The Posthyaluronidase Syndrome: Dosing Strategies for Hyaluronidase in the Dissolving of Facial Filler and Independent Predictors of Poor Outcomes.

Background: Hyaluronic acid dermal fillers are used extensively in periocular aesthetic medicine, and the incidence of filler-related complications is increasing. This study aimed to investigate the optimal dosing strategy for hyaluronidase and to identify predictors of poor outcomes. Methods: We performed a retrospective review of 157 orbits of 90 patients treated with hyaluronidase over a 4-year period. Demographic data, indication, and details of hyaluronidase treatment and outcomes were recorded. Results: The primary indication for dissolving filler was swelling in 52%, lumpiness in 20%, and before surgical blepharoplasty in 17%. The most frequently used hyaluronidase concentration was 150 U per mL in 66%, followed by 75 U per mL in 31%, 37.5 U per mL in 3%, and 100 U per mL in 1%. Outcomes were characterized as follows: 59% with a satisfactory result; 24% as insufficient treatment requiring further hyaluronidase; and 18% complaining of facial changes such as hollowing, indicating a post hyaluronidase syndrome. There was no statistical difference in outcomes between the 75 and 150 U per mL dosage groups (P = 0.625). A significant correlation was identified between posthyaluronidase syndrome and duration of filler in situ (P = 0.00019) and volume of filler (P = 0.000017). Conclusions: The posthyaluronidase syndrome may be related to previous filler volume and duration, rather than the concentration or dose of hyaluronidase used. All patients should be informed about the risks of adverse effects after hyaluronidase treatment; patients with longer histories of filler use and higher total volumes should be advised of the increased risk.

Purinergic signaling via P2X receptors and mechanisms of unregulated ATP release in the outer retina and age-related macular degeneration.

Age-related macular degeneration (AMD) is a chronic and progressive inflammatory disease of the retina characterized by photoceptor loss and significant central visual impairment due to either choroidal neovascularization or geographic atrophy. The pathophysiology of AMD is complex and multifactorial, driven by a combination of modifiable and non-modifiable risk factors, molecular mechanisms, and cellular processes that contribute to overall disease onset, severity, and progression. Unfortunately, due to the structural, cellular, and pathophysiologic complexity, therapeutic discovery is challenging. While purinergic signaling has been investigated for its role in the development and treatment of ocular pathologies including AMD, the potential crosstalk between known contributors to AMD, such as the complement cascade and inflammasome activation, and other biological systems, such as purinergic signaling, have not been fully characterized. In this review, we explore the interactions between purinergic signaling, ATP release, and known contributors to AMD pathogenesis including complement dysregulation and inflammasome activation. We begin by identifying what is known about purinergic receptors in cell populations of the outer retina and potential sources of extracellular ATP required to trigger purinergic receptor activation. Next, we examine evidence in the literature that the purinergic system accelerates AMD pathogenesis leading to apoptotic and pyroptotic cell death in retinal cells. To fully understand the potential role that purinergic signaling plays in AMD, more research is needed surrounding the expression, distribution, functions, and interactions of purinergic receptors within cells of the outer retina as well as potential crosstalk with other systems. By determining how these processes are affected in the context of purinergic signaling, it will improve our understanding of the mechanisms that drive AMD pathogenesis which is critical in developing treatment strategies that prevent or slow progression of the disease.

Müller cell degeneration and microglial dysfunction in the Alzheimer's retina.

Amyloid beta (Aß) deposits in the retina of the Alzheimer's disease (AD) eye may provide a useful diagnostic biomarker for AD. This study focused on the relationship of Aß with macroglia and microglia, as these glial cells are hypothesized to play important roles in homeostasis and clearance of Aß in the AD retina. Significantly higher Aß load was found in AD compared to controls, and specifically in the mid-peripheral region. AD retina showed significantly less immunoreactivity against glial fibrillary acidic protein (GFAP) and glutamine synthetase (GS) compared to control eyes. Immunoreactivity against ionized calcium binding adapter molecule-1 (IBA-1), a microglial marker, demonstrated a higher level of microgliosis in AD compared to control retina. Within AD retina, more IBA-1 immunoreactivity was present in the mid-peripheral retina, which contained more Aß than the central AD retina. GFAP co-localized rarely with Aß, while IBA-1 co-localized with Aß in more layers of control than AD donor retina. These results suggest that dysfunction of the Müller and microglial cells may be key features of the AD retina.

