Recent advances in the use of optical coherence tomography in neuro-ophthalmology: A review.

Optical coherence tomography (OCT) is an in vivo imaging modality that provides non-invasive, high resolution and fast cross-sectional images of the optic nerve head, retina and choroid. OCT angiography (OCTA) is an emerging tool. It is a non-invasive, dye-free imaging approach of visualising the microvasculature of the retina and choroid by employing motion contrast imaging for blood flow detection and is gradually receiving attention for its potential roles in various neuro-ophthalmic and retinal conditions. We will review the clinical utility of the OCT in the management of various common neuro-ophthalmic and neurological disorders. We also review some of the OCTA research findings in these conditions. Finally, we will discuss the limitations of OCT as well as introduce other emerging technologies.

Deep Learning System Outperforms Clinicians in Identifying Optic Disc Abnormalities.

BACKGROUND: The examination of the optic nerve head (optic disc) is mandatory in patients with headache, hypertension, or any neurological symptoms, yet it is rarely or poorly performed in general clinics. We recently developed a brain and optic nerve study with artificial intelligence-deep learning system (BONSAI-DLS) capable of accurately detecting optic disc abnormalities including papilledema (swelling due to elevated intracranial pressure) on digital fundus photographs with a comparable classification performance to expert neuro-ophthalmologists, but its performance compared to first-line clinicians remains unknown. METHODS: In this international, cross-sectional multicenter study, the DLS, trained on 14,341 fundus photographs, was tested on a retrospectively collected convenience sample of 800 photographs (400 normal optic discs, 201 papilledema and 199 other abnormalities) from 454 patients with a robust ground truth diagnosis provided by the referring expert neuro-ophthalmologists. The areas under the receiver-operating-characteristic curves were calculated for the BONSAI-DLS. Error rates, accuracy, sensitivity, and specificity of the algorithm were compared with those of 30 clinicians with or without ophthalmic training (6 general ophthalmologists, 6 optometrists, 6 neurologists, 6 internists, 6 emergency department [ED] physicians) who graded the same testing set of images. RESULTS: With an error rate of 15.3%, the DLS outperformed all clinicians (average error rates 24.4%, 24.8%, 38.2%, 44.8%, 47.9% for general ophthalmologists, optometrists, neurologists, internists and ED physicians, respectively) in the overall classification of optic disc appearance. The DLS displayed significantly higher accuracies than 100%, 86.7% and 93.3% of clinicians (n = 30) for the classification of papilledema, normal, and other disc abnormalities, respectively. CONCLUSIONS: The performance of the BONSAI-DLS to classify optic discs on fundus photographs was superior to that of clinicians with or without ophthalmic training. A trained DLS may offer valuable diagnostic aid to clinicians from various clinical settings for the screening of optic disc abnormalities harboring potentially sight- or life-threatening neurological conditions.

Should Aquaporin-4 Antibody Test Be Performed in all Patients With Isolated Optic Neuritis?

