Ocular features of NGLY1 deficiency from a prospective longitudinal cohort.

BACKGROUND: NGLY1 deficiency is a rare autosomal recessive disorder with core features of global developmental delay, liver enzyme abnormalities, movement disorder, polyneuropathy, and hypo- or alacrima. We characterized the full spectrum and evolution of the ocular phenotype in a prospective natural history of NGLY1 deficiency. METHODS: We collected ophthalmological data on 29 individuals with NGLY1 deficiency in a natural history study. Medical records were reviewed to confirm caregiver-reported symptoms. Of the 29, 15 participants appeared for at least one ophthalmological examination. RESULTS: Caregivers reported at least one ocular sign or symptom in 90% of participants (26/29), most commonly decreased tears, refractive error, and chronic infection. Daily eye medication, including artificial tears, ophthalmic ointment, and topical antibiotics were used by 62%. Ophthalmological examination confirmed refractive errors in 93% (14/15) and corneal abnormalities in 73% (11/15). CONCLUSIONS: Given nearly universal hypolacrima and additional prominent ocular findings in NGLY1 deficiency, a targeted ocular history and ophthalmologic examination may facilitate prompt diagnosis and early initiation of preventive eye care, preserving vision and overall ocular health.

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.

Isolated Sixth Nerve Palsies in a Child With Familial Hemophagocytic Lymphohistiocytosis Type 2.

ABSTRACT: A previously healthy 2-year-old boy presented with a left sixth cranial nerve palsy. There was a family history of multiple sclerosis and optic neuritis. Neuroimaging showed multiple foci of T2/FLAIR hyperintense signal abnormality in both cerebral hemispheres and in the brainstem. The initial diagnosis was suspicious for demyelinating disease. However, there was no clinical improvement after a course of corticosteroids, and there was no change in his follow-up MRI. He later developed bilateral sixth nerve palsies, with esotropia addressed with bilateral medial rectus botulinum toxin injections. A brain biopsy was planned. However, his 3-month-old sister was separately admitted for fever and pancytopenia. She had markedly elevated ferritin, D-dimer, triglycerides, sIL-2R, CXCL9, and IL-18 and low fibrinogen. Her bone marrow biopsy showed hemophagocytosis. Genetic testing of both siblings revealed biallelic mutations in the PRF1 locus. The final diagnosis of familial hemophagocytic lymphohistiocytosis Type 2 was made. Both siblings underwent chemotherapy. The boy's sixth nerve palsies and MRI abnormalities resolved. Both siblings then went on to undergo bone marrow transplant.

High Altitude as a Risk Factor for the Development of Nonarteritic Anterior Ischemic Optic Neuropathy.

BACKGROUND: Episodic high-altitude exposure leads to optic disc edema and retinopathy. It is uncertain whether high-altitude exposure is a risk factor for nonarteritic anterior ischemic optic neuropathy (NAION). METHODS: We performed a single-center, retrospective, cross-sectional case study of 5 patients with high-altitude-associated NAION (HA-NAION) from April 2014 to April 2019. Main study parameters included known vascular risk factors for NAION, evolution of visual acuity, visual field, optic disc, and macula measurements. RESULTS: We studied 5 eyes of 5 patients with HA-NAION that occurred at 7,000-9,000 ft above sea level, 28 patients with classic NAION that developed at sea level (normal altitude NAION or NA-NAION), and 40 controls. All 5 patients with HA-NAION had clinically confirmed NAION by a neuro-ophthalmologist within 3-21 days of onset and comprehensive follow-up evaluations (average follow-up of 23 months). Other than high-altitude exposure, 4 of 5 patients had undiagnosed obstructive sleep apnea (OSA, apnea-hypopnea index 5.4-22.2) and 1 had systemic vascular risk factors. All patients had disc-at-risk in the contralateral eye. The best-corrected distance visual acuity was 20/20 to 20/70 (median logMAR 0) at presentation and 20/70 to counting finger (median logMAR 0) at ≥6 months. Automated static perimetry revealed average mean deviation of -18.6 dB at presentation and -22.1 dB at ≥6 months. The average retinal nerve fiber layer was 244 µm (80-348 µm) at onset and 59 µm (55-80 µm) at ≥6 months. The average ganglion cell complex thickness was 50 µm (43-54 µm) at onset and 52 µm (50-55 µm) at ≥6 months. The patients with OSA were started on home continuous positive airway pressure treatment. Visual outcomes were similar in patients with HA-NAION and NA-NAION. - After addressing all NAION risk factors, no new events occurred in the HA-NAION group within 2-8 years with or without repeat high-altitude exposure. CONCLUSIONS: NAION can occur under high-altitude conditions. HA-NAION is associated with relatively younger age at onset, disc-at-risk, and OSA. These patients exhibit a relatively progressive course of vision loss after initial onset and severe thinning of optic nerves on optical coherence tomography. Treatment for OSA is recommended, especially with repeated high-altitude exposure.

