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.

Low conversion rate of ocular to generalized myasthenia gravis in Singapore.

INTRODUCTION: Ocular myasthenia gravis (OMG) is a common condition of the neuromuscular junction that may convert to generalized myasthenia gravis (GMG). Our aim in this study was to determine the conversion rate and predictive factors for generalization in OMG, in an Asian population. METHODS: The investigation consisted of a retrospective study of OMG patients with a minimum 2 years of follow-up. RESULTS: Among 191 patients with OMG, 155 had the minimum 2-year follow-up. The conversion rate at median follow-up (40.8 months) was 10.6% (95% confidence interval 7.9%-13.3%), and at the 2-year follow-up it was 7.7% (95% confidence interval 5.6%-9.8%). At baseline, the predictive factors for generalization were positive acetylcholine receptor antibodies (hazard ratio 3.71, P = 0.024), positive repetitive nerve stimulation (RNS) studies (hazard ratio 4.42, P = 0.003), and presence of radiologically presumed or pathologically confirmed thymoma (hazard ratio 3.10, P = 0.013). DISCUSSION: The conversion rate of OMG to GMG in Asian patients is low, as predicted by presence of acetylcholine receptor antibodies, presence of thymoma, and positive RNS studies. Muscle Nerve 57: 756-760, 2018.

Cerebral neural correlates of differential melanopic photic stimulation in humans.

Photic stimulation of rods, cones and intrinsically photosensitive melanopsin-containing retinal ganglion cells (ipRGCs) mediates non-visual light responses, including entrainment of circadian rhythms and pupillary light reflex. Unlike visual responses to photic stimulation, the cerebral correlates of non-visual light responses in humans remains elusive. In this study, we used functional magnetic resonance imaging (fMRI) in 14 healthy young participants, to localize cerebral regions which are differentially activated by metameric light that gave rise to different levels of melanopic excitation. Mean blood oxygen-level dependent (BOLD) responses disclosed bilateral activation of the frontal eye fields during exposure to light geared towards melanopsin. Furthermore, multivariate pattern analyses showed distinct bilateral pattern activity in the inferior temporal gyri and the caudate nuclei. Taken together, our findings suggest that melanopsin-based photoreception activates a cerebral network including frontal regions, classically involved in attention and ocular motor responses.

Ocular manifestations and the clinical course of carotid cavernous sinus fistulas in Asian patients.

PURPOSE: To study the clinical course with regard to both the angiographic and visual outcomes of carotid cavernous fistulas (CCFs). BACKGROUND: Carotid cavernous sinus fistulas (CCFs) are conditions which often present with ocular signs and symptoms. The clinical presentation of CCFs is varied according to the anatomy, haemodynamics and size of the CCF. CCFs causing significant symptoms or vision loss should be treated with embolization. METHODS: This is a retrospective review of the medical records of all CCF cases seen in the Singapore National Eye Centre from September 2002 to December 2011. RESULTS: 45 patients who had confirmed CCF on conventional cerebral angiography were included. Anterior draining CCFs presented with orbital congestion while posterior draining CCFs presented with pain, diplopia and cranial nerve palsies. Mild residual symptoms were still present in 85% of treated direct CCFs despite complete angiographic closure however 52% of treated dural CCFs had complete resolution of symptoms despite only half of those achieving angiographic closure. Treated and untreated dural CCFs had similar outcomes (87% versus 76% recovered or improved (p > 0.05)). Poor outcomes can result from residual diplopia or vision loss from complications of the CCF itself (e.g. compressive optic neuropathy, glaucoma, retinopathy) or complications from CCF embolization treatment (e.g. central retinal artery occlusion). CONCLUSION: Presenting symptoms and signs are related to the angiographic drainage of CCFs. Angiographic outcomes after embolization treatment may not always correlate with clinical outcomes.

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.

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.

Visual recovery following emergent orbital decompression in traumatic retrobulbar haemorrhage.

