DR. HIRIKA GOSALIA

DR. VIRNA SHAH, Dr. KARAN A.K., Dr. SARAVANAN V.R.

Semi Final

Abstract

The most common optic neuropathy worldwide is glaucomatous optic neuropathy (GON), but few non- glaucomatous optic neuropathies (NGON) also present with optic nerve head changes and visual field defects. Hence, distinguishing GON from NGON is a clinical challenge due to their natural histories, treatments, systemic association and varied progression to visual morbidity. This retrospective study was conducted in 40 eyes, 20 with NGON and 20 with GON. All patients underwent a complete ophthalmic examination followed by radial Optical Coherence Tomography (OCT) optic disc scan to calculate Bruch’s membrane opening minimum rim width (BMO-MRW). The 5-fold cross validated area under the curve for GON versus NGON from logistic regression models using BMO-MRW values from all sector was 0.92(95%CI :0.86-1.00). The results showed that the values were significantly lower in GON than NGON group. Hence, OCT based BMO-MRW values could be used as an objective tool to differentiate GON from NGON.

Full Text  

COMPARISON OF GLAUCOMATOUS FROM NON-GLAUCOMATOUS OPTIC NEUROPATHY USING OPTICAL COHERENCE TOMOGRAPHY.

Abstract :

The most common optic neuropathy worldwide is glaucomatous optic neuropathy (GON), but few non- glaucomatous optic neuropathies (NGON) also present with optic nerve head changes and visual field defects. Hence, distinguishing
GON from NGON is a clinical challenge due to their management, systemic association and varied progression to visual morbidity. This retrospective study was conducted in 40 eyes, 20 with NGON and 20 with GON. All patients
underwent a complete ophthalmic examination followed by radial Optical Coherence Tomography (OCT) optic disc scan to calculate Bruch’s membrane opening minimum rim width (BMO-MRW).

The 5-fold cross validated area under the curve for GON versus NGON from logistic regression models using BMO-MRW values from all sector was 0.95(95%CI :0.86-1.00). The results showed that the values were significantly lower in
GON than NGON group. Hence, OCT based BMO-MRW values could be used as an objective tool to differentiate GON from NGON.

Introduction:

The most common optic neuropathy worldwide is Glaucomatous optic neuropathy (GON) presenting with optic nerve head changes and visual field defects. Non glaucomatous optic neuropathy (NGON) includes ischemic optic neuropathy,
previous optic neuritis, compressive optic neuropathies, toxic or nutritional optic neuropathy and traumatic optic neuropathies which also present with optic nerve head changes along with visual field defects. Therefore, the
diagnosis of NGON is often missed or misinterpreted as GON during ophthalmoscopic examination or by fundus photography assessment.[1] It is important to differentiate between GON and NGON because of the different management,
systemic associations and visual impairment propensity is completely varied for each disease especially for compressive optic neuropathy (CON).

Prompt and accurate diagnosis of CON is critical as it can be life threatening.[2] Previous studies have reported 6.5% of patients having intracranial compressive lesions involving anterior visual pathways who were previously
diagnosed with normal tension glaucoma (NTG). Only 21% CON were correctly diagnosed by ophthalmologists by viewing fundus photographs.[3]The cup size assessment is challenging in most cases due to the arbitrary reference plane
distinguishing the rim from the cup. Elevated intraocular pressure (IOP) is a risk factor for GON but not useful for differentiating between GON and NGON. Recent reports suggested that newly diagnosed GON had IOP <22 mm of Hg in 50% of US population and 92% of Japanese population. [1]

Hence, there is a need to develop objective measurement to aid in differentiating GON from NGON in patients with optic nerve disease. Both GON and NGON show decrease in diameter of retinal arteriole and loss of retinal nerve
fibre layer (RNFL) and hence doesn’t differentiate between GON and NGON.[4] Optical Coherence Tomography (OCT) is a novel, non-contact, non-invasive technique that allows cross sectional imaging of the anterior and posterior eye
segment.[5] The recent description of the measurement of the minimum rim width at Bruch’s membrane opening (MRW-BMO) is said to provide an objective measurement of cupping. The aim of this study was to differentiate GON from
NGON patients on the basis of MRW-BMO measurements.

