diffuse cerebral ischemia
1. Stone EM, Fingert JH, Wallace LM, et al: Identification of a gene that causes primary open angle
glaucoma. Science 1997; 275:668–670.
2. Mabuchi F, Tang S, Kashiwagi K, Yamagata Z, Iijima H, Tsukahara S. The OPA1 gene polymorphism is
associated with normal tension and high tension glaucoma. Am J Ophthalmol. 2007;143(1):125–130.
3. Shibuya et al. Association of Toll-like Receptor 4 Gene Polymorphisms with Normal Tension
Glaucoma. Invest. Ophthalmol. Vis. Sci. 2008;49(10):4453-4457.

18. Pathogenesis
Follows a cascade of pathophysiological events that includes impaired axonal
transport, ischemia and free radical formation that leads to apoptosis

19. DIAGNOSIS
 Standard diagnostic criteria for NTG consist of glaucomatous structural
changes in the optic nerve head/RNFL and functional changes on visual field,
the same as those established for POAG.
 In addition, IOP measurements by GAT should consistently be 21 mm Hg or
less.

20.  Characteristics of Structural Damage
 Localized RNFL defect patterns closer to the fovea and wider than in high-
IOP POAG eyes - visual field defects are more localized and central than
in high-IOP POAG eyes.
 NTG eyes shows larger cupping, smaller rims, and
thinner RNFL than high-IOP POAG eyes.
 Disc haemorrhage, the only predictive factor.

21.  Intraocular pressure in normal-tension glaucoma
 The only parameter for which we currently have proven treatment.
 Patients with NTG have wider diurnal fluctuations of IOP as compared to the
healthy population.
 IOP spikes may occur at night, and thus IOPs measured during office hours may
miss nocturnal spikes in many patients.
 Also IOP is higher in the supine than sitting position.

22. Basic work up…
 Ocular history – H/O steroid use, H/O ocular trauma.
 Systemic history – h/o vasospasm (Raynauds syndrome, maigraine), systemic
nocturnal hypotension, any autoimmune disorders, sleep apnea,
coagulopahthies etc.
 Family history of glaucoma.

23. Clinical evaluation
 General medical examination – BP, DPP, Carotid status.
 Ocular Evaluation
 CCT
 IOP –
 Perform Diurnal variation in IOP
 May be assymetric, higher in left eye.
 Fluctuation leads to greater VF loss in NTG
 Corneal thickness compensated IOP.

24.  Refractive error
 Gonioscopy
 r/o angle closure, angle recession, increased pigmentation,
 Optic disc evaluation
 Focal ischemic NTG – polar notching usually inferiorly due to thin or
absent neuro-retinal rim.
 Myopic NTG – obliquely inserted disc
 Large discs with large PPA.
 Narrow vessels in PPA.

25.  Visual fields
 Focal
 Closer to fixation
 Deeper
 Inferotemporally narrower
optic disc rims and larger
cups might be 2 of the
possible explanations for
the greater significance
of paracentral scotoma
in early NTG.

26. NTG :
When is neuro-imaging indicated
 Rapidly progressing
 Patient less than 50 yo
 Unilateral condition
 Disc palor> cupping+++
 Dyschromatopsia or VA reduction
 Discrepancy between disc and VF defect

27. Documentation of progress
 Functional progression
 Standard automated perimetry, which is still the criterion, standard for
monitoring functional change
 Visual field - Before progression identify baseline
 2 to 3 examinations per year.

28.  Structural progression
 Ophthalmoscopy
 Dilated, indirect or direct
 Sterio Disc photograph
 Imaging of disc and RNFL: HRT, OCT, GDX
• Focal or diffuse narrowing of Neuroretinal rim.
• Increase of CDR.
• Narrowing of vessels.
• Increase f PPA.

29. Differential Diagnosis

30. Comparison Of Glaucomatous Progression Between
Untreated Patients With Normal-tension Glaucoma
And Patients With Therapeutically Reduced
Intraocular Pressures: Collaborative Normal-tension
Glaucoma Study
 AUTHORS: Anderson DR, Drance SM, Schulzer M
 ORIGINAL ARTICLES:
1. Ophthalmology. 1992 Sep;99(9):1468-70.
2. Am J Ophthalmol. 1998 Oct;126(4):487-97.
3. Am J Ophthalmol. 1999 Dec;128(6):776-7.
4. J Ophthalmol. 2003 Nov;136(5):820-9.