INTRODUCTION: Acute retrobulbar haemorrhage is a potentially sight-threatening condition, and can follow retrobulbar anaesthesia or trauma to the orbit. Acute loss of vision can occur with retrobulbar haemorrhage and is reversible if the condition is recognised and treated early. CLINICAL PICTURE: We report a case of acute retrobulbar haemorrhage following orbital trauma in a 78-year-old Chinese lady. TREATMENT: The patient was on follow-up for a mature cataract in the right eye and had been scheduled for cataract surgery. The patient presented to the emergency department with acute loss of vision in the right eye, severe proptosis and tense periorbital haematoma after she hit her right face following a fall. Computed tomography scans revealed fractures of the floor, lateral and medial walls of the right orbit as well as retrobulbar and periorbital haematoma. There was marked proptosis and tenting of the globe with stretching of the optic nerve. Emergent lateral canthotomy and cantholysis was performed at the emergency department. The patient subsequently underwent surgical evacuation of the orbital haematoma. OUTCOME: The patient's vision in the right eye recovered from no perception of light to light perception over the next few days. After a month of follow-up, the patient underwent right cataract surgery, and her best corrected visual acuity was 6/12 part. CONCLUSION: In severe acute retrobulbar haemorrhage, prompt surgical evacuation of the haematoma can reverse visual loss.

Long-term outcome in children with gliomas of the anterior visual pathway.

We performed a retrospective assessment of the long-term visual, neurologic, and systemic outcomes of 47 patients with anterior visual pathway gliomas seen at the Johns Hopkins Hospital. All of the patients had follow-up of at least 10 years or died during the follow-up period. Two patients died before 10 years of follow-up were achieved. The remaining 45 patients (including three patients who subsequently died) had follow-up of 10-28 years (mean, 15.3 years; median, 15 years). Sixteen of the patients in this study, most of whom had neurofibromatosis type 1 (NF1), received no treatment. None of these patients died or developed neurologic morbidity as a result of their tumor. Thirty-one of the patients, most of whom did not have evidence of NF1, received treatment. Many of these patients subsequently developed neurologic, endocrine, or visual morbidity. However, although patients with anterior visual pathway gliomas who were not treated fared better visually, neurologically, and systemically than patients who were treated, patients who required treatment for progression generally had a good overall prognosis, particularly patients with tumors that did not involve the hypothalamus. Most of these patients survived and maintained useful vision in at least one eye. We believe that patients with anterior visual pathway gliomas, particularly those with NF1, should not be treated unless there is clear clinical or neuroimaging evidence of progression.

Acute visual loss in a patient with optic disc drusen.

Here we report a case of sudden, unilateral, painless visual loss in a middle-aged patient. A 45-year-old gentleman with no known past medical history presented with acute painless left visual impairment. Clinically, he was found to have a left optic neuropathy associated with a swollen and hyperemic left optic disc. The right optic disc was noted to be small and crowded, and both optic discs were noted to have irregular margins. Humphrey perimetry revealed a constricted visual field in the left eye. Fundus autofluorescence imaging revealed autofluorescence, and B-scan ultrasonography showed hyperreflectivity within both nerve heads. Blood investigations for underlying ischemic and inflammatory markers revealed evidence of hyperlipidemia but were otherwise normal. A diagnosis of left nonarteritic anterior ischemic optic neuropathy (NAAION) was made, with associated optic disc drusen and hyperlipidemia. NAAION typically occurs in eyes with small, structurally crowded optic discs. The coexistence of optic disc drusen and vascular risk factors may further augment the risk of developing NAAION.

Clinical spectrum of tuberculous optic neuropathy.

