Aberrant regeneration of accommodation in pediatric inferior division oculomotor palsy.

Aberrant regeneration occurs in forms of oculomotor motor nerve palsy and frequently involves the pupil, but the incidence and functional impact of ciliary muscle involvement in pediatric patients is sparsely reported in the literature. A 4-year-old girl presented with inflammatory oculomotor motor nerve paresis affecting the inferior division. Initial treatment focused on her inability to accommodate through her physiologic +2.5 D hyperopia and the prevention and treatment of amblyopia. She subsequently developed aberrant regeneration of the pupil, with miosis on adduction. Following eye muscle surgery for residual exotropia and hypertropia, her dry refraction was noted to be more myopic in the affected eye on adduction, mirroring aberrant pupillary constriction. Recognition of pediatric aberrant regeneration of accommodation may influence surgical planning for oculomotor nerve palsy and/or management of amblyopia.

Artificial Intelligence to Differentiate Pediatric Pseudopapilledema and True Papilledema on Fundus Photographs.

Purpose: To develop and test an artificial intelligence (AI) model to aid in differentiating pediatric pseudopapilledema from true papilledema on fundus photographs. Design: Multicenter retrospective study. Subjects: A total of 851 fundus photographs from 235 children (age < 18 years) with pseudopapilledema and true papilledema. Methods: Four pediatric neuro-ophthalmologists at 4 different institutions contributed fundus photographs of children with confirmed diagnoses of papilledema or pseudopapilledema. An AI model to classify fundus photographs as papilledema or pseudopapilledema was developed using a DenseNet backbone and a tribranch convolutional neural network. We performed 10-fold cross-validation and separately analyzed an external test set. The AI model's performance was compared with 2 masked human expert pediatric neuro-ophthalmologists, who performed the same classification task. Main Outcome Measures: Accuracy, sensitivity, and specificity of the AI model compared with human experts. Results: The area under receiver operating curve of the AI model was 0.77 for the cross-validation set and 0.81 for the external test set. The accuracy of the AI model was 70.0% for the cross-validation set and 73.9% for the external test set. The sensitivity of the AI model was 73.4% for the cross-validation set and 90.4% for the external test set. The AI model's accuracy was significantly higher than human experts on the cross validation set (P < 0.002), and the model's sensitivity was significantly higher on the external test set (P = 0.0002). The specificity of the AI model and human experts was similar (56.4%-67.3%). Moreover, the AI model was significantly more sensitive at detecting mild papilledema than human experts, whereas AI and humans performed similarly on photographs of moderate-to-severe papilledema. On review of the external test set, only 1 child (with nearly resolved pseudotumor cerebri) had both eyes with papilledema incorrectly classified as pseudopapilledema. Conclusions: When classifying fundus photographs of pediatric papilledema and pseudopapilledema, our AI model achieved > 90% sensitivity at detecting papilledema, superior to human experts. Due to the high sensitivity and low false negative rate, AI may be useful to triage children with suspected papilledema requiring work-up to evaluate for serious underlying neurologic conditions. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Ocular lichen planus as a cause of recurrent restrictive strabismus.

We report the case of an 80-year-old man with restrictive strabismus in lateral gaze following multiple oculoplastic procedures for idiopathic epiphora. Despite excellent initial response to nasal conjunctival recession with lysis of adhesions and a miminal recession of the medial rectus muscle, the patient suffered recurrence of diplopia associated with limitation of abduction due to aggressive, deep, subconjunctival scarring. Given the history of oral lichen planus (LP), the patient was diagnosed with ocular involvement of LP. He underwent a second conjunctival recession, this time accompanied by an intensive LP treatment regimen. Nine months after surgery, he remained diplopia free and orthophoric in primary gaze. Surgeons treating restrictive strabismus in patients with LP should consider implementing systemic and topical immunosuppressive treatment simultaneously with surgical management.

Using high-resolution functional MRI to differentiate impacts of strabismic and anisometropic amblyopia on evoked ocular dominance activity in humans.

