Primary retinal tauopathy: A tauopathy with a distinct molecular pattern.

BACKGROUND: Phosphorylated tau (p-tau) accumulation, a hallmark of Alzheimer's disease (AD), can also be found in the retina. However, it is uncertain whether it is linked to AD or another tauopathy. METHODS: Retinas from 164 individuals, with and without AD, were analyzed for p-tau accumulation and its relationship with age, dementia, and vision impairment. RESULTS: Retinal p-tau pathology showed a consistent pattern with four stages and a molecular composition distinct from that of cerebral tauopathies. The stage of retinal p-tau pathology correlated with age (r = 0.176, P = 0.024) and was associated with AD (odds ratio [OR] 3.193; P = 0.001), and inflammation (OR = 2.605; P = 0.001). Vision impairment was associated with underlying eye diseases (ß = 0.292; P = 0.001) and the stage of retinal p-tau pathology (ß = 0.192; P = 0.030) in a linear regression model. CONCLUSIONS: The results show the presence of a primary retinal tauopathy that is distinct from cerebral tauopathies.

Role of immune checkpoint inhibitors in metastatic uveal melanoma: a single-center retrospective cohort study.

BACKGROUND: Uveal melanoma is an orphan malignancy with very limited data on treatment options in metastatic setting. METHODS: In this single-center retrospective study, we describe real-world epidemiological and survival data on 121 metastatic uveal melanoma (MUM) patients registered in our institution. As a large tertiary referral center, almost 30% of all diagnoses in the Flemish region of Belgium were covered. Primarily, we determined whether introduction of immune checkpoint inhibitors (ICI) led to improved overall survival (OS) in MUM patients. Secondarily, response rates to ICI were assessed and we evaluated whether first-line ICI could be a valid alternative to liver-directed therapy (LDT) in liver-only disease. RESULTS: The initially perceived 10.8 months survival benefit from treatment with ICI disappeared after correction for immortality bias. By analyzing treatment type as time-varying covariate on OS, no significant benefit of ICI over other systemic therapies (HR = 0.771) or best supportive care (BSC) (HR = 0.780) was found. Also comparison of the pre-ICI versus ICI era showed no OS improvement after introduction of ICI in our center (p = 0.7994). Only liver-directed and local oligometastatic approaches were associated with a lower chance of mortality when compared to ICI (p = 0.0025), other systemic therapies (p = 0.0001) and BSC (p = 0.0003), yet without correction for selection bias. We reported overall response rates on ICI ranging from 8-15% and we found some support for neoadjuvant strategies with ICI resulting in remission or downsizing, allowing oligometastatic approaches later on. In first-line liver-only disease, median real-world progression-free survival and OS did not significantly differ between patients treated with LDT or ICI upfront (p = 0.2930 and p = 0.5461 respectively). CONCLUSION: Although we documented responses to ICI, our analyses do not demonstrate an OS benefit of ICI over alternative treatment strategies for MUM. However, local treatment options, whether liver-directed or for oligometastatic disease, may be beneficial and should be considered.

Delayed orbital fibrosing inflammation from a retained crayon.

A 39-year-old woman presented with sudden onset of double vision, right upper eyelid swelling and ptosis, and orbital pain. Imaging revealed an irregular mass of the upper right orbit with central non-enhancing areas. Upon inquiry, the patient recalled an intraorbital trauma with a crayon in her childhood, 35 years ago. Via translid anterior orbitotomy, remnants of a blue crayon embedded in an orbital fat mass were removed. Histopathology showed scavenger reaction of macrophages and sclerosis. Energy-dispersive X-ray spectroscopy revealed the presence of silicate particles. Repeated courses of corticosteroids were given. The patient deteriorated with reduced vision and frozen globe owing to severe orbital fibrosis of the entire orbit.

Clinical presentation, pathological features and natural course of metastatic uveal melanoma, an orphan and commonly fatal disease.

