DYSFUNCTIONAL AUTONOMIC REGULATION OF THE CHOROID IN CENTRAL SEROUS CHORIORETINOPATHY.

PURPOSE: To study the effect of changing perfusion pressures on retinal and choroidal structure in central serous chorioretinopathy (CSC). METHODS: This prospective observational case series included seven healthy volunteers (14 eyes) and seven patients (14 eyes) with CSC. Each patient underwent spectral domain optical coherence tomography with enhanced depth imaging in the upright (sitting) and supine positions. Image segmentation focused on central macular thickness, subretinal fluid, total macular volume, choroidal thickness, and choriocapillaris thickness. Blood pressure and heart rate were measured in the upright and supine positions. RESULTS: Choriocapillaris thickness was thicker in CSC participants (34.23 µm; range, 30.9-36.5 µm) compared with healthy controls (13.96 µm; range, 7.15-23.87 µm) (P ≤ 0.001). The choroid was similarly thicker in CSC participants (371.4 µm; range, 200.2-459.4 µm) compared with healthy controls (231.4 µm; range 161.8-287.5 µm) (P ≤ 0.001). Choroidal thickness increased in patients with CSC when transitioning from upright (371.4 µm) to supine (377.8 µm) (P ≤ 0.01). By contrast, there was an 11.97% decrease in choroid thickness in normal controls when transitioning from upright (231.4 µm) to supine (203.9 µm). There were no significant hemodynamic changes. CONCLUSION: We demonstrated that choroidal thickness increased in response to increased perfusion pressures in patients with CSC and not in normal controls. These findings likely represent an autonomic dysregulation of choroidal blood flow in patients with CSC.

OCULAR HYPERTENSION AFTER INTRAVITREAL DEXAMETHASONE (OZURDEX) SUSTAINED-RELEASE IMPLANT.

PURPOSE: To evaluate ocular hypertension (OHT) after Ozurdex injection to determine the incidence of OHT, therapy for OHT, and any associative factors such as diagnosis, underlying glaucoma and therapy, or sequential Ozurdex injection(s). METHODS: Retrospective consecutive case series with patients receiving one or more intravitreal Ozurdex implantations at a tertiary care academic center. Ocular hypertension was defined as a single measurement of ≥30 mmHg or an increase of ≥10 mmHg from baseline. RESULTS: Ninety-four injections in 52 patients (59 eyes) were reviewed. Forty eyes received a single injection, and 19 eyes received multiple injections. Ocular hypertension developed in 14 patients (26.9%). Thirteen patients (25%) had preexisting glaucoma or suspicion of glaucoma, and 6 of these developed OHT. Glaucoma eye drops were initiated after 13 injections (13.8%). Invasive surgery for glaucoma was required in 3 patients (3.2%): all had glaucoma or suspicion of glaucoma (one case was related to neovascular glaucoma and unlikely related to steroid response after Ozurdex). There was no difference in relative intraocular pressure increase (i.e., difference between final follow-up or subsequent intravitreal injection vs. baseline) between single versus multiple Ozurdex injections (P = 0.883). CONCLUSION: Patients (26.9%) who received Ozurdex developed OHT. Glaucoma or glaucoma-suspicion factors were present in all patients who required invasive surgery for glaucoma. A greater proportion of patients who received multiple injections had an intraocular pressure elevation, but the relative intraocular pressure increase was not significant.

Management of Pediatric Aphakic Glaucoma With Vitrectomy and Tube Shunts.

