Michael Marmor, MD

All Publications

• Lupus review is misleading about risk of hydroxychloroquine retinal toxicity. Survey of ophthalmology Marmor, M. F. 2024

  View details for DOI 10.1016/j.survophthal.2024.07.007

  View details for PubMedID 39059609

• Risk Factors for Hydroxychloroquine Retinopathy and Its Subtypes. JAMA network open Jorge, A. M., Melles, R. B., Marmor, M. F., Zhou, B., Zhang, Y., Choi, H. K. 2024; 7 (5): e2410677

  Abstract

  The major toxic effect of hydroxychloroquine is retinopathy. Thus, current guidelines recommend limiting the dose and screening annually for retinopathy among all long-term users, but individual patient factors may be associated with retinopathy risk.To identify risk factors beyond hydroxychloroquine dose and duration of use for hydroxychloroquine retinopathy.This cohort study of 4677 patients in the Kaiser Permanente Northern California integrated health network who initiated hydroxychloroquine, continued treatment, and underwent retinopathy screening after 5 years of use was conducted from July 1, 1997, to December 31, 2020, with up to 15 years of follow-up. Statistical analysis was performed in August 2023.Candidate risk factors included age at hydroxychloroquine initiation, sex, race and ethnicity, indications, chronic kidney disease (CKD), liver disease, diabetes, tamoxifen use, and medications that interact with hydroxychloroquine metabolism. Hydroxychloroquine dose was assessed from pharmacy dispensing records.Incident hydroxychloroquine retinopathy was adjudicated from masked review of guideline-recommended screening studies and classified as parafoveal or pericentral pattern. Multivariable Cox proportional hazards regression was used to assess potential risk factors for hydroxychloroquine retinopathy within 15 years of initiation.Of 4677 long-term hydroxychloroquine users (mean [SD] age at initiation, 52.4 [14.1] years; 3877 women [82.9%]), 125 patients developed hydroxychloroquine retinopathy within 15 years (102 parafoveal, 23 pericentral). Older age at time of hydroxychloroquine initiation was associated with retinopathy risk, with adjusted hazard ratios (HRs) of 2.48 (95% CI, 1.28-4.78) for those aged 45 to 54 years, 3.82 (95% CI, 2.05-7.14) for those aged 55 to 64 years, and 5.68 (95% CI, 2.99-10.79) for those aged 65 years or older compared with those younger than 45 years. The risk of retinopathy was higher among females than males (HR, 3.83 [95% CI, 1.86-7.89]), among patients with CKD stage 3 or greater (HR, 1.95 [95% CI, 1.25-3.04]), and among individuals with tamoxifen use (HR, 3.43 [95% CI, 1.08-10.89]). The likelihood of pericentral retinopathy was higher among Asian patients (HR, 15.02 [95% CI, 4.82-46.87]) and Black patients (HR, 5.51 [95% CI, 1.22-24.97]) compared with non-Hispanic White patients.This study suggests that increasing age, female sex, CKD stage 3 or greater, and tamoxifen use were associated with a higher risk of hydroxychloroquine retinopathy, whereas being younger than 45 years at hydroxychloroquine initiation and male sex were associated with a lower risk. Race and ethnicity were also associated with the pattern of retinopathy. These factors should be incorporated into hydroxychloroquine dosing decisions.

  View details for DOI 10.1001/jamanetworkopen.2024.10677

  View details for PubMedID 38722628

• Questioning accelerated hydroxychloroquine retinopathy. Documenta ophthalmologica. Advances in ophthalmology Marmor, M. F. 2024

  View details for DOI 10.1007/s10633-024-09973-y

  View details for PubMedID 38613609

• Most paintings by Turner and Monet show stylistic evolution, not changes in pollution. Proceedings of the National Academy of Sciences of the United States of America Marmor, M. F. 2023; 120 (16): e2302177120

  View details for DOI 10.1073/pnas.2302177120

  View details for PubMedID 37036989

• Hydroxychloroquine Dose and Risk for Incident Retinopathy : A Cohort Study. Annals of internal medicine Melles, R. B., Jorge, A. M., Marmor, M. F., Zhou, B., Conell, C., Niu, J., McCormick, N., Zhang, Y., Choi, H. K. 2023

