Leber Hereditary Optic Neuropathy in Southwestern Ontario: A Growing List of Mutations.

BACKGROUND: Leber hereditary optic neuropathy (LHON) is a rare but bilaterally blinding disease. Three characteristic disease-causing point mutations, and other less common mutations, are most often found on the mitochondrially encoded genes of NADH-ubiquinone oxidoreductase core subunits (MT-ND). The purpose of this study is to provide an overview of LHON mutations in Southwestern Ontario and to describe the associated demographic and clinical characteristics. METHODS: A retrospective genetic and clinical chart review was performed from January 2015 to 2020. Patients were identified within a mitochondrial mutation database and included if a mutation was detected on the MT-ND1, -ND4, or -ND6 genes. A clinical chart review was done on all available patients. RESULTS: Forty-five of 63 patients identified had classic disease-causing mutations (6.7% m.3460G>A, 44.4% m.11778G>A, and 48.9% m.14484T>C). Several of the remaining 18 patients had rare mutations previously documented in association with LHON. Of the 14 patients with clinical charts accessible for review, 12 had symptomatic disease, and all but one had bilateral optic neuropathies. Nine patients had classic LHON mutations and 3 had possible novel mutations; 7 were males; 9 had final visual acuity ≤ 20/200 in at least one eye; and 6 of those had ≤20/400 in both eyes. CONCLUSIONS: This study adds to the literature on LHON in Canada, and specifically Southwestern Ontario. The demographic and clinical data regarding LHON in this geographic location, as well as possible novel disease-causing mutations, provide important information to aid clinicians in recognizing cases of LHON that may otherwise be disregarded.

Spastic Paraplegia Type 7-Associated Optic Neuropathy: A Case Series.

BACKGROUND: Hereditary optic neuropathies comprise a group of clinically and genetically heterogeneous disorders. Optic neuropathy has been previously reported in families with spastic paraplegia type 7 (SPG7) gene mutations. However, the typical time course and clinical presentation of SPG7-associated optic neuropathy is poorly understood. We report a series of 5 patients harboring pathogenic SPG7 mutations who originally presented to a neuro-ophthalmology clinic with symptoms of optic neuropathy. METHODS: Retrospective case series of 5 patients with pathogenic SPG7 mutations and optic atrophy from 3 neuro-ophthalmology clinics. Demographic, clinical, diagnostic, and treatment data were collected and reported by the clinician authors. RESULTS: Five patients ranging in age from 8 to 48 years were evaluated in the neuro-ophthalmology clinic. Although there were variable clinical presentations for each subject, all noted progressive vision loss, typically bilateral, and several also had previous diagnoses of peripheral neuropathy (e.g., Guillain-Barré Syndrome). Patients underwent neuro-ophthalmic examinations and testing with visual fields and optic coherence tomography of the retinal nerve fiber layer. Genetic testing revealed pathogenic variants in the SPG7 gene. CONCLUSIONS: Five patients presented to the neuro-ophthalmology clinic with progressive vision loss and were diagnosed with optic atrophy. Although each patient harbored an SPG7 mutation, this cohort was phenotypically and genotypically heterogeneous. Three patients carried the Ala510Val variant. The patients demonstrated varying degrees of visual acuity and visual field loss, although evaluations were completed during different stages of disease progression. Four patients had a previous diagnosis of peripheral neuropathy. This raises the prospect that a single pathogenic variant of SPG7 may be associated with peripheral neuropathy in addition to optic neuropathy. These results support the consideration of SPG7 testing in patients with high suspicion for genetic optic neuropathy, as manifested by symmetric papillomacular bundle damage without clear etiology on initial workup. Applied judiciously, genetic testing, including for SPG7, may help clarify the cause of unexplained progressive optic neuropathies.

Extraocular Muscle Enlargement in Acromegaly.