PURPOSE: To review the impact of vitrectomy and tube shunts on mean intraocular pressure (IOP) and number of glaucoma medications in pediatric aphakic glaucoma. METHODS: A retrospective review of pediatric patients who underwent combined vitrectomy and glaucoma tube shunt surgery for aphakic glaucoma was conducted. Inclusion criteria were: age 18 years or younger, diagnosis of aphakic glaucoma, preoperative IOP data, and postoperative IOP data for at least 6 months. Mean IOP lowering at 1 year, number of glaucoma medications at 1 year, and surgical complications, including tube occlusion in the postoperative period, were noted. RESULTS: The mean ± standard deviation preoperative IOP was 33.9 ± 10.6 mm Hg (range: 18 to 57 mm Hg) with a mean of three topical IOP-lowering medications. A total of 5 (36%) Ahmed and 9 (64%) Baerveldt tube shunts were placed. One of the Baerveldt tube shunt procedures was combined with revision of a traumatically dislocated tube. The mean IOP at 12 months postoperatively was 16.6 ± 5.8 mm Hg (range: 6 to 28 mm Hg; P < .01, t = 3.74, df = 13) with a mean of 2.3 glaucoma medications. There were no cases of tube occlusion, corneal decompensation, endophthalmitis, or retinal detachment over the 12 months of follow-up. CONCLUSIONS: Combined vitrectomy and placement of a glaucoma tube shunt can be safe and effective in lowering IOP based on mean IOP values and number of glaucoma medications at 1 year. [J Pediatr Ophthalmol Strabismus. 2016;53(6):339-343.].

TREATMENT OF RETINOPATHY AND MACULAR EDEMA SECONDARY TO A CAROTID-CAVERNOUS FISTULA.

PURPOSE: To present a case report on a patient with retinal complications from a carotid-cavernous fistula. METHODS: Observational case report. RESULTS: A 26-year-old patient sustained head trauma following a motorcycle accident. Examination and retinal imaging demonstrated a venous stasis retinopathy with cystoid macular edema. The edema resolved with aflibercept, but not with bevacizumab. CONCLUSION: The patient was diagnosed with venous stasis retinopathy secondary to carotid-cavernous fistula. Pathologic findings completely resolved with appropriate management.

Blurry vision after orbital decompression surgery.

Pathologic myopia may be associated with abnormal vitreomacular adhesions that can portend a higher risk of retinal detachment. The authors report a case of rhegmatogenous retinal detachment with a complex macular tear after orbital decompression surgery in a patient with pathologic myopia. This case highlights the importance of retinal detachment in the setting of orbital decompression.

Wiley Post, around the world with no stereopsis.

In 1933, famed aviator Wiley Post (1898-1935) was the first pilot to fly around the world solo. In addition, during one of his many stratospheric flights, he discovered the jet stream. What makes his accomplishments even more remarkable is that he did this monocularly, having lost his left eye from traumatic endophthalmitis following an oil rig accident. He underwent a period of self-imposed visual training to maximize his depth perception, and then accomplished what no one had before.

Genetic modulation of horizontal cell number in the mouse retina.

Neuronal populations display conspicuous variability in their size among individuals, but the genetic sources of this variation are largely undefined. We demonstrate a large and highly heritable variation in neuron number within the mouse retina, affecting a critical population of interneurons, the horizontal cells. Variation in the size of this population maps to the distal end of chromosome (Chr) 13, a region homologous to human Chr 5q11.1-11.2. This region contains two genes known to modulate retinal cell number. Using conditional knock-out mice, we demonstrate that one of these genes, the LIM homeodomain gene Islet-1 (Isl1), plays a role in regulating horizontal cell number. Genetic differences in Isl1 expression are high during the period of horizontal cell production, and cis-regulation of Isl1 expression within the retina is demonstrated directly. We identify a single nucleotide polymorphism in the 5' UTR of Isl1 that creates an E-box sequence as a candidate causal variant contributing to this variation in horizontal cell number.

The LIM-homeobox gene Islet-1 is required for the development of restricted forebrain cholinergic neurons.

