A challenging clinical scenario is distinguishing between normal tension glaucoma (NTG) and non-glaucomatous optic neuropathies (NGON). The key to the assessment remains identifying the presence of optic nerve head cupping. Recent optical coherence tomography (OCT) measurements now allow objective assessment of cupping by minimum rim width at Bruch’s membrane opening (MRW-BMO). This study assessed the hypothesis that the MRW-BMO measurement quantifies cupping and therefore can differentiate between NTG and NGON.
Diagnostic evaluation with area under the curve.
Setting: multicenter tertiary hospitals and outpatient clinics. Patient population: 81 eyes of 81 patients were enrolled, 27 with NTG and 54 with NGON, including ischemic optic neuropathy, previous optic neuritis, and compressive and inherited optic neuropathies. All NGON patients with intraocular pressure >21 mm Hg, narrow drainage angles, or a family history of glaucoma were excluded. Observational procedure: optic disc OCT images were obtained of both the retinal nerve fiber layer thickness and the MRW-BMO. Main outcome measurements: the utility of the MRW-BMO in differentiating GON from NGON was assessed using the area under the curve (AUC) estimated from a logistic regression model.
The 5-fold cross-validated AUC for glaucoma versus nonglaucoma from logistic regression models using MRW-BMO values from all sectors was 0.95 (95% confidence interval: 0.86-1.00).
The measurement of MRW-BMO effectively differentiates between NTG and NGON with a high level of sensitivity and specificity. Incorporating this measurement into routine glaucoma assessment may provide a robust method of assisting clinicians to improve diagnosis and therefore treatment of optic nerve diseases.
Optic nerve dysfunction occurs among a heterogeneous group of diseases that may affect visual function. Glaucomatous optic neuropathy (GON) is the most common optic neuropathy worldwide, but a range of nonglaucomatous optic neuropathies (NGON) also present with optic nerve head changes and visual field defects. These neuropathies include ischemic optic neuropathy, optic neuritis, compressive optic neuropathy, optic disc drusen, and inherited optic neuropathies.
Clinically differentiating between GON and NGON is critical as their natural histories, treatments, systemic associations, and propensity for visual impairment are different. A 15-year UK analysis found the highest payouts for medicolegal insurance claims related to missed or poorly followed intracranial tumors causing optic nerve head and visual field changes.
The pathognomonic signs of GON are progressive loss of retinal ganglion cells with characteristic excavation of tissue at the optic nerve head, that is, optic disc cupping. There have been case reports of cupping in NGON, but those cases are the exception rather than the rule. Although the assessment of optic nerve head cupping may be more straightforward in advanced disease, for many cases, the cup size assessment is challenging in part because the there is an arbitrary reference plane distinguishing the rim from the cup.
This distinction has been tested empirically, and expert clinical assessment of the optic nerve head alone was found to be inaccurate in diagnosing different types of optic nerve pathologies. A number of clinicians in the study diagnosed glaucoma in patients with nonglaucomatous diseases. The relatively poor performance of expert assessment is likely to be exacerbated by more widespread adoption of optical coherence tomography (OCT) by other health professionals including optometrists.
A number of different clinical tests have been suggested for differentiating between GON and NGON. Although elevated intraocular pressure (IOP) is a risk factor for GON, it is not useful for differentiating between GON and NGON. Population-based studies confirm that GON with “normal” IOP is common. In a US population, 50% of new diagnoses of GON had an IOP <22 mm Hg, whereas the figure for a Japanese population was 92%. Conversely, having a common disease such as glaucoma does not protect against dual pathology such as an intercurrent pituitary tumor. Color vision has also been suggested to be useful in differentiating GON from NGON, but the empirical evidence in support of this assertion is limited. There is therefore a need to develop an objective measurement to assist in differentiating GON from NGON in patients with optic nerve disease.