We employed high-resolution functional MRI (fMRI) to distinguish the impacts of anisometropia and strabismus (the two most frequent causes of amblyopia) on the evoked ocular dominance (OD) response. Sixteen amblyopic participants (8 females), comprising 8 individuals with strabismus, 7 with anisometropia, 1 with deprivational amblyopia, along with 8 individuals with normal visual acuity (1 female), participated in this study for whom, we measured the difference between the response to stimulation of the two eyes, across early visual areas (V1-V4). In controls, as expected from the organization of OD columns, the evoked OD response formed a striped pattern that was mostly confined to V1. Compared to controls, the OD response in amblyopic participants formed larger fused patches that extended into downstream visual areas. Moreover, both anisometropic and strabismic participants showed stronger OD responses in V1, as well as in downstream visual areas V2-V4. Although this increase was most pronounced in V1, the correlation between the OD response level and the interocular visual acuity difference (measured behaviorally) was stronger in higher-level visual areas (V2-V4). Beyond these common effects, and despite similar densities of amblyopia between the anisometropic and strabismic participants, we found a greater increase in the size of V1 portion that responded preferentially to fellow eye stimulation in anisometropic compared to strabismic individuals. We also found a greater difference between the amplitudes of the response to binocular stimulation, in those regions that responded preferentially to the fellow vs. amblyopic eye, in anisometropic compared to strabismic subjects. In contrast, strabismic subjects demonstrated increased correlation between the OD responses evoked within V1 superficial and deep cortical depths, whereas anisometropic subjects did not. These results provide some of the first direct functional evidence for distinct impacts of strabismus and anisometropia on the mesoscale functional organization of the human visual system, thus extending what was inferred previously about amblyopia from animal models.

Cauterization-mediated restriction from penetrating orbital trauma.

A healthy 32-year-old woman presented with binocular diplopia immediately after sustaining a penetrating injury to the left periocular adnexa with a hot metal skewer. Examination revealed an incomitant esotropia, with complete limitation of abduction of the left eye with downshoot in left gaze and normal afferent visual function. Computed tomography and magnetic resonance imaging demonstrated no fracture, but there was mild thickening of the medial rectus muscle and associated fat stranding. Lack of orbitomuscular tethering or hematoma led to the presumptive diagnosis of thermal cauterization injury causing left medial rectus restriction. Given the lack of literature on this mechanism of injury, the patient was monitored closely. She exhibited remarkable spontaneous improvement in motility over 6 months, with near orthophoria in primary gaze. However, bothersome residual esotropic diplopia in left gaze prompted a left medial rectus recession, with a good outcome. This case demonstrates that isolated extraocular muscle thermal injuries and consequential strabismus can recover spontaneously; longitudinal observation before surgical intervention may be appropriate in such cases.

Amblyopia treatment outcomes in patients with neurodevelopmental disorders.

PURPOSE: To compare amblyopia treatment outcomes between patients with neurodevelopmental disorders and their typically developing peers. METHODS: Of 2,311 patients diagnosed with amblyopia between 2010 and 2014 at Boston Children's Hospital, 460 met inclusion criteria (age 2-12 with anisometropic, strabismic, or mixed amblyopia [interocular difference (IOD) ≥2 lines]). Treatment and visual outcomes were analyzed according to neurodevelopmental status: neurodevelopmental delay (DD) versus typical development (TD). RESULTS: The DD group (n = 54) and TD group (n = 406) were similar in demographics, amblyogenic risk factors, baseline visual measures, prescribed therapy, and adherence (P ≥ 0.10). Between-visit follow-up time was longer for the DD group (0.65 [0.42- 0.97] years) than for the TD group (0.5 [0.36-0.82] years; P = 0.023). IOD improved similarly in each group by the last visit (DD, -0.15 logMAR [-0.31 to -0.02]; TD, -0.2 logMAR [-0.38 to -0.1]; P = 0.09). Each group reached amblyopia resolution by the last visit at similar frequencies (DD, 23/54 [43%]; TD, 211/406 [52%]; P > 0.2). DD diagnosis did not independently influence amblyopia resolution (HR, 0.77; 95% CI, 0.53-1.12; P = 0.17), but each additional month of interval time between follow-up visits reduced the likelihood of resolution by 2.7% (HR, 0.67; 95% CI, 0.51-0.87; P = 0.003). CONCLUSIONS: Patients with DD and those with TD responded similarly to amblyopia therapy; however, follow-up intervals were longer in patients with DD and correlated with the likelihood of persistent amblyopia, suggesting that greater efforts at assuring follow-up may benefit patients with DD.