Forebrain cholinergic neurons modulate complex mammalian behaviors such as reward-related learning and cognitive functions. Although their dysfunction is implicated in various psychiatric and neurodegenerative diseases, the factors governing cholinergic neuron differentiation and diversity are mostly unknown. We tested the role of the LIM-homeobox gene Isl1 in the development of forebrain cholinergic neurons by conditionally deleting Isl1 using a Six3-cre transgene. A depletion of cholinergic interneurons in the dorsal and ventral striatum, and cholinergic projection neurons in the nucleus basalis is observed and is ascribed to an early and persistent defect in cholinergic neuron differentiation. Notably, cholinergic innervation to the neocortex is abolished, whereas that to the hippocampus is unaltered. The unique pattern of cholinergic hypoinnervation encountered is supported by the presence of cholinergic projection neurons in the medial septum, the magnocellular preoptic area, and the substantia innominata. Together, these results demonstrate the requirement for Isl1 in the development of restricted telencephalic cholinergic neurons and link the development of cholinergic neurons in anatomically disparate sites to Isl1 function.

Islet-1 controls the differentiation of retinal bipolar and cholinergic amacrine cells.

Whereas the mammalian retina possesses a repertoire of factors known to establish general retinal cell types, these factors alone cannot explain the vast diversity of neuronal subtypes. In other CNS regions, the differentiation of diverse neuronal pools is governed by coordinately acting LIM-homeodomain proteins including the Islet-class factor Islet-1 (Isl1). We report that deletion of Isl1 profoundly disrupts retinal function as assessed by electroretinograms and vision as assessed by optomotor behavior. These deficits are coupled with marked reductions in mature ON- and OFF-bipolar (>76%), cholinergic amacrine (93%), and ganglion (71%) cells. Mosaic deletion of Isl1 permitted a chimeric analysis of "wild-type" cells in a predominantly Isl1-null environment, demonstrating a cell-autonomous role for Isl1 in rod bipolar and cholinergic amacrine development. Furthermore, the effects on bipolar cell development appear to be dissociable from the preceding retinal ganglion cell loss, because Pou4f2-null mice are devoid of similar defects in bipolar cell marker expression. Expression of the ON- and OFF-bipolar cell differentiation factors Bhlhb4 and Vsx1, respectively, requires the presence of Isl1, whereas the early bipolar cell marker Prox1 initially did not. Thus, Isl1 is required for engaging bipolar differentiation pathways but not for general bipolar cell specification. Spatiotemporal expression analysis of additional LIM-homeobox genes identifies a LIM-homeobox gene network during bipolar cell development that includes Lhx3 and Lhx4. We conclude that Isl1 has an indispensable role in retinal neuron differentiation within restricted cell populations and this function may reflect a broader role for other LIM-homeobox genes in retinal development, and perhaps in establishing neuronal subtypes.

Alterations in striatal dopamine catabolism precede loss of substantia nigra neurons in a mouse model of juvenile neuronal ceroid lipofuscinosis.

Batten disease, or juvenile neuronal ceroid lipofuscinosis (JNCL), results from mutations in the CLN3 gene. This disorder presents clinically around the age of 5 years with visual deficits progressing to include seizures, cognitive impairment, motor deterioration, hallucinations, and premature death by the third to fourth decade of life. The motor deficits include coordination and gait abnormalities, myoclonic jerks, inability to initiate movements, and spasticity. Previous work from our laboratory has identified an early reduction in catechol-O-methyltransferase (COMT), an enzyme responsible for the efficient degradation of dopamine. Alterations in the kinetics of dopamine metabolism could cause the accumulation of undegraded or unsequestered dopamine leading to the formation of toxic dopamine intermediates. We report an imbalance in the catabolism of dopamine in 3 month Cln3(-/-) mice persisting through 9 months of age that may be causal to oxidative damage within the striatum at 9 months of age. Combined with the previously reported inflammatory changes and loss of post-synaptic D1alpha receptors, this could facilitate cell loss in striatal projection regions and underlie a general locomotion deficit that becomes apparent at 12 months of age in Cln3(-/-) mice. This study provides evidence for early changes in the kinetics of COMT in the Cln3(-/-) mouse striatum, affecting the turnover of dopamine, likely leading to neuron loss and motor deficits. These data provide novel insights into the basis of motor deficits in JNCL and how alterations in dopamine catabolism may result in oxidative damage and localized neuronal loss in this disorder.