BACKGROUND: To determine whether acromegaly is associated with increased extraocular muscle (EOM) size at time of presentation. METHODS: Patients with a new diagnosis of acromegaly in a single tertiary care clinic with a CT scan that adequately delineated the EOMs were included. Control subjects were age- and sex-matched patients with a new diagnosis of nonfunctioning pituitary adenoma. Retrospective chart review was performed to extract baseline clinical and laboratory parameters including growth hormone, insulin-like growth factor 1, thyroid stimulating hormone, free T3, and free T4. A single neuroradiologist analyzed all CT scans and measured the maximum diameter and cross-sectional area of the superior rectus, inferior rectus, medial rectus, and lateral rectus in both eyes of all patients. RESULTS: We evaluated 17 patients with acromegaly and 18 control subjects. Mean maximum diameter of the superior, inferior, medial, and lateral recti were 4.80 mm (SD = 0.81), 4.67 mm (SD = 0.54), 4.86 mm (SD = 0.77), and 4.53 mm (SD = 0.70) respectively, in the acromegaly group. In the control group, they were 3.62 mm (SD = 0.58),3.71 mm (SD = 0.46), 3.66 mm (SD = 0.32), and 3.21 mm (SD = 0.44), respectively. The maximum diameter and cross-sectional area of all 4 EOMs measured in the acromegaly group were significantly larger ( P < 0.001) compared with the control group. CONCLUSIONS: Patients with acromegaly present with significantly enlarged EOMs compared with control subjects with nonfunctioning pituitary adenomas.

Validation and clinical performance of a combined nuclear-mitochondrial next-generation sequencing and copy number variant analysis panel in a Canadian population.

Diagnosing mitochondrial disorders is a challenge due to the heterogeneous clinical presentation and large number of associated genes. A custom next generation sequencing (NGS) panel was developed incorporating the full mitochondrial genome (mtDNA) plus 19 nuclear genes involved in structural mitochondrial defects and mtDNA maintenance. This assay is capable of simultaneously detecting small gene sequence variations and larger copy number variants (CNVs) in both the nuclear and mitochondrial components along with heteroplasmy detection down to 5%. We describe technical validations of this panel and its implementation for clinical testing in a Canadian reference laboratory, and report its clinical performance in the initial 950 patients tested. Using this assay, we demonstrate a diagnostic yield of 18.1% of patients with known pathogenic variants. In addition to the common 5 kb mtDNA deletion, we describe significant contribution of pathogenic CNVs in both the mitochondrial genome and nuclear genes in this patient population.

Optic Nerve Atrophy in N-methyl-D-aspartate (NMDA) Encephalitis.

N-methyl-D-aspartate receptor (NMDA) encephalitis is a recently described autoimmune disease that typically presents with prodromal symptoms including upper respiratory tract infection, headache, fever, nausea, vomiting and diarrhea. Psychiatric symptoms follow within weeks, including anxiety, insomnia, mania, paranoia and grandiose delusions. The diagnosis is confirmed by the detection of NMDA antibodies in the serum or cerebrospinal fluid (CSF).1 Tumours, especially teratomas, are frequently associated with NMDA encephalitis; however, only 5% of male patients older than 18 years have been found to have an underlying tumour. Optic neuropathy associated with NMDA encephalitis is being increasingly recognised in the literature2-6 and was reviewed most recently by Mugavin et al.2 in 2017. In this report, we present a case of bilateral optic neuropathy in a young man diagnosed with NMDA receptor encephalitis.

Positive Apraclonidine Test in Horner Syndrome Caused by Thalamic Hemorrhage.

Reversal of anisocoria following instillation of apraclonidine 0.5% has been reported in Horner syndrome caused by lesions of the central and peripheral nervous system. The shortest documented latency between symptom onset and a positive apraclonidine test is 36 hours, occurring in a patient with a pontomedullary infarct. We present the case of a 69-year-old man with Horner syndrome due to thalamic hemorrhage in whom apraclonidine testing demonstrated reversal of anisocoria 4 days after symptom onset. This is the first reported case of a positive apraclonidine test in a Horner syndrome caused by a lesion at this site. It suggests that apraclonidine testing is useful in confirming the diagnosis within days of onset even in a lesion located at the most proximal portion of the oculosympathetic pathway.

