Mitochondria Transplantation Promotes Corneal Epithelial Wound Healing.

Purpose: The integrity of the corneal epithelium is essential in maintaining normal corneal function. Conditions disrupting the corneal epithelial layer range from chemical burns to dry eye disease and may result in impairment of both corneal transparency and sensation. Identifying factors that regulate corneal wound healing is key for the development of new treatment strategies. Here, we investigated a direct role of mitochondria in corneal wound healing via mitochondria transplantation. Methods: Human corneal epithelial cells (hCECs) were isolated from human corneas and incubated with mitochondria which were isolated from human ARPE-19 cells. We determined the effect of mitochondria transplantation on wound healing and proliferation of hCECs. In vivo, we used a mouse model of corneal chemical injury. Mitochondria were isolated from mouse livers and topically applied to the ocular surface following injury. We evaluated the time of wound repair, corneal re-epithelization, and stromal abnormalities. Results: Mitochondria transplantation induced the proliferation and wound healing of primary hCECs. Further, mitochondria transplantation promoted wound healing in vivo. Specifically, mice receiving mitochondria recovered twice as fast as control mice following corneal injury, presenting both enhanced and improved repair. Corneas treated with mitochondria demonstrated the re-epithelization of the wound area to a multi-layer appearance, compared to thinning and complete loss of the epithelium in control mice. Mitochondria transplantation also prevented the thickening and disorganization of the corneal stromal lamella, restoring normal corneal dehydration. Conclusions: Mitochondria promote corneal re-epithelization and wound healing. Augmentation of mitochondria levels via mitochondria transplantation may serve as an effective treatment for inducing the rapid repair of corneal epithelial defects.

Diplopia in the Younger Adult (≤65 Years Old) Compared With Older Adult (>65 Years Old) Population-Presentation, Progression, and Outcome.

BACKGROUND: Despite the impact of new-onset diplopia on the quality of life, there are few studies concerning new-onset diplopia in seniors. This study aimed to describe the epidemiology, etiology, prognosis, and outcome of different treatments in the older adults compared with younger adult patients presenting with new-onset binocular diplopia. METHODS: A retrospective chart review of patients ≥18 YO with new-onset binocular diplopia presenting between 2010 and 2021. Data collected included age at presentation, gender, duration of time since diplopia onset, imaging results, known trigger, etiology, treatment, and follow-up. RESULTS: Two hundred ten patients were included. Of them, 75 patients were ≤65 YO (35.7%, the "younger adult group") and 135 > 65 YO (64.3%, the "older adults group"). The common etiology in both groups was neurogenic (54.7% ≤ 65 vs 62.2% >65, P = 0.29). Cranial nerve palsies were more commonly microvascular in the older adults (96.0% vs 74.1%, P = 0.005), whereas tumor-related cranial nerve palsies were more frequent in younger adults (14.81% vs 2.04%, P = 0.03). A restrictive etiology was observed in 20% of younger adult compared with 11.1% of older adults group (P = 0.08). Sagging eye syndrome (SES) was the second most common etiology in the older adults group at 11.9%, compared with 1.3% in the younger adult group (P = 0.01). Decompensated phoria/tropia appeared in 16% of younger adult group compared with 11.9% of older adults (P = 0.4), with an obvious trigger (mostly cataract surgery) in the latter (80% older adults vs 20% younger adults, P = 0.019). Positive imaging findings were found in 46.7% of patients ≤65 compared with 25.3% of >65 (P = 0.01) and complete spontaneous resolution of diplopia was noted in 32.1% of the older adults compared with 11.8% of younger adults (P = 0.003). CONCLUSIONS: Neurogenic diplopia was the most common etiology for both groups, but is more prominent in the older adults. Noticeable findings in the older adults were SES diagnosis, identification of triggers for impaired fusion/diplopia, and a paucity of positive findings in imaging results. It is important to know these differences not only for managing seniors better, but also to minimize symptoms of binocular diplopia after lens-related procedures.

Implantation and Evaluation of Melanoma in the Murine Choroid via Optical Coherence Tomography.

