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Patients with uncontrolled/refractory gout have heavy disease burden, but few treatment options. Pegloticase lowers serum urate (SU), but anti-drug antibodies can limit treatment efficacy. Evidence supports immunomodulator-pegloticase co-administration to increase sustained urate-lowering rates, but published cases are limited. This study investigated experience with pegloticase-immunomodulation co-therapy at two community rheumatology practices.Patients initiating pegloticase with immunomodulation in 2017 or later were included. Patient/treatment characteristics and proportion of responders (≥ 12 pegloticase infusions, SU 6 mg/dl at infusion-12) were examined. Patients on therapy at data collection with 12 infusions were excluded from response analyses. eGFR before and after therapy was examined.Thirty-four patients (79% male, 62.4 ± 16.3 years) with uncontrolled gout (SU = 9.1 ± 2.0 mg/dl, 91% tophaceous) were included. Most-reported comorbidities were hypertension (76%), obesity (71%), osteoarthritis (68%), and CKD (47%). Pre-therapy eGFR was 65.4 ± 25.2 ml/min/1.73 mThese real-world findings provide further support for increased pegloticase response rates when co-treatment with immunomodulating therapy is used.Patients with gout that does not respond to oral urate-lowering therapies have heavy disease burden and few treatment options. Pegloticase lowers serum urate levels (SU) and resolves tophi, but anti-drug antibodies can limit urate-lowering efficacy duration. Evidence increasingly supports co-administering an immunomodulator with pegloticase to increase the proportion of patients with sustained urate-lowering response. However, there are few published cases from real-world clinical practice. This study examined treatment with pegloticase + immunomodulation at two community rheumatology practices. Patients who began treatment with pegloticase and an immunomodulator in 2017 or later were included. The proportion of patients with sustained urate-lowering response (≥ 12 infusions received, SU 6 mg/dl at infusion 12) was investigated. Renal function before and after therapy was also examined. Thirty-four patients were included. Before treatment, SU averaged 9.1 mg/dl and most-reported comorbidities were hypertension (76%), obesity (71%), osteoarthritis (68%), and chronic kidney disease (47%). All patients began using an immunomodulator before or at first pegloticase infusion (subcutaneous methotrexate [20 patients], oral methotrexate [9 patients], mycophenolate mofetil [3 patients], and azathioprine [2 patients]). On average, 14.6 infusions were administered over 28.5 weeks and overall response rate was 89%. Response rate varied among different immunomodulators: subcutaneous methotrexate: 93%, oral methotrexate: 89%, mycophenolate mofetil: 100%, azathioprine: 50%. On average, kidney function improved, with chronic kidney disease stage stability/improvement in 85% of patients. Nineteen patients (56%) experienced gout flares. No infusion reactions or infections were noted and no new safety concerns were identified. These real-world findings provide further support for administering immunomodulation as co-therapy to pegloticase.

Thyroid eye disease (TED) is a debilitating autoimmune disease characterized by ocular and periorbital tissue inflammation, proptosis, and visual impairment. The known risk factors for TED include radioactive iodine therapy, female sex, and smoking. The risk factors for severe TED include hyperthyroidism, male sex, smoking, and diabetes; however, little is known about how diabetes mellitus (DM) influences TED. This claims-based analysis examined TED characteristics in patients with and without diabetes.Symphony database (2010-2015 U.S. claims) was mined for patients with ≥1 Graves' disease diagnosis code and ≥1 TED-associated eye code, including proptosis, strabismus, diplopia, lid retraction, exposure keratoconjunctivitis, and optic neuropathy (ON). DM status was determined based on type 1 or type 2 diabetes coding. Sight-threatening TED was defined as ≥1 ON or exposure keratoconjunctivitis code.A total of 51 220 patients were identified. Of them, 2618 (5.1%) and 12 846 (25.1%) had type 1 and type 2 DM, respectively. Patients with and without DM had similar characteristics, but patients with DM were more often men (type 1: 30.3%, type 2: 28.7% vs no DM: 20.5%; both P.001) and older at the first TED code. In patients with DM, strabismus (25.4%, 22.6% vs 19.9%) and diplopia (38.6%, 37.9% vs 29.9%) occurred more often but proptosis occurred less often (42.3%, 46.3% vs 58.5%; all P.001). Sight-threatening TED occurred more often in patients with DM because of higher ON rates.Patients with TED and DM may have more extraocular muscle involvement. Furthermore, the higher prevalence of severe TED stemmed from higher ON rates, possibly associated with diabetes-related vasculopathies. These hypothesis-generating data warrant further exploration.

