Ophthalmic and Systemic Factors of Acute Nonarteritic Anterior Ischemic Optic Neuropathy in the Quark207 Treatment Trial.

PURPOSE: We describe the baseline ophthalmic and cardiovascular risk factors across countries, race, and sex for the Quark207 treatment trial for acute nonarteritic anterior ischemic optic neuropathy (NAION). DESIGN: Prospective, randomized controlled clinical trial. PARTICIPANTS: Adults 50 to 80 years of age with acute NAION recruited from 80 sites across 8 countries. MAIN OUTCOME MEASURES: Ophthalmic features of NAION and cardiovascular risk factors. METHODS: We evaluated demographics and clinical and ophthalmologic data, including best-corrected visual acuity (BCVA) and average visual field total deviation (TD), in affected eyes and cup-to-disc ratio in fellow eyes at enrollment. We report the prevalence (mean and standard devition, and median and interquartile range [IQR]) of ophthalmic features and cardiovascular risk factors, stratified by country, race, and sex. We corrected for multiple comparisons using Dunn's test with Bonferroni correction for continuous variables and chi-square testing with Holm-Bonferroni correction for categorical variables. RESULTS: The study enrolled 500 men and 229 women with a median age of 60 and 61 years (P = 0.027), respectively. Participants were predominantly White (n = 570) and Asian (n = 149). The study eye BCVA was 71 characters (IQR, 53-84 characters; approximately 0.4 logarithm of the minimum angle of resolution), and the TD was -16.5 dB (IQR, -22.2 to -12.6 dB) for stimulus III and -15.7 dB (IQR, -20.8 to -10.9 dB) for stimulus V. The vertical and horizontal cup-to-disc ratio was 0.1 (IQR, 0.1-0.3) for unaffected fellow eyes. The prevalence of cardiovascular risk factors varied among countries. The most notable differences were in the baseline comorbidities and ophthalmologic features, which differed between Asian and White races. Men and women differed with respect to a few clinically meaningful features. CONCLUSIONS: The cardiovascular risk factors in the NAION cohort varied among the 7 countries, race, and sex, but were not typically more prevalent than in the general population. Ophthalmic features, typical of NAION, generally were consistent across countries, race, and sex, except for worse BCVA and TD in China. Men have a frequency of NAION twice that of women. Having a small cup-to-disc ratio in the fellow eye was the most prevalent risk factor across all demographics. This study suggests that factors, not yet identified, may contribute to the development of NAION. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Bilateral Dilated Superior Ophthalmic Veins in a Patient With an Arteriovenous Dialysis Fistula.

A 64-year-old man presented with 4 months of diplopia. He had end-stage renal disease requiring a cephalic transposition brachiocephalic fistula that was no longer in use following successful renal transplantation. On presentation, he had bilateral proptosis, extraocular movement restriction, chemosis, tortuous episcleral vessels, and caruncular injection. Non-contrast CT of the orbits demonstrated dilation of both superior ophthalmic veins, and CT angiography showed asymmetric enlargement of both cavernous sinuses and superior ophthalmic veins. A carotid-cavernous fistula was suspected, but cerebral angiography revealed shunting from the old fistula with intracranial drainage and cerebral venous hypertension. Aberrant retrograde drainage resulted from anatomical compression of the left brachiocephalic vein. The fistula was ligated, and at 1-week follow-up, the patient had marked improvement in extraocular movements and orbital congestion with near complete resolution of diplopia. Postoperative CT angiography obtained 2 months later demonstrated decreased size of both superior ophthalmic veins, consistent with improvement of venous hypertension.

The Association Between Craniofacial Fracture Patterns and Traumatic Optic Neuropathy.

Traumatic optic neuropathy (TON) is a rare but potentially devastating complication of craniofacial trauma. Approximately half of patients with TON sustain permanent vision loss. In this study, we sought to identify the most common fracture patterns associated with TON. We performed a retrospective review of craniomaxillofacial CT scans of trauma patients who presented to the R Adams Cowley Shock Trauma Center from 2015 to 2017. Included were adult patients who had orbital fractures with or without other facial fractures. Patients diagnosed with TON by a formal ophthalmologic examination were analyzed. Craniofacial fracture patterns were identified. Bivariate analysis and multivariate logistic regression were performed to identify craniofacial fracture patterns most commonly associated with TON. A total of 574 patients with orbital fractures who met inclusion criteria [15 (2.6%)] were diagnosed with TON. The median [interquartile range (IQR)] age was 44 (28-59) years. Patients with optic canal fractures and sphenoid sinus fractures had greater odds of TON compared with patients who did not have these fracture types [adjusted odds ratio (aOR) 95% confidence interval (CI) 31.8 (2.6->100), 8.1 (2.7-24.4), respectively]. Patients who sustain optic canal and sphenoid sinus fractures in the setting of blunt facial trauma are at increased odds of having a TON. Surgeons and other physicians involved in the care of these patients should be aware of this association.