Material and Methods:

Subjects were enrolled consecutively into a diagnostic evaluation study using area under the curve analysis (AUC) recruited a tertiary eye hospital in South India. The study was conducted according to the tenets of declaration
of Helsinki. An ethics committee approval was obtained for this review. An informed consent was taken from all patients. Inclusion criteria included patients with pale disc who had their diagnoses confirmed based on
characteristic optic disc appearance with matching glaucomatous visual field loss. IOP always below 21 mm Hg, and patients with open drainage angles on dark room gonioscopy.

Exclusion criteria included Secondary glaucoma such as pseudo-exfoliation and pigment dispersion syndrome, age younger than 18 years, significant media opacity, clinical evidence of diabetic retinopathy, and macular degeneration
or any other retinal disease, any participants unable or unwilling to undergo magnetic resonance imaging (MRI) of the brain and orbits with contrast, IOP >21 mm Hg, narrow drainage angles, or a known family history of glaucoma.
NGON was diagnosed by a neuro-ophthalmologist. Non-arteritic anterior ischemic optic neuropathy required previously documented painless disc swelling with visual field defects that either improved or stabilized over a 6-week
period and a ‘‘disc at risk’’ in the contralateral eye.

Prior optic neuritis was diagnosed based upon a clinical history consistent with optic neuritis and a contrast-enhanced MRI demonstrating optic nerve enhancement during the symptomatic phase of the patient. All subjects
underwent a complete ophthalmic examination including best-corrected visual acuity, near vision, colour vision (Ishihara plates), IOP with Goldmann applanation tonometry, Humphrey visual field and OCT [Heidelberg Engineering,
Heidelberg, Germany] BMO-MRW. All GON patients underwent MRI of the brain and orbits with gadolinium enhancement using a standard protocol. The OCT was performed by a trained technician.

The scanning protocols for the OCT followed previously published protocols. Briefly, the BMO-MRW scanning pattern is a radial scan consisting of 24 equally distributed high-resolution 15- degree B-scans which compute the
neuro-retinal rim measurements centred on the optic nerve head. The BMO-MRW scan was segmented into 6 sectors (temporal, nasal, superotemporal [ST], inferotemporal [IT], superonasal [SN], and inferonasal [IN]). The BMO was
manually marked by a single clinician. Only 1 eye for each patient was included in the study. If both eyes were eligible, the worst affected eye was included for analysis.

Statistical Analysis:

All statistical analysis were performed using univariate logistic regression model in order to assess the association between MRW-BMO and the presence of GON. The predictive value to classify GON and NGON was done by 5- fold
cross validated logistic regression model to calculate AUC, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and likelihood ratios. The positive likelihood ratio (PLR) was calculated as
sensitivity/ (1-specificity), and the negative likelihood ratio (NLR) was calculated as the (1-sensitivity)/specificity.

A higher PLR (>1) gives an increased probability of having a disease following a positive test result, whereas a lower NLR (between 0 and 1) gives a lower probability of having a disease following a negative test result. MRW-BMO
was calculated for 1) all sectors, 2) ST and IT sectors 3) SN and IN sectors 4) ST, IT and temporal sector 5) SN, IN and nasal sectors. All analyses were conducted using R version 3.5.1 software (R Project, Vienna, Austria) with
the caret application (Version 6.0-80) for cross-validation of logistic regression models and the pROC application (version 1.13.0) for plotting receiver operating characteristic (ROC) curves.

Results:

40 patients were recruited. this included 20 patients with GON and 20 patients with a range of other optic neuropathies including ischemic (9), previous optic neuritis (3), compressive (3), toxic/nutritional (3) and traumatic
(2). The mean age was 69.45 ± 1.55 for GON patients and 58.5 ± 2.32 for NGON patients. The MRI scan reports for the compressive optic neuropathy patients showed findings suggestive of meningioma. All GON patients had a normal
MRI brain and orbits with gadolinium, as assessed by a specialist neuro-radiologist.

Mean MRW-BMO measurements were taken. The BMO-MRW in the GON group were significantly lower than the NGON group. The models using all the sectors had mean AUC using the BMO-MRW values 0.95 [95% confidence interval [CI]: 0.86-1].
Sensitivity calculated was 100% with a corresponding specificity of 95%. The model using superonasal, inferonasal and nasal sectors had the highest PLR( 9 [ 95% CI]).