Establishing experimental choroidal melanoma models is challenging in terms of the ability to induce tumors at the correct localization. In addition, difficulties in observing posterior choroidal melanoma in vivo limit tumor location and growth evaluation in real-time. The approach described here optimizes techniques for establishing choroidal melanoma in mice via a multi-step sub-choroidal B16LS9 cell injection procedure. To enable precision in injecting into the small dimensions of the mouse uvea, the complete procedure is performed under a microscope. First, a conjunctival peritomy is formed in the dorsal-temporal area of the eye. Then, a tract into the sub-choroidal space is created by inserting a needle through the exposed sclera. This is followed by the insertion of a blunt needle into the tract and the injection of melanoma cells into the choroid. Immediately after injection, noninvasive optical coherence tomography (OCT) imaging is utilized to determine tumor location and progress. Retinal detachment is evaluated as a predictor of tumor site and size. The presented method enables the reproducible induction of choroid-localized melanoma in mice and the live imaging of tumor growth evaluation. As such, it provides a valuable tool for studying intraocular tumors.

[CASE SERIES OF EARLY NEUROIMAGING IN PATIENTS WITH VASCULAR RISK FACTORS AND ISOLATED SIX CRANIAL NERVE PALSY, DEMONSTRATING THE DILEMMA OF EARLY IMAGING].

INTRODUCTION: There are various etiologies for isolated third, fourth and sixth cranial nerve palsies. The most common etiology in adults aged 50 years and older with vascular risk factors such as diabetes, hyperlipidemia, and hyperlipidemia, is microvascular ischemia. The role of early neuroimaging in older patients with vascular risk factors presenting with acute isolated ocular motor nerve palsy is controversial. AIMS: We present six cases of patients aged 50 years and older, with vascular risk factors, who suffered from acute isolated paralysis of the sixth nerve. All cases were diagnosed with a non-microvascular ischemia etiology. RESULTS: The identified etiologies included petroclival meningioma with involvement of the cavernous sinus, metastatic hepatoma, plasmacytoma, venous thrombosis, arterial-venous malformation and aneurysm. CONCLUSIONS: Despite the high cost and presumed low yield, early neuroimaging can change the clinical management in certain cases. DISCUSSION: Previous studies have found the yield of early neuroimaging in older vasculopathic patients with acute 4th or 6th cranial nerve palsies to be 1-15%. In spite of these reports, our cases demonstrate the need for early onset imaging in these cases.

A Consensus Statement on the Terminology for Automated Visual Field Abnormalities.

BACKGROUND: A multitude of terms have been used to describe automated visual field abnormalities. To date, there is no universally accepted system of definitions or guidelines. Variability among clinicians creates the risk of miscommunication and the compromise of patient care. The purposes of this study were to 1) assess the degree of consistency among a group of neuro-ophthalmologists in the description of visual field abnormalities and 2) to create a consensus statement with standardized terminology and definitions. METHODS: In phase one of the study, all neuro-ophthalmologists in Israel were asked to complete a survey in which they described the abnormalities in 10 selected automated visual field tests. In phase 2 of the study, the authors created a national consensus statement on the terminology and definitions for visual field abnormalities using a modified Delphi method. In phase 3, the neuro-ophthalmologists were asked to repeat the initial survey of the 10 visual fields using the consensus statement to formulate their answers. RESULTS: Twenty-six neuro-ophthalmologists participated in the initial survey. On average, there were 7.5 unique descriptions for each of the visual fields (SD 3.17), a description of only the location in 24.6% (SD 0.19), and an undecided response in 6.15% (SD 4.13). Twenty-two neuro-ophthalmologists participated in the creation of a consensus statement which included 24 types of abnormalities with specific definitions. Twenty-three neuro-ophthalmologists repeated the survey using the consensus statement. On average, in the repeated survey, there were 5.9 unique descriptions for each of the visual fields (SD 1.79), a description of only the location in 0.004% (SD 0.01), and an undecided response in 3.07% (SD 2.11%). Relative to the first survey, there was a significant improvement in the use of specific and decisive terminology. CONCLUSIONS: The study confirmed a great degree of variability in the use of terminology to describe automated visual field abnormalities. The creation of a consensus statement was associated with improved use of specific terminology. Future efforts may be warranted to further standardize terminology and definitions.

Oxidative stress facilitates exogenous mitochondria internalization and survival in retinal ganglion precursor-like cells.