  Abstract

  Hydroxychloroquine is recommended for all patients with systemic lupus erythematosus and is often used for other inflammatory conditions, but a critical long-term adverse effect is vision-threatening retinopathy.To characterize the long-term risk for incident hydroxychloroquine retinopathy and examine the degree to which average hydroxychloroquine dose within the first 5 years of treatment predicts this risk.Cohort study.U.S. integrated health network.All patients aged 18 years or older who received hydroxychloroquine for 5 or more years between 2004 and 2020 and had guideline-recommended serial retinopathy screening.Hydroxychloroquine dose was assessed from pharmacy dispensing records. Incident hydroxychloroquine retinopathy was assessed by central adjudication of spectral domain optical coherence tomography with severity assessment (mild, moderate, or severe). Risk for hydroxychloroquine retinopathy was estimated over 15 years of use according to hydroxychloroquine weight-based dose (>6, 5 to 6, or ≤5 mg/kg per day) using the Kaplan-Meier estimator.Among 3325 patients in the primary study population, 81 developed hydroxychloroquine retinopathy (56 mild, 17 moderate, and 8 severe), with overall cumulative incidences of 2.5% and 8.6% at 10 and 15 years, respectively. The cumulative incidences of retinopathy at 15 years were 21.6% for higher than 6 mg/kg per day, 11.4% for 5 to 6 mg/kg per day, and 2.7% for 5 mg/kg per day or lower. The corresponding risks for moderate to severe retinopathy at 15 years were 5.9%, 2.4%, and 1.1%, respectively.Possible misclassifications of dose due to nonadherence to filled prescriptions.In this large, contemporary cohort with active surveillance retinopathy screening, the overall risk for hydroxychloroquine retinopathy was 8.6% after 15 years, and most cases were mild. Higher hydroxychloroquine dose was associated with progressively greater risk for incident retinopathy.National Institutes of Health.

  View details for DOI 10.7326/M22-2453

  View details for PubMedID 36645889

• Rapid Macular Thinning is an Early Indicator of Hydroxychloroquine Retinal Toxicity. Ophthalmology Melles, R. B., Marmor, M. F. 2022

  Abstract

  PURPOSE: To demonstrate rapid macular thinning as an early and objective sign of hydroxychloroquine (HCQ) retinopathy.DESIGN: Retrospective case cohort.SUBJECTS: Cohort of 301 long-term HCQ therapy patients at Kaiser Permanente Northern California who had a minimum of four optical coherence tomography (OCT) studies which included Early Treatment Diabetic Retinopathy Study (ETDRS) retinal thickness values over a minimum interval of four years.METHODS: Creation of sequential retinal thickness plots to show the rate of change in macular thickness within ETDRS regions.MAIN OUTCOME MEASURES: 1) Identification of rapid macular thinning, 2) Comparison of patients with rapid thinning to those with stable macular thickness, and 3) Comparison of rapid thinning patients with and without conventional OCT or 10-2 visual field signs of HCQ toxicity.RESULTS: Retina thinning in 219 stable patients on long-term HCQ therapy averaged 0.62 ± 0.45 (mean ± standard deviation) microns per year, while 82 patients showed a period of relatively linear rapid thinning with a loss of 3.75 ± 1.34 microns per year. Of the patients with rapid thinning, 38 eventually developed conventional OCT or 10-2 visual field signs of HCQ retinal toxicity. The cumulative retinal thinning in these patients was 25.1 ± 6.2 microns compared to 15.7 ± 4.0 microns in those without conventional toxicity (p < 0.01).CONCLUSIONS: Retinal thickness remains stable for many years in most patients on long-term HCQ therapy, but after a critical point the retina may begin to thin rapidly. Sequential plots of inner and outer ETDRS ring macular thickness provide objective evidence of this early structural change several years before conventional signs appear. This approach can alert patients and prescribing physicians to potential retinal damage and uses readily available OCT measurements that could be automated by manufacturers for use in comprehensive eyecare settings.