PURPOSE: Tuberculous optic neuropathy may follow infection with Mycobacterium tuberculosis or administration of the bacille Calmette-Guerin. However, this condition is not well described in the ophthalmic literature. METHODS: Ophthalmologists, identified through professional electronic networks or previous publications, collected standardized clinical data relating to 62 eyes of 49 patients who they had managed with tuberculous optic neuropathy. RESULTS: Tuberculous optic neuropathy was most commonly manifested as papillitis (51.6 %), neuroretinitis (14.5 %), and optic nerve tubercle (11.3 %). Uveitis was an additional ocular morbidity in 88.7 % of eyes. In 36.7 % of patients, extraocular tuberculosis was present. The majority of patients (69.4 %) had resided in and/or traveled to an endemic area. Although initial visual acuity was 20/50 or worse in 62.9 % of 62 eyes, 76.7 % of 60 eyes followed for a median of 12 months achieved visual acuities of 20/40 or better. Visual field defects were reported for 46.8 % of eyes, but these defects recovered in 63.2 % of 19 eyes with follow-up. CONCLUSION: Visual recovery from tuberculous optic neuropathy is common, if the diagnosis is recognized and appropriate treatment is instituted. A tuberculous etiology should be considered when evaluating optic neuropathy in persons from endemic areas.

The incidence of neuro-ophthalmic diseases in Singapore: a prospective study in public hospitals.

PURPOSE: To describe the incidence of neuro-ophthalmic diseases in a multi-ethnic Asian population in Singapore. METHODS: Prospective study in public hospitals in Singapore. All neuro-ophthalmic cases seen in four public sector hospitals over a 22-month period (September 2002 to June 2004) were identified using a standardized protocol. The 2004 Singapore population was used as a denominator to estimate annual incidence. The prevalence of ischemic risk factors (hypertension, diabetes, and hypercholesterolemia) among cases was compared to population data. RESULTS: A total of 1,356 patients with neuro-ophthalmic diseases were seen during the study period, of which 627 were new incident cases. The overall annual incidence of neuro-ophthalmic diseases was 9.81 per 100,000 (95% confidence interval, 8.80-10.90). The incidence increased with age. After controlling for age, the annual incidence was similar between men (10.75 per 100,000) and women (9.00 per 100,000), but was higher in Chinese (10.33 per 100,000) and Indians (9.34 per 100,000) than in Malays (6.62 per 100,000). The three commonest specific neuro-ophthalmic conditions were abducens nerve palsy (1.27 per 100,000), anterior ischemic optic neuropathy (1.08 per 100,000) and oculomotor nerve palsy (0.91 per 100,000). The incidence of optic neuritis was 0.83 per 100,000. Compared with the Singapore general population, the prevalence of diabetes was significantly higher in people aged 40-59, while the prevalence of hypercholesterolemia was significantly higher in 60-69 year age group. CONCLUSION: In this study of public hospitals in Singapore, the incidence of neuro-ophthalmic diseases was higher in Chinese and Indians compared to Malays.

Nasopharyngeal carcinoma with orbital involvement.

PURPOSE: To describe the clinical presentation of patients with nasopharyngeal carcinoma and orbital involvement. METHODS: A retrospective case series of 9 patients with nasopharyngeal carcinoma presenting with orbital involvement from March 2003 to April 2006 at the Singapore National Eye Centre were reviewed. The clinical profile, neuroradiologic evaluation, and clinical course of these patients were reviewed. RESULTS: There were 3 women and 6 men with stage T4 disease. The mean age was 49.2 years +/- 7.69 years (range, 37-57 years). The mean time from initial diagnosis of nasopharyngeal carcinoma to orbital involvement was 8.2 years (range, 0.8-29 years). One patient had no prior history of nasopharyngeal carcinoma. Four patients presented with an eyelid mass and 2 patients reported tearing. Other symptoms included diplopia, blurred vision, and protrusion of the eye. Imaging revealed tumor involvement of the orbital apex, inferior orbital fissures with intraconal spread, and infiltration of the lacrimal sac. The recurrences were confirmed histologically. Patients were treated with radiotherapy and/or chemotherapy. There were 3 deaths from advanced nasopharyngeal carcinoma during the follow-up period. The time interval from diagnosis of orbital involvement to death ranged from 8 months to 24 months. CONCLUSION: Ocular symptoms and signs may be the initial presentation of recurrent nasopharyngeal carcinoma. One must therefore be aware of possible tumor recurrence in patients with a prior history of nasopharyngeal carcinoma who present with symptoms of tearing or an eyelid mass, as this would enable prompt referral to the oncologist and otorhinolaryngologist.