BACKGROUND: Optic neuritis (ON) may be the initial manifestation of neuromyelitis optica spectrum disorder (NMOSD). Aquaporin-4 antibody (AQP4 Ab) is used to diagnose NMOSD. This has implications on prognosis and is important for optimal management. We aim to evaluate if clinical features can distinguish AQP4 Ab seropositive and seronegative ON patients. METHODS: We reviewed patients with first episode of isolated ON from Tan Tock Seng Hospital and Singapore National Eye Centre who tested for AQP4 Ab from 2008 to 2017. Demographic and clinical data were compared between seropositive and seronegative patients. RESULTS: Among 106 patients (120 eyes) with first episode of isolated ON, 23 (26 eyes; 22%) were AQP4 Ab positive and 83 (94 eyes; 78%) were AQP4 Ab negative. At presentation, AQP4 Ab positive patients had older mean onset age (47.9 ± 13.6 vs 36.8 ± 12.6 years, P < 0.001), worse nadir VA (OR 1.714; 95% CI, 1.36 to 2.16; P < 0.001), less optic disc swelling (OR 5.04; 95% CI, 1.682 to 15.073; p = 0.004), and higher proportions of concomitant anti-Ro antibody (17% vs 4%, p = 0.038) and anti-La antibody (17% vs 1%, p = 0.008). More AQP4 Ab positive patients received steroid-sparing immunosuppressants (74% vs 19%, p < 0.001) and plasma exchange (13% vs 0%, p = 0.009). AQP4 Ab positive patients had worse mean logMAR VA (visual acuity) at 12 months (0.70 ± 0.3 vs 0.29 ± 0.5, p = 0.051) and 36 months (0.37±0.4 vs 0.14 ± 0.2, p = 0.048) follow-up. CONCLUSION: Other than older onset age and retrobulbar optic neuritis, clinical features are non-discriminatory for NMOSD. We propose a low threshold for AQP4 Ab serology testing in inflammatory ON patients, particularly in high NMOSD prevalence populations, to minimize diagnostic and treatment delays.

Facial Nerve Involvement Accompanying Optic Neuritis Secondary to Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disorder.

ABSTRACT: We present the first reported case of facial nerve involvement accompanying an optic neuritis in myelin oligodendrocyte glycoprotein antibody-associated disorder.

Are isolated ocular motor nerve palsies in the elderly truly 'low risk' for abnormal neuro-imaging outcomes?

BACKGROUND: Neurologically isolated ocular motor nerve palsies often present a management dilemma. Neuroimaging is more likely to be offered to patients <50 years without coexisting ischaemic risk factors as their risk of sinister underlying causes is thought to be higher. However, populations are rapidly ageing and advanced neuroimaging is now more widely available. We thus investigated the incidence of abnormal neuroimaging outcomes in the traditionally low-risk older patient group. METHODS: This is a retrospective cohort study of 353 patients presenting with isolated ocular motor nerve palsies to a tertiary neuro-ophthalmology service in Singapore over a four-year (2015 to 2019) period. Clinical data was obtained through manual review of case records. Common aetiologies, age-based differences in prevalence of causes and abnormal neuroimaging outcomes were statistically analysed. RESULTS: Abnormal neuroimaging outcomes were significantly greater in the younger cohort only when age segregation was performed at 60 years of age. In a multivariate analysis, acute onset rather than ischaemic risk factors were independently predictive of normal neuroimaging outcomes. After adjusting for prior cancer risk and clinical bias from presumed ischaemic palsies, abnormal neuroimaging outcomes were seen in 14.1% ≥ 50 yrs, 10.9% ≥ 60 yrs and 15.1% ≥ 70 yrs. CONCLUSIONS: In patients presenting with isolated ocular motor nerve palsies, acute onset may be a more reliable indicator of an ischaemic palsy rather than advanced age or presence of ischaemic risk factors. If onset is not acute, neuroimaging should be considered irrespective of age and coexisting ischaemic risk factors.

Optic Neuritis in the Era of NMOSD and MOGAD: A Survey of Practice Patterns in Singapore.

PURPOSE: The Optic Neuritis Treatment Trial was a landmark study with implications worldwide. In the advent of antibody testing for neuromyelitis optica spectrum disease (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), emerging concepts, such as routine antibody testing and management, remain controversial, resulting mostly from studies in White populations. We evaluate the practice patterns of optic neuritis investigation and management by neuro-ophthalmologists and neurologists in Singapore. DESIGN: 21-question online survey consisting of 4 clinical vignettes. METHODS: The survey was sent to all Singapore Medical Council- registered ophthalmologists and neurologists who regularly manage patients with optic neuritis. RESULTS: Forty-two recipients (17 formally trained neuro-ophthalmol-ogists [100% response rate] and 25 neurologists) responded. Participants opted for routine testing of anti-aquaporin-4 antibodies (88.1% in mild optic neuritis and 97.6% in severe optic neuritis). Anti-MOG antibodies were frequently obtained (76.2% in mild and 88.1% in severe optic neuritis). Plasmapheresis was rapidly initiated (85.7%) in cases of nonresponse to intravenous steroids, even before obtaining anti-aquaporin-4 or anti-MOG serology results. In both NMOSD and MOGAD, oral mycophenolate mofetil was the preferred option if chronic immunosuppression was necessary. Steroids were given for a longer duration and tapered more gradually than in idiopathic optic neuritis cases. CONCLUSIONS: Serological testing for NMOSD and MOGAD is considered as a routine procedure in cases of optic neuritis in Singapore, possibly due to local epidemiological features of these conditions. Chronic oral immunosuppression is preferred for the long term, but further research is necessary to establish the efficacy and cost-effectiveness of these practices.