Factors associated with visual acuity improvement with a binocular digital therapeutic for amblyopia.

We combined data from 121 amblyopic children enrolled in two prospective open-label pilot studies and a randomized trial of a binocular digital therapeutic to identify factors associated with positive response to amblyopia treatment. Visual acuity improved ≥1 line in 81% of participants after 12 weeks of therapy. Treatment response was not found to be associated with age, severity of amblyopia, or prior treatment status. Although these findings may suggest broad efficacy for this treatment approach, further investigation in larger cohorts is needed to identify factors associated with treatment response.

Isolated Sixth Nerve Palsy and COVID-19: A Recurrent Case in a 7-Month-Old Child and Analysis of Reported Cases.

BACKGROUND: With the SARS-CoV-2 pandemic (COVID-19), data on central and peripheral nervous system involvement, including those causing cranial nerve 6 (CN6) palsy, have been limited to case reports. To extract clinically relevant features of COVID-19-related CN6 palsy, we report on a recurrent pediatric case and analysis of reported cases associated with infection or immunization. METHODS: A PubMed search revealed 18 cases of isolated CN6 palsy in addition to the index case (n = 19). Clinical characteristics, workup, and temporal associations between systemic symptoms onset or vaccination, symptoms onset, and resolution were compiled and analyzed. RESULTS: The median age of CN6 onset was 43 years (interquartile range [IQR]: 28-52). Sixteen cases (84.2%) were associated with COVID-19 illness and 3 (15.8%) were associated with COVID-19 vaccination. Four cases (23.5%) had positive neuroimaging findings. The median latency from first COVID-19 symptoms or vaccination to onset of CN6 palsy was 6 days (IQR: 2.3-16), and the median time from onset to resolution was 30 days (IQR: 14-60). Latency to onset of CN6 palsy was significantly and directly associated with time to resolution (R2 = 0.401, P = 0.010). Patients who had a positive SARS-CoV-2 antibody test had significantly longer days from symptoms to onset (6.0 vs 24.5, P = 0.030), and patients with a positive SARS-CoV-2 polymerase chain reaction test had a significantly shorter time to resolution (17.50 vs 90, P = 0.042). CONCLUSIONS: Isolated CN6 palsy from COVID-19 is rare, can occur in infants as young as 7 months, and can be recurrent. Longer latency from systemic symptoms onset portends greater recovery times, and this relationship may reflect multiple mechanisms by which COVID-19 (and/or an immune response thereto) causes cranial neuropathies with direct clinical relevance.

Recovery from Amblyopia in Adulthood: A Meta-Analysis.

Purpose: The effectiveness of traditional amblyopia therapies is largely restricted to childhood. However, recovery in adulthood is possible following removal or vision-limiting disease of the fellow eye. Study of this phenomenon is currently limited to isolated case reports and a few case series, with reported incidence ranging from 19-77% 1-5 . We set out to accomplish two distinct goals: (1) define the incidence of clinically meaningful recovery and (2) elucidate the clinical features associated with greater amblyopic eye gains. Methods: A systematic review of 3 literature databases yielded 23 reports containing 109 cases of patients ≥18 years old with unilateral amblyopia and vision-limiting fellow eye pathology. Results: Study 1 revealed 25/42 (59.5%) of adult patients gained ≥2 logMAR lines in the amblyopia eye after FE vision loss. The overall degree of improvement is clinically meaningful (median 2.6 logMAR lines). Study 2 showed that for cases with amblyopic eye visual acuity improvement, recovery occurs within 12 months of initial loss of fellow eye vision. Regression analysis revealed that younger age, worse baseline acuity in the amblyopic eye, and worse vision in the fellow eye independently conferred greater gains in amblyopic eye visual acuity. Recovery occurs across amblyopia types and fellow eye pathologies, although disease entities affecting fellow eye retinal ganglion cells demonstrate shorter latencies to recovery. Conclusions: Amblyopia recovery after fellow eye injury demonstrates that the adult brain harbors the neuroplastic capacity for clinically meaningful recovery, which could potentially be harnessed by novel approaches to treat adults with amblyopia.