Ocular cells are highly dependent on mitochondrial function due to their high demand of energy supply and their constant exposure to oxidative stress. Indeed, mitochondrial dysfunction is highly implicated in various acute, chronic, and genetic disorders of the visual system. It has recently been shown that mitochondrial transplantation (MitoPlant) temporarily protects retinal ganglion cells (RGCs) from cell death during ocular ischemia. Here, we characterized MitoPlant dynamics in retinal ganglion precursor-like cells, in steady state and under oxidative stress. We developed a new method for detection of transplanted mitochondria using qPCR, based on a difference in the mtDNA sequence of C57BL/6 and BALB/c mouse strains. Using this approach, we show internalization of exogenous mitochondria already three hours after transplantation, and a decline in mitochondrial content after twenty four hours. Interestingly, exposure of target cells to moderate oxidative stress prior to MitoPlant dramatically enhanced mitochondrial uptake and extended the survival of mitochondria in recipient cells by more than three fold. Understanding the factors that regulate the exogenous mitochondrial uptake and their survival may promote the application of MitoPlant for treatment of chronic and genetic mitochondrial diseases.

Clinical profile of 80-year-old and older thyroid eye disease patients.

PURPOSE: Thyroid eye disease (TED), an autoimmune orbital disorder, follows a time-of-onset bimodal peak: 40-44 and 60-64 years for women, 45-49 and 65-69 years for men. TED, however, can also commence in old age. The study's purpose was to evaluate TED in octo- and nonagenarians. METHODS: Medical records of 19 ≥ 80 years geriatric patients at time of diagnosis were compared to 122 TED patients, aged 20-79. A second analysis was performed after subdividing the control group into two age groups, ≤ 40 ("young group," 16 patients) and 41-79 years ("middle-aged group," 106 patients). RESULTS: The geriatric group's mean age was 84 years (80-94), 11 males and 8 females. Mean follow-up time was 16 months. Compared to the controls, the geriatric patients smoked less (p = 0.012), were more often hypothyroid (p = 0.019), and had concurrent myasthenia gravis (p = 0.02) at time of diagnosis. Diplopia was the most common presenting symptom among the elderly (p = 0.005) and proptosis among the controls, specifically the young group (p = 0.027). Bilateral signs were more common among seniors (p = 0.049). Optic neuropathy was diagnosed in 10% of the geriatric group (2/19) and 11% of middle-aged group (12/106), all being resolved after steroids or orbital decompression. Active disease (clinical activity score (CAS) score = > 3) was more common among the middle-aged group (p = 0.024) while the geriatric patients tended towards higher TED severity grades. Orbital decompression and eyelid repositioning surgeries were more common among the middle-aged group. Strabismus surgeries were more common among seniors. CONCLUSIONS: TED among octo- and nonagenarians has unique patterns, with different demographic features, more exposed to diplopia, hypothyroidism, association with myasthenia gravis, and bilateral involvement. Special attention should be given when medically managing this subgroup.

Endoscopic dacryocystorhinostomy among the old and oldest-old populations - A case control study.

OBJECTIVE: Despite increased risks of nasolacrimal duct obstruction (NLDO) with age, and the continuous growth of the old population proportion, data on endoscopic dacryocystorhinostomy (eDCR) among the old is lacking. This study aims to evaluate long-term eDCR efficacy and safety in the old and oldest-old population. METHODS: A retrospective case-control study of patients aged 80 ≤ (oldest-old) and 65-79 (old) compared with younger controls who underwent eDCR, between 2002 and 2017. Pre-, intra- and postoperative factors were collected using an integrated hospital-community system. Success rates were analyzed and measured at the first visit following surgery (immediate success), and after five years. Demographics, comorbidities, complications rates, and outcomes were compared between the groups. RESULTS: The study groups included 52 oldest-old patients (mean age 83.4 ± 3.6), 127 old patients (72.3 ± 4.14) and 142 control patients (57.8 ± 18.0). The immediate and success rates were 94.2%, 93.7% and 90.8% and five-year success rates were 80.0%, 76.6% and 80% among oldest-old, old and controls, respectively. No significant differences in success rates were found, even despite higher comorbidity rates among the study's group (96 and 92.8% vs. 63.2%, among oldest-old, old and controls respectively, p <0.001). Intra- and postoperative complications rates were low in all groups. CONCLUSIONS: Among older population, including oldest-old and old, eDCR safety and long-term outcomes are comparable with younger patients, suggesting that eDCR should be offered to NLDO patients, regardless of age.