BACKGROUND: Uveal melanoma (UM) is a rare disease characterized by an unpredictable course and a variable outcome. We assessed the natural course of patients with metastatic uveal melanoma (MUM). METHODS: Data from 76 patients with MUM who were treated in Leuven between 1957 and 2008 were examined retrospectively. Statistical analysis involved the nonparametric, Kaplan-Meier and log rank tests. RESULTS: The median age at diagnosis of UM was 58 years (range 30-94). Synchronous metastases were found in 9% of the cases; all other patients had metachronous disease after a median interval of 40 months (range 7-420). Statistical analysis failed to identify factors related to the time until metastatic spread with the exception of a significant negative correlation with age at UM diagnosis (Spearman: ρ = -0.4, p < 0.001). The most frequent metastatic site was the liver (in 96% of the patients). The median time from diagnosis of UM until death was 47 months (range 2-236) and only 5 months in patients with metastatic disease (range 1-128). CONCLUSIONS: MUM is an orphan disease. Advances in MUM can only be achieved by the networking of sites interested in this rare tumor type, with systematic collection of data and tumor tissue for improving our understanding of the molecular biology of this disease.

The Immunoarchitecture of Human Extraocular Muscles.

Purpose: The purpose of this study was to describe the immunoarchitecture of normal extraocular muscles (EOMs) in terms of presence, distribution, and organization of various immune cells. Methods: We performed unilateral orbital exenterations in six fresh human cadavers from elderly patients, followed by dissection of the medial, lateral, superior and inferior rectus, superior and inferior oblique, and superior palpebral levator muscle in their entirety. We further cross sectioned each EOM in an anterior, central, and posterior third. After immunohistochemical staining for CD3, CD8, CD20, CD138, CD68, and podoplanin, quantitative analysis was performed. Results: We found all EOMs (rectus, oblique, and levator muscles) to harbor both T- and B-lymphocytes, with a B-lymphocyte dominance and an absence of plasma cells. The highest prevalence of immune cells was seen in the muscle bellies, with, on average, 488 ± 63 CD3+ T-lymphocytes and 44 ± 110 CD20+ B-lymphocytes per mm2, and significant differences from the anterior (T-lymphocytes) and posterior (T- and B-lymphocytes) thirds. T- and B-lymphocytes were primarily organized in hotspots in the vicinity of blood vessels. In addition, a small resident population of macrophages scattered throughout the specimens was detected. No lymphatic vessels were found in any of the EOMs. Conclusions: These findings can serve as a reference dataset in the assessment of EOM biopsies in the diagnostic process of inflammatory orbital and systemic disorders. Moreover, from a regenerative perspective, our results highlight the importance of taking into account the presence of a resident immune cell population when studying the host immune response on transplanted tissues or engineered constructs.

Analysis of Vitreous Samples by the Cellient® Automated Cell Block System: A Six-year Review of Specimens in a Uveitis Population.

PURPOSE: To further evaluate the value of a standardized method to analyze vitreous samples using the Cellient® automated cell block system in the diagnosis of unsolved uveitis. METHODS: Six hundred sixty-four pure vitreous samples obtained from patients with unsolved uveitis between March 2012 and May 2018 at University Hospitals Leuven, fixed in PreservCyt® and processed by the Cellient tissue processor, were included in the study. RESULTS: n 86.3% of the cases, sufficient material was found for diagnosis. A diagnosis of acute inflammation was made in 20.2% of the cases. In 34.0% of the cases, the diagnosis was chronic active inflammation; in 26.5%, low-grade inflammation; and in 5.6%, a malignant process. CONCLUSION: Our standardized protocol can be used to diagnose endophthalmitis, lymphoma, granulomatous disease, inactive and storage disease, and metastatic infiltration. Cellient analysis of vitreous specimens had a diagnostic yield of 86.3% in unsolved uveitis cases.

Pseudoxanthoma elasticum: clinical, histologic, and genetic studies--a report of two sisters.