Model	Sensitivity	Specificity	PPV	NPV	LRP	LRN
All Sectors (ST, IT, SN &IN)	100	95	95.24	100	2	0
ST &IT sectors	100	95	95.24	100	2	0
SN &IN sectors	100	85	86.96	100	6.67	0
ST, IT and Temporal	100	100	100	100	–	–
SN, IN and Nasal	90	90	90	90	9	0.11

1. SN & IN

2. ST & IT:

3. ST, IT & Temporal

Discussion:

The study demonstrates that MRW-BMO provides a good objective differentiation between the 2 groups in tightly phenotypic clinic-based population of GON and NGON. Glaucoma refers to retinal ganglion cell death and the complex
interplay of biochemical factors related to glaucoma comprising of ischemia, physical compression of axonal bodies and tissue remodelling. The hall mark of glaucoma is optic nerve head cupping which refers to laminar or deep
cupping to distinguish it from other types of non-glaucomatous cupping.[1] Previous reports have suggested that glaucomatous cupping has a greater anterior laminar depth than non-glaucomatous cupping.[2]

NGON including arteritic ischemic optic neuropathy, dominant optic atrophy and few compressive optic neuropathies show non glaucomatous cupping.(5) GON being a more common pathology and with cognitive biases would mean that an
abnormal disc and visual field is more readily considered as signs of glaucoma, without the considerations of other possible pathologies. OCT is a routine investigation in most high resource centres for assessment of glaucoma
patients and hence MRW-BMO could be included as a routine investigation through the OCT platform. Chauhan et al. could prove that BMO-MRW had a better diagnostic performance compared with current confocal scanning laser
tomography or other SD-OCT–based ONH and RNFL parameters.[6]

The possibility of NGON could alert the clinician for prompt treatment and need for other investigations like MRI scan, colour vision, reassessing visual fields or re-examination of the disc to consider the evaluation of pallor
rather than cupping. These results only help in differentiating GON from NGON but do not provide any aid in subtyping the specific NGON which have been presented. Larger study samples for less common NGON like hereditary optic
neuropathies and CON may help to identify characteristic OCT findings that may assist in differentiating each of these conditions from glaucoma which is a big challenge otherwise. The current clinical limitation of detecting
NGON by clinicians is that they may not even consider it.

In conclusion this study has highlighted a practical meaning besides the presenting aspects for the pathogenesis of glaucomatous optic neuropathy. It may lead to rediscuss whether patients with the ophthalmological diagnosis of
normal-pressure glaucoma need a neuroradiological examination. Also, the need of objective assessment of optic head cupping with the aid of MRW-BMO measurements in OCT to differentiate GON from NGON.

References:

1. Leaney JC, Nguyen V, Miranda E, Barnett Y, Ahmad K, Wong S, et al. Bruch’s Membrane Opening Minimum Rim Width Provides Objective Differentiation between Glaucoma and Nonglaucomatous Optic Neuropathies. American Journal of
Ophthalmology. 2020 Oct;218:164–72.
2. Fard MA, Moghimi S, Sahraian A, Ritch R. Optic nerve head cupping in glaucomatous and non-glaucomatous optic neuropathy. Br J Ophthalmol. 2019 Mar;103(3):374–8.
3. Nakano E, Hata M, Oishi A, Miyamoto K, Uji A, Fujimoto M, et al. Quantitative comparison of disc rim color in optic nerve atrophy of compressive optic neuropathy and glaucomatous optic neuropathy. Graefes Arch Clin Exp
Ophthalmol. 2016 Aug;254(8):1609–16.
4. Qu Y, Wang YX, Xu L, Zhang L, Zhang J, Zhang J, et al. Glaucoma-like optic neuropathy in patients with intracranial tumours. Acta Ophthalmologica. 2011 Aug;89(5):e428–33.
5. Manor RS. Documented Optic Disc Cupping in Compressive Optic Neuropathy. Ophthalmology. 1995 Nov;102(11):1577.
6. Resch H, Mitsch C, Pereira I, Schwarzhans F, Wasserman L, Hommer A, et al. Optic nerve head morphology in primary open-angle glaucoma and nonarteritic anterior ischaemic optic neuropathy measured with spectral domain optical
coherence tomography. Acta Ophthalmol. 2018 Dec;96(8):e1018–24