In-vivo imaging for assessing tumor growth in mouse models of ocular melanoma.

Uveal melanoma (UM) and conjunctival melanoma (CM) are ocular malignancies that give rise to life-threatening metastases. Although local disease can often be treated successfully, it is often associated with significant vision impairment and treatments are often not effective against metastatic disease. Novel treatment modalities that preserve vision may enable elimination of small tumors and may prevent subsequent metastatic spread. Very few mouse models of metastatic CM and UM are available for research and for development of novel therapies. One of the challenges is to follow tumor growth in-vivo and to determine the right size for treatment, mainly of the posterior, choroidal melanoma. Hence, the purpose of this study was to establish a simple, noninvasive imaging tool that will simplify visualization and tumor follow-up in mouse models of CM and UM. Tumors were induced by inoculation of murine B16LS9 cells into the sub-conjunctival or the choroidal space of a C57BL/6 mouse eye under a surgical microscope. Five to ten days following injection, tumor size was assessed by Phoenix MicronIV™ image-guided Optical Coherence Tomography (OCT) imaging, which included a real-time camera view and OCT scan of the conjunctiva and the retina. In addition, tumor size was evaluated by ultrasound and histopathological examination of eye sections. Tumor growth was observed 5-9 days following sub-conjunctival or sub-retinal injection of seven-thousand or seventy-thousand cells, respectively. A clear tumor mass was detected at these regions using the MicronIV™ imaging system camera and OCT scans. Histology of eye sections confirmed the presence of tumor tissue. OCT allowed an accurate measurement of tumor size in the UM model and a qualitative assessment of tumor size in the CM model. Moreover, OCT enabled assessing the success rate of the choroidal tumor induction and importantly, predicted final tumor size already on the day of cell inoculation. In conclusion, by using a simple, non-invasive imaging tool, we were able to follow intraocular tumor growth of both CM and UM, and to define, already at the time of cell inoculation, a grading scale to evaluate tumor size. This tool may be utilized for evaluation of new mouse models for CM and UM, as well as for testing new therapies for these diseases.

Five- and 10-Year Outcomes for Primary Endoscopic Dacryocystorhinostomy: Failure Rate and Risk Factors.

INTRODUCTION: Endoscopic dacryocystorhinostomy (eDCR) is the preferred approach for nasolacrimal duct obstruction, yet quality data on long-term outcomes is lacking. STUDY DESIGN: A retrospective study in a single, academic institution. OBJECTIVE: To assess the 5- and 10-year success rates of eDCR, and its associated risks. PATIENTS AND METHODS: All eDCRs conducted at Kaplan Medical Center between the years 2002-2017 were included. For long-term follow-up analysis, two subgroups with a minimum of documented 5- and 10-year follow-up after surgery were defined. Surgical success was defined by both anatomical (observed patent lacrimal flow) and functional (symptomatic relief) success. Data was collected from the hospital's electronic medical records and was completed by phone interviews. Pre-, intra-, and postoperative variables were collected and stratified by multivariate analysis. RESULTS: After exclusions, 321, 168, and 65 patients were included for immediate, 5- and 10-year outcome analysis, respectively. Overall success rates were 92.5%, 86.3%, and 80%, respectively. The anatomical success rates were 93.8%, 89.9%, and 86.1%, respectively. Multivariate analysis revealed that older age (P < .001, P = .001) previous smoking (P = .043, P = .037), and postoperative complains of epiphora (even when a successful irrigation was observed, P < .001, P = .01) were all associated with eDCR failure 5 and 10 years following surgery. Male gender was also associated with eDCR failure (5 years, P = .045; 10 years, P = .063). CONCLUSIONS: Despite decreased rates over time, eDCR is beneficial for the majority of patients also at 10 years following surgery. Older age, smoking, postoperative epiphora, and male gender are related to long-term failure and should be discussed with the patients before surgery. LEVEL OF EVIDENCE: 3b Laryngoscope, 131:10-16, 2021.

Long-Term Follow-up of Pseudotumor Cerebri Syndrome in Prepubertal Children, Adolescents, and Adults.