CASE 1: A 24-year-old black woman was referred to our clinic in September 1999 by the department of dermatology. She was referred to confirm the diagnosis of pseudoxanthoma elasticum (PXE). Her medical history was normal. Dermatologic examination revealed confluent papules that gave the skin a "plucked chicken" appearance on the flexural surfaces in the neck, axillae, clavicle, thigh, and periumbilical area (Figure 1). The patient stated that the changes in her skin had begun in the periumbilical region at about 5 years of age and had since been slowly progressive. Physical examination showed brownish black pigmentation on the left side of the face, left eyelid, and left sclera, which was diagnosed as Nevus of Ota (Figure 2). Her visual acuity was 20/10 in both eyes, with no afferent pupillary defect. Intraocular pressure in both eyes was normal. Slit lamp examination showed no abnormalities. Findings from fundus examination revealed angioid streaks that formed an incomplete ring around the optic disc and anteriorly radiated toward the equator of the globe, multiple calcified drusen-like structures, and "peau d'orange" changes. Skin biopsy (skin tissue from the neck) was taken and the diagnosis of PXE was confirmed. Histopathologic findings revealed calcification of the elastic fibers and abnormalities of the collagen (Figure 3). The patient was not known to have sickle cell anemia or sickle cell trait, and her blood pressure levels had never elevated. Other systemic causes of angioid streaks were excluded by findings from extensive laboratory examination. Her relatives were asked to come in for examination but lived far away. One of the patient's sisters lived in Kinshasa, Africa, however, and is presented in case 2. CASE 2: The 27-year-old sister of the previous patient was examined on April 19, 2000. At examination, she was found to have PXE. Her medical history was significant for systemic hypertension since 1998 and genital hemorrhage. She underwent an ablation of a cyst of her left ovary in 1988. Her ocular history was unremarkable. On physical examination, raised (yellow) papillary lesions, typical of pseudoxanthoma, were found on the neck, axillae, clavicle, thigh, and periumbilical regions. External and anterior segment examinations (of her eyes) were unremarkable. She was found to have a best-corrected visual acuity of 20/10 in both eyes. Intraocular pressure was normal. Funduscopy revealed bilateral angioid streaks, crystalline bodies, and "peau d'orange," but to a lesser extent than in her sister. In both cases, after informed consent, peripheral blood cells were taken and sent for extraction of DNA. Analysis was performed but could not demonstrate the known gene defects of PXE.

Endogenous Endophthalmitis Caused by Isolated Listeria Monocytogenes Infection.

Purpose: The purpose of this report is to present an extremely rare case of endogenous Listeria monocytogenes endophthalmitis.Methods: A 72-year-old woman was diagnosed with endogenous endophthalmitis. Listeria monocytogenes was identified by culture of aqueous humor. Multiple investigations could not reveal any source of infection. An overview of other published cases is presented and a standardized treatment protocol is suggested.Results: Treatment consisted of topical therapy with antibiotics, corticosteroids, cycloplegics, and intraocular pressure-lowering agents, four intravitreal injections of vancomycin, an anterior chamber washout, intravenous amoxicillin, and eventually a pars plana vitrectomy. The inflammation subsided and the patient was discharged with a best-corrected visual acuity of 20/40.Conclusion: Our study emphasizes the importance of adequate microbiological testing and initiating appropriate treatment early in the management of endogenous endophthalmitis.

Investigation of the effectiveness of a new portable 'cryopen' probe for cryotherapy (CryoTreq®).

BACKGROUND: To test the effectiveness of a new, innovative, single-use handheld 'cryopen' (CryoTreq®), which has been developed and marketed by Vitreq. METHODS: Animal testing of cryopexy using the Cryotreq ® in two pig eyes was performed. RESULTS: The biological effects of cryopexy were observed. CONCLUSIONS: During the surgery, the handheld device was comfortable to use and offers the surgeon more freedom to move. The cryotherapy caused severe atrophy and thinning of retinal layers, pigment epithelium and choroidea in a relatively uniform thickness. The cryopen is effective and offers advantages over non-handheld cryotherapy devices.

Preoperative nonsteroidal anti-inflammatory drug or steroid and outcomes after trabeculectomy: a randomized controlled trial.