Grab regulates transferrin receptor recycling and iron uptake in developing erythroblasts.

Developing erythroblasts acquire massive amounts of iron through the transferrin (Tf) cycle, which involves endocytosis, sorting, and recycling of the Tf-Tf receptor (Tfrc) complex. Previous studies on the hemoglobin-deficit (hbd) mouse have shown that the exocyst complex is indispensable for the Tfrc recycling; however, the precise mechanism underlying the efficient exocytosis and recycling of Tfrc in erythroblasts remains unclear. Here, we identify the guanine nucleotide exchange factor Grab as a critical regulator of the Tf cycle and iron metabolism during erythropoiesis. Grab is highly expressed in differentiating erythroblasts. Loss of Grab diminishes the Tfrc recycling and iron uptake, leading to hemoglobinization defects in mouse primary erythroblasts, mammalian erythroleukemia cells, and zebrafish embryos. These defects can be alleviated by supplementing iron together with hinokitiol, a small-molecule natural compound that can mediate iron transport independent of the Tf cycle. Mechanistically, Grab regulates the exocytosis of Tfrc-associated vesicles by activating the GTPase Rab8, which subsequently promotes the recruitment of the exocyst complex and vesicle exocytosis. Our results reveal a critical role for Grab in regulating the Tf cycle and provide new insights into iron homeostasis and erythropoiesis.

Recurrent epiphora after dacryocystorhinostomy surgery: Structural abnormalities identified with dacryocystography and long term outcomes of revision surgery : Success rates of further surgery following failed dacryocystorhinostomy surgery.

BACKGROUND: To investigate the aetiopathology of recurrent epiphora or stickiness after dacryocystorhinostomy (DCR) surgery, identifiable on dacryocystography (DCG), and to assess the success rates of secondary corrective surgeries. METHODS: Consecutive post-DCR DCG images from patients with recurrent symptoms were reviewed between 2012 and 2015. RESULTS: One hundred fifty-nine eyes of 137 patients were evaluated. Fifty-eight DCGs showed normal postoperative findings, 4 an upper/lower canalicular block, 13 a common canalicular block, 31 a completely closed anastomosis, 50 a narrow anastomosis, and 3 an anastomosis draining into a nasal sinus. The most successful corrective procedures for each failure category were: Lester Jones Tube (LJT) for a normal post-operative DCG (17/18 success), Sisler trephination with tubes for upper/lower canalicular block (1/2 success), redo-DCR with tube for common canalicular blockage (5/6 success), redo-DCR +/- tube for completely closed anastomosis (12/16 success), LJT followed by redo-DCR +/- tube for narrow surgical anastomosis (1/1 and 17/27 success respectively), and redo-external-DCR with tube for anastomosis into a nasal sinus (1/1 success). Redo-DCR was ineffective in patients who had good post-DCR anatomical patency (22% success). CONCLUSION: This is the first study to report success rates of redo-DCR surgery according to anatomical findings confirmed by DCG. The outcome flow diagram help clinicians recommend procedures that are most likely to be successful for their patient's specific anatomical abnormality. It also provides a visual tool for the shared decision-making process. Notably, symptomatic patients with a normal DCG post DCR are unlikely to benefit from redo-DCR, with a LJT being the recommended next step.

Prevention and Management of Filler Induced Iatrogenic Stroke of the Eye [Formula: see text].