Child Neurology: Horner Syndrome in an Otherwise Well-Appearing Infant.

We report an exemplary case of acquired Horner syndrome secondary to neuroblastoma in infancy. The patient presented with ptosis, miosis, and heterochromia. In reviewing the patient's laboratory and imaging workup, we highlight key etiologic differences between the pediatric and adult populations. Other important teaching points included in the discussion are a review of sympathetic neuroanatomy and oculosympathetic paresis, the appropriate and evidence-based diagnostic workup in infants and children, and a review of pharmacologic testing using cocaine and apraclonidine drops.

Multicolor Imaging of Optic Disc Drusen.

ABSTRACT: Optic disc drusen (ODD) are calcified deposits at the anterior optic nerve that are often detectable by ophthalmic imaging, including optical coherence tomography and fundus autofluorescence imaging. Multicolor (MC) imaging is a novel modality that captures reflectance of blue, green, and near-infrared laser lights with confocal scanning laser ophthalmoscopy to rapidly acquire high-resolution reflectance images of the optic disc and retina. Here, we show an eye with 3 MC imaging features of ODD, including prominent green hyperreflectance of the optic disc, green sheathing of the papillary and peripapillary vasculature (arterioles > venules), and presence of orange superficial ODD. MC imaging can provide rapid high-resolution assessment of eyes with optic nerve head elevation to help distinguish pseudopapilledema vs papilledema in children and adults without dilation, and future large studies incorporating MC imaging will help determine its contribution in the diagnosis and monitoring of ODD and assessment of other causes of optic nerve head elevation.

CRB1-associated retinal dystrophy presenting as self-resolving opsoclonus and posterior uveitis.

PURPOSE: To describe the unusual case of inflammatory CRB1-associated retinal dystrophy that initially presented with self-resolving opsoclonus. OBSERVATIONS: We report the case of a now 2-year-old female who developed opsoclonus without myoclonus at the age of 4 months. An extensive workup for neuroblastoma and other systemic diseases was unremarkable, and all unusual eye movements self-resolved at age 10 months. Twenty-one months after initial presentation, she began having reduced visual behaviors, and comprehensive ophthalmic exam at that time revealed recurrent saccadic intrusions as well as severe, chronic retinal inflammation and dystrophic changes. An extensive infectious and inflammatory workup was negative. Genetic sequencing revealed two variants in CRB1: a heterozygous missense mutation and a heterozygous novel deletion involving exon 12. The patient was treated with monthly infliximab and methylprednisolone infusions with improvement in her optic disc and macular capillary leakage. The patient's 8-month-old sister also harbored the same variants in CRB1 and had early signs of retinal dystrophy and peripheral vascular leakage on exam. CONCLUSION: Saccadic intrusions may be the first sign of a retinal dystrophy, and infants and children with this presentation should undergo a complete eye exam. We further highlight the link between CRB1-associated retinal dystrophy and inflammation, and how systemic steroids and tumor necrosis factor alpha (TNF-α) inhibitors may be effective therapies. Finally, we report a novel deletion in CRB1 that is likely highly penetrant.

Optic chiasm involvement in AQP-4 antibody-positive NMO and MOG antibody-associated disorder.

BACKGROUND: Optic neuritis (ON) is often the presenting symptom in inflammatory central nervous system demyelinating disorders. OBJECTIVE: To compare the frequency and pattern of optic chiasm involvement in patients with aquaporin-4-immunoglobulin G (AQP4-IgG)-associated ON to patients with myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG)-associated ON. METHODS: Retrospective review of all patients evaluated at Mayo Clinic, Stanford University and Ramathibodi Hospital who were found to have: (1) ON, (2) either MOG-IgG or AQP4-IgG by cell-based assay, and (3) magnetic resonance imaging (MRI) at the time of ON. MRI was reviewed for contrast enhancement of the optic chiasm and the pattern of involvement. RESULTS: One hundred and fifty-four patients (74 AQP4-IgG and 80 MOG-IgG) were included. Among patients with AQP4-IgG-ON, 20% had chiasmal involvement, compared with 16% of patients with MOG-IgG-ON (p = 0.66). In patients with chiasmal involvement, longitudinally extensive optic nerve enhancement (from orbit extending to chiasm) was identified in 54% of MOG-IgG-ON patients, compared with 7% of AQP4-IgG-ON patients (p = 0.01). CONCLUSION: Chiasmal involvement of MOG-IgG-ON and AQP4-IgG-ON occur at more similar frequencies than previously reported. Furthermore, MOG-IgG-ON chiasmal involvement is more likely to be part of a longitudinally extensive optic nerve lesion.

Microphthalmia and orbital cysts in DiGeorge syndrome.