  View details for DOI 10.1016/j.ophtha.2022.05.002

  View details for PubMedID 35568277

• Risk Factors for Hydroxychloroquine Retinopathy and Its Subtypes - Prospective Adjudication Analysis of 4,899 Incident Users Jorge, A., Melles, R., Conell, C., Lu, N., Marmor, M., Young, L., McCormick, N., Zhang, Y., Choi, H. K. WILEY. 2021: 2068-2071

  View details for Web of Science ID 000744545204029

• Collaboration for the Management of Hydroxychloroquine. Ophthalmology Rosenbaum, J. T., Costenbader, K. H., Desmarais, J., Ginzler, E. M., Fett, N., Goodman, S. M., O'Dell, J. R., Schmajuk, G., Werth, V. P., Melles, R. B., Marmor, M. F. 2021

  View details for DOI 10.1016/j.ophtha.2021.02.015

  View details for PubMedID 33752915

• ACR, AAD, RDS, and AAO 2020 Joint Statement on Hydroxychloroquine Use with Respect to Retinal Toxicity. Arthritis & rheumatology (Hoboken, N.J.) Rosenbaum, J. T., Costenbader, K. H., Desmarais, J., Ginzler, E. M., Fett, N., Goodman, S. M., O'Dell, J. R., Schmajuk, G., Werth, V. P., Melles, R. B., Marmor, M. F. 2021

  Abstract

  Prescribing clinicians and eye care specialists share responsibility for safely prescribing hydroxychloroquine (HCQ) and screening for the potential risk of retinopathy. Two relevant national societies, the American College of Rheumatology (ACR) and the American Academy of Ophthalmology (AAO), have independently offered management guidelines (1, 2), but this is the first joint statement to emphasize points of agreement that should be recognized by practitioners in all specialties.

  View details for DOI 10.1002/art.41683

  View details for PubMedID 33559327

• An Examination of the Propositus of Enhanced S-Cone Syndrome 30 Years After Diagnosis. JAMA ophthalmology Marmor, M. F. 2020

  View details for DOI 10.1001/jamaophthalmol.2020.2556

  View details for PubMedID 32722798

• The Eyes of the Angel of Death: Ophthalmic experiments of Josef Mengele. Survey of ophthalmology Halioua, B., Marmor, M. F. 2020

  Abstract

  The infamous SS doctor Josef Mengele was known as the Angel of Death for choosing and condemning Jews, gypsies, and other prisoners to the gas chambers at the Auschwitz-Birkenau concentration camp. Less known was his active participation in ophthalmic research with equal disregard for life and ethical principles. Mengele was not an ophthalmologist, but he worked in close collaboration and complicity with two genetic researchers at the Kaiser-Wilhelm Institute in Berlin, Karin Magnussen and Otmar Von Verschuer. The objective of the Eye Colour Protocol was to demonstrate hereditary differences in iris structure determined by race, and ostensibly to "cure" heterochromia. Mengele sent heterochromous Gypsy eyes to Magnussen, extracted from the bodies of inmates who died (or he killed). Mengele injected adrenaline into children's eyes in an attempt to change eye color, and to study environmental influences. Mengele was undoubtedly influenced to conduct these human experiments by his great ambition to publish to obtain academic promotion. These ophthalmologic experiments not only solidify Mengele's reputation as an angel of death, but also show the symbiosis that existed between the concentration camp physicians and others in the Nazi medical establishment. Ophthalmology, like all of medicine, has had its share of unethical experimentation, but none with more disregard for life and ethical principles than that of Mengele at Auschwitz.

  View details for DOI 10.1016/j.survophthal.2020.04.007

  View details for PubMedID 32387532

• Night Blindness in a Healthy Middle-Class Child OPHTHALMIC SURGERY LASERS & IMAGING RETINA Marmor, M. F. 2020; 51 (5): 286–88

  Abstract

  How do you clinically approach a night-blind child in a vegetarian family, with no obvious dystrophy and no obvious malnutrition? This case reviews some of the issues, and it reminds us of some of the cautions. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:286-288.].

