Diagnosis of giant cell arteritis using clinical, laboratory, and histopathological findings in patients undergoing temporal artery biopsy.

OBJECTIVE: To identify the clinical, laboratory, and histopathological features that may predict the diagnosis of giant cell arteritis (GCA). METHODS: A retrospective chart review was performed on patients who underwent temporal artery biopsy (TAB) between January 1, 2011 and March 31, 2019. Patient demographics, clinical characteristics, laboratory features, histopathological features, and biopsy results were collected. GCA status was determined by a neuro-ophthalmologist (OOA). Stepwise logistic regression analysis was performed to identify features that predict GCA status. RESULTS: Of 101 patients who underwent TAB, 31 (31%) were diagnosed with GCA. Age was found to be statistically significant for the diagnosis of GCA (P = 0.009), with an average age of 74.4 years ( ± 8.1) in those with GCA vs. 68.9 years ( ± 10.0) in those without. The incidence of transient vision loss was higher in GCA than non-GCA patients (P = 0.005). Anterior arteritic ischemic optic neuropathy (n = 3), ophthalmic artery occlusion (n = 2), and posterior ischemic optic neuropathy (n = 1) were seen only in the GCA group. Of the 31 GCA patients, 15 had active GCA (48%), 3 (10%) had healed temporal arteritis (HTA), 8 (26%) had suggested HTA, and 5 (16%) had false negative biopsies. Of the 70 non-GCA patients, 63 (90%) had negative biopsies, 2 (3%) had HTA, and 5 (7%) had suggested HTA. Histopathological analysis revealed that CD68 staining had a sensitivity of 69% and specificity of 86%. Both presence of multinucleated giant cells (MNGC) and transmural inflammation had 100% specificity; however, sensitivity was ≤ 50%. In patients with negative TABs and complete risk factor data available (n = 66), the odds of GCA increased 2.16-fold every 5 years of age, and 1.08-fold every mg/day of oral steroid use. A biopsy result of HTA had an odds ratio of 84.7 and suggested HTA of 49.2 against a negative TAB for diagnosis of GCA. CONCLUSION: Age at time of biopsy, HTA, and suggested HTA are predictive for the diagnosis of GCA. Transient vision loss is more commonly seen in GCA, and anterior arteritic ischemic optic neuropathy, ophthalmic artery occlusion, and posterior ischemic optic neuropathy are important ophthalmic manifestations of GCA. CD68 staining is more sensitive but less specific for diagnosing GCA in comparison to other histopathologic findings such as presence of MNGC and transmural inflammation. Further work is recommended to investigate the importance of the specific histopathologic finding of CD68 staining in the diagnosis of GCA.

PLATELET FUNCTION IN TRAUMA: IS CURRENT TECHNOLOGY IN FUNCTION TESTING MISSING THE MARK IN INJURED PATIENTS?

ABSTRACT: Platelets are subcellular anucleate components of blood primarily responsible for initiating and maintaining hemostasis. After injury to a blood vessel, platelets can be activated via several pathways, resulting in changed shape, adherence to the injury site, aggregation to form a plug, degranulation to initiate activation in other nearby platelets, and acceleration of thrombin formation to convert fibrinogen to fibrin before contracting to strengthen the clot. Platelet function assays use agonists to induce and measure one or more of these processes to identify alterations in platelet function that increase the likelihood of bleeding or thrombotic events. In severe trauma, these assays have revealed that platelet dysfunction is strongly associated with poor clinical outcomes. However, to date, the mechanism(s) causing clinically significant platelet dysfunction remain poorly understood. We review the pros, cons, and evidence for use of many of the popular assays in trauma, discuss limitations of their use in this patient population, and present approaches that can be taken to develop improved functional assays capable of elucidating mechanisms of trauma-induced platelet dysfunction. Platelet dysfunction in trauma has been associated with need for transfusions and mortality; however, most of the current platelet function assays were not designed for evaluating trauma patients, and there are limited data regarding their use in this population. New or improved functional assays will help define the mechanisms by which platelet dysfunction occurs, as well as help optimize future treatment.