In the past few decades, minimally-invasive esthetic treatments and the use of injectable Hyaluronic Acid Gels and other filling agents to treat facial esthetics have increased dramatically. Although extremely rare, a filler can cause ocular and orbital ischemia by retrograde flow from the ophthalmic artery when injected in any of the anastomosis of the face. Once filler reaches the central retinal artery, blindness is inevitable, and no treatment is effective. While the risk of blindness happening with any filler injection is rare, the life-altering irreversible consequence of a procedure that was anticipated to be simple and beautifying is a reality that each injector must be prepared for with every injection. The parameters associated with an iatrogenic stroke of the eye are the site of injection, the injection technique, patient characteristics, and the material injected. Understanding the interplay of each of these variables might help us reduce the possibility of blindness during the injection of a soft-tissue cosmetic filler. Here, we explore the causes of Hyaluronic Acid Gels Filler embolic phenomena, review the natural course of the process, and discuss appropriate immediate interventions. We also (1) propose an education plan for injectors and describe how to carry out a focused ophthalmologic examination and procedural activities for a referral to an ophthalmologist, (2) outline steps to prevent emboli during filler injection, and (3) how to manage and support a patient with a sudden loss of vision during or immediately after a Hyaluronic Acid Gels filler treatment.

Impact of Upper Eyelid Surgery on Symptom Severity and Frequency in Benign Essential Blepharospasm.

OBJECTIVE: To assess the impact of periocular surgery, other than orbicularis stripping, on the severity and frequency of blepharospasm symptoms. METHODS: Consecutive patients with benign essential blepharospasm (BEB) who underwent eyelid/eyebrow surgery with the aim of improving symptoms were retrospectively reviewed over a 5-year period. Patients who had completed the Jankovic Rating Scale (JRS) and Blepharospasm Disability Index (BDI) pre- and at least 3 months postoperatively were included. RESULTS: Twenty-four patients were included. JRS scores significantly improved from 7.0 preoperatively to 4.1 postoperatively (p < 0.001), and BDI scores significantly improved from 18.4 preoperatively to 12.7 postoperatively (p < 0.001); the mean percentage improvements were 41% and 30%, respectively. Patients were followed for a median of 24 months postoperatively. CONCLUSION: Periocular surgery significantly reduced BEB symptoms in the majority (83%) of patients by an average of 33% and may therefore be offered for suitable patients. An important minority (17%) of patients experienced symptom worsening.

Inversion modeling of japonica rice canopy chlorophyll content with UAV hyperspectral remote sensing.

Chlorophyll content is an important indicator of the growth status of japonica rice. The objective of this paper is to develop an inversion model that can predict japonica rice chlorophyll content by using hyperspectral image of rice canopy collected with unmanned aerial vehicle (UAV). UAV-based hyperspectral remote sensing can provide timely and cost-effective monitoring of chlorophyll content over a large region. The study was based on hyperspectral data collected at the Shenyang Agricultural College Academician Japonica Rice Experimental Base in 2018 and 2019. In order to extract the salient information embedded in the high-dimensional hyperspectral data, we first perform dimension reduction by using a successive projection algorithm (SPA). The SPA extracts the characteristic hyperspectral bands that are used as input to the inversion model. The characteristic bands extracted by SPA are 410 nm, 481 nm, 533 nm, 702 nm, and 798 nm, respectively. The inversion model is developed by using an extreme learning machine (ELM), the parameters of which are optimized by using particle swarm optimization (PSO). The PSO-ELM algorithm can accurately model the nonlinear relationship between hyperspectral data and chlorophyll content. The model achieves a coefficient of determination R2 = 0.791 and a root mean square error of RMSE = 8.215 mg/L. The model exhibits good predictive ability and can provide data support and model reference for research on nutrient diagnosis of japonica rice.

Amyloid Beta Immunoreactivity in the Retinal Ganglion Cell Layer of the Alzheimer's Eye.

