Undiagnosed papilledema in a morbidly obese patient population: a prospective study.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a rare condition that can lead to significant morbidity from visual loss. The cause of IIH is unknown, but IIH is known to be associated with obesity. Obese patients may be at particularly high risk for suffering vision loss from IIH. The purpose of the present study is to determine the prevalence of undiagnosed or asymptomatic papilledema in a population of morbidly obese individuals and to determine if these patients should undergo routine screening for papilledema. METHODS: Patients presenting to the UC Davis Bariatric Surgery Clinic between February 2008 and January 2011 who met the National Institutes of Health criteria for bariatric surgery were invited to participate in the study. Those patients who met the inclusion criteria and consented to the study were included. Participants were screened for IIH by nonmydriatic fundus photographs and by concerning symptoms prompting direct referral for neuro-ophthalmologic evaluation. Images were reviewed by a neuro-ophthalmologist, and patients with suspicious optic discs underwent neuro-ophthalmologic evaluation. Patients with findings consistent with IIH were sent for neurological evaluation. RESULTS: A total of 606 patients with an average body mass index of 47 kg/m2 were included in the study. Seventeen of these patients had photographic optic disc findings or symptoms suspicious for IIH. Seven of these patients did not have disc edema on clinical examination. Six patients were not evaluated in the clinic. Four of the 17 patients had subtle optic disc edema confirmed by clinical evaluation and were referred for full neurological workup. These 4 patients had normal neuroimaging, 3 of whom underwent lumbar punctures with borderline high opening pressures. All 4 patients had unremarkable visual field examinations. Fundus abnormalities other than optic disc edema were discovered in 33 patients. CONCLUSION: Our study suggests that in a morbidly obese patient population, papilledema with significant visual loss is rare. Routine screening with fundus photography of morbidly obese patients likely is not warranted.

Functional comparison of RGS9 splice isoforms in a living cell.

Two isoforms of the GTPase-activating protein, regulator of G protein signaling 9 (RGS9), control such fundamental functions as vision and behavior. RGS9-1 regulates phototransduction in rods and cones, and RGS9-2 regulates dopamine and opioid signaling in the basal ganglia. To determine their functional differences in the same intact cell, we replaced RGS9-1 with RGS9-2 in mouse rods. Surprisingly, RGS9-2 not only supported normal photoresponse recovery under moderate light conditions but also outperformed RGS9-1 in bright light. This versatility of RGS9-2 results from its ability to inactivate the G protein, transducin, regardless of its effector interactions, whereas RGS9-1 prefers the G protein-effector complex. Such versatility makes RGS9-2 an isoform advantageous for timely signal inactivation across a wide range of stimulus strengths and may explain its predominant representation throughout the nervous system.

RGS expression rate-limits recovery of rod photoresponses.

Signaling through G protein-coupled receptors (GPCRs) underlies many cellular processes, yet it is not known which molecules determine the duration of signaling in intact cells. Two candidates are G protein-coupled receptor kinases (GRKs) and Regulators of G protein signaling (RGSs), deactivation enzymes for GPCRs and G proteins, respectively. Here we investigate whether GRK or RGS governs the overall rate of recovery of the light response in mammalian rod photoreceptors, a model system for studying GPCR signaling. We show that overexpression of rhodopsin kinase (GRK1) increases phosphorylation of the GPCR rhodopsin but has no effect on photoresponse recovery. In contrast, overexpression of the photoreceptor RGS complex (RGS9-1.Gbeta5L.R9AP) dramatically accelerates response recovery. Our results show that G protein deactivation is normally at least 2.5 times slower than rhodopsin deactivation, resolving a long-standing controversy concerning the mechanism underlying the recovery of rod visual transduction.

Long-lasting increases in intrinsic excitability triggered by inhibition.

Although experience-dependent changes in neural circuits are commonly assumed to be mediated by synaptic plasticity, modifications of intrinsic excitability may serve as a complementary mechanism. In whole-cell recordings from spontaneously firing vestibular nucleus neurons, brief periods of inhibitory synaptic stimulation or direct membrane hyperpolarization triggered long-lasting increases in spontaneous firing rates and firing responses to intracellular depolarization. These increases in excitability, termed firing rate potentiation, were induced by decreases in intracellular calcium and expressed as reductions in the sensitivity to the BK-type calcium-activated potassium channel blocker iberiotoxin. Firing rate potentiation is a novel form of cellular plasticity that could contribute to motor learning in the vestibulo-ocular reflex.

Phosducin regulates the expression of transducin betagamma subunits in rod photoreceptors and does not contribute to phototransduction adaptation.

For over a decade, phosducin's interaction with the betagamma subunits of the G protein, transducin, has been thought to contribute to light adaptation by dynamically controlling the amount of transducin heterotrimer available for activation by photoexcited rhodopsin. In this study we directly tested this hypothesis by characterizing the dark- and light-adapted response properties of phosducin knockout (Pd- / -) rods. Pd- / - rods were notably less sensitive to light than wild-type (WT) rods. The gain of transduction, as measured by the amplification constant using the Lamb-Pugh model of activation, was 32% lower in Pd- / - rods than in WT rods. This reduced amplification correlated with a 36% reduction in the level of transducin betagamma-subunit expression, and thus available heterotrimer in Pd- / - rods. However, commonly studied forms of light adaptation were normal in the absence of phosducin. Thus, phosducin does not appear to contribute to adaptation mechanisms of the outer segment by dynamically controlling heterotrimer availability, but rather is necessary for maintaining normal transducin expression and therefore normal flash sensitivity in rods.

Increased Frequency of Topical Steroids Provides Benefit in Patients With Recalcitrant Postsurgical Macular Edema.