  View details for DOI 10.3928/23258160-20200501-06

  View details for Web of Science ID 000539315500006

  View details for PubMedID 32511732

• COVID-19 and Chloroquine/Hydroxychloroquine: is there Ophthalmological Concern? American journal of ophthalmology Marmor, M. F. 2020

  View details for DOI 10.1016/j.ajo.2020.03.028

  View details for PubMedID 32247518

• TOPOGRAPHIC OPTICAL COHERENCE TOMOGRAPHY SEGMENTATION SHOWS LIMITED ELLIPSOID ZONE RECOVERY IN MILD HYDROXYCHLOROQUINE RETINOPATHY. Retinal cases & brief reports de Sisternes, L., Pham, B. H., Durbin, M., Marmor, M. F. 2020

  Abstract

  PURPOSE: Optical coherence tomography (OCT) cross-sections have shown limited ellipsoid zone (EZ) improvement in mild hydroxychloroquine (HCQ) retinopathy within a few years after drug cessation. However, the extent, functional significance, and stability of such changes over time remain unclear.METHODS: We created en face EZ maps using automated pixel-by-pixel segmentation for four patients with early-moderate HCQ toxicity followed for 6-8 years after drug cessation. These maps were compared with OCT cross-sections, fundus autofluorescence, and automated 10-2 visual fields.RESULTS: One patient had no EZ line loss; one had stable EZ loss throughout follow-up; two showed 30 to 40% reduction in the area of loss, largely in the first 2 years. This limited recovery mostly occurred in regions where the EZ line was only thinned or fragmented; other similar areas did not improve. Fundus autofluorescence hyperfluorescence and visual fields did not show consistent correlation with topography.CONCLUSION: Anatomic EZ recovery, when present, was restricted to regions of mild damage and did not correlate with fundus autofluorescence or improvement in visual fields. Topographic mapping seemed no more sensitive locally than cross-sectional OCT but may aid detection and longitudinal follow-up of toxicity by showing early damage or changes in the macula that could be missed with individual cross-sections.

  View details for DOI 10.1097/ICB.0000000000000993

  View details for PubMedID 32150114

• Sequential Retinal Thickness Analysis Shows Hydroxychloroquine Damage Before Other Screening Techniques. Retinal cases & brief reports Marmor, M. F., Durbin, M. n., de Sisternes, L. n., Pham, B. H. 2020; Publish Ahead of Print

  Abstract

  We sought to determine the earliest diagnostic signs of HCQ retinopathy up to the point of clinical recognition.Spectral domain optical coherence tomography (sdOCT) cross-sections, fundus autofluorescence (FAF) and visual fields were generated clinically. Stored sdOCT data were re-examined later to generate topographic ellipsoid zone (EZ) maps, minimum intensity (MI) analysis and sequential plots of regional retinal thickness.Retrospective series of 6 patients (5 parafoveal disease; 1 pericentral disease) with at least 3 examinations over 3.5 years or more preceding diagnosis of HCQ retinopathy.SdOCT cross-sections and fields showed similar sensitivity; FAF was not helpful. In parafoveal cases, EZ topography and MI analysis were no more reliable. Sequential thickness plots from 4 parafoveal cases showed dramatic retinal thinning across the posterior pole beginning 4-5 years before clinical diagnosis, with parafoveal regions thinning even faster. The pericentral case showed thinning only outside the central macula. Peripheral EZ loss was more dramatic with EZ topography than sdOCT cross-sections.Sequential retinal thickness plots reveal definitive thinning years before current diagnostic procedures. We hope that OCT manufacturers will develop software to display such measurements. EZ topography was not more sensitive than sdOCT cross-sections but important for recognizing pericentral disease.