Alzheimer's disease (AD) is the most prevalent form of dementia, accounting for 60-70% of all dementias. AD is often under-diagnosed and recognized only at a later, more advanced stage, and this delay in diagnosis has been suggested as a contributing factor in the numerous unsuccessful AD treatment trials. Although there is no known cure for AD, early diagnosis is important for disease management and care. A hallmark of AD is the deposition of amyloid-ß (Aß)-containing senile neuritic plaques and neurofibrillary tangles composed of hyperphosporylated tau in the brain. However, current in vivo methods to quantify Aß in the brain are invasive, requiring radioactive tracers and positron emission tomography. Toward development of alternative methods to assess AD progression, we focus on the retinal manifestation of AD pathology. The retina is an extension of the central nervous system uniquely accessible to light-based, non-invasive ophthalmic imaging. However, earlier studies in human retina indicate that the literature is divided on the presence of Aß in the AD retina. To help resolve this disparity, this study assessed retinal tissues from neuropathologically confirmed AD cases to determine the regional distribution of Aß in retinal wholemounts and to inform on future retinal image studies targeting Aß. Concurrent post-mortem brain tissues were also collected. Neuropathological cortical assessments including neuritic plaque (NP) scores and cerebral amyloid angiopathy (CAA) were correlated with retinal Aß using immunohistochemistry, confocal microscopy, and quantitative image analysis. Aß load was compared between AD and control (non-AD) eyes. Our results indicate that levels of intracellular and extracellular Aß retinal deposits were significantly higher in AD than controls. Mid-peripheral Aß levels were greater than central retina in both AD and control eyes. In AD retina, higher intracellular Aß was associated with lower NP score, while higher extracellular Aß was associated with higher CAA score. Our data support the feasibility of using the retinal tissue to assess ocular Aß as a surrogate measure of Aß in the brain of individuals with AD. Specifically, mid-peripheral retina possesses more Aß deposition than central retina, and thus may be the optimal location for future in vivo ocular imaging.

Long-Term Outcomes of StopLoss Jones Tubes for Epiphora in Patients With Early or Multiple Loss of Lester Jones Tubes.

PURPOSE: Extrusion is the most common cause of failure in conventional Lester Jones tubes (LJTs). StopLoss Jones tubes (SLJTs) with distal flange are designed to reduce this complication. This study compared the survival of SLJTs with their prior LJTs and control patients with LJTs-only. METHODS: Retrospective review of consecutive LJT or SLJT insertion between January 2014 and December 2016. RESULTS: Twenty-eight eyes of 23 patients had 31 SLJTs. Before their SLJTs, these patients had 116 cumulative failed LJTs. Forty-seven eyes of 34 patients had 59 LJTs only. Fifty-two percent of SLJT group and 18% of LJT-only group had complex medial canthal conditions (p = 0.003). Compared to their previous LJTs, the SLJTs were less likely to extrude (3% SLJT vs. 64% prior LJT, p < 0.0001); there was no statistical difference in rates of sinking in (26% SLJT vs. 13% prior LJT, p = 0.0964). The median survival of LJTs in those who went on to have a SLJT was 3.5 months. SLJT insertion significantly lengthened the median survival to 26 months (p < 0.0001), comparable to the LJT-only group (25.5 months, p = 0.45). While extrusion was also the most common complication in the LJT-only group, this occurred only in 20% of eyes; tube failure from sink-in occurred in 14% of eyes. CONCLUSIONS: SLJTs, in patients prone to multiple or early prior LJT losses, can be used to rescue this group and allow them to regain a similar survival curve to the less complicated LJT-only group. Rates of tube extrusion are significantly reduced with the use of SLJT.

Immunohistochemical analysis of benign and malignant melanocytic lesions of the conjunctiva using double-staining.

OBJECTIVE: To implement a double-staining technique to identify the most sensitive and specific combinations of melanoma antigen recognized by T cells (Melan-A), microphthalmia-associated transcription factor (MITF), human melanoma black 45 (HMB45), and Ki67 aiming to assist in the diagnosis of atypical melanocytic conjunctival lesions that are more prone to malignant progression. METHODS: Eight specimens of conjunctival melanoma and of primary acquired melanosis with moderate to severe atypia were double-immunostained with a combination of a cytoplasmic marker (anti-Melan-A or anti-HMB45), and a nuclear marker (anti-MITF or anti-Ki67). Eight specimens of normal conjunctiva and of conjunctival nevi served as controls. The specimens were processed using 3,3-diaminobenzidine substrate for nuclear stains and the fast-red substrate for cytoplasmic stains. Each slide was analyzed by light microscopy and provided a percent scale and a 0 to 4+ score for each nuclear and cytoplasmic component. RESULTS: Melan-A and MITF were strongly positive markers for all melanocytic cells, whereas Ki67 and HMB45 provided a variable response for identifying potentially proliferative or aggressive cells. HMB45 and MITF proved to be the best combination for differentiating between atypical and benign lesions on a percent scale and a 0 to 4+ scale (p = 0.0004), with the 3 other combinations providing mainly confirmatory diagnostic information (p < 0.05). CONCLUSIONS: Our study used an immunohistochemical double-staining approach to differentiate between atypical and benign melanocytic lesions of the conjunctiva. Our findings should aid in a more complete immunohistopathological diagnosis of conjunctival melanocytic lesions, particularly in diagnostically difficult cases.