Paired Recording to Study Electrical Coupling Between Photoreceptors in Mouse Retina.

Gap junction-mediated electrical coupling between retinal photoreceptors is an important determinant of photoreceptor function. Yet, quantitative measurements of the junctional conductance between coupled photoreceptors are required to fully assess the effects of coupling on visual performance. Such measurements have been obtained in salamander and other lower vertebrate retinas but are difficult to acquire in mammalian retinas, in part because of the much smaller size of photoreceptors in mammals. Here, we describe in detail a dual whole-cell patch-clamp technique we recently developed to measure the junctional conductance between photoreceptor pairs in the mouse retina. With this method, electrical coupling strength between mouse photoreceptors can be estimated with high accuracy and its impact on retinal processing of visual information further evaluated.

Effect of Laser Peripheral Iridotomy on Anterior Chamber Angle Anatomy in Primary Angle Closure Spectrum Eyes.

PURPOSE: To evaluate the change in trabecular-iris circumference volume (TICV) after laser peripheral iridotomy (LPI) in primary angle closure (PAC) spectrum eyes. PATIENTS AND METHODS: Forty-two chronic PAC spectrum eyes from 24 patients were enrolled. Eyes with anterior chamber abnormalities affecting angle measurement were excluded. Intraocular pressure, slit lamp examination, and gonioscopy were recorded at each visit. Anterior segment optical coherence tomography (ASOCT) with 3D mode angle analysis scans were taken with the CASIA SS-1000 before and after LPI. Forty-two pre-LPI ASOCT scans and 34 post-LPI ASOCT scans were analyzed using the Anterior Chamber Analysis and Interpretation (ACAI) software. A mixed-effect model analysis was used to compare the trabecular-iris space area (TISA) changes among 4 quadrants, as well as to identify potential factors affecting TICV. RESULTS: There was a significant increase in all average angle parameters after LPI (TISA500, TISA750, TICV500, and TICV750). The magnitude of change in TISA500 in the superior angle was significantly less than the other angles. The changes in TICV500 and TICV750 were not associated with any demographic or ocular characteristics. CONCLUSIONS: TICV is a useful parameter to quantitatively measure the effectiveness of LPI in the treatment of eyes with PAC spectrum disease.

Optimal number of angle images for calculating anterior angle volume and iris volume measurements.

PURPOSE: We determined the optimal number of angle images required to obtain reliable measurements of trabecular-iris circumferential volume (TICV) and iris volume (IV) using swept-source Fourier domain anterior segment optical coherence tomography (SSFD-ASOCT) scans in narrow angle eyes. METHODS: Scleral spur landmarks (SSL) were manually identified on ASOCT angle images from 128 meridians from each of 24 eyes with chronic primary angle closure (PAC) spectrum of disease. The anterior and posterior corneal curves, and the anterior and posterior iris surfaces were identified automatically by the anterior chamber analysis and interpretation (ACAI) software, then manually examined and edited by the reader if required. Trabecular-iris circumferential volume at 750 µm from SSL (TICV750) and IV were subsequently calculated using varying numbers of angle images. Threshold error was determined to be less than the lower 95% confidence limit of mean absolute percent error (MAPE) of the change in TICV or IV resulting from laser peripheral iridotomy, which would be 17% for TICV and 5% for IV, based on previous studies. The optimal number of angle images was the smallest number of images where MAPE was less than this threshold for TICV and IV. RESULTS: A total of 32 equally-spaced angle images (16 meridians) was required to estimate TICV750 and 16 angle images (8 meridians) to estimate IV. Both were within 4.6% and 1.6% of MAPE, respectively. CONCLUSIONS: It is possible to determine TICV and IV parameters reliably in narrow angles without evaluating all 128 meridians obtained with SSFD-ASOCT.

Trabecular-iris circumference volume in open angle eyes using swept-source fourier domain anterior segment optical coherence tomography.