  View details for DOI 10.1097/ICB.0000000000001108

  View details for PubMedID 33394957

• COVID-19 and Chloroquine/Hydroxychloroquine: Is There Ophthalmological Concern? American journal of ophthalmology Marmor, M. F. 2020

  View details for DOI 10.1016/j.ajo.2020.03.029

  View details for PubMedID 32439074

  View details for PubMedCentralID PMC7205730

• The rapid N-wave as a potentially useful measure of the photopic negative response. Documenta ophthalmologica. Advances in ophthalmology Pham, B. H., Goldberg, J. L., Marmor, M. F. 2020

  Abstract

  The photopic negative response (PhNR) correlates with ganglion cell function and has previously been examined as an indicator of glaucomatous optic nerve damage. However, it is a prolonged response that is measured against baseline, and its clinical utility has been limited by extensive variability, poor repeatability, and baseline instability. We have observed a distinct brief negative wave ("N-wave") commonly present within the slow PhNR trough, which may provide practical and analytic advantages as a clinical measure.We reviewed data from an interventional trial of 59 glaucoma patients who had 4 exams over an 8-month period. The PhNR was recorded with standard ISCEV stimuli (1 Hz and in some cases 4 Hz stimulation), and N-waves were measured manually, relative to return to baseline.N-waves, when present, could be measured easily despite shifting baselines and a degree of background noise. The PhNR median amplitude centered around 18 μV, while the N-wave median centered around 7 μV, with a distribution of responses skewed toward low or zero amplitudes.The N-wave appears to be a component of the longer PhNR, though its exact origin and significance remain unclear. As a rapid waveform that is independent of baseline, the N-wave is in many ways easier to measure accurately than the slower PhNR, which is highly dependent on baseline stability. The N-wave may prove useful clinically if further studies can optimize its stimulation, show its behavior in normal individuals and find correlation with markers of optic nerve disease.

  View details for DOI 10.1007/s10633-020-09769-w

  View details for PubMedID 32507902

• The 2016 American Academy of Ophthalmology Recommendations for Hydroxychloroquine Dosing Give Accurate Advice for All Patients. Ophthalmology. Retina Marmor, M. F. 2019; 3 (10): 807–8

  View details for DOI 10.1016/j.oret.2019.06.014

  View details for PubMedID 31585708

• SEQUENTIAL CHANGES IN HYDROXYCHLOROQUINE RETINOPATHY UP TO 20 YEARS AFTER STOPPING THE DRUG Implications for Mild Versus Severe Toxicity RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES Pham, B. H., Marmor, M. F. 2019; 39 (3): 492–501

  View details for DOI 10.1097/IAE.0000000000002408

  View details for Web of Science ID 000480740100009

• Night Blindness, Ring Scotoma, and a Nonrecordable Electroretinogram in an Elderly Woman JAMA OPHTHALMOLOGY Grassi, M. A., Maker, M. P., Marmor, M. F. 2019; 137 (1): 109–10

  View details for DOI 10.1001/jamaophthalmol.2018.3408

  View details for Web of Science ID 000455657000027

• Leonardo da Vinci Probably Did Not Have Strabismus. JAMA ophthalmology Marmor, M. F. 2019

  View details for DOI 10.1001/jamaophthalmol.2019.2214

  View details for PubMedID 31513244

• Transplantation of Mature Photoreceptors in Rodents With Retinal Degeneration. Translational vision science & technology Lorach, H. n., Kang, S. n., Bhuckory, M. B., Trouillet, A. n., Dalal, R. n., Marmor, M. n., Palanker, D. n. 2019; 8 (3): 30

  Abstract

  To demonstrate survival and integration of mature photoreceptors transplanted with the retinal pigment epithelium (RPE).Full-thickness retina with attached RPE was harvested from healthy adult rats. Grafts were implanted into two rat models of retinal degeneration, Royal College of Surgeons (RCS) and S334ter-3. Survival of the host and transplanted retina was monitored using optical coherence tomography (OCT) for up to 6 months. The retinal structure and synaptogenesis between the host and transplant was assessed by histology and immunohistochemistry.OCT and histology demonstrated a well-preserved photoreceptor layer with inner and outer segments, while the inner retinal layers of the transplant largely disappeared. Grafts, including RPE, survived better than without and the transplanted RPE appeared as a monolayer integrated with the native one. Synaptogenesis was observed through sprouting of new dendrites from the host bipolar cells and synaptic connections forming with cells of the transplant. However, in many samples, a glial fibrillary acidic protein-positive membrane separated the host retina and the graft.Presence of RPE in the graft improved the survival of transplanted photoreceptors. Functional integration between the transplant and the host retina is likely to be further enhanced if formation of a glial seal could be prevented. Transplantation of the mature photoreceptors with RPE may be a practical approach to restoration of sight in retinal degeneration.This approach to restoration of sight in patients with photoreceptor degeneration can be rapidly advanced to clinical testing. In patients with central scotoma, autologous transplantation of the peripheral retina can be an option.