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.).

Guidelines of the International Headache Society for Controlled Clinical Trials in Idiopathic Intracranial Hypertension.

The quality of clinical trials is essential to advance treatment, inform regulatory decisions and meta-analysis. With the increased incidence of idiopathic intracranial hypertension and the emergence of clinical trials for novel therapies in this condition, the International Headache Society Guidelines for Controlled Clinical Trials in Idiopathic Intracranial Hypertension aims to establish guidelines for designing state-of-the-art controlled clinical trials for idiopathic intracranial hypertension.

Myopathy and Ophthalmologic Abnormalities in Association With Multiple Skeletal Muscle Mitochondrial DNA Deletions.

BACKGROUND: Establishing a molecular diagnosis of mitochondrial diseases due to pathogenic mitochondrial DNA (mtDNA) variants can be difficult because of varying levels of tissue heteroplasmy, and identifying these variants is important for clinical management. Here, we present clinical and molecular findings in 8 adult patients with classical features of mitochondrial ophthalmologic and/or muscle disease and multiple mtDNA deletions isolated to muscle. METHODS: The patients were identified via a retrospective review of patients seen in both a tertiary ophthalmology center and a genetics clinic with a clinical diagnosis of chronic progressive external ophthalmoplegia, optic nerve abnormalities, and/or mitochondrial myopathy. Age at onset of symptoms ranged from 18 to 61 years. Ocular manifestations included bilateral optic neuropathy in one patient, bilateral optic disc cupping without optic neuropathy in 2 patients, ptosis in 4 patients, and ocular motility deficits in 2 patients. Five patients had generalized weakness. RESULTS: Pathogenic variants in mtDNA were not found in the blood or buccal sample from any patient, but 7 of 8 patients had multiple mtDNA deletions identified in muscle tissue. One patient had a single mtDNA deletion identified in the muscle. Heteroplasmy was less than 15% for all of the identified deletions, with the exception of one deletion that had a heteroplasmy of 50%-60%. None of the patients were found to have a nuclear gene variant known to be associated with mitochondrial DNA maintenance. CONCLUSIONS: mtDNA deletions were identified in adult patients with ophthalmologic and/or musle abnormalities and may underlie their clinical presentations.

Optic Neuropathies: Current and Future Strategies for Optic Nerve Protection and Repair.

Processes that damage the optic nerve, including elevated intraocular pressure, trauma, ischemia, and compression, often cause visual loss for which there is no current treatment [...].

Post-cataract surgery optic neuropathy: a chronological narrative review of the literature and speculation on pathogenesis.

PURPOSE OF REVIEW: To appraise the literature on the incidence of an acute anterior optic neuropathy resembling spontaneous nonarteritic anterior ischemic optic neuropathy (NAION) following uncomplicated cataract surgery and to explore the proposed pathogenesis of both immediate and delayed onset post-cataract surgery optic neuropathy (PCSON). RECENT FINDINGS: A number of case reports, case series, and retrospective case-controlled, big data, and population-based studies have identified an apparent association between cataract surgery and the occurrence of an acute anterior optic neuropathy that can either be immediate or delayed in onset. However, a recent study found no link between modern day cataract surgery and an increased risk of an acute anterior optic neuropathy. SUMMARY: Immediate PCSON appears to be related to negative perfusion pressure at the level of the optic disc due to increased intraocular pressure. The pathogenesis of delayed PCSON is unknown but probably multifactorial. Patients who have experienced spontaneous NAION or PCSON in one eye may be at risk of PCSON in the fellow eye.

Cavernous Malformation of the Optic Nerve and Chiasm: Prompt Suspicion and Surgery Matter.

