Artificial Intelligence to Detect Papilledema from Ocular Fundus Photographs.

BACKGROUND: Nonophthalmologist physicians do not confidently perform direct ophthalmoscopy. The use of artificial intelligence to detect papilledema and other optic-disk abnormalities from fundus photographs has not been well studied. METHODS: We trained, validated, and externally tested a deep-learning system to classify optic disks as being normal or having papilledema or other abnormalities from 15,846 retrospectively collected ocular fundus photographs that had been obtained with pharmacologic pupillary dilation and various digital cameras in persons from multiple ethnic populations. Of these photographs, 14,341 from 19 sites in 11 countries were used for training and validation, and 1505 photographs from 5 other sites were used for external testing. Performance at classifying the optic-disk appearance was evaluated by calculating the area under the receiver-operating-characteristic curve (AUC), sensitivity, and specificity, as compared with a reference standard of clinical diagnoses by neuro-ophthalmologists. RESULTS: The training and validation data sets from 6779 patients included 14,341 photographs: 9156 of normal disks, 2148 of disks with papilledema, and 3037 of disks with other abnormalities. The percentage classified as being normal ranged across sites from 9.8 to 100%; the percentage classified as having papilledema ranged across sites from zero to 59.5%. In the validation set, the system discriminated disks with papilledema from normal disks and disks with nonpapilledema abnormalities with an AUC of 0.99 (95% confidence interval [CI], 0.98 to 0.99) and normal from abnormal disks with an AUC of 0.99 (95% CI, 0.99 to 0.99). In the external-testing data set of 1505 photographs, the system had an AUC for the detection of papilledema of 0.96 (95% CI, 0.95 to 0.97), a sensitivity of 96.4% (95% CI, 93.9 to 98.3), and a specificity of 84.7% (95% CI, 82.3 to 87.1). CONCLUSIONS: A deep-learning system using fundus photographs with pharmacologically dilated pupils differentiated among optic disks with papilledema, normal disks, and disks with nonpapilledema abnormalities. (Funded by the Singapore National Medical Research Council and the SingHealth Duke-NUS Ophthalmology and Visual Sciences Academic Clinical Program.).

Tonic Pupil Following COVID-19.

ABSTRACT: A 37-year-old patient presented to our emergency department with sudden onset decreased vision with a history of being treated for COVID 19 3 weeks earlier. On examination, she was found to have a tonic right pupil, which was confirmed with a dilute pilocarpine test. As tonic pupils are known to be caused by neurotropic viruses and our current understanding of the SARS-CoV-2 is that it does affect the nervous system, we feel that the tonic pupil in our patient may be secondary to COVID 19.

Visual Outcomes and Clinical Manifestations of Pediatric Optic Neuritis in Indian Population: An Institutional Study.

BACKGROUND: Optic neuritis in children is an uncommon disorder which usually occurs after a viral illness or vaccination and, less frequently, occurs as a manifestation of a demyelinating disorder. Pediatric optic neuritis usually is bilateral and presents with optic disc edema, recovers rapidly with steroid therapy, and generally has low conversion rate to multiple sclerosis or neuromyelitis optica spectrum disorder. We report the clinical features and treatment outcomes of pediatric optic neuritis in Indian population, for which little data are available. METHODS: We reviewed the medical case records of patients with optic neuritis who were younger than 18 years, from 1999 to 2016. All patients were assessed and managed in the Neuro-Ophthalmology Department of Sankara Nethralaya, a unit of Medical Research Foundation and Pediatric Neurology Department of Kanchi Kamakoti-Childs Trust Hospital, Chennai, India. RESULTS: One hundred seventeen eyes of 78 children with mean age of 11.84 (±4.58) years were identified. Forty-two (53.8%) were females and 36 (46.2%) were males. Thirty-nine patients (50%) had bilateral involvement and a similar number had unilateral involvement. Fifty-nine eyes (50.4%) had optic disc edema, 20 eyes (17.1%) had disc pallor, and 38 eyes (32.4%) had normal discs. Of 63 patients who had neuroimaging, 36 had MRI, and 27 underwent computed tomography. Eighty-four eyes (of 59 patients) received steroid therapy according to the protocol of the Optic Neuritis Treatment Trial (ONTT). Thirty-three eyes that were treated with other steroid protocols were excluded from the final visual outcome analyses. Sixty of the 84 eyes (72.3%) recovered visual acuity of 20/40 or better. Visual acuity improvement was statistically significant between initial and final visual acuity (logMAR) in our patients treated with the ONTT protocol (P ≤ 0.001). CONCLUSIONS: Our Indian pediatric population had good visual recovery after steroid treatment for optic neuritis. Profound loss of visual acuity on presentation and bilateral involvement were significantly associated with poor visual outcome.