Purpose. To introduce a new anterior segment optical coherence tomography parameter, trabecular-iris circumference volume (TICV), which measures the integrated volume of the peripheral angle, and establish a reference range in normal, open angle eyes. Methods. One eye of each participant with open angles and a normal anterior segment was imaged using 3D mode by the CASIA SS-1000 (Tomey, Nagoya, Japan). Trabecular-iris space area (TISA) and TICV at 500 and 750 µm were calculated. Analysis of covariance was performed to examine the effect of age and its interaction with spherical equivalent. Results. The study included 100 participants with a mean age of 50 (±15) years (range 20-79). TICV showed a normal distribution with a mean (±SD) value of 4.75 µL (±2.30) for TICV500 and a mean (±SD) value of 8.90 µL (±3.88) for TICV750. Overall, TICV showed an age-related reduction (P = 0.035). In addition, angle volume increased with increased myopia for all age groups, except for those older than 65 years. Conclusions. This study introduces a new parameter to measure peripheral angle volume, TICV, with age-adjusted normal ranges for open angle eyes. Further investigation is warranted to determine the clinical utility of this new parameter.

Age-related changes in trabecular meshwork imaging.

PURPOSE: To evaluate the normal aging effects on trabecular meshwork (TM) parameters using Fourier domain anterior segment optical coherence tomography (ASOCT) images. PATIENTS AND METHODS: One eye from 45 participants with open angles was imaged. Two independent readers measured TM area, TM length, and area and length of the TM interface shadow from 3 age groups (18-40, 41-60, and 61-80). Measurements were compared using stepwise regression analysis. RESULTS: The average TM parameters were 0.0487 (± 0.0092) mm(2) for TM area, 0.5502 (± 0.1033) mm for TM length, 0.1623 (± 0.341) mm(2) for TM interface shadow area, and 0.7755 (± 0.1574) mm for TM interface shadow length. Interobserver reproducibility coefficients ranged from 0.45 (TM length) to 0.82 (TM area). TM area and length were not correlated with age. While the TM interface shadow length did not correlate with age, the TM interface shadow area increased with age. Race, sex, intraocular pressure, and gonioscopy score were not correlated with any TM parameters. CONCLUSION: Although the TM measurements were not correlated with age, the TM interface shadow area increased with age. Further study is required to determine whether there is any relationship between the age-related ASOCT findings of the TM interface shadow area and physiologic function.

Short-Term Outcomes of KeraSys Patch Graft for Glaucoma Drainage Devices: A Case Series.

Purpose. Tube-related exposure is a known complication of glaucoma drainage device (GDD) surgery. Our objective is to report the early (approximately 1 year) tube exposure rate of implants covered with a keraSys (IOP Inc., Costa Mesa, CA, USA) tissue reinforcement graft. Patients and Methods. A retrospective, noncomparative, consecutive case series of 42 eyes with GDD implantation with keraSys patch grafts was performed. Main outcome measurements included patch-related complications: patch exposure, tube exposure, wound dehiscence, and patch migration. Results. Forty-two eyes were followed for an average of 15.24 ± 10.44 months (range 1.0-32.3 months). Four (10%) eyes experienced patch-related complications: two with exposure 8 months postoperatively, one with exposure 13 months postoperatively, and one with exposure 4 weeks postoperatively. Conclusion. The effectiveness of the keraSys patch graft is limited by the higher than expected early exposure rate found in this case series. These results should be confirmed in other studies.

Aqueous shunt exposure: a retrospective review of repair outcome.

PURPOSE: To describe the patient outcomes and factors affecting those outcomes after aqueous shunt exposure repair. PATIENTS AND METHODS: Forty-three eyes from Robert Cizik Eye Clinic and Bascom Palmer Eye Institute from 1995 to 2007 suffered from aqueous shunt exposure and were repaired by participating surgeons. Thirty-three were tube exposures and 7 were plate exposures. The remaining 3 exposure classified complications included a patch graft exposure, an elbow exposure, and 1 unknown complication. Forty eyes were followed for evidence of additional aqueous shunt exposures or additional surgical interventions for 46.6 weeks (40.2 wk) (range: 3 to 168 wk). RESULTS: Seventeen of 40 eyes required additional surgical intervention: 15 (45%) from the tube exposure group and 2 (29%) from the plate exposure group. Five (13%) eyes needed eventual removal of the shunt. Black race, diabetes mellitus, a high number of glaucoma medications before shunt implantation, a history of multiple glaucoma laser procedures, and combination of an initial aqueous shunt implantation with another surgery were found to be associated with a worse outcome after exposure repair. CONCLUSIONS: Intraocular pressure, number of medications, and visual acuity remained stable during follow-up after revision. Diabetes mellitus was associated with a shorter average time between initial repair and reintervention, and 4 other variables were associated with a higher likelihood of reintervention.