We report the case of a 4-month-old boy diagnosed with DiGeorge syndrome with novel ocular features. The patient was diagnosed through genetic testing, with a noted 22q11.2 deletion, and had the additional clinical findings of cardiac anomalies, Hirschsprung's disease, and intracranial microhemorrhages. Eye findings included bilateral microphthalmia, persistent fetal vasculature, chorioretinal coloboma, and a unilateral orbital cyst. Given no known additional inciting exposures, a dysgenic mechanism resulting in failed closure of developmental fissures associated with the chromosomal deletion likely gave rise to these combined pathologies.

Feasibility and acceptability of virtually coaching residents on communication skills: a pilot study.

BACKGROUND: Developing communication skills is a key competency for residents. Coaching, broadly accepted as a training modality in medical education, has been proven a successful tool for teaching communication skills. Little research is available thus far to investigate virtual coaching on communication skills for telemedicine encounters. The purpose of the study was to test the hypothesis that virtually coaching residents on communication skills is feasible and acceptable. We surveyed 21 resident-faculty pairs participating in a "fully virtual" coaching session (patient, coach, and resident were virtual). METHODS: We asked 50 neurology resident-faculty coach pairs to complete one "fully virtual" coaching session between May 20 and August 31, 2020. After each session, the resident and coach completed a 15-item survey, including Likert-style scale and open-ended questions, assessing feasibility and acceptability. Descriptive statistics and qualitative content and thematic analyses were performed. RESULTS: Forty-two percent (21/50) of all eligible residents completed "fully virtual" coaching sessions. The overall survey response rate was 91 % (38/42). The majority of respondents agreed that the direct observation and debriefing conversation were easy to schedule and occurred without technical difficulties and that debriefing elements (self-reflection, feedback, takeaways) were useful for residents. Ninety-five percent of respondents rated the coach's virtual presence to be not at all disruptive to the resident-patient interaction. Virtual coaching alleviated resident stress associated with observation and was perceived as an opportunity for immediate feedback and a unique approach for resident education that will persist into the future. CONCLUSIONS: In this pilot study, residents and faculty coaches found virtual coaching on communication skills feasible and acceptable for telemedicine encounters. Many elements of our intervention may be adoptable by other residency programs. For example, residents may share their communication goals with clinic faculty supervisors and then invite them to directly observe virtual encounters what could facilitate targeted feedback related to the resident's goals. Moreover, virtual coaching on communication skills in both the in-person and telemedicine settings may particularly benefit residents in challenging encounters such as those with cognitively impaired patients or with surrogate decision-makers.

A tearfully painful darkness.

A 70-year-old woman presented with new onset of left eye and facial pain. Ophthalmic and neurological examinations, magnetic resonance imaging brain, erythrocyte sedimentation rate, and C-reactive protein were unrevealing. A few days later, she developed vision loss in her left eye. Examination revealed decreased visual acuity with a relative afferent pupillary defect in the left eye and a diffuse mild swelling of the left optic nerve head. Repeat magnetic resonance imaging showed T2 hyperintensity and enhancement of the intraorbital optic nerve and surrounding tissues with no other intracranial abnormalities. Serum studies showed elevated myelin oligodendrocyte glycoprotein IgG titer. She was treated with IV methylprednisolone 1000 mg daily for 3 days and was discharged on prolonged prednisone taper with return of vision to baseline.

Risdiplam treatment has not led to retinal toxicity in patients with spinal muscular atrophy.

OBJECTIVE: Evaluation of ophthalmologic safety with focus on retinal safety in patients with spinal muscular atrophy (SMA) treated with risdiplam (EVRYSDI®), a survival of motor neuron 2 splicing modifier associated with retinal toxicity in monkeys. Risdiplam was approved recently for the treatment of patients with SMA, aged ≥ 2 months in the United States, and is currently under Health Authority review in the EU. METHODS: Subjects included patients with SMA aged 2 months-60 years enrolled in the FIREFISH, SUNFISH, and JEWELFISH clinical trials for risdiplam. Ophthalmologic assessments, including functional assessments (age-appropriate visual acuity and visual field) and imaging (spectral domain optical coherence tomography [SD-OCT], fundus photography, and fundus autofluorescence [FAF]), were conducted at baseline and every 2-6 months depending on study and assessment. SD-OCT, FAF, fundus photography, and threshold perimetry were evaluated by an independent, masked reading center. Adverse events (AEs) were reported throughout the study. RESULTS: A total of 245 patients receiving risdiplam were assessed. Comprehensive, high-quality, ophthalmologic monitoring assessing retinal structure and visual function showed no retinal structural or functional changes. In the youngest patients, SD-OCT findings of normal retinal maturation were observed. AEs involving eye disorders were not suggestive of risdiplam-induced toxicity and resolved with ongoing treatment. INTERPRETATION: Extensive ophthalmologic monitoring conducted in studies in patients with SMA confirmed that risdiplam does not induce ophthalmologic toxicity in pediatric or adult patients with SMA at the therapeutic dose. These results suggest that safety ophthalmologic monitoring is not needed in patients receiving risdiplam, as also reflected in the United States Prescribing Information for risdiplam.