PURPOSE: To investigate the benefit of preoperative treatment with either topical nonsteroidal anti-inflammatory drug (NSAID) or steroid in terms of clinical outcomes following trabeculectomy. DESIGN: Prospective, randomized placebo-controlled trial. PARTICIPANTS: Sixty-one patients. METHODS: Between July 2005 and October 2007, 61 consecutive medically uncontrolled glaucoma patients scheduled for first-time trabeculectomy were randomized to 1 of 3 study topical medication groups: nonsteroidal anti-inflammatory drugs (ketorolac), steroids (fluorometholone), or placebo (artificial tears). Patients instilled 1 drop 4 times daily for 1 month before the procedure and were examined on days 1 and 2, at weeks 1, 2, and 4, and at months 3, 6, 12, 18, and 24 after trabeculectomy. MAIN OUTCOME MEASURES: Incidence of postoperative surgical or medical interventions (needling, laser suture lysis, needling revision, and intraocular pressure [IOP]-lowering medication). RESULTS: Fifty-four patients (54 eyes) were entered for analysis. The mean number of preoperative medications was 2.3+/-0.9. The mean baseline IOP was 21.0+/-6.0 mmHg. The mean postoperative target IOP was 16.5+/-1.8 mmHg. The mean follow-up was 23.6+/-4.0 months. The percentage of patients requiring needling within the first year was 41% in the placebo group, 6% in the NSAID, and 5% in the steroid group (P = 0.006). The percentage of patients requiring IOP-lowering medication to reach the target IOP at 1 year was 24% in the placebo group, 18% in the NSAID group, and 0% in the steroid group (P = 0.054 overall; P = 0.038 for steroids vs. others). The log-rank test showed a significant (P = 0.019) difference in medication-free survival curves between the different groups. More specifically, patients in the steroid group needed significantly less medication over the total follow-up (P = 0.007). CONCLUSIONS: Topical ketorolac or fluorometholone for 1 month before surgery was associated with improved trabeculectomy outcomes in terms of likelihood of postoperative needling. In the steroid group, there was a significantly reduced need for additional postoperative IOP-lowering medication compared with the other groups. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

How a Devastating Case of Acanthamoeba Sclerokeratitis Ended up with Serious Systemic Sequelae.

A 35-year old soft contact lens wearer with a proven bilateral Acanthamoeba keratitis developed a nodular scleritis. Based on the stepladder approach described by Iovieno et al. [Ophthalmology. 2014 Dec;121(12):2340-7], nonsteroidal anti-inflammatory drugs, methylprednisolone, and later azathioprine were added to the antiamoebic treatment. Unfortunately, there was further deterioration and an endophthalmitis developed. Unbearable pain and concerns of spread to the brain urged an enucleation. Histopathological examination confirmed Acanthamoeba cysts in the cornea, sclera, retina, choroid, and vitreous body. As a side effect of the immunosuppressive treatment, the patient developed myopathy, pulmonary aspergillosis, and an avascular necrosis of the hip. Scleritis is a devastating complication of Acanthamoeba keratitis with a poor prognosis and a high enucleation rate. Acanthamoeba sclerokeratitis is, due to cyst-free biopsies, mostly assigned to an immune-mediated mechanism, justifying the use of immunosuppressive treatment. Scleritis in our case contributed to the extracorneal spread of Acanthamoeba. Our case is the first documented extracorneal spread of Acanthamoeba without previous surgery. Extracorneal spread of Acanthamoeba should be considered, even in the case of false-negative biopsies. We strongly recommend serial sections of the retrieved scleral specimen in case of negative histopathological examination to exclude an infection. Even when an immune-mediated scleritis is suspected, systemic immunosuppressive treatment should always be used with the greatest caution. Awareness of the side effects and monitoring by an experienced physician is mandatory.

Primary vitreous cysts.