Introduction Thyroid eye disease (TED) is an autoimmune condition producing ocular pain, dysmotility, and ocular structure and function changes. As disease activity changes, redness, swelling, and pain can improve, but eye comfort, appearance, and motility alterations often persist. There are limited data on chronic TED patient-reported outcomes. This study examined chronic US TED patient-reported symptoms and quality of life (QOL). Methods Existing data from an online survey regarding chronic TED signs/symptoms and patient QOL were retrospectively examined. The Graves’ Ophthalmopathy QOL instrument (GO-QOL; 0–100, 100 = highest QOL) evaluated overall, appearance, and vision-related QOL. Influencing factors were examined by stratifying patients into low (overall QOL ≤ 50), moderate (> 50 and, Plain Language Summary Thyroid eye disease (TED) occurs when loss of immune tolerance results in orbital and retro-orbital inflammation. Fat and muscle tissue can swell severely, causing debilitating symptoms, including pain around/behind the eyes, eye movement abnormalities, bulging eyes (proptosis), and double vision (diplopia), manifesting in appearance and vision quality of life (QOL) changes. Some improvement can occur as inflammation quiets and TED becomes chronic/inactive. However, appearance and visual changes often remain due to persistent proptosis and eye muscle and eyelid changes. This study examined TED symptoms and QOL in 100 chronic TED patients. They answered questions about symptoms, how TED affected them, and their medical care. The average duration of TED was 6 years (3 years inactive), patients had an average of 20 TED-related doctor visits/year, and nearly one-half (42%) of patients reported having anxiety and/or depression. Prior TED treatments included steroids (25% when TED-related inflammation was present), orbital radiation (5%), and surgery (25%). Disease-specific QOL scores (average score: 60.5 of 100) indicated that these chronic patients reported similar QOL impact as those with moderate-to-severe, active disease. Compared with the least impacted group, the most impacted patients reported higher rates of hypothyroidism (18% vs. 0%), anxiety (48% vs. 17%), disability/unemployment (21% vs.3%), number of doctor visits (40 vs. 5 visits/person/year), pain (39% vs. 13%), blurry vision (30% vs. 17%), diplopia (27% vs. 3%), and surgical treatment for TED (45% vs. 10%). This study demonstrates that QOL continues to be severely impacted by TED long after TED-related inflammation has quieted. Supplementary Information The online version contains supplementary material available at 10.1007/s40123-021-00385-8.

Introduction Gout is a common, progressive, systemic inflammatory arthritis caused by hyperuricemia. Current guidelines recommend that serum uric acid (sUA) levels be maintained below 6.0 mg/dl to minimize acute gout attacks, tophi development, and long-term joint and organ damage. This study examined the influence of uncontrolled gout on post-diagnosis comorbidities and medication use. Methods The Humana Research Database (2007–2016, commercial insurance and Medicare) was searched (PearlDiver tool) for patients who had a gout diagnosis code, claims data for at least 6 months before and after diagnosis, and at least 90 days of continuous urate-lowering therapy within 1 year of diagnosis. Patients with controlled (all sUA measurements