Accuracy of a Deep Learning System for Classification of Papilledema Severity on Ocular Fundus Photographs.

OBJECTIVE: To evaluate the performance of a deep learning system (DLS) in classifying the severity of papilledema associated with increased intracranial pressure on standard retinal fundus photographs. METHODS: A DLS was trained to automatically classify papilledema severity in 965 patients (2,103 mydriatic fundus photographs), representing a multiethnic cohort of patients with confirmed elevated intracranial pressure. Training was performed on 1,052 photographs with mild/moderate papilledema (MP) and 1,051 photographs with severe papilledema (SP) classified by a panel of experts. The performance of the DLS and that of 3 independent neuro-ophthalmologists were tested in 111 patients (214 photographs, 92 with MP and 122 with SP) by calculating the area under the receiver operating characteristics curve (AUC), accuracy, sensitivity, and specificity. Kappa agreement scores between the DLS and each of the 3 graders and among the 3 graders were calculated. RESULTS: The DLS successfully discriminated between photographs of MP and SP, with an AUC of 0.93 (95% confidence interval [CI] 0.89-0.96) and an accuracy, sensitivity, and specificity of 87.9%, 91.8%, and 86.2%, respectively. This performance was comparable with that of the 3 neuro-ophthalmologists (84.1%, 91.8%, and 73.9%, p = 0.19, p = 1, p = 0.09, respectively). Misclassification by the DLS was mainly observed for moderate papilledema (Frisén grade 3). Agreement scores between the DLS and the neuro-ophthalmologists' evaluation was 0.62 (95% CI 0.57-0.68), whereas the intergrader agreement among the 3 neuro-ophthalmologists was 0.54 (95% CI 0.47-0.62). CONCLUSIONS: Our DLS accurately classified the severity of papilledema on an independent set of mydriatic fundus photographs, achieving a comparable performance with that of independent neuro-ophthalmologists. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that a DLS using mydriatic retinal fundus photographs accurately classified the severity of papilledema associated in patients with a diagnosis of increased intracranial pressure.

Evaluation of Intraocular Pressure After Water Drinking Test in Patients with Unilateral Hemifacial Spasm.

PURPOSE: The aim of the study is to examine the baseline intraocular pressure (IOP) and its changes after performing a water drinking test (WDT) in patients with unilateral hemifacial spasm (HFS). PATIENTS AND METHODS: In this prospective observational study, patients aged 21 years and above diagnosed with unilateral HFS were recruited from the Singapore National Eye Centre between January 2015 and August 2016. The unaffected eye of each patient served as a matched control. An interviewer-administered standardized questionnaire on HFS symptoms and ophthalmic examination was performed. Automated perimetry, optical coherence tomography (OCT) of the optic nerve head, color disc stereophotography and water drinking test (WDT) were done. The primary outcome measure was the difference in IOP between eyes affected by HFS and fellow eyes at baseline and at 15, 30 and 45 minutes of the WDT. RESULTS: Fifty-four patients with unilateral HFS were included. Mean age was 59.8±9.9 years (range, 37.0-84.0). Of these, 54% were female and 94% were Chinese. Mean baseline IOP was significantly higher in eyes with HFS (13.9±3.1mmHg) compared to fellow eyes (13.3±2.8mmHg) (p=0.008). There was no significant difference in absolute or percentage change in IOP from baseline between the 2 groups at 15, 30 and 45 minutes of the WDT. Mean vertical cup-disc ratio (VCDR) on clinical examination was significantly higher in eyes with HFS (0.5±0.2) compared to fellow eyes (0.4±0.2) (p=0.02). There was no significant difference between the groups for visual field parameters and mean retinal nerve fiber layer thickness on OCT. CONCLUSION: Hemifacial spasm is associated with a small but significant difference in mean baseline IOP and VCDR between affected and fellow eyes. However, when eyes affected by HFS and fellow eyes were challenged with the WDT, both responded in similar ways.