Objective: To report two cases of vitreous cysts with discussion of their pathophysiology and management. Methods: Clinical examination with fundus photography, ultrasound and optical coherence tomography. Histopathology was performed in the first case. Results: The first case illustrates a pigmented, free-floating cyst, which was removed during a 27-gauge vitrectomy. The histopathology shows a single layer of pigmented epithelium and confirms the previously reported presence of a PAS-positive basement membrane. The second case shows a sessile, non-pigmented cyst associated with significant anisometropia. Conclusion: Primary vitreous cysts are rare and can have a wide range in their clinical aspect. This likely reflects whether they originate either from the pigment epithelium or the primary hyaloidal system. The management of vitreous cysts is mostly conservative, but pars plana vitrectomy can be used safely if the symptoms are debilitating.

Ectopic Tubular Papillary Apocrine Adenoma on the Eyelid: A Case Report of Misleading Clinical Presentation and Location.

We report the case of a 38-year-old patient with a tubular apocrine adenoma with papillary differentiation. The clinician was challenged in her diagnosis by the initially misleading appearance and ectopic location. Histopathological findings and immunohistochemistry delivered conclusive proof for the correct diagnosis. Therefore, it is important for the ophthalmologist to request histopathological analysis to diagnose and differentiate from malignancy. A complete local excision is recommended to prevent recurrence.

Orbital tumor associated with a microphthalmic eye and colobomatous cleft: Pilocytic astrocytoma (glioma) or massive retinal gliosis.

A 11-year-old boy with congenital microphthalmos of the right eye presented with gradual protrusion of his ocular prosthesis. MRI showed an orbital mass adjacent to the microphthalmic eye. After removal of the eye and the orbital soft tissue mass a gliotic mass, resembling a pilocytic astrocytoma WHO grade 1 (glioma) was diagnosed. Through a colobomatous cleft in the eye the tumour spread in the orbit. There were no clinical signs of neurofibromatosis 1. This case showed a very rare association between a microphthalmic and colobomatous eye and pilocytic astrocytoma, grade 1. However a far advanced and infiltrative massive retinal gliosis cannot be definitively excluded as differential diagnosis.

Sub-inner limiting membrane haemorrhage: causes and treatment with vitrectomy.

BACKGROUND: Preretinal haemorrhages usually occur at the interface between the posterior hyaloid and inner limiting membrane (ILM). Less frequently, they are located between the ILM and the retinal nerve fibre layer. Sub-ILM haemorrhages have been described in a variety of clinical settings and often lead to severe visual impairment because of their predilection for the macular region. METHODS: A consecutive series of five cases in which sub-ILM haemorrhages were clinically suspected and confirmed during early vitrectomy with ILM peeling were reviewed. RESULTS: Sub-ILM haemorrhages were clinically suspected in five patients (median age 32 years) based on the fundoscopic appearance and clinical setting of Terson's syndrome (n = 1), Valsalva retinopathy (n = 2), blood dyscrasia (n = 1) and blunt facial trauma (n = 1). Vision was severely impaired in all patients (to hand movements in four of five) because of a premacular location of the haemorrhage. All patients were treated with early pars plana vitrectomy because of insufficient spontaneous visual recovery after a median of 6 weeks. The sub-ILM location of the haemorrhage could be confirmed intraoperatively in all patients by biostaining of the membrane overlying the haemorrhage. ILM peeling and aspiration of the haemorrhage resulted in excellent visual recovery in all patients. No procedure-related complications were observed. CONCLUSIONS: Sub-ILM haemorrhages often occur in a specific clinical context and can lead to severe visual impairment in young patients. Given the excellent results and low complication rates, timely surgical intervention is justified when spontaneous resorption is insufficient.

Precipitation of calcium salts on a hydrophilic acrylic intraocular lens after a vitreous hemorrhage: case report and histopathologic correlation.

We describe the formation of calcium phosphate deposits on the external anterior surface of a single-piece foldable 26% hydrophilic acrylic intraocular lens (IOL) after vitreal bleeding. The IOL was explanted 20 months after uneventful phacotrabeculectomy because opacification was causing significant visual disturbance. Light microscopy and Raman spectroscopy of the explanted IOL showed that the opacification consisted of calcium phosphate on the IOL surface.

A second decorin frame shift mutation in a family with congenital stromal corneal dystrophy.