PURPOSE: Pseudotumor cerebri syndrome can have a recurrent course. We compared the long-term disease course, recurrences, and final visual outcomes in prepubertal children, adolescents, and adults. METHODS: In this retrospective observational study, patients were divided into prepubertal children (group A) adolescents (group B), and adults (group C). RESULTS: Sixty-five patients (56 females, nine males) were included, 26.2% in group A, 24.6% in group B, and 49.2% in group C. Age at diagnosis was 8.6 ± 2.0 years, 14.3 ± 1.5 years, and 31.9 ± 9.7 years for the prepubertal children, adolescents, and adults, respectively. Medical treatment duration was similar (2.4 to 3.3 years, P > 0.05). Recurrences were observed in 23.5% of prepubertal children, 50% of adolescents, and 28.1% of adults. Recurrences occurred within 1.3 ± 0.6 years from treatment cessation in the prepubertal group compared with 3.8 ± 5.1 years in adolescents and 2.7 ± 2.0 years in adults (P = 0.267). Optic neuropathy was evident in 41% of group A, 31% of group B, and 87.5% of group C (P < 0.001). Obesity and cerebrospinal fluid opening pressures were unassociated with either relapsing rates or final visual outcomes in all groups. CONCLUSIONS: Pseudotumor cerebri syndrome exhibits a relapsing course in a third of cases. Recurrences tend to occur within one year after treatment cessation in prepubertal children, and within three years in older patients, revealing the importance of longer follow-up, especially in adults. Optic neuropathy was more common in adults along with a tendency for visual decline. Longer treatment times were associated with fewer recurrences.

Traumatic Cataracts in Children, Long-Term Follow-up in an Israeli Population: A Retrospective Study.

BACKGROUND: Ocular trauma in the pediatric population may lead to cataract formation. Managing traumatic cataracts in a visually immature child is a major challenge and can result in poor visual outcome. OBJECTIVES: To review our long-term surgical experience with childhood unilateral traumatic cataracts. METHODS: A retrospective observational study of children with unilateral traumatic cataracts with minimal follow-up of 5 years was conducted. Main outcomes included final visual acuity (VA) and occurrence of complications. RESULTS: Of the 18 children included in the study, 83% were male. Mean follow-up time was 12.5 years. Median age at injury was 7.5 years. Eleven patients (61%) presented with penetrating trauma injuries and 7 (39%) with blunt trauma. Sixteen patients (89%) had cataracts at presentation, while in two the cataracts developed during follow-up. Of the 18 total, cataract removal surgery was conducted in 16 (89%) with intraocular lens (IOL) implantation in 14 (87.5%), while 2 remained aphakic (12.5%). Two (11%) were treated conservatively. Long-term complications included IOL dislocation in 5 (36%), glaucoma in 8 (44%), and posterior capsular opacity in 10 (71%). No correlation was found between final visual acuity and the time interval between injury and IOL implantation nor between final VA and age at trauma. However, the final VA did correlate with time of follow-up. CONCLUSIONS: Severe complications occurred in over 30% of the patients during a long follow-up (mean 12.5 years). This finding shows the importance of discussions between the operating physician and the parents regarding the prognosis and necessity of scheduled follow-up.

Bilateral Transient Myopia with Sulfasalazine Treatment.

PURPOSE: Several case reports of transient drug-induced myopia have been reported, mainly due to sulfa drugs. We present a case of a sudden and significant increase in myopia associated with initiation of Sulfasalazine for long-standing ulcerative colitis in an adult Caucasian female. CASE REPORT: Our patient presented to the emergency room with acute bilateral visual loss. Ocular examination was normal, except for myopia of -4 Diopters (D) in both eyes (BE). The patient was advised to stop the medication, and her vision improved within 4 days to best corrected visual acuity (BCVA) of 6/7.5 with a refractive correction of -0.75 D in her right eye (RE) and BCVA of 6/6 with a refractive correction of -0.50 D in her left eye (LE). CONCLUSION: To the best of our knowledge, this is the second reported case of transient Sulfasalazine-induced myopia.

Familial Intracranial Hypertension in 2 Brothers With PTEN Mutation: Expansion of the Phenotypic Spectrum.