Introduction Thyroid eye disease (TED) is an autoimmune disease that causes retro-orbital inflammation and subsequent proptosis, corneal exposure, strabismus, and variable vision changes. European studies have shown that TED can severely impact quality of life (QOL), but little is known about the QOL of patients with TED in the USA. Given that patient QOL influences TED severity classifications and subsequent treatment, understanding physician-perceived patient QOL is extremely important. Methods This retrospective chart review (conducted in 2018) examined QOL in US patients with moderate-to-severe TED, as reported by treating physicians who regularly manage patients with TED (≥ 5 patients in prior 12 months). The physicians graded patients’ overall QOL (7-point Likert scale; 1 = “not at all impaired”, 7 = “extremely impaired”), assessing mental health, vision changes, and ocular structural signs/symptoms. Patient demographics and clinical findings were examined to understand the impact of disease presentation on physician-perceived QOL. Results Medical record data of 714 US patients with moderate-to-severe TED were provided by 181 physicians (73 endocrinologists, 108 ophthalmologists). Patients had a mean age of 49.4 (standard deviation [SD] 13.6) years, and 102 cases (14%) were severe. Anxiety and/or depression was reported in 36% of patients (an increase from the 18.9% prevalence reported for the USA in 2017 by the US National Institute of Mental Health; P, Plain Language Summary Little is known on how thyroid eye disease (TED) affects patient quality of life (QOL) in the USA. Patient QOL can affect how TED is treated; consequently, it is important to understand how physicians perceive QOL in patients with TED. We evaluated 714 patients, as reported by physicians, with this rare condition to better understand QOL in US patients with TED. The medical records of 612 patients with moderate TED and 102 patients with severe TED were examined. QOL impact was rated from 1 to 7, with 1 being “not at all impaired” and 7 being “extremely impaired.” Overall QOL, as assessed by treating physicians, is heavily impacted by both moderate and severe TED in US patients, with these patients also reported to have a higher frequency of mental health diagnoses than reported in the general US adult population. Higher levels of inflammation on and around the eye and more severe disease led to a higher QOL impairment. More specifically, pain, visual disturbances (including double vision), and changes to the face and tissues around the eye all negatively affected QOL.

Pegloticase, a PEGylated uricase for uncontrolled gout, rapidly lowers serum urate (SU). Not all patients complete a full-therapy course because anti-pegloticase antibodies can develop, causing efficacy loss and infusion reactions. The literature and clinical trial data indicate that methotrexate co-administration markedly improves pegloticase response rates from the established monotherapy response rate of 42%. Unfortunately, methotrexate use is restricted by kidney disease, which is often present in uncontrolled gout patients. Leflunomide is less restricted in patients with renal dysfunction. This study examined the treatment response rate of pegloticase co-administered with leflunomide.Patients co-treated with pegloticase (8 mg biweekly infusion) and oral leflunomide (20 mg/day) were included. Patient/treatment characteristics and safety parameters (adverse events [AEs], laboratory parameters) were examined. Pre-infusion prophylaxis was administered (day of infusion: IV solumedrol, night before and morning of infusion: oral fexofenadine or diphenhydramine). Patients were considered treatment responders if ≥ 12 pegloticase infusions were administered and pre-infusion SU 6 mg/dl at infusion-12.Ten patients (five male, 72.7 ± 12.5 years) were included. The most common comorbidities were chronic kidney disease (90%), hypertension (70%), diabetes mellitus (60%), obesity (60%), and congestive heart failure (50%). Baseline SU was 7.1 ± 2.4 mg/dl and nine patients (90%) had subcutaneous tophi noted. Seven patients (70%) met responder criteria, receiving 26.6 ± 14.0 infusions (range 13-55) with a pre-infusion-12 SU of 0.9 ± 1.5 mg/dl. The three non-responders received 12 infusions because of unrelated AEs or loss of follow-up. Three patients (30%) experienced AEs. One had unrelated cardiac disease worsening and three gout flares, one had a pre-infusion solumedrol reaction (wooziness/loss of consciousness), and one had two mild, transient increases in liver enzymes.This study supports leflunomide as co-therapy to pegloticase in uncontrolled gout patients. Heterogeneity and high comorbidity burden in uncontrolled gout patients makes having a variety of immunomodulators options important.