Aquaporin 4 antibody [NMO Ab] status in patients with severe optic neuritis in India.

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system that causes attacks of optic neuritis and transverse myelitis. The discovery of a specific serum marker for NMO-IgG antibody [aquaporin 4 antibody/AQP4 Ab] has revolutionised the treatment of demyelinating diseases. Severe vision loss can be seen in optic neuritis (ON) associated with both multiple sclerosis (MS) and NMO. Identifying this antibody in optic neuritis patients can help us to establish the likelihood of these patients developing NMO (Jarius et al. Neurol Sci 298:158-162, 2010). It is important to differentiate these two entities as the treatment strategies of MS and NMO are different. To the best of our knowledge, there is no published literature regarding the importance of identifying this antibody in severe optic neuritis in Indian patients. Hence we decided to screen our severe optic neuritis patients for this AQP4 Ab. To investigate the presence of aquaporin 4 antibody and determine its prognostic value for visual and neurological outcome, in patients with bilateral and recurrent [severe] ON without any previous neurological manifestations presenting to a neuro-ophthalmology clinic in India. Single centre, prospective study. 40 patients (27 female patients and 13 male) with severe optic neuritis [patients with no visual improvement by 4 weeks from onset of vision loss] who presented either as recurrent attacks or as bilateral and severe optic neuritis between January 2010 and June 2011 were enrolled. Clinical features, visual outcome and sequential neurological events were compared between the seropositive and the seronegative groups. Aquaporin 4 antibodies were detected from serum using ELISA technique and IIF technique. Presence of this antibody in the serum was considered to be seropositive status and patients who did not have this antibody were considered seronegatives. AQP4 antibodies were detected in 8 of the 40 patients with severe ON (20 %).The female to male ratio in the seropositive group was 8:0. The NMO antibody titer ranged from 0.3 to 760 U/ml. ANA positivity in seropositive patients was statistically significant (p = 0.043). All seropositive patients had significantly poorer visual outcome as compared with the seronegative patients (p = 0.04).

Infectious optic neuropathy (ION), how to recognise it and manage it.

Optic neuropathy can be of infectious or non-infectious/idiopathic aetiology. Many infectious organisms can cause optic neuropathy that can be of varied presentation including papillitis, retrobulbar optic neuritis, neuroretinitis, and optic perineuritis. Detailed history, ocular, systemic/neurologic examination along with appropriate laboratory evaluation can help clinicians to identify the infectious agent causing optic neuropathy. In spite of recent advanced techniques in serological testing and molecular diagnostics like polymerase chain reaction (PCR), the identification of these pathogens is still a diagnostic challenge. It is ideal to have an infectious disease (ID) consultant in the management team, as most of these infections are multisystem involving diseases. Most infectious agents can be effectively treated with specific antibiotics, with or without corticosteroid therapy, but visual recovery is highly variable and depends entirely on early diagnosis of the causative agent. This review article will provide an overview of common pathogens involved in ION and will describe their management paradigms.

Optical coherence tomography in papilledema: A probe into the intracranial pressure correlation.

PURPOSE: To study the optic nerve head characteristics on optical coherence tomography (OCT) in patients with papilledema and correlate them with intracranial pressure (ICP). METHODS: A retrospective hospital-based study of 46 eyes of 23 patients with bilateral optic disc edema secondary to increased ICP. The clinical profile and the OCT features in terms of retinal nerve fiber layer thickness (RNFL), ganglion cell inner plexiform layer (GCIPL) thickness, and enhanced depth imaging (EDI) B scan images of the optic nerve head were studied and correlated with the ICP. RESULTS: Papilledema was secondary to idiopathic intracranial hypertension (IIH) ( n = 20), obstructive hydrocephalus ( n = 2), and communicating hydrocephalus ( n = 1). The mean ICP in 20 IIH patients was 347 mmH 2 O. The ICP and RNFL thickness in all four quadrants were found to be weakly positively correlated: superior RNFL r (38) = 0.17, P = 0.30, and nasal RNFL r (38) = 0.30, P = 0.05, inferior RNFL r (38) = 0.29, P = 0.07, and temporal RNFL, r (38) = -0.001, P = 0.99. The GCIPL layer thickness and the ICP were weakly negatively correlated in all sectors: superior (38) = -0.23, P = 0.16, superonasal, r (38) = -0.07, P = 0.67, inferonasal r (38) = -0.08, P = 0.64, inferior r (38) = -0.21, P = 0.19, inferotemporal r (38) = -0.23, P = 0.17, superotemporal, r (38) -0.21, P = 0.20. Descriptive features on the B scan, such as peripapillary hyperreflective ovoid mass-like structures and microcystic spaces, were observed most commonly with an ICP of 251-350 mmH 2 O, and the hyperreflective dots in the RNFL layer and Bruch's membrane inward denting were observed more commonly with an ICP of 351-450 mmH 2 O. CONCLUSION: The RNFL thickness in all four quadrants had a weak positive correlation, and the GCIPL layer had a weak negative correlation with the ICP. The EDI descriptive features on OCT may vary with ICP.

