Up date Normal Tension Glaucoma (NTG)

SaAO Lucerne, 8.3.19

Frances Meier-Gibbons, RapperswilJörg Stürmer, Winterthur

Switzerland

Financial disclosures: FMG: Alcon, Allergan, Heidelberg

Ingeneering,Glaukos, Novartis, SantenJS: Alcon, Allergan, Heidelberg Ingeneering,

Novartis, Santen, Thea

Glaucoma general information

Estimation glaucoma and blindness for 2020:

80 million patients with glaucoma, 74% PAOG

>11 million patients gone blind bilaterally with glaucoma

Quigley HA et al, Br J Ophthalmol. 2006;90:262-7Tielsch JM et al. JAMA 1991; 266:369-74 FMG 2019

Estimation:

> 50% of the patients with glaucoma in the developed world are not detected – the number in the less developed world is much higher

1. Caprioli J, Garway-Heath DF. Ophthalmol 2007;114:S1–412. Heijl A et al. Arch Ophthalmol 2002;120:1268–793. Leske MC et al. Arch Ophthalmol 2003;121:48–564. Heilj. AIGS 2007

What is the definition of glaucoma?

Glaucoma is an optic neuropathy characterized by irreversible damage to the optic nerve that can lead to visual disability

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Elevated intraocular pressure (IOP) is the most significant risk factor for the development and progression of glaucoma1–3

Glaucoma is a progressive disease – all patients will progress if followed long enough4

1. Greenfield D, in ophthalmologytimes.com, Jan 1, 20162. Anderson A Indian J Ophthalmol 20113. Cho HK, Surv Ophthalmol 2014

What is the definition of normal tension glaucoma (NTG)?

A multifactorial disease entity along a continuum of IOP measurements1:

At 35 mm Hg about 50% of the patients develop glaucomatous changes over the years2

NTG has an IOP < 21 mm Hg per definition

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Percentage of 30% (Caucasians)-90% (Asians)3 of POAG

Glaucoma is a progressive disease, but NTG progression is usually slower

1.Costagliola C et al, Prev Chron Dis 2019

NTG: An oxymoron?1

Three main questions:

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- Does NTG belong in the disease spectrum of POAG?

- Is the ONH appearance secondary to ON hypoperfusion due to vascular disease?

- Is it a spectrum of congenital or aquired ON features that can simulate glaucoma?

1.Trivli A et al, Exp Ther Med 2019

Typical features of NTG

Three main components1:

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1) Vascular dysregulation and dysfunction of the neurovascular unit

2) Mechanical factors concerning the ONH and the lamina cribrosa

3) Genetic components: Growing importance

1.Esporcatte B et al, Arq Bras Oftalmol 20162 Koniezcka K et al, EMPA J 2014 3 Trivli A et al, Exp Ther Med 2019

Typical features of NTG

1) Vascular dysregulation and dysfunction of the neurovascular unit

Primary vascular dysfunction or Flammer Syndrome1,2:

Improper adaption of healthy vessels to blood flow and therefore insufficient blood supply

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Consequences: In 65%3 vasospasm/Raynaud symptomatic, low BP, prolonged sleep onset, reduced feeling of thirst

1.Trivli A et al, Exp Ther Med 2019

Typical features of NTG

2) Mechanical factors concerning the ONH and the lamina cribrosa

Hypotheses:

- ONH of NTG patients has lower threshold to IOP induced damage, by demographically different tolerance and/or genetic susceptibility of the lamina cribrosato different IOP levels

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- Reduced intracranial pressure can lead to an elevation of the retrograde trans-laminar pressure gradient and a damage of the ONH

1 Trivli A et al, Exp Ther Med 20192 Mi XS et al, Clin Interv Aging 2014

Typical features of NTG

3) Genetic components: Growing importance!1

Myocilin (1997), Optineurin (2002), Toll-like Receptor 4 (2013), Optic Atrophy 1 (2014), RAR-related Orphan Receptor C gene (2013), Matrix Metallopeptidase 9 /14 (2004), S1 RNA Binding domaine 1 (2010), ELOVL Fatty Acid elongase 5 (2010), Cyclin-dependant kinase inhibitor 2B (2012), Atonal Drosophila Homolog of, 7 (2012), doublecortin- like kinase 1 (2012), RE repeats -encoding gene (2012), retinitis pigmentosa GTPaseregulator -interacting protein 1 (2011), Apolipoprotei E (2013), heat shock 70-kDa protein 1A (2010), 5,10-methylenetretra-hydrofolate reductase (2009)….