PTEN (Phosphatase and Tensin Homolog on chromosome TEN) encodes a vastly expressed tumor suppressor protein that antagonizes the PI3 K signaling pathway and alters the MTOR pathway. Mutations in PTEN have been described in association with a number of syndromes including PTEN hamartoma-tumor syndrome, macrocephaly/autism, and juvenile polyposis of infancy. Although there is a wide variability in the clinical and radiologic presentations of PTEN-related phenotypes, the most consistent features include macrocephaly and increased tumorigenesis. Intracranial hypertension may be idiopathic or secondary to multiple etiologies. We describe 2 siblings harboring a PTEN mutation who presented with macrocephaly and intracranial hypertension. Repeat brain MRIs were normal in both. Acetazolamide treatment normalized intracranial pressure, but several trials of medication tapering led to recurrence of intracranial hypertension symptoms. The clinical presentation of our patients expands the PTEN-related phenotypes. We discuss the possible pathophysiology in view of PTEN function.

Long-term follow-up of benign positional vertical opsoclonus in infants: retrospective cohort.

BACKGROUND/AIMS: Benign positional vertical opsoclonus in infants, also described as paroxysmal tonic downgaze, is an unsettling phenomenon that leads to extensive work-up, although benign course has been reported in sporadic cases. We describe long-term follow-up of a series of infants with the phenomenon. METHODS: This retrospective cohort included all infants diagnosed with rapid downgaze eye movement in 2012-2015 and followed until 2016. The databases of two medical centres were retrospectively reviewed. Benign positional vertical opsoclonus was diagnosed based on clinical findings of experienced neuro-ophthalmologists. Data were collected on demographics, symptoms and signs, neuro-ophthalmological and neurological evaluations, and outcome. Imaging studies were reviewed. Main outcome measures were long-term outcome and findings of the thorough investigation. RESULTS: The cohort included six infants. All infants were born at term. Age at presentation was several days to 12 weeks. Episodes lasted a few seconds and varied in frequency from <10 to dozens per day. In five infants, symptoms occurred in the supine position. There was a wide variability in the work-up without any pathological findings. Follow-up ranged from 1 to 2.5 years. Ocular symptoms gradually decreased until resolution. Infants reached normal developmental milestones. CONCLUSIONS: Our identification of six patients in only 3 years suggests benign positional vertical opsoclonus may be more prevalent than previously described. In our experience, it affects otherwise healthy infants and resolves spontaneously. In view of the good long-term outcome, a comprehensive clinical investigation may not be necessary.

[BISPHOSPHONATES AND OCULAR INFLAMMATION].

INTRODUCTION: Bisphosphonates are a group of drugs used for treatment in several bone diseases such as osteoporosis in women, Paget's disease, hypercalcemia of malignancy, primary malignancies of the bone and metastatic bone disease (breast and prostate carcinoma). Numerous reports in the medical literature described ocular side effects in patients treated with these drugs. We report on two patients, treated with bisphosphonates due to malignancy, who presented with unilateral and bilateral uveitis. Treatment of the ocular inflammation should include local and systemic treatment and stopping the systemic use of bisphosphonates. Another alternative is switching to another bisphosphonate with less ocular side effects.

Age differences in clinical manifestation and prognosis of thyroid eye disease.

PURPOSE: To examine the clinical differences in manifestation, course, treatment, and prognosis of thyroid eye disease (TED) in patients younger than 40 years of age at diagnosis compared to older patients. METHODS: Medical record review of 131 TED patients was performed. The patients were divided into two age groups, Group 1 ≤ 40 years (23 patients) and Group 2 > 40 years (108 patients). RESULTS: Younger patients had more eyelid retraction and proptosis at initial presentation, whereas older patients were more likely to have diplopia (P = 0.001). Acute inflammatory signs were more common in the Group 2 patients (P = 0.04). Corrected visual acuity was 20/20 and 20/25 in both groups. Optic neuropathy was diagnosed only in Group 2 patients (n = 12; 11 %), and it resolved after steroids or orbital decompression surgery in all cases. The mean follow-up time was 36 months (36 ± 7.7; 59.3 ± 5.8). Systemic steroid use, orbital surgery, and strabismus surgery were more common in Group 2 (P < 0.0001, P < 0.05 respectively). CONCLUSIONS: TED under the age of 40 years has different clinical features. In our group of younger patients, the clinical presentation was milder than in the older group with a higher rate of lid retraction and proptosis and lower rate of restrictive myopathy and optic neuropathy. Their disease course was less severe and required less aggressive medical treatment and less surgical procedures.