31.  PURPOSE: To determine if intraocular pressure plays a part in the pathogenic
process of normal-tension glaucoma.
 METHODS:
 One eye of each eligible subject was randomized either to be untreated
as a control or to have intraocular pressure lowered by 30% from baseline.
 Eyes were randomized if they met criteria for diagnosis of normal-tension
glaucoma and showed documented progression or high-risk field defects
that threatened fixation or the appearance of a new disk haemorrhage.
 The clinical course (visual field and optic disk) of the group with IOP was
compared with the clinical course when IOP remained at its spontaneous
untreated level.

32.  RESULTS:
 One hundred-forty eyes of 140 patients were used in this study. Sixty-one
were in the treatment group, and 79 were untreated controls.
 Twenty-eight (35%) of the control eyes and 7 (12%) of the treated eyes
reached end points (specifically defined criteria of glaucomatous optic
disk progression or visual field loss).
 An overall survival analysis showed a statistically significant difference
between the two groups (P < .0001).
 The mean survival time +/-SD of the treated group was 2,688 +/- 123 days
and for the control group, 1,695 +/- 143 days. Of 34 cataracts developed
during the study, 11 (14%) occurred in the control group and 23 (38%) in
the treated group (P = .0075), with the highest incidence in those whose
treatment included filtration surgery.

33. IMPORTANT POINTS TO REMEMBER:
Summary of Results over 5 year span of study:
 Progression to disc change or visual field loss significantly higher in the
control vs. treated group (35% vs 12%)
 Time to progression longer in the treated vs control group
 Progression of visual field loss was greater in the control vs treated group
(after adjusting for effect of cataract)
 65% of untreated eyes showed no progression over 5 years
 Some patients continued to progress despite a 30% IOP lowering
 Disc heme is a strong negative prognostic sign (faster progression)
 Progression was faster in patients with migraine headaches and in females

34. Conclusions of CNGTS:
 Different factors may contribute to the glaucomatous optic neuropathy in
different cases of normal tension glaucoma
• Gender, ethnic background, migraine and the presence of disc haemorrhage
adversely influence the course of the disease and may therefore account for
some of the variability in the course of the disease
 IOP plays a significant role in the pathogenesis of NTG
 Supports aggressive lowering of IOP in patients at high risk for progression
 Given that not all patients progress, treatment ideally should be low in side
effects; decision to treat aggressively must be weighed against the individual
likelihood of progression.

35. Treatment
 Indication - any patient with documented progression or with threatened
fixation.
 Goal – at least 30% IOP reduction.
 Target IOP –
 Untreated pressures are in the high teens - 15 mmHg or less.
 Untreated pressures are in the mid teens - 10–12 mmHg range

36.  MEDICAL TREATMENT
 Prostaglandin analogues. [1]
 Current gold standard for medical glaucoma therapy.
 Single most effective agent in reducing IOP with adequate diurnal control.
 Latanoprost , bimatoprost and travoprost.
 Reduction in 20% of mean IOP.
1. Gulati V, Fan S, Zhao M, Maslonka MA, Gangahar C, Toris CB. Diurnal and nocturnal variations
in aqueous humor dynamics of patients with ocular hypertension undergoing medical therapy.
Arch Ophthalmol. 2012;130:677–84.

37.  Beta blockers –
 Beta blockers and adrenergic drugs (dipivefrine) should better be avoided.
 Probability of nocturnal systemic hypotension and optic nerve
hypoperfusion. [1}
 Betaxolol eye drops have a beneficial effect on optic nerve blood flow in
addition to IOP reduction. [2]
1. Hayreh SS, Podhajsky P, Zimmerman MB. Betablocker eyedrops and nocturnal arterial hypotension.
Am J Ophthalmol. 1999;128:301–19.
2. Kanski JJ, Bowling B, Nischal K, Pearson R. Clinical Ophthalmology: A Systematic Approach. 7th ed.
Edinburgh: Elsevier Saunders; 2011. p. 346-348.