  View details for DOI 10.1167/tvst.8.3.30

  View details for PubMedID 31171997

  View details for PubMedCentralID PMC6543858

• SEQUENTIAL CHANGES IN HYDROXYCHLOROQUINE RETINOPATHY UP TO 20 YEARS AFTER STOPPING THE DRUG: Implications for Mild Versus Severe Toxicity. Retina (Philadelphia, Pa.) Pham, B. H., Marmor, M. F. 2018

  Abstract

  PURPOSE: To characterize the stability or progression of different stages of hydroxychloroquine (HCQ) retinopathy up to 20 years after stopping the drug.METHODS: We reviewed findings from 13 patients with initial HCQ retinopathy classified as early (patchy photoreceptor damage), moderate (ring of photoreceptor thinning or scotoma), or severe (retinal pigment epithelial [RPE] damage). Patients had been off HCQ for as many as 14 years at initial examination and were subsequently followed for 5 years to 8 years with repeated fundus autofluorescence and spectral domain optical coherence tomography.RESULTS: Early and moderate cases stabilized in fundus autofluorescence appearance, foveal thickness, ellipsoid zone line length, and visual acuity for up to 9 years after stopping HCQ. By contrast, severe cases demonstrated a continual loss of these parameters for up to 20 years off the drug. The presence of RPE damage at initial examination predicted progressive retinopathy over many years.CONCLUSION: The steady progression of severe HCQ retinopathy in eyes showing RPE damage after drug cessation suggests a metabolic insult that chronically destabilizes rather than destroys cellular function, with a clinical course resembling that of genetic dystrophies. Our findings stress the importance of early detection to minimize progression and visual loss.

  View details for PubMedID 30550532

• Unilateral retinitis pigmentosa in children JOURNAL OF AAPOS Mercado, C. L., Pham, B. H., Beres, S., Marmor, M. F., Lambert, S. R. 2018; 22 (6): 457–61

  View details for DOI 10.1016/j.jaapos.2018.08.003

  View details for Web of Science ID 000453638000013

• Night Blindness, Ring Scotoma, and a Nonrecordable Electroretinogram in an Elderly Woman. JAMA ophthalmology Grassi, M. A., Maker, M. P., Marmor, M. F. 2018

  View details for PubMedID 30452517

• Baseline Retinal Examinations in Patients With Systemic Lupus Erythematosus Newly Initiating Hydroxychloroquine Treatment in a US Medicaid Systemic Lupus Erythematosus Population, 2000-2010 ARTHRITIS CARE & RESEARCH Lin, T., Marmor, M. F., Barbhaiya, M., Guan, H., Chen, S. K., Feldman, C. H., Costenbader, K. H. 2018; 70 (11): 1700–1706

  Abstract

  Baseline retinal examinations have long been recommended for patients beginning treatment with hydroxychloroquine (HCQ), but it is unknown how well this guideline is followed. We investigated baseline eye examinations among US SLE patients enrolled in Medicaid in whom HCQ treatment was newly initiated.Using billing codes, we identified SLE patients ages 18-65 years who were enrolled in Medicaid and residing in the 29 most populated US states, from 2000 to 2010. New users of HCQ were identified by filled prescriptions, with none filled in the preceding 12 months. Retinal examinations that were performed within 30 days before to 1 year after the index prescription were identified. We examined the proportions of patients receiving retinal examinations over the study years and compared the characteristics of those who did and those who did not receive examinations, using bivariable and multivariable logistic regression models.Among 12,755 SLE patients newly starting HCQ treatment, 32.5% received baseline dilated eye examinations. The proportions of patients receiving baseline eye examinations did not significantly change from 2000 to 2010 (31.0-34.4%; P for linear trend = 0.12). Factors associated with an increased likelihood of having an examination included female sex, Asian versus white race, and a higher number of laboratory tests performed during the preceding year. Compared with white patients, lower proportions of black and Native American patients with SLE had baseline retinal examinations.Only one-third of patients with SLE enrolled in Medicaid and in whom HCQ was newly initiated received the recommended baseline retinal examinations, and this proportion did not significantly increase from 2000 to 2010. The sociodemographic variation in this recommended care has been observed for other recommended medical care in SLE and requires both further investigation and interventions to address it.