Introduction Pegloticase is a recombinant PEGylated uricase that converts relatively insoluble urate to highly water-soluble allantoin, which is readily excreted by the kidneys. It is the first and only biologic treatment indicated for refractory or uncontrolled gout. Clinical trials showed a 6-month pegloticase responder rate of 42%, with the non-responder rate largely being attributed to the development of high-titer anti-drug antibodies (ADAs) against pegloticase. Immunomodulation attenuates ADA formation to biologics in a number of autoimmune conditions, but their use with pegloticase for uncontrolled gout is less established. This systematic review examined published cases of refractory gout patients treated with immunomodulation in combination with pegloticase. Methods Published cases of immunomodulation with pegloticase were identified in a PubMed search and in abstract databases of major rheumatology society meetings (2012–2020). Duplicate and review articles were excluded, as were those that did not include cases of pegloticase use with immunomodulation. Cases with off-label pegloticase administration schedules were also excluded. Pegloticase response was defined according to each study's specified standard. Results Ten publications describing 82 cases of pegloticase use in the setting of immunomodulation were identified. Overall pegloticase response rate was 82.9%. Patients co-treated with an individual immunomodulator had the following response rates: methotrexate: 87.5% (35 of 40 patients), mycophenolate mofetil: 86.4% (19 of 22 patients vs. pegloticase monotherapy [placebo]: 40% [4 of 10 patients]), azathioprine: 63.6% (7 of 11 patients), and leflunomide: 66.7% (4 of 6 patients). A single patient was co-treated with cyclosporin and was a responder. The two patients treated with more than one immunomodulator were both responders. Conclusion Published reports suggest that immunomodulation co-therapy has the potential to markedly improve pegloticase responder rates in patients with uncontrolled gout.

Introduction Limited data exist on US referral/management patterns for moderate-to-severe thyroid eye disease (TED), a disabling condition. Methods US ophthalmologists and endocrinologists experienced in treating TED provided medical record data of moderate-to-severe TED patients and information on referral/treatment practices. Data on signs/symptoms, medical/surgical treatments, treatment response, and referral history were collected. Moderate and severe cases were stratified to interrogate treatment/practice differences. Results A total of 181 physicians provided data on 714 patients (49.4 ± 13.6 years old, 65% women, 14% severe disease). Reporting physicians diagnosed 55% of patients themselves and solely managed 37% of cases, with similar referral/comanagement patterns between moderate and severe cases. Topical therapies included lubricating (79%) and glucocorticoid (39%) eye drops. Systemic therapies included oral glucocorticoids (36%), IV glucocorticoids (15%), and rituximab and/or tocilizumab (12%). Few patients underwent orbital radiation (4%) or surgical intervention (4%). IV glucocorticoids (33% vs. 12%), biologics (26% vs. 10%), orbital radiation (11% vs. 3%), and ocular surgery (12% vs. 3%) were used more often in severe versus moderate cases (all P Conclusions Participating physicians were primarily responsible for just over one-half of TED diagnoses, but solely treated