BACKGROUND: Cavernous malformations (CMs) of the optic nerve and chiasm are extremely rare, accounting for less than 1% of all intracranial CMs. Acute, subacute, or progressive visual loss from CM may occur with or without hemorrhage. Prompt surgical excision of the CM offers the best hope to improve or stabilize vision. Given its rarity, optic nerve and chiasm CMs may not be readily suspected. We provide 3 cases of optic nerve and chiasm CM, highlighting key neuroimaging features and the importance of expedited intervention. METHODS: Case records of the neuro-ophthalmology clinics of the Bascom Palmer Eye Institute and the University of Colorado, and literature review of reported cases of optic CM. RESULTS: A 49-year-old woman reported acute progressive painless vision loss in the right eye. MRI showed a suprasellar mass with heterogeneity in signal involving the right prechiasmatic optic nerve. Surgical excision of the CM 5 days after onset of visual loss improved vision from 20/300 to 20/30. A 29-year-old woman with acute painless blurred vision in the right eye had anterior chiasmal junctional visual field defects corresponding to a heterogeneously minimally enhancing mass with blood products enlarging the optic chiasm and proximal right optic nerve. Surgical excision of the CM 8 weeks after onset of visual loss improved vision from 20/40 to 20/15 with improved visual fields. A 33-year-old woman with a history of familial multiple CMs, diagnosed at age 18, reported new-onset severe headache followed by blurred vision. MRI showed a hemorrhagic lesion of the optic chiasm and right optic tract. She was 20/20 in each eye with a reported left superior homonymous hemianopia. No intervention was recommended. Vision of the right eye worsened to 20/400 2 months later. The patient was followed over 13 years, and the MRI and visual function remained unchanged. Literature review yielded 87 optic CM cases occurring across gender and nearly all ages with visual loss and headache as the most common presenting symptoms. Optic chiasm is the most common site of involvement (79%). Nearly 95% of reported CM cases were treated with surgery with 81% with improved vision and 1% with worsened vision. CONCLUSION: MRI features are critical to the diagnosis of optic nerve and chiasm CM and may mimic other lesions. A high index of suspicion by the neuro-ophthalmologist and neuroradiologist leads to early recognition and intervention. Given optic CM displaces and does not infiltrate neural tissue, expedited surgical resection by a neurosurgeon after consideration of other diagnostic possibilities improves visual function in most cases.

Neuroprotection and Neuroregeneration Strategies Using the rNAION Model: Theory, Histology, Problems, Results and Analytical Approaches.

Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common cause of sudden optic nerve (ON)-related vision loss in humans. Study of this disease has been limited by the lack of available tissue and difficulties in evaluating both treatments and the window of effectiveness after symptom onset. The rodent nonarteritic anterior ischemic optic neuropathy model (rNAION) closely resembles clinical NAION in its pathophysiological changes and physiological responses. The rNAION model enables analysis of the specific responses to sudden ischemic axonopathy and effectiveness of potential treatments. However, there are anatomic and genetic differences between human and rodent ON, and the inducing factors for the disease and the model are different. These variables can result in marked differences in lesion development between the two species, as well as in the possible responses to various treatments. These caveats are discussed in the current article, as well as some of the species-associated differences that may be related to ischemic lesion severity and responses.

Cranial Polyneuropathy Secondary to Remote Iophendylate Myelography.

A 68-year-old woman with controlled hypertension, and degenerative joint disease of the spine for which she had undergone several myelograms and three surgeries 30-32 years earlier, presented with a 2 year history of painless, oblique, binocular diplopia. Her prior ophthalmic evaluations were consistent with an isolated left trochlear nerve paresis. She had magnetic resonance imaging (MRI) showing multiple foci of T1-weighted hyperintensities around the midbrain and brainstem thought to represent subarachnoid fat from a ruptured dermoid cyst. An extensive evaluation revealed a left trochlear nerve paresis as well as diminished sensation in the distributions of the first and second divisions of the left trigeminal nerve. Review of her MRI and history of myelograms raised the possibility of focal inflammation from intrathecal iophendylate (Pantopaque®). Repeat MRI was obtained that showed T1-weighted hyperintensities similar to her previous MRI, but in this study, T1-weighted fat suppression imaging also was performed and revealed these foci to be of low signal intensity, consistent with retained iophendylate.

Atypical Blepharospasm with Oromandibular Dystonia Associated with Cerebral Amyloid Angiopathy.

A case of atypical blepharospasm with oromandibular dystonia is presented in a patient found to have cerebral amyloid angiopathy on magnetic resonance imaging and a shared mechanism is discussed.

Use of En Face Optical Coherence Tomography to Monitor Papilledema in Idiopathic Intracranial Hypertension: A Pilot Study.