Regression of Sebaceous Carcinoma of the Eyelid after a Small Incisional Biopsy: Report of Two Cases.

PURPOSE: To report 2 cases of regression of sebaceous carcinoma of the eyelid after a small incisional biopsy. METHODS: Clinical, imaging, and histopathological findings are presented, with a literature review on regressing ocular tumors. RESULTS: Our first patient was a 79-year-old man who presented with a 10-month history of progressive left upper eyelid ptosis caused by an eyelid tumor with orbital involvement and confirmed on magnetic resonance imaging. Our second patient was a 70-year-old woman who presented with ptosis with a left upper eyelid mass. Both patients underwent a small incisional biopsy of their lesion. The histopathological diagnoses in both cases were consistent with sebaceous carcinoma. Both patients refused exenteration. Follow-up clinical examination and imaging disclosed total regression of the ptosis and of the neoplasm with no sign of recurrence in both patients over a 4-year period for Case 1 and a 7-year period for Case 2. CONCLUSION: Regression following incisional biopsy of basal cell, squamous cell, and Merkel cell carcinoma, including of the eyelid, is well documented. To the best of our knowledge, our 2 cases of sebaceous carcinoma are the first to be reported with total involution clinically and on imaging of the tumor following partial incisional biopsy.

Pathological Features and Clinical Course in Patients With Recurrent or Malignant Orbital Solitary Fibrous Tumor/Hemangiopericytoma.

PURPOSE: A risk assessment score for metastasis based on age, tumor size, and mitotic figures has been suggested for nonorbital solitary fibrous tumor (SFT)/hemangiopericytoma. The authors herein examine the clinicopathological features of recurrent and metastatic orbital SFT and evaluate the existing risk assessment score for orbital SFT. METHODS: The American Society of Ophthalmic Plastic and Reconstructive Surgery Oncology Database was queried for patients with recurrent or malignant orbital hemangiopericytoma/SFT. The medical records were reviewed for clinical and pathologic findings, treatments, and outcomes. RESULTS: Eight patients from 3 institutions were identified with recurrent orbital hemangiopericytoma/SFT. Median age at diagnosis was 59 years, and 4 patients were women. The mean size of tumor was 2.1 ± 1.1 cm. All patients were initially treated with surgery and experienced local recurrence after a median of 4 (range 0.5-10) years. Five patients were treated with orbital radiation. Two patients also developed distant metastases and eventually died of their disease. Median Ki-67 was 5% (range 1-65%) and 5 mitotic figures/10 high-power fields (range 2-30). The previously described risk stratification model for nonorbital SFT did not correlate with the propensity to develop metastases in this cohort; however, both patients with distant metastasis had > 4 mitotic figures /10 high-power fields. CONCLUSIONS: In this cohort of recurrent orbital hemangiopericytoma/SFT, median time to recurrence was 4 years underscoring the importance of careful continued follow-up. The current risk stratification models have limited use for orbital lesions, mostly due to the fact that orbital SFTs are smaller than even the smallest size criteria in this risk assessment model.

Correlating the Expression and Functional Activity of ABCA4 Disease Variants With the Phenotype of Patients With Stargardt Disease.