Visual outcomes in patients with paranasal mucoceles.

PURPOSE: To describe the ophthalmic complications and visual outcome of patients with paranasal mucoceles. METHODS: This is a retrospective case series of patients with a diagnosis of paranasal mucocele. Their medical records were examined with particular emphasis on the location of the paranasal mucoceles, presence of inflammation (mucocele vs. pyelocele), presence of optic neuropathy, and final visual outcome. RESULTS: Ten patients with an average age of 57.6 years (range, 30-71 years) were studied. Seven mucoceles were in the frontal or fronto-ethmoidal sinuses, one was in the sphenoidal sinus, one was within an Onodi cell, and one was in the maxillary sinus. Four patients developed optic neuropathy, of which 2 cases were related to fronto-ethmoidal mucoceles. Four patients had pyeloceles. Two of these 4 patients had resultant loss of light perception: one case was associated with a fronto-ethmoid sinus and the other with an Onodi cell). CONCLUSIONS: Our series highlights the greater risk of optic neuropathy and poor visual outcome with sphenoid sinus and Onodi cell mucoceles because of their proximity to the optic nerve. However, fronto-ethmoidal mucoceles are not benign and may compromise vision, especially if a posterior ethmoid component is present, or if treatment is delayed and secondary infection has ensued to form a pyelocele. Management of paranasal mucoceles should be prompt, particularly when signs of inflammation are present.

Rationale and methodology for a population-based study of eye diseases in Malay people: The Singapore Malay eye study (SiMES).

PURPOSE: Although there are approximately 200 million people of Malay ethnicity living in Asia, the burden and risk factors of blinding eye diseases in this ethnic group are unknown. This study summarizes the rationale and study design of a population-based study of eye diseases among adult Malays in Singapore. METHODS: A population-based cross-sectional study of Malays was designed in Singapore. The sampling frame consisted of all Malays aged 40-79 living in designated study areas in southwestern Singapore. From a list of 16,069 names provided by the Ministry of Home Affairs, age-stratified random sampling was used to select 5,600 names (1,400 people from each decade of 40-49, 50-59, 60-69, and 70-79 years). The target sample size for this study was 3,150 persons. Selected individuals were invited to a centralized clinic by letters, telephone calls, and home visits. Participants underwent standardized interview and assessment of blood pressure, anthropometry, presenting and best-corrected visual acuity, subjective refraction, ocular biometry, Goldmann tonometry, slit-lamp biomicroscopy, optic disc imaging, digital lens, and retinal photography. Blood and urine samples were collected for biochemical analyses and further stored for future studies. Selected participants also had gonioscopic examination, visual fields test, and assessment of ankle and brachial blood pressure to detect presence of peripheral vascular disease. CONCLUSIONS: This study provides population-based data on the prevalence of and risk factors for age-related eye diseases in people of Malay ethnicity in Singapore. Data from this study allow further understanding of the etiology and impact of eye diseases in this ethnic group.

A reappraisal of diagnostic tests for myasthenia gravis in a large Asian cohort.