All genes involved in the IOP-independent mechanism of causingdegenerating events in NTG2

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Esporcatte B et al, Arq Bras Oftalmol 2016Anderson A Indian J Ophthalmol 2011

Differences NTG-HTG

Differences to High Tension Glaucoma (HTG):

- Discs larger with deeper cups. „Focal ischemic type“ vs„senile sclerotic type“

- Crescent/halo: Region of absent retinal pigmentepithelium at the disc border

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- Thinner LC leading to rim/splinter hemorrhages

- Visual field differences: scotomas deeper and closer to fixation

Anderson A Indian J Ophthalmol 2011Stein J et al, Eyenet magazine, 2007

Differential diagnosis of NTG

1) „Pseudoglaucoma“

2) “High-pressure” glaucoma

3) Other disorders of the optic nerve

4) Special forms / systemic drugs

5) Compressive lesions

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Anderson A Indian J Ophthalmol 2011

Differential diagnosis of NTG

1) „Pseudoglaucoma“

Large physiologic cup seen in children without glaucoma

Congenital anomaly of the disc with a colobomatous defect and/or rim defect

Optic drusen with/without visual field defect

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Anderson A Indian J Ophthalmol 2011

Differential diagnosis of NTG

2) „High pressure“ glaucoma

Inadequate tonometry

Changes in the corneal thickness, especially thin corneas

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Past elevation of IOP, so called “burn-out” glaucomas, seen often in elderly patients with pigment glaucoma or intermittent angle closure glaucoma

Seldom but possible: Systemically (Betablocker) treated POAG

Anderson A Indian J Ophthalmol 2011

Differential diagnosis of NTG

3) Other disorders of the optic nerve

Vascular diseases (AION, branch retinal occlusion)

Hereditary diseases of the ONH: Leber’s atrophy

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4) Special forms/ systemic drugs

Systemic diseases: Syphilis, TBC, Sarcoidosis, MS

Systemic drugs: Ethambutol, Isoniazid

Stein J et al, Eyenet magazine, 2007

Differential diagnosis of NTG

5) Compressive lesions

Important signs/symptoms requiring neuroimaging:

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- Pallor of the ON rim- Prechiasmal type of visual field defects- Age of patient younger than 65 years- Rapid progression of visual field defects- Marked asymmetry between the two ONH- Disturbed color vision

General principles

Goal of every glaucoma therapy:

A therapy which is easy to apply, has few side effects and is costeffective:

„Quality of life, quality of vision, cost-effectiveness“

FMG 2019Modified from the EGS Guidelines 4. Edition, 2014

Therapy:

Reduction of the IOP is still the only therapy witha proven effect. Neuroprotection?

Decreasing aqueous humorinflow

Increasing uveoscleraloutflow

Increasing trabecular outflow

Mechanism of action for lowering IOP

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Physiology of the aqueous humor

• Aqueous production: 3 mechanism(mainly active secretion, combined with diffusion andultrafiltration)

C.B. Toris, Current Molecular Medicine 2010, 10, 824-840 FMG 2019

Amount: ca 2.4 Microliter/Minute in a circadian rhythm (little production during the night)

• Outflow: Mainly through the trabecular meshwork, less through uveoscleral outflow (uveoscleral outflow25% in young patients, only 3% in elderly patients)

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Med therapy 2019

Single drugs

1) PA

1) BB (selective, non selective, ISA)

1) CAI

1) AA

2) Adrenergica, Cholinergica

Modified from the EGS Guidelines 4. Edition, 2014Sambhara et al, Ther Adv Chronic dis, 2014

Antiglaucomatous drugs

1962

Parasympaticomimetic agents (1862)Adrenergic agonists (1901)Systemic CAI (early 1950)

New drug: Rho-kinase („ROCK“) inhibitor:Netarsudil

- IOP reduction of 25-30% of the original value

- Application: 1 time/day

- Effects: 1) Increases trabecular outflow

2) Reduces episcleral venous pressure

3) Reduction of aqueous production

- Local side effect: Slight hyperemia, systemic side effect:

minimal

Modified from the EGS Guidelines 4. Edition, 2014Serle J et al,://doi.org/10.1016/j.ajo.2017.11.019