Vision Loss Caused by Retinal and Lateral Geniculate Nucleus Infarction in H1N1 Influenza.

A 13-year-old girl developed encephalopathy and severe bilateral vision loss to the level of light perception within 24 hours of having fever and myalgias heralding H1N1 influenza A. Ophthalmoscopy demonstrated findings of confluent ischemic retinopathy. Brain MRI disclosed lateral geniculate body signal abnormalities indicative of hemorrhagic infarction. Despite aggressive treatment with intravenous corticosteroids, intravenous immunoglobulin, and plasmapheresis, vision did not substantially improve. This case demonstrates that H1N1 can cause simultaneous retinal and lateral geniculate body infarctions, a combination of findings not previously described in any condition. We postulate an immunologic response to the virus marked by occlusive damage to arteriolar endothelium.

Congenital trochlear-oculomotor synkinesis.

Synkinesis of the extraocular muscles forms a subset of congenital ocular motility abnormalities termed congenital cranial dysinnervation disorders. Synkinesis most frequently involves the abducens or oculomotor nerves and rarely the trochlear nerve. Only 3 such patients have been described in the literature. We report an isolated case of trochlear-oculomotor synkinesis in a healthy 6-year-old boy and discuss the proposed pathophysiology of this disorder.

Low-grade intraductal carcinoma of the lacrimal gland.

Intraductal carcinoma has been described in the salivary glands as a relatively benign tumour with low-grade histopathologic features. To our knowledge, this tumour has not previously been reported in the lacrimal gland. We report the first case of low-grade intraductal carcinoma occurring in the lacrimal gland. This tumour was discovered incidentally on neuro-imaging in an asymptomatic 65-year-old patient. Incisional biopsy revealed uniform, polygonal cells with eosinophilic cytoplasm and minimal nuclear atypia, arranged in solid, cribiform and micropapillary nests. The patient underwent complete surgical excision with no evidence of recurrence at 8 months of follow-up.

Utility of online GCA risk models in predicting the result of temporal artery biopsy within a clinical setting: study of diagnostic and screening tests.

BACKGROUND: Temporal artery biopsy (TAB) is the gold standard for the diagnosis of giant cell arteritis (GCA) but has many limitations. The Ing model, González-López model, and Weis model are tools to estimate a patient's likelihood of GCA. This study investigates the utility of these prediction models in triaging patients referred for TAB. METHODS: This study is a retrospective examination of patients who underwent TAB by a neuro-ophthalmologist over a 5-year period. Data collected through chart review were inputted into prediction models to evaluate GCA risk and compared with TAB results and clinical diagnosis. Cut-off values for 100% sensitivity and specificity for TAB result were used to determine whether TAB could be avoided where there was preoperative certainty of the result. RESULTS: Among 155 eligible patients, mean age was 73 years, and 78.1% were female. TAB was negative in 103 patients (66.5%) and positive in 42 patients (27.1%). Twenty-three patients (22.3%) were diagnosed clinically and treated for biopsy-negative GCA. The Ing model had no positive biopsies below 10.59% and no negative biopsies above 68.44%. The González-López model had no positive biopsies below 0.27% and no negative biopsies above 98.08%. The Weis model had no positive biopsies with a score less than zero. CONCLUSION: Forty-one biopsies (28.9%) could have been avoided using the Ing model, 9 (6.34%) using the González-López model, and 28 (19.7%) using the Weis model. The findings suggest that the Ing and Weis models are useful screening tools for GCA with the potential to improve the effective use of health care resources.

An Eye on Childbearing, Fertility, and Lactation Experiences: A Survey of Canadian Ophthalmologists and Trainees.