PURPOSE: To compare standard and frequent topical steroids for postsurgical macular edema (ME). DESIGN: Randomized clinical trial. METHODS: Subjects with postsurgical ME stratified into post-cataract surgery ME (PCSME) and post-other surgery ME (POSME) were randomized to ketorolac 4 times a day (qid) + 1% prednisolone acetate (PA) every hour while awake (q1hWA, Group 1) or qid (Group 2). Mean change from baseline best-corrected visual acuity (BCVA) was determined at week 12, after which group 2 subjects with persistent edema were crossed over to PA q1hWA. RESULTS: Twenty-two subjects (13 PCSME and 9 POSME) were randomized to Group 1 and 20 (12 PCSME and 8 POSME) to Group 2. At week 12, change from baseline BCVA (ETDRS letters) in Group 1 vs 2 was +11.6 vs +8.5 (P = .32) and for subgroups was +10.6 vs +7.8 (P = .23) for PCSME and +13.1 vs +9.4 (P = .47) for POSME. Mean change from baseline central subfield thickness (CST, µm) at week 12 in Group 1 vs 2 was -100.8 vs -63.9 (P = .30). Mean change from baseline intraocular pressure was +2.6 vs +1.7 mm Hg (P = .52). Eight subjects in Group 2 with residual ME at week 12 were switched to PA q1hWA and at week 24, the mean changes from week 12 BCVA and CST were +7.0 letters (P = .01) and -108.25 µm (P = .04). CONCLUSIONS: Our data suggest that patients with postsurgical ME should initially be treated with ketorolac and PA qid, but if edema does not resolve after 12 weeks, a switch to ketorolac qid and PA q1hWA may provide benefit.

Prolonged photoresponses and defective adaptation in rods of Gbeta5-/- mice.

Timely deactivation of G-protein signaling is essential for the proper function of many cells, particularly neurons. Termination of the light response of retinal rods requires GTP hydrolysis by the G-protein transducin, which is catalyzed by a protein complex that includes regulator of G-protein signaling RGS9-1 and the G-protein beta subunit Gbeta5-L. Disruption of the Gbeta5 gene in mice (Gbeta5-/-) abolishes the expression of Gbeta5-L in the retina and also greatly reduces the expression level of RGS9-1. We examined transduction in dark- and light-adapted rods from wild-type and Gbeta5-/- mice. Responses of Gbeta5-/- rods were indistinguishable in all respects from those of RGS9-/- rods. Loss of Gbeta5-L (and RGS9-1) had no effect on the activation of the G-protein cascade, but profoundly slowed its deactivation and interfered with the speeding of incremental dim flashes during light adaptation. Both RGS9-/- and Gbeta5-/- responses were consistent with another factor weakly regulating GTP hydrolysis by transducin in a manner proportional to the inward current. Our results indicate that a complex containing RGS9-1-Gbeta5-L is essential for normal G-protein deactivation and rod function. In addition, our light adaptation studies support the notion than an additional weak GTPase-accelerating factor in rods is regulated by intracellular calcium and/or cGMP.

Novel form of adaptation in mouse retinal rods speeds recovery of phototransduction.

Photoreceptors of the retina adapt to ambient light in a manner that allows them to detect changes in illumination over an enormous range of intensities. We have discovered a novel form of adaptation in mouse rods that persists long after the light has been extinguished and the rod's circulating dark current has returned. Electrophysiological recordings from individual rods showed that the time that a bright flash response remained in saturation was significantly shorter if the rod had been previously exposed to bright light. This persistent adaptation did not decrease the rate of rise of the response and therefore cannot be attributed to a decrease in the gain of transduction. Instead, this adaptation was accompanied by a marked speeding of the recovery of the response, suggesting that the step that rate-limits recovery had been accelerated. Experiments on knockout rods in which the identity of the rate-limiting step is known suggest that this adaptive acceleration results from a speeding of G protein/effector deactivation.

Ranibizumab in diabetic macular edema.

By 2050 the prevalence of diabetes will more than triple globally, dramatically increasing the societal and financial burden of this disease worldwide. As a consequence of this growth, it is anticipated that there will be a concurrent rise in the numbers of patients with diabetic macular edema (DME), already among the most common causes of severe vision loss worldwide. Recent available therapies for DME target the secreted cytokine, vascular endothelial growth factor (VEGF). This review focuses on the treatment of DME using the first humanized monoclonal antibody targeting VEGF that has been Food and Drug Administration-approved for the use in the eye, ranibizumab (Lucentis(®)).

Absence of the RGS9.Gbeta5 GTPase-activating complex in photoreceptors of the R9AP knockout mouse.

Timely termination of the light response in retinal photoreceptors requires rapid inactivation of the G protein transducin. This is achieved through the stimulation of transducin GTPase activity by the complex of the ninth member of the regulator of G protein signaling protein family (RGS9) with type 5 G protein beta subunit (Gbeta5). RGS9.Gbeta5 is anchored to photoreceptor disc membranes by the transmembrane protein, R9AP. In this study, we analyzed visual signaling in the rods of R9AP knockout mice. We found that light responses from R9AP knockout rods were very slow to recover and were indistinguishable from those of RGS9 or Gbeta5 knockout rods. This effect was a consequence of the complete absence of any detectable RGS9 from the retinas of R9AP knockout mice. On the other hand, the level of RGS9 mRNA was not affected by the knockout. These data indicate that in photoreceptors R9AP determines the stability of the RGS9.Gbeta5 complex, and therefore all three proteins, RGS9, Gbeta5 , and R9AP, are obligate members of the regulatory complex that speeds the rate at which transducin hydrolyzes GTP.