The availability of OCT has introduced a new level of quantitative assessment of optic nerve disease. Thinning of the peripapillary retinal nerve fiber layer (RNFL) occurs regardless of the underlying optic neuropathy and so does not distinguish between GON and NGON. However, the recent description of the measurement of the minimum rim width at Bruch’s membrane opening (MRW-BMO) now provides an objective quantitative measurement of cupping. One study has reported that MRW-BMO is able to distinguish between GON and nonarteritic anterior ischemic optic neuropathy, but it has not been established whether this is the case with a more heterogenous group of patients with NGON.
We hypothesized that in a cohort of patients with established optic nerve disease and RNFL thinning, NGON patients will have relatively normal MRW-BMO measurements (no cupping), whereas GON will have abnormal MRW-BMO, ie both cupping and peripapillary RNFL loss. Recruitment was limited to patients with normal-tension glaucoma (NTG) rather than high-tension glaucoma as this is the group of patients most frequently investigated for causes of NGON.
A tightly phenotyped group of patients with NTG was examined and compared to patients with a range of NGON to assess whether the MRW-BMO was effective in differentiating the two groups.
Subjects and Methods
Subjects were enrolled consecutively into a diagnostic evaluation study using area under the curve analysis (AUC) recruited from 2 centers, one in Sydney, Australia, and the other in London, United Kingdom. The protocol and study design in Australia were approved prospectively by the South Eastern Sydney Area Health Network Human Research Ethics Committee (reference number 16/055). In the United Kingdom, the study was registered retrospectively as an audit of practice (institutional review board reference CA18/NO/01). Informed consent was obtained from all patients. All testing was conducted according to the tenets of the Declaration of Helsinki.
Inclusion and Exclusion C riteria
NTG patients had their diagnoses confirmed by a fellowship-trained glaucoma subspecialist based on characteristic optic disc appearance with matching glaucomatous visual field loss. IOP had never to have been recorded above 21 mm Hg, and all patients had open drainage angles with dark room gonioscopy. Secondary glaucomas such as pseudoexfoliation and pigment dispersion syndrome were excluded.
Other exclusion criteria included 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 were excluded.
NGON was diagnosed by a fellowship-trained neuro-ophthalmologist. Non-arteritic anterior ischemic optic neuropathy required documented painless disc swelling with visual field defects that either improved or stabilized over a 6-week period. A “disc at risk” was required in the contralateral eye and, if the patient was older than 50 years of age, an erythrocyte sedimentation rate and a C-reactive protein assay with normal results were also required. Arteritic anterior ischemic optic neuropathy or posterior ischemic optic neuropathy required a positive temporal artery biopsy. Prior optic neuritis was diagnosed based upon a clinical history consistent with optic neuritis and a contrast-enhanced MRI demonstrating optic nerve enhancement at the time the patient was symptomatic. Patient conditions were diagnosed with drusen on the basis of the International Drusen Collaboration recommendations. All hereditary optic neuropathies were included only if genetic testing confirmed a known mutation for the condition. Any NGON patient with IOP >21 mm Hg, narrow drainage angles, or a known family history of glaucoma were excluded.
All subjects underwent a complete ophthalmic examination including best-corrected visual acuity, near vision, color vision (Ishihara plates), IOP with Goldmann applanation tonometry, Humphrey visual field ([Humphrey Field Anaylser 2 [HFA2], Carl Zeiss Meditec, Dublin, CA] 24-2; SITA-standard, white on white), optical coherence tomography (OCT) (Spectralis OCT [Heidelberg Engineering, Heidelberg, Germany] MRW-BMO, retinal nerve fibre layer [RNFL] thickness [RNFLT], ganglion cell complex), and optic nerve head photos [Zeiss Visucam, Carl Zeiss Meditec, Jena, Germany]).
All NTG patients underwent blood tests for full blood count, electrolytes, urea, creatinine, vitamin B 12 , and folate and an MRI of the brain and orbits with gadolinium enhancement using a standard protocol.
The OCT was performed by a trained technician at each facility. Only OCT scans with a mean quality score >15 were included for analysis. The scanning protocols for the Spectralis OCT followed previously published protocols. Briefly, the MRW-BMO scanning pattern is a radial scan consisting of 24 equally distributed high-resolution 15-degree B-scans which compute the neuroretinal rim measurements. B-scans were averaged from 20 to 30 individual B-scans, with 768 A-scans per B-scan, centered on the optic nerve head. The RNFLT is a circumpapillary 12-degree circular scan with 1,536 A-scans centered on the optical nerve head. The data is averaged from 16 individual B-scans.