38.  Alfa agonist
 Brimonidine treated patients were less likely to have visual field
progression compared to timolol treated patients (9.1 and 39.2%,
respectively) despite similar reductions in IOP by both drugs. [1]
 Retinal vascular autoregulation in NTG patients.
 Alpha agonists, specifically brimonidine, have been shown to be
neuroprotective in animal models of optic nerve and retinal injury. [2]
1. Krupin T, Liebmann JM, Greenfield DS, Ritch R, Gardiner S. LowPressure Glaucoma Study Group. A
randomized trial of brimonidine versus timolol in preserving visual function: Results from the
LowPressure Glaucoma Treatment Study. Am J Ophthalmol. 2011;151:671–81.
2. Saylor M, McLoon HK, Harrison AR, Lee MS. Experimental and clinical evidence for brimonidine as
an optic nerve and retinal neuroprotective agent: An evidencebased review. Arch Ophthalmol.
2009;127:402–6.

39.  Carbonic anhydrase inhibitors
 Both, acetazolamide and Dorzolamide are useful as adjunctive.
 May provide better diurnal IOP control than timolol
 Dorzolamide-timolol fixed combination (DTFC) is a safe and effective
IOP-lowering agent in patients with NTG. [1]
1. Kim TW, Kim M, Lee EJ, Jeoung JW, Park KH. Intraocular pressure-lowering efficacy of
dorzolamide/timolol fixed combination in normal-tension glaucoma. J Glaucoma
2014;23:329-332.

40.  LASERS
 Because NTG patients have baseline IOPs in the statistically normal range,
it is often difficult to achieve IOPs in the single digits with medications
alone.
 Argon laser trabeculoplasty
 May provide better diurnal control than some of the commonly used
ocular hypotensive agents. [1]
 Bulk of the evidence suggests that argon laser trabeculoplasty is of
limited benefit in normal-tension glaucoma.
 Worth trying in patients who are reluctant to undergo, or are high-risk
candidates for surgical intervention. [2]
 Selective laser trabaculoplasty
1. Sharpe ED, Simmons RJ: Argon laser trabeculoplasty as a means of decreasing intraocular pressure
from ‘normal’ levels in glaucomatous eyes, Am J Ophthalmol 99:704, 1985.
2. Schulzer M: The Normal-Tension Glaucoma Study Group: intraocular pressure reduction in normal-
tension glaucoma patients, Ophthalmology 99:1468, 1992.

41.  GLAUCOMA FILTERING SURGERY
 Trabaculectomy
 INDICATION - No adequate control with medical therapy or laser
trabeculoplasty.
 The most effective method of achieving low IOPs.
 It blunts diurnal and nocturnal IOP fluctuations even in the setting of postural
changes. [1]
1. Klink T, Praetorius S, Leippi S, Klink J, Grehn FJ. Diurnal and nocturnal intraocular
pressure fluctuations after trabeculectomy. Ophthalmologica. 2012;227:160–5.

42.  AQUEOUS SHUNTS
 Lower failure rate and fewer complications than trabeculectomy
 Trabeculectomy have a significantly higher 5 year cumulative probability of success
[1]
 Trabeculectomy is likely a more suitable surgical option than glaucoma drainage
devices in NTG [2]
1. Gedde SJ, Herndon LW, Brandt JD, Budenz DL, Feuer WJ, Schiffman JC. Tube versus
Trabeculectomy Study Group. Postoperative complications in the Tube Versus Trabeculectomy
Study (TVT) during five years of followup. Am J Ophthalmol. 2012;153:804–14.
2. Tran DH, Souza C, Ang MJ, Loman J, Law SK, Coleman AL, et al. Comparison of longterm
surgical success of Ahmed Valve implant versus trabeculectomy in openangle glaucoma. Br J
Ophthalmol. 2009;93:1504–9.

43.  NONPENETRATING GLAUCOMA SURGERY
 Nonpenetrating deep sclerectomy
 Less complications compared with more invasive procedures.
 Lachkar et al., showed that nonpenetrating deep sclerectomy was
associated with an IOP reduction of 33.73 ± 20.9% after 6 years with few
complications. [1]
 Results are comparable with trab with less complications than trab. [2]
1. Lachkar Y, Neverauskiene J, JeanteurLunel MN, Gracies H, Berkani M, Ecoffet M,
et al. Nonpenetrating deep sclerectomy: A 6year retrospective study. Eur J
Ophthalmol. 2004;14:26–36.
2. Leszczynski R, ForminskaKapuscik M, BubulaStachowicz B, MrukwaKominek E,
Filipek E, Pawlicki K. Nonpenetrating very deep sclerectomy with hyaluronic acid
implant vs trabeculectomy—A 2year followup. Graefes Arch Clin Exp Ophthalmol.
2012;250:1835–41.