Clinical profile, imaging features and short term visual outcomes of Indian optic neuritis patients with and without seromarkers for myelin oligodendrocyte glycoprotein and neuromyelitis optica.

PURPOSE: To analyze clinical profile, imaging features, and short-term visual outcomes of optic neuritis patients in Indian population with and without seromarkers for myelin oligodendrocyte glycoprotein (MOG)/neuromyelitis optica (NMO). METHODS: Electronic medical records of 203 optic neuritis patients who presented between June 2018 and December 2019 to the Neuro-ophthalmology services of a tertiary care center in India were retrospectively analyzed. RESULTS: Of 203 patients, 57 patients (28.08%) were positive for MOG-antibody and 20 patients (9.85%) were positive for NMO antibody. 114 patients (56.16%) were double-negative (negative for both antibodies) and 12 patients (5.91%) were diagnosed as multiple sclerosis (MS). None of the patients had both antibodies. Mean age of presentation was 31.29 ± 1.035 years. There was female preponderance in NMO-optic neuritis (NMO-ON) and MS-optic neuritis (MS-ON) groups (1:5). Mean vision on presentation was worse (logMAR 1.570 ± 0.863) in NMO-ON group. The mean visual acuity showed statistically significant recovery (logMAR 0.338 ± 0.639) in the final follow-up in MOG-optic neuritis (MOG-ON) group. Multivariate logistic regression analysis revealed poor visual outcome in patients presenting with retrobulbar neuritis, optic disc pallor, bilateral sequential optic nerve involvement, and with positive NMO antibody. Optic neuritis patients presenting with disc edema associated with pain and positive for MOG antibody were found to have a better visual outcome. CONCLUSION: In this Indian optic neuritis cohort, the prevalence of MOG-ON was higher than NMO-ON. MOG-ON had a better visual outcome than NMO-ON. The incidence of MS-ON was less compared to the western literature. A significant number of patients (114 patients, 56.16%) were double negative for both seromarkers and yet had presented with optic neuritis with no clinical or imaging features suggestive of MS/MOG associated disease (MOG AD)/NMO spectrum disorder (NMO SD).

Visual outcomes of toxic optic neuropathy secondary to Ethambutol: A retrospective observational study from India, an endemic country.

Purpose: Ethambutol (EMB) is one of the first-line drugs used for treating tuberculosis. Vision loss due to optic nerve toxicity is a well-known potential side effect of the drug. Our aim was to evaluate the clinical features and visual outcomes of patients with EMB optic neuropathy (EON). Methods: A retrospective, observational, single-center study of all patients who were diagnosed to have EON during January 2017-December 2019 was done. All these patients were screened in the Department of Neuro-ophthalmology at a referral tertiary eye care institution in India. Clinical features, visual outcomes, and neuroimaging findings of these patients were analyzed. Results: Two hundred and fifty-six eyes of 128 patients were included. Of these, 73 were male and 55 were female. Mean age was 50.55 ± 15 years. Mean visual acuity at presentation was 1.12 ± 0.45 logarithm of the minimum angle of resolution (logMAR). One hundred and forty three eyes had normal optic disk on presentation, 111 had disk pallor, and two eyes had disk edema. The most common field defect was central/paracentral scotoma (26.2%) followed by temporal defects (24.6%). Magnetic resonance imaging (MRI) brain and orbit showed optic nerve signals in 19.6% and chiasmal signals in 5.2%. At the final follow-up, a ≥2-line vision improvement was noted in 161 eyes (62.9%), which was statistically significant. Conclusion: Multiple prognostic factors were analyzed to predict the visual recovery of EON. We observed that patients presenting with visual acuity worse than 6/60 had poor visual outcome and long duration of follow-up showed better visual recovery, proving the possibility of a gradual recovery pattern of EON. Interestingly, we found in our study that the chances of favorable visual outcome were directly proportionate to early diagnosis and cessation of EMB.