OBJECTIVE: To synthesize the experiences of childbearing, fertility, and lactation among Canadian ophthalmologists and trainees. DESIGN: Online, cross-sectional survey. METHODS: A survey was distributed to Canadian ophthalmologists and trainees between April and August 2022. Likert-type scales were used to measure respondents' agreement with each survey item. Fisher's exact test was used to identify significant differences based on gender. RESULTS: Data were obtained from a total of 137 survey respondents (46% females). Women more than men reported that training and clinical practice influenced the number of children they chose to have (p = 0.002), as well as their ability to conceive (p < 0.001). Compared to their male counterparts, more women had concerns about future fertility (p = 0.040) and parental leave (p = 0.037). Among factors affecting parental leave, pressure from colleagues (p = 0.046) and difficulty finding coverage for clinical practice (p = 0.022) were statistically significant among women more than men. More women reported taking parental leave during medical school, residency, and clinical practice than men (p < 0.001). Childbearing (p = 0.005) and parental leave (p = 0.031) influenced pursuit of leadership roles and opportunities for career advancement among women more than men. Of those with lactation experiences, one-third of women felt they did not have adequate space or storage to facilitate their breastfeeding goals in the workplace. CONCLUSIONS: Over the span of their careers, female ophthalmologists and trainees face unparalleled challenges related to childbearing and parenthood duties, coping with infertility and obstetric risks, stigma, inadequate parental leaves, and poor supports for lactation and childcare, while balancing their career demands and aspirations. Garnering an understanding of gender inequities is essential to promote work-family integration within the surgical culture and address the systemic and structural barriers which impose a glass ceiling for female surgeons.

Association of pre-residency publications with research productivity in residency, fellowship, and academic career choice among Canadian ophthalmologists.

OBJECTIVE: This study aimed to assess whether the research output of medical students who matched into a Canadian ophthalmology residency program influences their subsequent research productivity during residency, decision to pursue a fellowship, or engagement in academic practice. DESIGN: Retrospective database review. PARTICIPANTS: A total of 369 trainees commencing ophthalmology residency from 2004 to 2015 at 15 residency programs. METHODS: Each trainee's publication record was queried in Scopus before and after the date they started residency. Multiple public sources were searched to identify fellowship placement and the type of subsequent practice (i.e., academic or community). Predictors of research productivity during residency, fellowship, and practice setting were assessed using multivariable regression analyses. RESULTS: Trainees with pre-residency publications (n = 187) demonstrated significantly higher research productivity during residency than those without pre-residency publications (n = 182), with a mean of 5.17 ± 5.97 versus 1.60 ± 2.38 publications on any topic (p < 0.001). Pre-residency research output was a predictor of research productivity during residency (relative risk = 1.17; 95% CI, 1.09-1.27; p < 0.001), pursuing fellowship (odds ratio, 2.9; 95% CI, 1.74-4.83), and an academic career (odds ratio = 1.85; 95% CI, 1.07-3.2). CONCLUSION: Pre-residency research output is a significant predictor of research productivity during residency and subsequent career choices, suggesting that pre-residency publishing reflects a propensity toward an academic trajectory. Residency publication count moderates this association, underscoring the role of the residency program environment in fostering research productivity. Addressing barriers such as mentorship, funding, and curriculum may be key to incentivizing trainees to pursue academic medicine.

Eyelid and eye movements following fourth to third nerve anastomosis.

A 34-year-old woman presented with brainstem compression from a large third nerve schwannoma although third nerve function was intact. At surgery, preservation of the proximal third nerve was not possible. Because of preexisting amblyopia of the contralateral eye, an attempt was made to surgically reinnervate the affected third nerve. The fourth nerve was divided at its entry into the tentorium and anastomosed to the distal stump of the third nerve. Partial recovery of third function occurred over several months and is still present 6 years later. Successful long-term reinnervation of the third nerve by direct anastomosis with the fourth nerve may be useful when third repair is not possible.

Patient perspective on the participation of ophthalmology residents in their cataract surgery.