The MRW-BMO scan has a global value which is segmented into 6 sectors (temporal, nasal, superotemporal [ST], inferotemporal [IT], superonasal [SN], and inferonasal [IN]). The BMO was identified automatically by the software but was manually checked by a single operator and corrected in case of any segmentation or BMO location errors.
Only 1 eye for each patient was included in the study. If both eyes were eligible, the worst affected eye was included for analysis.
Univariate logistic regression models were used to assess whether the MRW-BMO measurement was significantly associated with the presence of GON. This was analysis was followed by 5-fold cross-validated logistic regression to assess the model’s predictive power to classify GON versus NGON. AUC, sensitivity, specificity, positive predictive values (PPV), negative predictive values (NPV), and likelihood ratios were calculated from the cross-validated model. 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. For reference, a PLR of 5 represents an approximate increase of 30% in the post-test probability of having a disease, whereas an NLR of 0.2 represents an approximate decrease of 30% in the post-test probability of a patient having a disease. Four pre-specified models were analyzed using different combinations of MRW-BMO measurements: 1) all 6 sectors; 2) of only the global measurement; 3) of only the ST and IT sectors; and 4) of only the ST, IT, and temporal sectors. For each of the sectors, both the MRW-BMO alone, to distinguish GON from NGON, and the MRW-BMO-to-RNFL ratio were analyzed. The rationale for the latter was that it would anatomically match the sector of cupping with any associated RNFL loss in that particular sector.
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.
81 patients were recruited. This included 27 patients with NTG and 54 patients with a range of other optic neuropathies including ischemic (22), previous optic neuritis (14), compressive (8), disc drusen (4), inherited (3), toxic/nutritional (2) and traumatic (1). All NTG patients had a normal MRI brain and orbits with gadolinium, as assessed by a specialist neuro-radiologist. Baseline blood tests for the NTG subjects were within normal limits.
Mean MRW-BMO measurements and mean ratios of MRW-BMO:RNFL of the primary (ST, IT, temporal sectors) and secondary outcome measures (global, nasal, SN, IN) are shown in Table 1 . Both the MRW-BMO and ratio measurements in the GON group were significantly lower than the NGON group. Visual field MD was more negative in the NGON group compared with the GON group (-11.6 vs. -7.7; P = .054).
|Number of Eyes||27||54|
|Mean ± SD MD visual field||−7.7 ± 7.2||−11.6 ± 8.6||.054|
|Mean ± SD MRW-BMO|
|PO1-ST||180.3 ± 84.7||264.6 ± 102.3||.004|
|PO2-IT||145.4 ± 61.2||318.3 ± 107.3||<.001|
|PO3-Temporal||155.4 ± 52.9||214.1 ± 78.8||.004|
|SO1-Global||196.9 ± 55.5||291.9 ± 85.0||<.001|
|SO2-Nasal||239.0 ± 69.9||319.5 ± 96.2||.003|
|SO3-SN||229.8 ± 71.2||315.0 ± 99.8||.003|
|SO4-IN||210.1 ± 76.0||366.3 ± 106.8||<.001|
|Mean ± SD ratio (MRW-BMO/RNFLT)|
|PO1-ST||2.1 ± 0.9||3.8 ± 1.8||.002|
|PO2-IT||2.1 ± 1.3||3.6 ± 1.8||.004|
|PO3-Temporal||2.9 ± 1||4.7 ± 2.1||.002|
|SO1-Global||2.8 ± 0.6||4.8 ± 1.6||<.001|
|SO2-Nasal||3.5 ± 0.8||7.1 ± 3.6||.001|
|SO3-SN||2.6 ± 0.7||5.6 ± 2.8||.001|
|SO4-IN||2.8 ± 1.3||5.4 ± 2.3||<.001|