PURPOSE: To identify the genetic defect in a Belgian family with congenital stromal corneal dystrophy. DESIGN: Case report and result of deoxyribonucleic acid (DNA) analyses. METHODS: DNA sequencing of polymerase chain reaction (PCR) products generated from amplification of exons and adjacent introns of the decorin gene. RESULTS: The family consisted of a mother and her son, both suffering from congenital stromal corneal dystrophy. In both individuals, a single base pair deletion (c.941delC) in the coding sequence of the decorin gene was demonstrated, predicting a C-terminal truncation of the decorin protein (p.Pro314fsX14). CONCLUSION: This is the second family with congenital stromal corneal dystrophy of the cornea in which a frame shift mutation in the decorin gene has been detected. Both in this family and in a previously reported Norwegian family, a decorin protein missing the 33 C-terminal amino acids is predicted. This observation strongly supports a role for decorin in the pathogenesis of this disorder.

The Conjunctiva in Normal Tension Glaucoma Patients is Thinner Than in Primary Open-Angle Glaucoma Patients: A Comparative Histologic Study.

PURPOSE: To compare histologically the thickness of conjunctival specimens of normal tension glaucoma (NTG) patients with primary open-angle glaucoma (POAG) patients. MATERIALS AND METHODS: In this prospective study, 54 patients scheduled for trabeculectomy were categorized into NTG and POAG based on their maximum untreated intraocular pressure at any time (IOPmax) as measured by Goldmann applanation tonometry. Sixteen patients with NTG (IOPmax≤21 mm Hg) and 36 patients with high tension POAG (IOPmax>21 mm Hg) were included in the study. Biopsies were taken from the superior bulbar conjunctiva during trabeculectomy. The specimens were fixed in formalin, embedded in methacrylate, histologically sectioned, stained with toluidine blue, and analyzed with a light microscope. The stromal conjunctival thickness (CT) was measured in a standardized way and compared between the 2 groups. Intergroup comparisons were performed using the Mann-Whitney U test for continuous variables and the Fisher exact test for categorical variables. The correlation between the central cornea thickness (CCT) and the CT was investigated by the Spearman test. RESULTS: The stromal CT was significantly thinner in NTG compared with POAG (64±31 vs. 103±44 µm, respectively; P=0.002). Stromal CT of the whole group was positively correlated with IOPmax (r=0.41; P=0.002; 95% confidence interval, 0.15-0.62) but not with central cornea thickness (r=-0.005; P=0.97; 95% confidence interval, -0.28 to 0.27). CONCLUSIONS: The conjunctiva in patients with NTG was thinner than in POAG patients. This finding is an additional feature in the pattern of thinner ocular structures in patients with NTG.

Trypan blue staining of epiretinal membranes in proliferative vitreoretinopathy.

OBJECTIVE: To determine whether trypan blue staining facilitates epiretinal membrane (ERM) removal in proliferative vitreoretinopathy. METHODS: In 10 patients undergoing vitrectomy for proliferative vitreoretinopathy, ERM peeling was performed without staining the tissue, until no additional ERMs were clearly visible. Then, after a fluid-air exchange, 0.06% trypan blue solution was applied onto the retinal surface. After 1 minute, all excess dye was removed and, after an air-fluid exchange, ERM peeling was completed. Excised ERM specimens were analyzed by transmission electron microscopy. MAIN OUTCOME MEASURES: For each patient, the efficacy of trypan blue staining of ERMs during surgery was scored. RESULTS: In all patients, intraoperative staining of ERMs with trypan blue was found to be a useful adjunct, since the dye consistently improved direct visualization and delineation of ERMs and facilitated ERM removal. A clear contrast was created between the stained ERMs and the nonstaining, underlying retina. Electron microscopy showed that only ERM tissue was removed. No adverse reactions related to the use of the dye were observed up to 3 months after surgery. CONCLUSIONS: Trypan blue may be an important new tool in the surgical management of proliferative vitreoretinopathy, since it may allow a more complete and safer ERM removal.