OBJECTIVE: To determine the proportion of patients consenting to resident participation in cataract surgery and to identify factors predictive of consent. DESIGN: Prospective cross-sectional study. PARTICIPANTS: The 330 consecutive patients referred for cataract evaluation from February-April 2021 to 3 surgeons at a tertiary care referral centre in London, Ontario. METHODS: Using a standardized disclosure script, individuals were asked about resident participation in their cataract surgery. A phone survey and medical record review were conducted to obtain clinical and demographic information. Predictors of consent were assessed using logistic regression modelling. RESULTS: Responses were received from 279 individuals (85% response rate), with a mean age of 71.7 ± 8.6 years, and 113 were female. The consent rate was 71%. Prior negative experience with any medical trainee was an independent predictor for refusing resident participation (odds ratio [OR] = 3.10; 95% CI, 1.32-7.28; p = 0.009). Nonconsenters also had more prior negative experiences with other physicians (35% vs 23%; p = 0.031) and knew someone who had had a problem after eye surgery (36% vs 22%; p = 0.016). Individuals with an occupation involving apprenticeship (OR = 2.87; 95% CI, 1.08-7.67; p = 0.035) and those with a preoperative acuity of 20/200 or worse (OR = 2.78; 95% CI, 1.03-7.14; p = 0.043) were more likely to consent. CONCLUSIONS: Patients should be explicitly asked about resident involvement. Negative experiences can make individuals reluctant to have learners involved in their future care. Patient education describing the apprenticeship model in medicine may increase consent.

Strabismus outcomes in pediatric patients undergoing disconnective hemispheric surgery for intractable epilepsy: a systematic review.

BACKGROUND: Children undergoing hemispheric surgery for intractable seizures are susceptible to visual complications including strabismus. This systematic review aims to investigate the rates and characteristics of strabismus development after hemispheric surgery and evaluate clinical implications for ophthalmologic care. METHODS: A systematic search of MEDLINE, EMBASE, Cochrane, PsychINFO, and Web of Science databases was performed from database inception to May 2022. Included articles referred to strabismus outcomes in pediatric populations after hemispherectomy or hemispherotomy. Reviews and non-English-language publications were excluded. Risk of bias was assessed using Joanna Briggs Institute critical appraisal tools. Demographic data and characteristics of strabismus were extracted and tabulated. RESULTS: Of 41 articles identified, 10 studies consisting of 384 pediatric participants (48% females) and age at surgery between 6 months and 16 years were included. Preoperative strabismus rates ranged between 3% and 56%, whereas postoperative rates ranged between 38% and 100%. With respect to the site of hemispheric surgery, contralateral exodeviation was the most common (16%-67%; n = 7) and then ipsilateral exodeviation (16%-56%; n = 2), whereas ipsilateral esodeviation was infrequent (4%-9%; n = 3). CONCLUSIONS: Contralateral exotropia and ipsilateral esotropia may occur after hemispheric surgery and may have the potential to be field expanding. Concerns regarding negative social reactions should be balanced with the risk of visual field reduction and (or) diplopia by strabismus surgery. Higher-quality articles with large, homogeneous, and well-described populations (i.e., complete pre- and postoperative ophthalmologic assessments) are required to establish the risks and rates of strabismus development after hemispheric surgery.

A Comparison of Diagnostic Accuracy of Imaging Modalities to Detect Optic Disc Drusen: The Age of Enhanced Depth Imaging Optical Coherence Tomography.