Durable recovery from amblyopia with donepezil.

An elevated threshold for neuroplasticity limits visual gains with treatment of residual amblyopia in older children and adults. Acetylcholinesterase inhibitors (AChEI) can enable visual neuroplasticity and promote recovery from amblyopia in adult mice. Motivated by these promising findings, we sought to determine whether donepezil, a commercially available AChEI, can enable recovery in older children and adults with residual amblyopia. In this open-label pilot efficacy study, 16 participants (mean age 16 years; range 9-37 years) with residual anisometropic and/or strabismic amblyopia were treated with daily oral donepezil for 12 weeks. Donepezil dosage was started at 2.5 or 5.0 mg based on age and increased by 2.5 mg if the amblyopic eye visual acuity did not improve by 1 line from the visit 4 weeks prior for a maximum dosage of 7.5 or 10 mg. Participants < 18 years of age further patched the dominant eye. The primary outcome was visual acuity in the amblyopic eye at 22 weeks, 10 weeks after treatment was discontinued. Mean amblyopic eye visual acuity improved 1.2 lines (range 0.0-3.0), and 4/16 (25%) improved by ≥ 2 lines after 12 weeks of treatment. Gains were maintained 10 weeks after cessation of donepezil and were similar for children and adults. Adverse events were mild and self-limited. Residual amblyopia improves in older children and adults treated with donepezil, supporting the concept that the critical window of visual cortical plasticity can be pharmacologically manipulated to treat amblyopia. Placebo-controlled studies are needed.

Neuro-ophthalmic Complications in Pediatric Leukemia.

BACKGROUND: Optic neuropathy in childhood leukemia occurs through multiple direct and indirect mechanisms, including leukemic infiltration of the optic nerve, infection, blood dyscrasias, or adverse effects of treatment. We aimed to characterize visual outcomes in pediatric patients with leukemia-associated neuro-ophthalmic manifestations. METHODS: We retrospectively identified patients with leukemia and optic nerve pathology over 13 years by diagnostic billing codes. We collected information on demographics, presentation, treatment course, and visual outcomes directly from medical records. RESULTS: Of the 19 patients who met inclusion criteria, 17 (89.5%) had pseudotumor cerebri and 2 had direct optic nerve infiltration. Causes of increased intracranial pressure included central nervous system infiltration (6 of 17), hyperviscosity/leukemia (2 of 17), venous sinus thrombosis (3 of 17), medication induced (5 of 17), and bacterial meningitis (1 of 17). 47.1% (8 of 17) had papilledema at the time of leukemia diagnosis, and 94.1% (16 of 17) of patients with pseudotumor cerebri were treated with acetazolamide. At presentation, 3 patients had decreased vision secondary to macular ischemia, subhyaloid vitreous hemorrhage, or steroid induced glaucoma. Following treatment of pseudotumor cerebri, binocular visual acuity was ≥20/25 in all patients. One patient with optic nerve infiltration had a final visual acuity of count fingers in the affected eye. CONCLUSIONS: In our chart review, the most common mechanism of neuro-ophthalmic involvement in pediatric leukemia was elevated intracranial pressure from a myriad of causes. Visual outcomes from patients with elevated intracranial pressure were excellent. Understanding the mechanisms by which leukemia can cause optic nerve disease in pediatric patients can facilitate earlier diagnosis and treatment and potentially improve visual outcomes.

Outcomes of Zone 3 Open Globe Injuries by Wound Extent: Subcategorization of Zone 3 Injuries Segregates Visual and Anatomic Outcomes.