Clinical outcomes of peripheral iridotomy in patients with the spectrum of chronic primary angle closure.

Purpose. To evaluate outcomes of peripheral iridotomy (PI) for initial management of primary angle closure suspects (PACS), chronic primary angle closure (CPAC), and chronic primary angle closure glaucoma (CPACG). Patients and Methods. Seventy-nine eyes with PACS, CPAC, or CPACG and better than 20/50 visual acuity that underwent PI as initial management were included. Eyes with previous acute angle closure attacks, laser trabeculoplasties, surgeries, or intraocular injections were excluded. Additional treatments, glaucomatous progression, intraocular pressure, visual acuity, and the number of medications were evaluated. Results. The mean followup was 57.1 ± 29.0 months (range 13.8-150.6 months). Sixty-eight eyes (86.1%) underwent additional medical, laser, or surgical treatment. Forty eyes (50.6%) underwent lens extraction due to reduced visual acuity. The mean 10× logMAR visual acuity score for all patients significantly declined from 0.94 ± 1.12 at baseline to 1.83 ± 3.49 (N = 79, P = 0.0261) at the last followup. Conclusions. Most patients who undergo PI for CPAC spectrum will require additional intervention for either IOP lowering or improvement of visual acuity. This suggests that a procedure that not only deepens the angle but also lowers IOP and improves visual acuity would be desirable as further intervention could be avoided. Evaluation of techniques that achieve all 3 goals is warranted.

Reproducibility of scleral spur identification and angle measurements using fourier domain anterior segment optical coherence tomography.

Purpose. To evaluate intraobserver and interobserver agreement in locating the scleral spur landmark (SSL) and anterior chamber angle measurements obtained using Fourier Domain Anterior Segment Optical Coherence Tomography (ASOCT) images. Methods. Two independent, masked observers (SR and AZC) identified SSLs on ASOCT images from 31 eyes with open and nonopen angles. A third independent reader, NPB, adjudicated SSL placement if identifications differed by more than 80 µm. Nine months later, SR reidentified SSLs. Intraobserver and interobserver agreement in SSL placement, trabecular-iris space area (TISA750), and angle opening distance (AOD750) were calculated. Results. In 84% of quadrants, SR's SSL placements during 2 sessions were within 80 µm in both the X- and Y-axes, and in 77% of quadrants, SR and AZC were within 80 µm in both axes. In adjudicated images, 90% of all quadrants were within 80 µm, 88% in nonopen-angle eyes, and 92% in open-angle eyes. The intraobserver and interobserver correlation coefficients (with and without adjudication) were above 0.9 for TISA750 and AOD750 for all quadrants. Conclusions. Reproducible identification of the SSL from images obtained with FD-ASOCT is possible. The ability to identify the SSL allows reproducible measurement of the anterior chamber angle using TISA750 and AOD750.

Intermediate term safety and efficacy of transscleral cyclophotocoagulation after tube shunt failure.