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New drug: Latanoprostene-Bunod (butanediol mononitrate)

- IOP reduction around 25-30% of the original value

- Application: 1 time/day

- Effect: 1) Lat: Improves uveoscleral outflow

2) NO: Increases trabecular outflow

- Local side effect: like Prostaglandins, systemic side effect:

Very little

From medscape.com, Nov 2017Aliancy J, et al. Ophthalmol Ther 6: 221-232 DOI10.1007/s40123-017-0094-6

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Differences in the therapy NTG-HTG

Level of IOP lowering:

Collaborative Normal Tension Glaucoma Study (CNTGS) showed a 35% reduction of progression in the treated arm versus 12% in the untreated arm.

However: 65% did not progress in 5 years

1 Reaini T, Ophthalmologist, 2017FMG 2019

Treatment: 30% reduction of original IOP

In HTG: 20-25% IOP reduction recommended

Which NTG patient should be treated?

Immediate treatment at diagnosis if

- Sight- threatening visual field loss at initial diagnosis

- Clear history of progression (ONH and/or visual field) at the current IOP

- Blindness in one eye

- A strong family history glaucoma with vision loss

1 Reaini T, Ophthalmologist, 2017FMG 2019

Take Home Messages

- NTG: Multifactorial disease entity at low IOP levels

- Differences in clinical appearance and in risk factors

- Strong influence of vascular disorders and of genetics

- Same therapeutic approach, but lower IOP levels required

- Often surgery necessary to reach target IOP

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Question 1

Which sign/symptom does not typically mimic NTG:

A) Optic drusen

B) Physiologically enlarged ONH

C) Color vision disturbances

D) Thick corneas

E) Optic neuropathies because of sytemic medication

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Question 2

Which examination is not recommended in case of an NTG-suspect:

A) Diurnal IOP curves

B) 24-hour blood pressure measurement

C) Color vision test

D) Visual field test

E) Genetic test

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Affiliated Academic Hospital of the Faculty of Medicine at the University of Zurich

Case-presentationLow-tension glaucoma

Jörg StürmerAugenklinik

Kantonsspital Winterthur & Universität Zürich

Mrs S.A. 1964 (718779) Diagnosis of glaucoma suspect because large optic

disc with glaucomatous appearance 2007 (aged 43 years)

At that time normal IOP and normal visual fields Myopia of -7.0 Dpt in both eyes Visual acuity 1.2 in both eyes Reffered for 2° Opinion 2013 because of progressive

visual field defects in left eye and IOP up to 18 mm Hgin both eyes

Visual field at first visit in 2007

Mrs S.A. 1964 (718779)

Findings 20/09/2013 Visual acuity 1.2 BE IOP 11 mmHg (Rx with Saflutan 1/d BE) Pascal®: RE 18.5/OPA 2.5 mmHg, LE 13.8/1.8 mmHg Pachymetry: RE 571, LE 570 µm Chamber angle wide open, pigmentation ++ Optic nerve heads (Disc area RE 3.20 mm² LE

3.19mm²) HRT's Visual fields

Visual field 2013

Mrs S.A. 1964 (718779)

Diagnosis: Myopic Low-Tension glaucoma Differential Diagnosis: Pigmentary Glaucoma BE No migraine No signs of Vasospasm No iris transillumination IOP phasing: RE 13-14 mmHg, LE 14 mmHg No IOP-Peak after climbing staircase to 5. Floor Decision was taken to add Timogel 0.1% 1/d BE Watchful waiting under IOP-lowering Treatment

Follow up

1/02/2019 Visual acuity RE 1.2, LE 1.0-1.2p IOP RE 10 mmHg, LE 12 mmHg (under Ganfort 1x/d

BE) Pascal®: RE 15.0/OPA 2.8 mmHg, LE 15.1/2.9 mmHg Optic nerve heads HRT's OCT's Visual fields

HRT'S 2013-2016

Visual field 2019

OCT'S 2019

OCT's 2016-2019 (Global & TI)

Discussion

Large optic nerve heads: Tendency to over-estimationof glaucomatous cupping

Morphological & Functional progression= Prove of glaucomatous disease

Typically small paracentral visual field defects– Visual acuity and reading may be affected earlier

Discussion

Splinter haemorrhage suspected RE (and remnant LE)

Further IOP-lowering mandatory– Surgery should be discussed (life-expectancy)

24h BD pressure reading organized by GP