PURPOSE: Open globe injuries (OGIs) are categorized by zone, with zone 3 (Z3) comprising wounds > 5 mm beyond the limbus. Outcomes of Z3 OGIs are highly heterogeneous. Open globe injuries with far posterior Z3 (pZ3) wounds were hypothesized to have worse visual and anatomic outcomes. DESIGN: Single-center retrospective cohort study. PARTICIPANTS: A total of 258 eyes with Z3 OGIs. METHODS: A retrospective review of Z3 OGIs treated at a tertiary center over 12 years. Wounds ≥ 10 mm posterior to the limbus were defined as pZ3. Outcomes were compared between pZ3 and anterior Z3 (aZ3) eyes. MAIN OUTCOME MEASURES: Visual acuity on a logarithm of the minimum angle of resolution (logMAR) scale. Secondary outcomes included anatomic outcomes, development of retinal detachment and proliferative vitreoretinopathy, and the number of secondary surgeries. RESULTS: A total of 258 Z3 OGI eyes with > 30 days follow-up were assessed; 161 (62%) were pZ3. At 3-month follow-up, pZ3 OGIs were more likely to exhibit no light perception (pZ3: 38%; aZ3: 17%; P < 0.003), lack count fingers vision (pZ3: 72%; aZ3: 43%; P < 0.002), and fail to read a letter on the eye chart (pZ3: 83%; aZ3: 64%; P < 0.001). The visual acuity distribution at 3 months was significantly worse for pZ3 compared with aZ3 injuries (P < 0.004). Similar results were found at final follow-up. Multiple linear regression showed that pZ3 location was independently associated with worse visual acuity (ß = 0.29, 95% confidence interval [CI], 0.09-0.50, P < 0.006) in addition to presenting acuity, age, vitreous hemorrhage, uveal prolapse, and afferent pupillary defect. Far posterior wounds injuries were more likely to develop retinal detachments (pZ3: 87%; aZ3: 71%; P < 0.01) and proliferative vitreoretinopathy (pZ3 66%; aZ3 47%; P < 0.03). Patients with pZ3 OGIs were significantly more likely to reach poor anatomic outcome (phthisis, enucleation, need for keratoprosthesis) compared with patients with aZ3 OGI (pZ3: 56%; aZ3: 40%; P < 0.03). CONCLUSIONS: Posterior OGI extension independently portends worse visual and anatomic outcomes. The effect on visual outcome was durable and clinically relevant compared with established predictors of OGI outcomes. Application of these findings improves the prognostic precision and will guide future research efforts to optimize surgical decision-making in severe OGI cases. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Periodic Trends in Internet Searches for Ocular Symptoms in the US.

PURPOSE: To identify periodic trends in internet searches for ocular symptoms and to determine the seasonal peaks and troughs. METHODS: This cross-sectional study examined publicly available Google Trends data from the United States (01/01/2015 to 12/31/2019). A list of common ocular symptoms was compiled from the American Academy of Ophthalmology Eye Health website and Wills Eye Manual. Ocular symptoms were stratified into categories involving vision change, eye pain, or eye redness. The search volume over time for each term was modeled using periodic regression functions and the goodness-of-fit was reported. Fisher's exact tests were used to compare the characteristics of periodic vs. non-periodic query terms. RESULTS: Seasonal trends were demonstrated by 45% (48/106) of the ocular symptoms included in this investigation. Search terms with best fit to the periodic model included stye (r2 = 0.89), pink eye (r2 = 0.82), dry eye (r2 = 0.76), blurry vision (r2 = 0.72), and swollen eye (r2 = 0.71). Periodic search terms were more likely to involve eye redness (21% vs. 11%, p = .014) and less likely to involve vision change (11% vs. 36%; p < .001). Periodic queries involving eye redness most often peaked in the spring and those involving eye pain peaked in the summer. CONCLUSION: Ocular symptom queries directly reflect seasonal trends for allergic eye disease and ocular trauma. Search query analyses can serve as accurate epidemiological tools with research and real-world clinical applications.