PURPOSE: To identify the most accurate diagnostic imaging modality to detect optic disc drusen (ODD) between B-scan ultrasonography (US), fundus photography, fundus autofluorescence (FAF), and enhanced depth imaging optical coherence tomography (EDI-OCT). DESIGN: Comparative diagnostic analysis. METHODS: Two hundred five eyes of 105 patients referred to 2 tertiary care neuro-ophthalmology clinics for suspected ODD were recruited: 108 eyes had ODD and 97 did not have ODD. All eyes received a full in-person ophthalmic exam with 3D view of the optic nerve and all 4 imaging modalities. Images were independently reviewed by 3 masked neuro-ophthalmologists to determine the presence or absence of ODD. Final interpretation was made through consensus. The reference standard was defined as the attending ophthalmologist's clinical judgement based on open chart review, with access to all image modalities and clinical information, including disease course. Main outcome measures were sensitivity, specificity, accuracy, and precision for each imaging modality. Examiner confidence was quantified as the proportion of eyes in which the reviewers were certain of their decision. RESULTS: The EDI-OCT had the highest sensitivity and accuracy (95%, 97%) to detect ODD, compared with FAF (84%, 92%), US (74%, 86%), and fundus photography (38%, 66%), respectively. All image modalities had high specificity (> 97%) and precision (> 93%). The EDI-OCT also had highest examiner confidence (96%) compared with all others (88%). CONCLUSIONS: Among all modalities, EDI-OCT was the imaging modality with the highest diagnostic utility for the detection of ODD and should be considered as the preferred initial diagnostic modality.

Prognostic effect of HIV on visual acuity in ocular syphilis: a systematic review.

BACKGROUND/OBJECTIVES: Ocular syphilis is a vision-threatening disease that can lead to permanent blindness if left untreated. The global re-emergence of syphilis warrants greater investigations into the visual prognosis of eyes affected by this potentially devastating disease. This systematic review investigates the impact of HIV on visual acuity (VA) outcomes in ocular syphilis. METHODS: A literature search of Medline, PubMed, Embase, Clinicaltrials.gov and Cochrane Reviews was conducted for studies published between 01 January 2011 and 19 March 2022, reporting non-aggregate initial and post-treatment VA data of eyes with ocular syphilis and corresponding HIV status in patients ≥ 18 years. RESULTS: A total of 95 studies, including 364 patients and 568 eyes, were evaluated. Among people living with HIV with a diagnosis of ocular syphilis, affected eyes were more likely to have optic nerve involvement and panuveitis. However, HIV status, CD4 cell count, and HIV viral load were not predictive of VA outcomes of treated ocular syphilis. Prognostic factors of final VA worse than 1.00 logMAR were female sex, the presence of macular edema, and VA ≥ 1.00 at presentation. The strongest predictor of a worse final VA was VA ≥ 1.00 at presentation. CONCLUSIONS: This systematic review demonstrates that HIV status, CD4 cell count, and HIV viral load are not significant factors impacting VA outcomes of eyes with ocular syphilis. While visual prognosis is generally good, poor visual outcome is most strongly predicted by poor VA at presentation. This underscores the importance of early recognition and treatment prior to permanent vision loss.

Conjunctival lymphangiectasia and retinal angiopathy in hereditary transthyretin amyloidosis.

BACKGROUND: Hereditary transthyretin amyloidosis (ATTR amyloidosis) is a rare condition where a mutation in the transthyretin gene leads to systemic deposition of amyloid. The manifestations and prognosis of ATTR amyloidosis depends on the specific ATTR mutation, with over 100 mutations reported in the literature. The manifestations of many rare forms of ATTR amyloidosis have not been well described, particularly the late-onset ophthalmic findings. CASE PRESENTATION: We present the case of a 43-year-old Caucasian male with a diagnosis of ATTRD18E amyloidosis confirmed by fat pad biopsy. He had diffuse systemic involvement, including cardiovascular, pulmonary, and gastrointestinal symptoms. He also had significant ocular involvement including vitreous opacities, retinal angiopathy, and conjunctival lymphangiectasia. These ocular findings modestly progressed at 2-year follow-up. DISCUSSION: The ATTRD18E mutation is a rare variant, with few described cases. To our knowledge, this is the first documented case of ATTRD18E amyloidosis with significant ocular involvement. These ocular findings may serve as a relevant biomarker for severe disease prognosis in ATTRD18E amyloidosis. With improving treatments addressing the systemic symptoms of ATTR amyloidosis, a better understanding of the late-onset ocular symptoms is becoming increasingly relevant.