Introduction: Thyroid eye disease (TED) is an autoimmune condition that negatively impacts patient’s quality of life (QOL). The GO-QOL questionnaire was originally developed in the Netherlands to quantify how TED and treatments affect patient QOL. This questionnaire includes eight questions each on visual functioning and appearance related QOL; the items are answered on a 3-point Likert scale and transformed to a 0 (worst) to 100 (best) scale. Though widely used and validated outside the US, the questionnaire has not been validated in the United States (US). Here we examine the content validity. Methods: Patients with moderate or severe TED were identified using an existing market research patient database, clinician referrals, patient groups, and social media. Interested participants were screened for eligibility prior to completing the GO-QOL. Subjects were also questioned about TED-related signs, symptoms, and treatments and underwent a cognitive interview following GO-QOL completion. Results: Thirteen TED patients completed the assessments (mean age = 44.8 ± 11.5 years, range: 26-67); all were female. Mean TED duration was 4.6 ± 5.5 years (range: 0.4-20.7). Twelve patients (92.3%) had Graves’ disease and one had Hashimoto’s thyroiditis. Descriptions of how TED signs and symptoms impacted quality of life were consistent with GO-QOL items, and qualitative interviews indicated that patients found the GO-QOL content relevant and complete. Responses indicated that minor wording changes may be needed to account for US cultural and language conventions and prevent confusion (specifically related to a bicycling question [12/13 reported not regularly riding a bike before TED symptom onset]). Visual functioning impacts most commonly-reported during the interview were difficulty driving a motor vehicle (92% of participants), difficulty with electronic screens (e.g., televisions, smart phones, and computers; 77%), difficulty moving around outdoors (including issues with light sensitivity, uneven surfaces, and depth perception; 69%), and difficulty doing hobbies or pastimes (69%). Emotional/psychological impacts frequently reported by participants were change in appearance (92%), depression and anxiety (including fear and worry; 77%), and frustration and anger (including moodiness; 69%). Negative reactions from others (staring, asking questions), social impacts and isolation, and lack of self-confidence and embarrassment were also reported (each 62%). Conclusion: This analysis of US patient interviews offered strong support for GO-QOL content validity. Therefore, the GO-QOL is appropriate to quantify TED-related QOL impact in a US population. However, a few slight wording modifications may be needed for future optimal use in the US.Reference: Terwee CB. Br J Ophthalmol 1998;82:773-779

Purpose To evaluate a kindred with familial uveal and cutaneous melanoma and to identify potential genetic and environmental factors that may predispose individuals to develop uveal melanoma. Design Family-based case report with detailed clinical and genetic evaluation. Participants Ten siblings in a single nuclear family. Methods Evaluation of a large sibship via family history, complete eye and skin examinations, environmental risk factor questionnaire, and genetic testing, as well as a MEDLINE search of familial uveal melanoma kindreds. Main Outcome Measures Cutaneous and ocular nevi, benign and malignant neoplasms of skin and other sites, brief skin cancer risk assessment tool risk classification for cutaneous melanoma, DNA sequencing of p16INK4a and p14ARF genes, and citations on familial uveal melanoma. Results The proband and his mother had uveal melanoma, 3 cutaneous melanomas occurred among 2 siblings, and 2 other siblings had basal cell carcinomas. No germline mutations were detected in the melanoma-associated tumor suppressor genes p16INK4a and p14ARF . Seven out of 10 siblings had a history of cutaneous and/or ocular nevi. Of the 3 subjects without nevi, 2 had histories of eye or skin malignancies (1 uveal melanoma, 1 basal cell carcinoma). Three of the 10 siblings had relevant ocular findings (2 choroidal nevi, 1 uveal melanoma). Six were also found to be in the "high-risk" classification for cutaneous malignancies based on scores from a previously validated risk assessment tool. This family, combined with the 91 previously reported familial uveal melanoma kindreds, brings to 92 the total number thus far recorded. Conclusions Our results strengthen the association between uveal melanoma, atypical nevi, and cutaneous melanoma. This relationship supports the recommendation that individuals with a personal or family history of uveal melanoma, particularly in combination with atypical nevi, should be regularly screened for uveal and cutaneous melanoma.

PURPOSE To evaluate presumed iatrogenic graft failure (PIGF) in Descemet stripping automated endothelial keratoplasty (DSAEK). METHODS Deidentified data were collected retrospectively from the Illinois Eye Bank between April 2007 and May 2010. PIGF was defined as cases in which a repeat corneal transplant was performed