BACKGROUND: Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disease characterized by weakness of bodily skeletal muscles. Office-based diagnostic tests such as repetitive nerve stimulation (RNS), single fiber electromyography (SFEMG), and the ice test, are used to refine the differential clinical diagnosis of this disease. Evaluating the clinical sensitivity and specificity of these tests, however, may be confounded by lack of a gold standard, non-blinding, incorporation bias, use of non-representative populations and retrospective data. OBJECTIVE: In this study comprising a large Asian cohort of 127 patients recruited from a Neuro-ophthalmology clinic, we minimized aforementioned confounders and tested the diagnostic value of 3 office-based tests against 2 reference standards of MG by virtue of clinical features, antibody assay and response to treatment. RESULTS: Regardless of the reference standard used, the ice and SFEMG tests displayed a higher sensitivity (86.0 to 97.3%) compared to the RNS test (21.3 to 30.6%). Conversely, the specificity of the ice (31.3%) and SFEMG (21.7% and 17.2%) tests were reduced compared to the RNS test (82.6% and 84.4%). The combined use of the ice test and SFEMG, improved the specificity of MG diagnosis to 63.6% and 64.3%, without affecting the sensitivity of those tests. CONCLUSION: Our findings indicate, in an Asian population, high sensitivity of the SFEMG test and suggest the ice test as a valid, affordable and less technically demanding approach to diagnose MG with ocular involvement. Both ice test and SFEMG alone, however, yielded poor specificity. We suggest that the combination of SFEMG and ice test provides a more reliable diagnosis of MG.

Can long-term corticosteriods lead to blindness? A case series of central serous chorioretinopathy induced by corticosteroids.

INTRODUCTION: Long-term, high-dose corticosteroid therapy is well-known to cause systemic and ocular complications. A lesser known complication is chronic central serous chorioretinopathy (CSCR). Although idiopathic central serous chorioretinopathy (CSCR) is known to be mild with spontaneous recovery and minimal effects on the final visual acuity, chronic CSCR as a complication of long- term steroid therapy behaves differently, and may cause irreversible visual impairment. CLINICAL PICTURE: Three cases of chronic, recurrent CSCR were precipitated by longterm corticosteroids prescribed for post-renal transplant immunosuppressive therapy, postpituitary surgery and pemphigus vulgaris. TREATMENT AND OUTCOME: Two cases resolved with tapering of corticosteroids while one case was treated by focal laser photocoagulation. Two eyes had severe impairment of vision as a result of subretinal scar formation while the other 4 eyes had mild reduction of visual acuity from retinal epithelium pigment atrophy. CONCLUSION: Long-term corticosteroid therapy can be complicated by severe, chronic and recurrent CSCR and occasionally peripheral exudative retinal detachment. This may result in subretinal fibrosis and permanent loss of vision.

Use of optical coherence tomography in predicting post-treatment visual outcome in anterior visual pathway meningiomas.

PURPOSE: To determine the prognostic value of pretreatment optical coherence tomography (OCT) measurement of the peripapillary retinal nerve fibre layer (PRNFL) in final visual outcomes of patients with anterior visual pathway meningioma and optic neuropathy. METHODS: Retrospective case series from a tertiary care academic referral centre. Fourteen eyes (12 patients) in which pretreatment and post-treatment OCT, visual field and comprehensive neuro-ophthalmic exam data were available were evaluated for visual acuity, colour vision and visual field change after neurosurgical and/or radiation oncologic treatment. RESULTS: Twelve patients and 14 eyes were analysed. Patients had tumours centred at the tuberculum sella (3), planum sphenoidale (3), anterior clinoid (2), optic nerve sheath (2), sphenoid wing (2) and olfactory groove (1). Nine eyes had normal PRNFL thickness (mean 95.5 µm± 11.0), whereas five eyes had thin PRNFL (mean 66.0 µm ± 14.2). The mean duration of follow-up was 9.7 months. There was no significant difference in age, duration of symptoms or duration of follow-up between both groups (p=0.22). After treatment, the normal PRNFL group experienced significant improvement in the visual acuity (p=0.03), colour vision (p=0.016), perimetric mean deviation (p=0.019) and foveal threshold (p=0.016) but not pattern SD (p=0.074) compared with the group with thin PRNFL. On multivariate analysis, duration of symptoms, but neither age nor follow-up duration, predicted final visual outcome. CONCLUSIONS: Patients with compressive optic neuropathy due to anterior pathway meningiomas are more likely to improve post-treatment if they have a normal pretreatment PRNFL and shorter duration of symptoms.