BACKGROUND: En face optical coherence tomography (OCT) uses the data acquired during OCT of the optic disc, which typically is used to determine measurements of the peripapillary retinal nerve fiber layer (ppRNFL), to generate a coronal composite fundus image rather than a cross-sectional image. En face OCT has been reported to identify retinal changes related to papilledema in idiopathic intracranial hypertension (IIH) but has not been evaluated for monitoring papilledema. This study aimed to assess the reliability and validity of en face OCT for monitoring papilledema. METHODS: Using the Pearson correlation coefficient (R), these measurements were compared with ppRNFL thickness as well as average diameter and estimated area. Four fellowship-trained neuro-ophthalmologists were asked to qualitatively rank en face images by the area of optic disc edema while masked from all other clinical data. Rankings were compared with ppRNFL thickness as a gold standard and with en face OCT characteristics using the Pearson correlation coefficient (R). RESULTS: Experts were able to correctly identify an increase in average ppRNFL thickness >10 µm with a mean (SD) of 91% (±7%) accuracy. A ranking error among experts corresponded to a mean (standard error) change in the ppRNFL thickness of 6 (±6) µm. The mean Pearson correlation coefficient by the area of disc edema among experts was 0.92 (±0.13). CONCLUSIONS: Multiple objective parameters of en face OCT of optic disc edema have an excellent correlation with ppRNFL thickness. These results suggest that en face OCT is a valid clinical tool for monitoring papilledema in IIH.

Detection of Optic Disc Abnormalities in Color Fundus Photographs Using Deep Learning.

BACKGROUND: To date, deep learning-based detection of optic disc abnormalities in color fundus photographs has mostly been limited to the field of glaucoma. However, many life-threatening systemic and neurological conditions can manifest as optic disc abnormalities. In this study, we aimed to extend the application of deep learning (DL) in optic disc analyses to detect a spectrum of nonglaucomatous optic neuropathies. METHODS: Using transfer learning, we trained a ResNet-152 deep convolutional neural network (DCNN) to distinguish between normal and abnormal optic discs in color fundus photographs (CFPs). Our training data set included 944 deidentified CFPs (abnormal 364; normal 580). Our testing data set included 151 deidentified CFPs (abnormal 71; normal 80). Both the training and testing data sets contained a wide range of optic disc abnormalities, including but not limited to ischemic optic neuropathy, atrophy, compressive optic neuropathy, hereditary optic neuropathy, hypoplasia, papilledema, and toxic optic neuropathy. The standard measures of performance (sensitivity, specificity, and area under the curve of the receiver operating characteristic curve (AUC-ROC)) were used for evaluation. RESULTS: During the 10-fold cross-validation test, our DCNN for distinguishing between normal and abnormal optic discs achieved the following mean performance: AUC-ROC 0.99 (95 CI: 0.98-0.99), sensitivity 94% (95 CI: 91%-97%), and specificity 96% (95 CI: 93%-99%). When evaluated against the external testing data set, our model achieved the following mean performance: AUC-ROC 0.87, sensitivity 90%, and specificity 69%. CONCLUSION: In summary, we have developed a deep learning algorithm that is capable of detecting a spectrum of optic disc abnormalities in color fundus photographs, with a focus on neuro-ophthalmological etiologies. As the next step, we plan to validate our algorithm prospectively as a focused screening tool in the emergency department, which if successful could be beneficial because current practice pattern and training predict a shortage of neuro-ophthalmologists and ophthalmologists in general in the near future.

Persistent Globe Flattening in Astronauts following Long-Duration Spaceflight.

Posterior globe flattening has been well-documented in astronauts both during and after long-duration space flight (LDSF) and has been observed as early as 10 days into a mission on the International Space Station. Globe flattening (GF) is thought to be caused by the disc centred anterior forces created by elevated volume and/or pressure within the optic nerve sheath (ONS). This might be the result of increased intracranial pressure, increased intraorbital ONS pressure from compartmentalisation or a combination of these mechanisms. We report posterior GF in three astronauts that has persisted for 7 years or more following their return from LDSFs suggesting that permanent scleral remodelling may have occurred.

William F. Hoyt's Role in Identifying the Pathogenesis of Duane Retraction Syndrome.

For many years, it was unclear whether Duane retraction syndrome was a myopathic or neuropathic condition. This article describes the direct and indirect contributions of William F. Hoyt, MD, to the eventual determination that the condition is caused by a congenital absence of the sixth nerve combined with innervation of the lateral rectus muscle by branches of the third nerve.

Deep Learning and Transfer Learning for Optic Disc Laterality Detection: Implications for Machine Learning in Neuro-Ophthalmology.