Background: Optical coherence tomography (OCT) provides microscopic retinal images. Optical coherence tomography is noninvasive, using light waves to produce detailed retinal images. Here, we investigate the ability of OCT to detect early choroidal neovascularization in age-related macular degeneration. Methods: Seventy-nine patients, diagnosed with nonexudative macular degeneration in one eye and exudative macular degeneration in the other were enrolled in this prospective, observational, nonrandomized study. Participants underwent examination (visual acuity, intraocular pressure, biomicroscopy, and ophthalmoscopy) followed by OCT in the study eye (nonexudative macular degeneration eye) every 3 months for 2 years. If examination did not show choroidal neovascularization, but OCT images raised suspicion, patients were reexamined in 4 weeks to 6 weeks and/or fluorescein angiography was performed. Visual acuity, OCT anomaly detected, and time between OCT and fluorescein angiography detection were examined. Results: Fifteen (19%) patients developed exudative macular degeneration, as confirmed by fluorescein angiography, in the study eye. Four additional patients showed potential exudative macular degeneration on OCT only. Of the 15 patients who developed exudative macular degeneration, 13 had disease progression identified on OCT before examination and/or fluorescein angiography showed changes. Subretinal pigment epithelium fluid was the most common OCT anomaly, with development of sub-/intraretinal fluid also visible. Conclusion: Optical coherence tomography could be a powerful screening tool for patients with age-related macular degeneration at high risk for developing choroidal neovascularization.

Purpose To investigate the effects of a hereditary retinal degeneration on retinal oxygenation and determine whether it is responsible for the severe attenuation of retinal circulation in hereditary photoreceptor degenerations. Methods Seven adult Abyssinian cats affected by hereditary retinal degeneration were studied. Oxygen microelectrodes were used to collect spatial profiles of retinal oxygenation in anesthetized animals. A one-dimensional model of oxygen diffusion was fitted to the data to quantify photoreceptor oxygen utilization (Qo(2)). Results Photoreceptor Qo(2) progressively decreased until it reached zero in the end stage of the disease. Average inner retinal oxygen tension remained within normal limits at all disease stages, despite the observed progressive retinal vessel attenuation. Light affected photoreceptors normally, decreasing Qo(2) by approximately 50% at all stages of the disease. Conclusions Loss of photoreceptor metabolism allows choroidal oxygen to reach the inner retina, attenuating the retinal circulation in this animal model of retinitis pigmentosa (RP) and probably also in human RP. As the degeneration progresses, there is a strong relationship between changes in the a-wave of the ERG and changes in rod oxidative metabolism, indicating that these two functional measures change together.

To evaluate a kindred with familial uveal and cutaneous melanoma and to identify potential genetic and environmental factors that may predispose individuals to develop uveal melanoma.Family-based case report with detailed clinical and genetic evaluation.Ten siblings in a single nuclear family.Evaluation of a large sibship via family history, complete eye and skin examinations, environmental risk factor questionnaire, and genetic testing, as well as a MEDLINE search of familial uveal melanoma kindreds.Cutaneous and ocular nevi, benign and malignant neoplasms of skin and other sites, brief skin cancer risk assessment tool risk classification for cutaneous melanoma, DNA sequencing of p16INK4a and p14ARF genes, and citations on familial uveal melanoma.The proband and his mother had uveal melanoma, 3 cutaneous melanomas occurred among 2 siblings, and 2 other siblings had basal cell carcinomas. No germline mutations were detected in the melanoma-associated tumor suppressor genes p16INK4a and p14ARF. Seven out of 10 siblings had a history of cutaneous and/or ocular nevi. Of the 3 subjects without nevi, 2 had histories of eye or skin malignancies (1 uveal melanoma, 1 basal cell carcinoma). Three of the 10 siblings had relevant ocular findings (2 choroidal nevi, 1 uveal melanoma). Six were also found to be in the "high-risk" classification for cutaneous malignancies based on scores from a previously validated risk assessment tool. This family, combined with the 91 previously reported familial uveal melanoma kindreds, brings to 92 the total number thus far recorded.Our results strengthen the association between uveal melanoma, atypical nevi, and cutaneous melanoma. This relationship supports the recommendation that individuals with a personal or family history of uveal melanoma, particularly in combination with atypical nevi, should be regularly screened for uveal and cutaneous melanoma.