Prevalence and causes of low vision and blindness in an urban malay population: the Singapore Malay Eye Study.

OBJECTIVE: To describe the prevalence and causes of low vision and blindness in a Malay population. METHODS: A population-based, cross-sectional study of 3280 participants of Malay ethnicity, aged 40 to 79 years, was conducted. Participants underwent standardized ophthalmic assessments to determine (1) presenting and best-corrected visual acuity according to US and modified World Health Organization definitions of blindness and low vision and (2) the primary causes of visual impairment. RESULTS: Of 4168 eligible individuals, 3280 participated in the study (78.7%). The population-weighted prevalence of bilateral blindness was 0.3% and of bilateral low vision, 4.4% (US definition of presenting visual acuity). After best-corrected visual acuity, the population-weighted prevalence of bilateral blindness was reduced to 0.1% and bilateral low vision to 1.0%. Cataract was the main cause of presenting unilateral (38.9%) and bilateral (65.2%) blindness, whereas undercorrected refractive error was the main cause of presenting unilateral (68.8%) and bilateral (52.2%) low vision. Diabetic retinopathy, age-related macular degeneration, and glaucoma were the other leading causes of blindness and low vision. CONCLUSIONS: The age-standardized prevalences of bilateral blindness and low vision in a Malay population were lower when compared with other Asian studies. Undercorrected refractive error and cataract are the leading causes of visual impairment among the Malay adult population in Singapore.

The prevalence and types of glaucoma in malay people: the Singapore Malay eye study.

PURPOSE: To assess the prevalence and types of glaucoma in an Asian Malay population. METHODS: The Singapore Malay Eye Study is a population-based, cross-sectional survey that examined 3280 (78.7% response) persons aged 40 to 80 years. Participants underwent a standardized clinical examination including slit-lamp biomicroscopy, Goldmann applanation tonometry, and dilated optic disc assessment. Participants who were suspected to have glaucoma also underwent visual field examination (24-2 SITA standard, Humphrey Visual Field Analyzer II), gonioscopy, and repeat applanation tonometry. Glaucoma was defined according to International Society for Geographical and Epidemiologic Ophthalmology criteria. RESULTS: Of the 3280 participants, 150 (4.6%) had diagnosed glaucoma, giving an age- and sex-standardized prevalence of 3.4% (95% confidence interval [CI], 3.3%-3.5%). The age- and sex-standardized prevalence of primary open-angle glaucoma was 2.5% (95% CI, 2.4%-2.6%), primary angle-closure glaucoma 0.12% (95% CI, 0.10%-0.14%), and secondary glaucoma 0.61% (95% CI, 0.59%-0.63%). Of the 150 glaucoma cases, only 12 (8%) had a previous known history of glaucoma. Twenty-seven (18%) eyes had low vision (based on best corrected visual acuity logarithm of the minimal angle of resolution [logMAR] >0.30 to <1.00 in the eye with glaucoma for unilateral cases; and based on the better eye for bilateral cases) and 15 (10%) were blind (logMAR, >/=1.00). CONCLUSIONS: The prevalence of glaucoma among Malay persons 40 years of age and older in Singapore is 3.4%, comparable to ethnic Chinese people in Singapore and other racial/ethnic groups in Asia. As in Chinese, Caucasians, and African people, primary open-angle glaucoma was the main form of glaucoma in this population. More than 90% of glaucoma cases were previously undetected.