44. Non IOP lowering treatment modalities/
Neuroprotection
 GLUTAMATE ANTAGONISTS
 Glutamate is an excitatory neurotransmitter in the CNS and retina.
 Excitotoxic at high extracellular levels.
 Glutamate excitotoxicity is associated with retinal ganglion cell death [1]
 N-methyl D-aspartate (NMDA), has been proposed as a potential
therapeutic target for neuroprotection in glaucoma [2]
1. Martin KR, LevkovitchVerbin H, Valenta D, Baumrind L, Pease ME, Quigley HA. Retinal glutamate
transporter changes in experimental glaucoma and after optic nerve transection in the rat. Invest
Ophthalmol Vis Sci. 2002;43:2236–43.
2. Guo L, Salt TE, Maass A, Luong V, Moss SE, Fitzke FW, et al. Assessment of neuroprotective effects of
glutamate modulation on glaucomarelated retinal ganglion cell apoptosis in vivo. Invest Ophthalmol Vis
Sci. 2006;47:626–33.

45.  UNOPROSTONE
 It is prostanoid and synthetic docosanoid.
 Increases aqueous outflow via the trabecular meshwork
 Approved by the US-FDA for IOP reduction in OAG and OHT.
 May prolong neuronal survival independent of its ability to lower IOP,
due to improved ocular blood flow via antagonism of ET1. [1]
1. Munemasa Y, Kitaoka Y, Hayashi Y, Takeda H, Fujino H, OhtaniKaneko R, et al. Effects of
unoprostone on phosphorylated extracellular signalregulated kinase expression in endothelin
1induced retinal and optic nerve damage. Vis Neurosci. 2008;25:197–208.

46.  CALCIUM CHANNEL BLOCKERS (CCBS)
 Centrally acting CCBs, such as nimodipine and nifedipine, improve ocular
blood flow and color sensitivity in glaucoma patients. [1]
 Lowdose nifedipine has also been shown to reverse ET1 induced ocular
hemodynamic effects. [2]
1 Luksch A, Rainer G, Koyuncu D, Ehrlich P, Maca T, Gschwandtner ME, et al. Effect of nimodipine on
ocular blood flow and colour contrast sensitivity in patients with normal tension glaucoma. Br J
Ophthalmol. 2005;89:221–5.
2. Strenn K, Matulla B, Wolzt M, Findl O, Bekes MC, Lamsfuss U, et al. Reversal of endothelin1 induced
ocular hemodynamic effects by lowdose nifedipine in humans. Clin Pharmacol Ther. 1998;63:54–63.

47.  3- HYDROXYL 3-METHYL GLUTARYL COENZYME A (HMG CO-A) REDUCTASE
INHIBITORS
 Possess an antiapoptotic and neuroprotective effect suggesting that
longterm use may reduce the risk of glaucoma [1]
 GINKGO BILOBA
 Indigenous to Korea, Japan and China.
 Ginkgo extracts may have antioxidative properties. [2]
 Recent study found improved peripapillary blood flow in NTG patients
consuming ginkgo biloba extract when compared to control patients. [3]
1. Owen CG, Carey IM, Shah S, de Wilde S, Wormald R, Whincup PH, et al. Hypotensive
medications, statins and the risk of glaucoma. Invest Ophthalmol Vis Sci. 2010;51:3524–30.
2. Ou HC, Lee WJ, Lee IT, Chiu TH, Tsai KL, Lin CY, et al. Ginkgo biloba extract attenuates
oxLDLinduced oxidative functional damages in endothelial cells. J Appl Physiol. 2009;106:1674–
85.
3. Park JW, Kwon HJ, Chung WS, Kim CY, Seong GJ. Shortterm effects of gingko biloba extract on
peripapillary retinal blood flow in normal tension glaucoma. Korean J Ophthalmol. 2011;25:323–
8.

48.  Disorders such as anemia, arrhythmia, and congestive heart failure should be
treated to prevent ischemia of the optic nerve.

49. THANK YOU…