Ocular features of patients with Parkinson's disease examined at a Neuro-Optometry Clinic in a tertiary eye care center.

PURPOSE: To report the ocular features of patients with PD who presented with visual complaints to a tertiary eye care center. METHODS: This was a retrospective study carried out between January 2015 and March 2020 at the Neuro-Optometry clinic of a tertiary eye care center in Southern India. All PD patients with ocular complaints examined by the neuro- ophthalmologists were referred to Neuro-Optometry Clinic for detailed evaluation. Patients with other neurodegenerative disorders, brain injury, and other causes of vision loss or extraocular motility disorders were excluded. RESULTS: A total of 43 patients (7 females, 36 males) between 50 and 86 years of age (mean: 70 ± 8.9 years) with a mean duration of PD of 4.5 ± 4.5 years were studied. Decreased vision associated with reading difficulty (40%) was common in PD patients. In terms of gaze restriction, vertical gaze involvement (35%) was more than horizontal involvement (7%). Convergence insufficiency (CI) was the most common binocular vision dysfunction (30%), followed by CI with oculomotor dysfunction (14%) and vertical gaze palsy (18%). Ground prisms were recommended for 26 patients (61%) and home vision therapy for 5 patients (12%) as corrective measures. CONCLUSION: Binocular vision dysfunction is highly prevalent among PD patients. This could potentially contribute to the reading difficulties and double vision encountered by these patients. Assessment of binocular vision and oculomotor parameters thus becomes important to understand and manage the reading difficulties in patients with PD.

Simultaneous screening for antibodies to myelin oligodendrocyte glycoprotein and aquaporin-4 in patients with optic neuritis using cell-based assay.

Background: This study was aimed to test simultaneous detection of antibodies to myelin oligodendrocyte glycoprotein (MOG)/aquaporin4 (AQP4) in serum samples of patients with clinically-diagnosed optic neuritis (ON), by fixed cell-based immunofluorescence assay (CBIFA). Methods: The study involved 237 serum samples of patients with ON which were tested for MOG and AQP4 antibodies using fixed CBIFA kit which utilizes AQP4 or MOG protein transfected cells as a substrate. Results: Of 237 serum samples, 22 (9%) were positive for AQP4, 66 (28%) were positive for MOG, and 138 (58%) were negative for both AQP4 and MOG antibodies. 11 (5%) patients with clinically-diagnosed multiple sclerosis (MS) were negative for both antibodies. None of the samples were positive for both AQP4 and MOG. Among 237, 132 women [18 (13.6%) and 37 (28%)] and 105 men [4 (3.8%) and 29 (27.6%)] were positive for AQP4/MOG antibodies and remaining percentage belonged to double negative and MS. Seropositivity rate was higher in women than men. Antibodies to MOG were significantly higher than AQP4 antibodies and evenly found in all age groups. There was no ambiguous result encountered in the study. Conclusion: In this study, the seropositivity for antibodies to MOG is more than AQP4 antibody in patients with ON. Fixed CBIFA is a useful tool for laboratory diagnosis of ON in the clinical setting of neuro-ophthalmology to plan the next line of treatment management effectively.

Bilateral optic neuritis with spine demyelination associated with influenza A H1N1 infection.

PURPOSE: To report a rare case of optic neuritis with spine demyelination following H1N1 virus infection. OBSERVATION: A 66-year-old female presented with decreased vision in both eyes (left > right) following a recent episode of fever and flu. She was diagnosed as H1N1 infection confirmed by viral antigen analysis of throat swab. On examination, she had a profound vision drop in the left eye with optic disc edema. MRI brain and orbit revealed bilateral optic nerve and frontal dural thickening with a ring-enhancing lesion in the right frontal lobe. MRI spine showed long cord signals at T1-T7 suggestive of demyelination. The patient had a complete recovery of vision and visual fields after intravenous and oral steroids. CONCLUSION/IMPORTANCE: Influenza A virus can manifest with a wide range of symptoms including flu-like illness to neurological complications. This case highlights optic neuritis as a presenting feature of H1N1 infection.

Leber's Hereditary Optic Neuropathy-Specific Mutation m.11778G>A Exists on Diverse Mitochondrial Haplogroups in India.