Expression of the LIM-homeodomain protein Isl1 in the developing and mature mouse retina.

The mammalian retina is comprised of six major neuronal cell types and is subdivided into more morphological and physiological subtypes. The transcriptional machinery underlying these subtype fate choices is largely unknown. The LIM-homeodomain protein, Isl1, plays an essential role in central nervous system (CNS) differentiation but its relationship to retinal neurogenesis remains unknown. We report here its dynamic spatiotemporal expression in the mouse retina. Among bipolar interneurons, Isl1 expression commences at postnatal day (P)5 and is later restricted to ON-bipolar cells. The intensity of Isl1 expression is found to segregate the pool of ON-bipolar cells into rod and ON-cone bipolar cells with higher expression in rod bipolar cells. As bipolar cell development proceeds from P5-10 the colocalization of Isl1 and the pan-bipolar cell marker Chx10 reveals the organization of ON-center bipolar cell nuclei to the upper portion of the inner nuclear layer. Further, whereas Isl1 is predominantly a ganglion cell marker prior to embryonic day (E)15.5, at E15.5 and later its expression in nonganglion cells expands. We demonstrate that these Isl1-positive, nonganglion cells acquire the expression of amacrine cell markers embryonically, likely representing nascent cholinergic amacrine cells. Taken together, Isl1 is expressed during the maturation of and is later maintained in retinal ganglion cells and subtypes of amacrine and bipolar cells where it may function in the maintenance of these cells into adulthood.

Early changes in gene expression in two models of Batten disease.

Infantile and juvenile neuronal ceroid lipofuscinosis (NCLs) are progressive neurodegenerative disorders of childhood with distinct ages of clinical onset, but with a similar pathological outcome. Infantile and juvenile NCL are inherited in an autosomal recessive manner due to mutations in the CLN1 and CLN3 genes, respectively. Recently developed Cln1- and Cln3-knockout mouse models share similarities in pathology with the respective human disease. Using oligonucleotide arrays we identified reproducible changes in gene expression in the brains of both 10-week-old Cln1- and Cln3-knockout mice as compared to wild-type controls, and confirmed changes in levels of several of the cognate proteins by immunoblotting. Despite the similarities in pathology, the two mutations affect the expression of different, non-overlapping sets of genes. The possible significance of these changes and the pathological mechanisms underlying NCL diseases are discussed.

The neuronal ceroid lipofuscinoses: mutations in different proteins result in similar disease.

The neuronal ceroid-lipofuscinoses (NCL) are the most common group of progressive neurodegenerative diseases in children, with an incidence as high as one in 12,500 live births. The main features of this disease are failure of psychomotor development, impaired vision, seizures, and premature death. Many biochemical and physiological studies have been initiated to determine the cellular defect underlying the disease, although only a few traits have been truly associated with the disorders. One of the paradox's of the NCL-diseases is the characteristic accumulation of autofluorescent hydrophobic material in the lysosomes of neurons and other cell types. However, the accumulation of this lysosomal storage material, which no doubt contributes to the neurologic disease, does not apparently lead to disease outside the CNS, and how these cellular alterations relate to the neurodegeneration in NCLs is unknown. Mutations have been identified in six distinct genes/proteins, namely CLN1, which encodes PPT1, a protein thiolesterase; CLN2, which encodes TPP1, a serine protease; and CLN3, CLN5, CLN6, and CLN8, which encode novel transmembrane proteins. Mutation in any one of these CLN-proteins results in a distinct type of NCL-disease. However, there are many shared similarities in the pathology of these diseases. The most obvious connection between PPT1, TPP1, CLN3, CLN5, CLN6, and CLN8 is their subcellular localization. To date, three of the four proteins whose subcellular localization has been confirmed, namely PPT1, TPP1, and CLN3, reside in the lysosome. We review the function of the CLN-proteins and discuss the possibility that a disruption in a common biological process leads to an NCL-disease.