PURPOSE: To determine the efficacy and safety of diode transscleral cyclophotocoagulation (TSCPC) after tube shunt failure. PATIENTS AND METHODS: The patient population consisted of 32 eyes of 31 patients with uncontrolled glaucoma. Each eye had a previously implanted aqueous tube shunt and was currently on maximally tolerated medication. Each eye also underwent TSCPC treatment using the Iridex (Mountain View, CA) diode laser with a maximum of 360 degrees of treatment. All 31 charts were reviewed for data pertaining to demographics, treatment, ocular history, and follow-up clinical examinations. Safety was evaluated by complication data. Efficacy was evaluated in terms of TSCPC treatment parameters (number of laser applications, laser power, application duration, and degrees of ciliary body treated), intraocular pressure, number of hypotensive medications, and any further treatment required. RESULTS: With a mean (SD) follow-up of 17.1 (16.3) (median=11.7) months from the last treatment, the mean intraocular pressure decreased from 28.6 (10.2) mm Hg to 16.8 (7.5) mm Hg (35% reduction) at 3 months (n=30, P<0.0001) and to 14.7 (7.9) mm Hg (43% reduction) at 1 year (n=13, P<0.0001). Complications included hypotony (n=4), hyphema (n=2), failed corneal transplant (n=1), and loss of light perception (n=5). CONCLUSIONS: TSCPC has a significant ocular hypotensive effect on glaucoma refractory to both tube shunt and medical therapy. The safety of this intervention remains unclear in this high risk patient population and warrants further study.

Chemical interplay in the mechanism of partial agonist activation in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors.

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, one subtype in the family of ionotropic glutamate receptors, are the main receptors responsible for excitatory signaling in the mammalian central nervous system. Previous studies utilitizing the isolated ligand binding domain of these receptors have provided insight into the role of specific ligand-protein interactions in mediating receptor activation. However, these studies relied heavily on the partial agonist kainate, in which the alpha-amine group is constrained in a pyrrolidine ring. Here we have studied a series of substituted and unsubstituted willardiines with primary alpha-amine groups similar to that of the full agonist glutamate whose activation can be varied depending on the size of the substituent. The specific ligand-protein interactions in the mechanism of partial agonism in this subtype were investigated using vibrational spectroscopy, and the large-scale conformational changes in the ligand binding domain were studied with fluorescence resonance energy transfer (FRET). These investigations show that the strength of the interaction at the alpha-amine group correlates with the extent of cleft closure and extent of activation, with the agonist of higher efficacy showing larger cleft closure and stronger interactions at this group, suggesting that this is one of the mechanisms by which the agonist controls receptor activation.

Role of the chemical interactions of the agonist in controlling alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor activation.

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are the main excitatory neurotransmitter receptors in the mammalian central nervous system. Structures of the isolated ligand binding domain of this receptor have provided significant insight into the large-scale conformational changes, which when propagated to the channel segments leads to receptor activation. However, to establish the role of specific molecular interactions in controlling fine details such as the magnitude of the functional response, we have used a multiscale approach, where changes at specific moieties of the agonists have been studied by vibrational spectroscopy, while large-scale conformational changes have been studied using fluorescence resonance energy transfer (FRET) investigations. By exploiting the wide range of activations by the agonists, glutamate, kainate, and AMPA, for the wild type and Y450F and L650T mutants of the GluR2 subtype, and by using the multiscale investigation, we show that the strength of the interactions at the alpha-amine group of the agonist with the protein in all but one case tracks the extent of activation. Since the alpha-amine group forms bridging interactions at the cusp of the ligand binding cleft, this appears to be a critical interaction through which the agonist controls the extent of activation of the receptor.

Allosteric mechanism in AMPA receptors: a FRET-based investigation of conformational changes.

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are the primary mediators of fast excitatory synaptic transmission in the mammalian CNS. Structures of the extracellular ligand-binding domain suggest that the extent of cleft closure in the ligand-binding domain controls the extent of activation of the receptor. Here we have developed a fluorescence resonance energy transfer-based probe that allows us to study the extent of cleft closure in the isolated ligand-binding domain in solution. These investigations show that the wild-type protein exhibits a graded cleft closure that correlates to the extent of activation, which is in qualitative agreement with the crystal structures. However, the changes in extent of cleft closure between the apo and agonist-bound states are smaller than that observed in the crystal structures. We have also used this method to study the L650T mutant and show that in solution the alpha-amino-5-methyl-3-hydroxy-4-isoxazole propionate-bound form of this mutant exists primarily in a conformation that is more closed than predicted based on the activity, indicating that the degree of cleft closure alone cannot be used as a measure of extent of activation of the receptor, and there are possibly other mechanisms in addition to cleft closure that mediate the subtleties in extent of activation by a given agonist.