BACKGROUND: Deep learning (DL) has demonstrated human expert levels of performance for medical image classification in a wide array of medical fields, including ophthalmology. In this article, we present the results of our DL system designed to determine optic disc laterality, right eye vs left eye, in the presence of both normal and abnormal optic discs. METHODS: Using transfer learning, we modified the ResNet-152 deep convolutional neural network (DCNN), pretrained on ImageNet, to determine the optic disc laterality. After a 5-fold cross-validation, we generated receiver operating characteristic curves and corresponding area under the curve (AUC) values to evaluate performance. The data set consisted of 576 color fundus photographs (51% right and 49% left). Both 30° photographs centered on the optic disc (63%) and photographs with varying degree of optic disc centration and/or wider field of view (37%) were included. Both normal (27%) and abnormal (73%) optic discs were included. Various neuro-ophthalmological diseases were represented, such as, but not limited to, atrophy, anterior ischemic optic neuropathy, hypoplasia, and papilledema. RESULTS: Using 5-fold cross-validation (70% training; 10% validation; 20% testing), our DCNN for classifying right vs left optic disc achieved an average AUC of 0.999 (±0.002) with optimal threshold values, yielding an average accuracy of 98.78% (±1.52%), sensitivity of 98.60% (±1.72%), and specificity of 98.97% (±1.38%). When tested against a separate data set for external validation, our 5-fold cross-validation model achieved the following average performance: AUC 0.996 (±0.005), accuracy 97.2% (±2.0%), sensitivity 96.4% (±4.3%), and specificity 98.0% (±2.2%). CONCLUSIONS: Small data sets can be used to develop high-performing DL systems for semantic labeling of neuro-ophthalmology images, specifically in distinguishing between right and left optic discs, even in the presence of neuro-ophthalmological pathologies. Although this may seem like an elementary task, this study demonstrates the power of transfer learning and provides an example of a DCNN that can help curate large medical image databases for machine-learning purposes and facilitate ophthalmologist workflow by automatically labeling images according to laterality.

Cerebrospinal fluid and optic nerve sheath compartment syndrome: A common pathophysiological mechanism in five different cases?

IMPORTANCE: Optic nerve (ON) dysfunction is a common feature of different diseases. The pathophysiology is not yet fully understood. BACKGROUND: This study describes five patients with ON sheath (ONS) compartment syndrome (ONSCS) and contributes to the hypothesis that impaired cerebrospinal fluid (CSF) flow can play a role in the development of ON dysfunction. DESIGN: Retrospective case series. PARTICIPANTS: Five patients with ONSCS were included in the study. METHODS: Elaboration of medical histories and clinical and diagnostic findings over a long time period was carried out by analysing medical records and by a detailed medical consultation. MAIN OUTCOME MEASURES: The main outcome measures include clinical history; visual acuity; field, intraocular and CSF pressures; and contrast-loaded computed tomographic (CT) cisternography. RESULTS: Compartmentation of the ONS demonstrated by contrast-loaded CT cisternography was the consistent finding in all five patients who demonstrated findings of ON dysfunction. The aetiologies varied and included meningitis, papilloedema, sphenoid wing meningioma, disc herniation and normal-tension glaucoma. CONCLUSION AND RELEVANCE: Compartmentation of the ONS with consecutively impaired CSF dynamics within the ON subarachnoid space can lead to ON dysfunction. Different aetiologies can cause the development of ONSCS.

MRI findings in Parinaud's syndrome: a closer look at pineal masses.

PURPOSE: The association between MRI findings in patients with pineal lesions and the presence or absence of Parinaud's syndrome (PS) remains poorly described. We sought to better understand what MRI characteristics of a pineal lesion make PS more likely. Can these features predict prognosis for clinical resolution? Based on the anatomical relationship of the pineal gland and midbrain, we hypothesized that the degree of midbrain injury by a pineal mass as assessed by abutment, displacement, or intrinsic midbrain signal abnormality (IMSA) may predict PS. METHODS: We reviewed our institution's databases to find patients with MRI evidence of an intrinsic lesion of the pineal gland. Seventy-seven patients with intrinsic pineal gland lesions, 26 with PS and 51 without PS (NPS), were identified. Data regarding clinical history were collected, and an experienced neuroradiologist reviewed all MRI studies and recorded mass size, midbrain abutment, displacement by the pineal lesion, and presence or absence of IMSA. RESULTS: IMSA occurred with increased frequency in pineal lesions with PS (85%) when compared with NPS (39.2%) (p = 0.0001). Midbrain abutment, compression, and displacement occurred with similar frequencies in both groups, with no statistically significant difference. Hydrocephalus was present in 80.8% of patients with PS and 84% without PS (p = 0.75). CONCLUSION: IMSA in a patient with an intrinsic pineal gland mass is associated with PS. Other findings such as hydrocephalus and midbrain displacement are common in patients with pineal masses both with and without PS and do not have any predictive value.