To evaluate and compare the visual outcomes and accommodative amplitude in cataract patients after implantation of the Crystalens intraocular lens (IOL) (Eyeonics) versus standard monofocal IOLs.Ten clinics in a nationwide multicenter study in the United States.A multicenter comparative interventional case series with masked randomized postoperative examination of 224 eyes of 112 patients was performed by a single observer. Patients were divided into 2 groups (56 patients; 112 eyes each) depending on which IOL was implanted (Crystalens or monofocal). Accommodation was measured using 1 objective (dynamic retinoscopy) and 2 subjective methods (defocus and near point of accommodation). Visual acuity measurements were performed under the same conditions with standard visual acuity charts.Uncorrected monocular near vision was significantly better in the Crystalens group than in the standard monofocal group, with 101 of 112 eyes (90%) and 17 of 112 (15%), respectfully, reading J3 or better postoperatively. All 56 Crystalens patients had a binocular uncorrected near visual acuity of J3 or better compared with 16 of 56 (29%) standard monofocal patients. The mean postoperative monocular (0.85 +/- 0.30 [SD] versus 0.70 +/- 0.19, P.01) and binocular (1.16 +/- 0.17 versus 1.01 +/- 0.14, P.01) distance uncorrected visual acuities were also better in the Crystalens group than in the control group. All patients in the study achieved a corrected distance visual acuity of 20/20 or better. Measures of accommodation were significantly higher in Crystalens patients than in the monofocal IOL patients (dynamic retinoscopy 2.42 +/- 0.39 diopters [D] versus 0.91 +/- 0.24 D, P.01; monocular defocus 1.74 +/- 0.48 D versus 0.75 +/- 0.25 D, P.01; monocular near point of accommodation 9.5 +/- 3.1 inches versus 34.7 +/- 9.8 inches, P.01). Perceived accommodation (5.79 D) was significantly greater than the measured accommodation (1.96 to 2.42 D) in Crystalens patients (paired t test, P.01).The Crystalens IOL provided better uncorrected near and distance visual outcomes than standard monofocal IOLs in all analyses performed. Patients perceived a greater accommodation than measured. Understanding why this occurred could lead to valuable advances in accommodating IOL technology.

To examine intraretinal extracellular H+ concentration([H+]o) in diabetic cats.Double-barreled H+-selective microelectrodes were used to measure [H+]o as a function of retinal depth ([H+]o profiles) in four cats with different stages of diabetic retinopathy. Profiles from "normal"and "damaged" areas of the retina were compared to profiles previously obtained from healthy cats.In the healthy retina, [H+]o is generally highest in the middle of the retina and decreases toward the choroid and the vitreous. In 48 % of the profiles from diabetic animals with visible retinopathy, the inner retinal gradient was reversed so that the vitreous was more acidic than the middle of the retina. The profiles with reversed inner retinal gradients were classified as damaged. On the average, the inner retina tended to be 0.07-0.08 pH units more acidic in diabetic animals than in healthy normoglycemic animals, but of similar acidity to healthy hyperglycemic animals. In areas with damaged inner retinal gradients, net H+ production in the outer retina was also impaired.While the number of animals is small, we conclude that the [H+](O) distribution varied from normal to damaged in the same retina. Diabetes seems to lead to an acidification of the inner retina that appears to be at least partly related to hyperglycemia and which may be important in the progression of retinopathy.