Purpose: Leber's hereditary optic neuropathy (LHON; OMIM 535000) is one of the most common maternally inherited mitochondrial disorders. Three mitochondrial DNA point mutations-m.3460G>A (MT-ND1), m.11778G>A (MT-ND4), and m.14484T>C (MT-ND6)-account for the majority of reported LHON cases. Only approximately 50% of males and approximately 10% of females carrying these mutations develop optic neuropathy and blindness. Additional factors, such as mtDNA/nuclear genetic background and environmental modifiers, are likely to contribute toward the observed incomplete penetrance and gender bias. We aimed to investigate whether mtDNA haplogroup influences LHON clinical expression in Indian patients harboring the m.11778G>A mutation. Methods: Detailed clinical assessment and complete mitochondrial genome sequencing was undertaken in 64 LHON families harboring the m.11778G>A mutation. Mitochondrial haplogroup was assigned based on evolutionarily conserved mtDNA variations. Results: A total of 543 individuals (295 male, 248 female) from 64 unrelated families harboring the m.11778G>A mutation were recruited to the study. The overall disease penetrance was 27.07% (146 of 543) and higher in males (37.9%; 112 of 295) than females (13.7%; 34 of 248). The mtDNA haplogroup analysis revealed that all affected probands belonged to different mtDNA haplogroups. No association between the m.11778G>A mutation and the background mtDNA haplogroup was detected. Conclusions: The first detailed study of Indian LHON patients confirm that the m.11778G>A-related LHON in India coexists with multiple different mtDNA haplogroups, unlike the preferential association of west Eurasian haplogroup J and the reported increased clinical penetrance with the J2 subhaplogroup. However, we observed variable penetrance of LHON in different Indian mtDNA haplogroup backgrounds, indicating their possible influence on clinical expression. These data suggest that a similar heterogeneity, resulting from the mtDNA haplogroup, might also exist in other mitochondrial diseases among Indian populations.

The diagnostic yield of neuroimaging in sixth nerve palsy--Sankara Nethralaya Abducens Palsy Study (SNAPS): Report 1.

AIMS: The aim was to assess the etiology of sixth nerve palsy and on the basis of our data, to formulate a diagnostic algorithm for the management in sixth nerve palsy. DESIGN: Retrospective chart review. RESULTS: Of the 104 neurologically isolated cases, 9 cases were attributable to trauma, and 95 (86.36%) cases were classified as nontraumatic, neurologically isolated cases. Of the 95 nontraumatic, isolated cases of sixth nerve palsy, 52 cases were associated with vasculopathic risk factors, namely diabetes and hypertension and were classified as vasculopathic sixth nerve palsy (54.7%), and those with a history of sixth nerve palsy from birth (6 cases) were classified as congenital sixth nerve palsy (6.3%). Of the rest, neuroimaging alone yielded a cause in 18 of the 37 cases (48.64%). Of the other 19 cases where neuroimaging did not yield a cause, 6 cases were attributed to preceding history of infection (3 upper respiratory tract infection and 3 viral illnesses), 2 cases of sixth nerve palsy were found to be a false localizing sign in idiopathic intracranial hypertension and in 11 cases, the cause was undetermined. In these idiopathic cases of isolated sixth nerve palsy, neuroimaging yielded no positive findings. CONCLUSIONS: In the absence of risk factors, a suggestive history, or positive laboratory and clinical findings, neuroimaging can serve as a useful diagnostic tool in identifying the exact cause of sixth nerve palsy. Furthermore, we recommend an algorithm to assess the need for neuroimaging in sixth nerve palsy.

Haplogroup heterogeneity of LHON patients carrying the m.14484T>C mutation in India.

PURPOSE: To investigate the clinical and mitochondrial DNA (mtDNA) haplogroup background of Indian Leber hereditary optic neuropathy (LHON) patients carrying the m.14484T>C mutation. METHODS: Detailed clinical investigation and complete mtDNA sequencing analysis was carried out for eight Indian LHON families with the m.14484T>C mutation. Haplogroup was constructed based on the evolutionarily important mtDNA variants. RESULTS: In the present study, we characterized eight unrelated probands selected from 187 LHON cases. The overall penetrance of the disease was estimated to be 19.75% (16/81) in eight pedigrees with the m.14484T>C mutation and showed substantially higher sex bias (male: female = 13:3). The mtDNA haplogrouping revealed that they belong to diverse haplogroups; i.e., F1c1, M31a, U2a, M*, I1, M6, M3a1, and R30a. Interestingly, we did not find an association of the m.14484T>C mutation with any specific haplogroup within the Indian population. We also did not find any secondary mutation(s) in these pedigrees, which might affect the clinical expression of LHON. CONCLUSIONS: Contrary to earlier reports showing preferential association of the m.14484T>C mutation with western Eurasian haplogroup J and increased clinical penetrance when present in J1 subhaplogroup background, the present study shows that m.14484T>C arose independently in a different mtDNA haplogroup and ethnic background in India, which may influence the clinical expression of the disease.