Purpose: Stargardt disease (STGD1), the most common early-onset recessive macular degeneration, is caused by mutations in the gene encoding the ATP-binding cassette transporter ABCA4. Although extensive genetic studies have identified more than 1000 mutations that cause STGD1 and related ABCA4-associated diseases, few studies have investigated the extent to which mutations affect the biochemical properties of ABCA4. The purpose of this study was to correlate the expression and functional activities of missense mutations in ABCA4 identified in a cohort of Canadian patients with their clinical phenotype. Methods: Eleven patients from British Columbia were diagnosed with STGD1. The exons and exon-intron boundaries were sequenced to identify potential pathologic mutations in ABCA4. Missense mutations were expressed in HEK293T cells and their level of expression, retinoid substrate binding properties, and ATPase activities were measured and correlated with the phenotype of the STGD1 patients. Results: Of the 11 STGD1 patients analyzed, 7 patients had two mutations in ABCA4, 3 patients had one detected mutation, and 1 patient had no mutations in the exons and flanking regions. Included in this cohort of patients was a severely affected 11-year-old child who was homozygous for the novel p.Ala1794Pro mutation. Expression and functional analysis of this variant and other disease-associated variants compared favorably with the phenotypes of this cohort of STGD1 patients. Conclusions: Although many factors contribute to the phenotype of STGD1 patients, the expression and residual activity of ABCA4 mutants play a major role in determining the disease severity of STGD1 patients.

Bilateral carotid cavernous sinus fistula: a case report and review of the literature.

Carotid cavernous fistula (CCF) is an abnormal vascular shunt from the carotid artery to the cavernous sinus. They are commonly classified based on hemodynamics, etiology or anatomically. Hemodynamic classification refers to whether the fistula is high or low flow. Etiology is commonly secondary to trauma or can occur spontaneously in the setting of aneurysm or medical conditions predisposing to arterial wall defects. Bilateral carotid cavernous fistulas are rare. We present a case of bilateral CCF secondary to trauma. Ophthalmology was urgently consulted to assess the patient in the intensive care unit (ICU) for red eye. The patient was found to have decreased vision, increased intraocular pressure, an afferent pupillary defect, proptosis, chemosis, and ophthalmoplegia. Subsequent neuro-imaging confirmed a bilateral CCF. The patient underwent two endovascular embolization procedures. Trauma is the most common cause of CCF and accounts for up to 75% of cases. Most common signs of CCF depend on whether it is high or low flow. High-flow CCF may present with chemosis, proptosis, cranial nerve palsy, increased intraocular pressure, diplopia, and decreased vision. Cerebral angiography is the gold standard diagnostic modality. First-line treatment consists of endovascular embolization with either a metallic coil, endovascular balloon or embolic agent. It is unclear in the literature if bilateral cases are more difficult to treat or have a different prognosis. Our patient required two endovascular procedures suggesting that endovascular intervention may have reduced efficacy in bilateral cases.

Graft-free Ahmed valve implantation through a 6 mm scleral tunnel.

OBJECTIVE: To evaluate the safety, efficacy, and cost savings of Ahmed glaucoma valve (AGV) tube implantation through a 6-mm scleral tunnel (graft-free technique). DESIGN: Retrospective cohort study. METHODS: The 95% confidence interval for fractional survival at any particular time was calculated using the Kaplan-Meier method. Failure was defined as (i) intraocular pressure (IOP) <6 mm Hg or >21 mm Hg or <20% IOP reduction on 2 consecutive visits after 12 months; (ii) additional surgical intervention to control IOP; or (iii) no light perception. RESULTS: Eighty-four eyes were implanted with graft-free AGV with a success rate of 83% at 2 years. Fourteen eyes failed: 4 no light perception, 1 hypotony, 1 elevated IOP, 5 secondary glaucoma surgeries, 2 AGV extractions, and 1 corneal decompensation. The rate of transient hypotony peaked at 33% on postoperative day 1, reducing to 4% by 6 weeks. Transient flat anterior chamber developed in 8% of eyes. Eight percent of eyes experienced a hypertensive phase (mean IOP = 28 mm Hg). Preoperatively, eyes received 3.8 units of glaucoma medication on average. Postoperatively, 8 eyes required no medication for IOP control. Of the eyes requiring postoperative glaucoma medication, 33% restarted during week 4; an additional 25% of eyes were restarted 6 weeks postoperatively. By 6 months, eyes were on average using 2.2 units of glaucoma medication. Hyphema (18%) was the most common early postoperative complication. The rates of conjunctival and scleral erosion by 2 years were 2.4% and 0%, respectively. Within our institution, excluding valve cost, there was a 39%-45% ($192-$376) cost reduction with the graft-free technique. CONCLUSIONS: The safety and efficacy of a 6-mm scleral tunnel is comparable to conventional scleral-graft method.