We examined intraretinal [H + ] in the intact retina of anesthetized cats using H + -sensitive microelectrodes to obtain spatial profiles of extracellular [H + ]. One H + is produced when an anaerobically generated ATP is utilized. We theorized that H + production directly reflects anaerobic glucose consumption. From the choroid (pH ∼7.40), [H + ] o steadily increased to a maximum concentration in the proximal portion of the outer nuclear layer (pH∼7.20). The shape of the profile was always concave down, indicating that a net production of H + occurred across the avascular outer retina. A three-layer diffusion model of the outer retina was developed and fitted to the data to quantify photoreceptor H + extrusion into the extracellular space (Q OR-H +). It was determined that the outer segment (OS) layer had negligible H + extrusion. The data were then refitted to a special three-layer model in which the OS layer Q H + was set equal to zero, but in which the inner segments and outer nuclear layer produced H + . The resulting Q OR-H + was several orders of magnitude lower than previous measurements of Q OR-lactate , which were based on choroidal mass balances of lactate. Stoichiometrically, one H + is produced for each lactate produced, so we concluded that Q OR-H + is a measure of net rather than total H + production. Because retinal acid production is so high, the retina must contain efficient H + clearance and/or neutralization mechanisms that prevent severe acidosis. The effect of light on retinal extracellular [H + ] and Q OR-H + was also examined. As expected, light adaptation caused a retinal alkalinization that resulted from a 52% reduction in Q OR-H +. This is in agreement with previous studies that have shown that both oxidative (e.g. Haugh et al., 1990) and glycolytic metabolism (Wang et al., 1997a,c) in the photoreceptor are decreased by a factor of 2 during light adaptation. Although we could not obtain absolute values for outer retinal glycolysis, changes in Q OR-H+ appear to directly reflect changes in glycolytic metabolism.

Objective: To examine the effects of acute hypoxemia and hyperglycemia on retinal pH to understand hyperglycemia-induced changes in the normal intact cat retina. Methods: Spatial profiles of extracellular hydrogen ion (H) concentration were obtained from the cat retina, in vivo, using pH-sensitive microelectrodes during normoxia ( arterial p artial p ressure o f o xygen [PaO2]=114.5±7.9 mm Hg), normoglycemia (plasma glucose concentration, 117±19 mg/dL), acute hypoxemia (PaO2= 29.5 ±2 .2 mm Hg), and acute hyperglycemia (plasma glucose concentration, 303±67 mg/dL). An H diffusion model was fitted to the outer retinal data to quantify photoreceptor H production. The inner retinal pH was also examined. Results: Hypoxemia induced a mean acute panretinal acidification of 0.16 pH units that originated from a 2.55fold increase in net photoreceptor H production. Hyperglycemia induced an acute panretinal acidification of 0.12 pH units; however, photoreceptor H production levels remained unchanged. Retinal pH changes followed the course of arterial PaO2 and blood glucose changes. Conclusions: The increase in photoreceptor H production during hypoxemia confirms the importance of glycolysis in the retina. Hyperglycemia-induced pH changes resulted from either increased inner retinal H production or decreased H clearance/neutralization. Clinical Relevance: The hyperglcemia-induced acidification that originates in the inner retina suggests that retinal acidosis may contribute to the development of diabetic retinal disease. Arch Ophthalmol. 2005;123:1684-1690

PURPOSE The Crabtree effect is the phenomenon of inhibition of respiration by glycolysis, as a result of elevated glucose levels. It is not certain whether the Crabtree effect occurs in the retina, which has a high glycolytic capacity. In the current study, in vivo photoreceptor oxygen consumption was examined during the normo- and hyperglycemic states in the dark-adapted cat retina to determine whether the Crabtree effect occurs in the outer retina. METHODS Spatial profiles of oxygen tension were obtained in the cat retina, in vivo, with the use of oxygen microelectrodes during control conditions and acute (5.19 +/- 0.83 hour) episodes of hyperglycemia (blood glucose, >350 mg/dL). The outer retinal portions of the profiles were fitted to a model of oxygen diffusion to quantify photoreceptor oxygen consumption. RESULTS Photoreceptor oxygen consumption did not significantly change during hyperglycemia compared with control conditions. Choroidal PO(2) decreased during hyperglycemia by an average of 5.8 +/- 7.4 mm Hg. This led to an increase in the fraction of O(2) used by the photoreceptors that was derived from the inner retina. Choroidal PO(2) did not recover when blood glucose levels were returned to normal. Average inner retinal PO(2) was not affected by the episodes of hyperglycemia. CONCLUSIONS The Crabtree effect does not occur to any significant degree in the outer retina, because hyperglycemia did not affect photoreceptor oxygen consumption. Choroidal PO(2) decreased during hyperglycemia, and the oxygen deficit was made up by the retinal circulation.