  View details for PubMedID 29409142

• Riggs-type dominant congenital stationary night blindness: ERG findings, a new GNAT1 mutation and a systemic association DOCUMENTA OPHTHALMOLOGICA Marmor, M. F., Zeitz, C. 2018; 137 (1): 57–62

  View details for DOI 10.1007/s10633-018-9651-0

  View details for Web of Science ID 000440423900007

• Clinical display of mfERG data DOCUMENTA OPHTHALMOLOGICA Marmor, M. F., Cabael, L. 2018; 137 (1): 63–70

  View details for DOI 10.1007/s10633-018-9650-1

  View details for Web of Science ID 000440423900008

• Riggs-type dominant congenital stationary night blindness: ERG findings, a new GNAT1 mutation and a systemic association. Documenta ophthalmologica. Advances in ophthalmology Marmor, M. F., Zeitz, C. 2018

  Abstract

  PURPOSE: Complete congenital stationary night blindness (CSNB) is most often x-linked or recessive, and associated with a transmission defect from photoreceptors to bipolar cells. This produces a characteristic "negative" Schubert-Bornschein type of scotopic rod-cone electroretinogram (ERG) with a large a-wave and minimal b-wave. CSNB from abnormalities in phototransduction can be recessive or dominant and is much less common. This produces a Riggs type of ERG with loss of the rod a-wave as well as the b-wave. We report the clinical and ERG findings from a family with autosomal dominant CSNB that was shown previously to have a new GNAT1 mutation with a novel mechanism of action. They provide a classic demonstration of the Riggs-type ERG and have an unusual systemic association.METHODS: Clinical case report of a father and daughter.RESULTS: A Chinese father and daughter presented with good visual acuity, moderate myopia, and lifelong night blindness. Both show normal fundi except for mild myopia, and fundus autofluorescence and OCT images are normal. Their ERGs illustrate the typical Riggs-type ERG with no rod a-wave (they have only a small cone-dominated combined response). They also have postural orthostatic tachycardia syndrome (POST), which is an autonomic dysfunction disorder thought usually to be sporadic. The retinal gene analyses revealed no abnormalities that might account for POST.CONCLUSIONS: Our family's ERG showed essentially no rod response, consistent with a Danish GNAT1 pedigree but different from the Nougaret GNAT1 pedigree that shows partial preservation of rod signal. A genetic connection between CSNB and POST would be intriguing, but we found no evidence for this.

  View details for PubMedID 30051303

• Clinical display of mfERG data. Documenta ophthalmologica. Advances in ophthalmology Marmor, M. F., Cabael, L. 2018

  Abstract

  PURPOSE: Many mfERG displays show normal responses that are larger at the center than peripherally, and the typical linear display of signals is inaccurate with respect to the retinal location of the signals. Printouts do not always indicate retinal or field view, they sometimes emphasize 3-D topographic plots which are not always representative of physiologic signals, and they show ring response densities which are different in every ring and hard to interpret without norms. These problems limit the clinical usefulness of the mfERG and limit communication in the literature. We share our Stanford Display to illustrate possible solutions to these problems.METHODS: We have changed the scaling factor for our mfERG unit to produce a trace array with near equal signals everywhere. We display responses is a spatially scaled array, in a retinal view, so that signals appear in their correct anatomic locations relative to a fundus image. The 3-D display is minimized on the page of signal analysis, and we emphasize ring response averages rather than ring response densities.RESULTS: The new scaling and trace array display greatly facilitate the analysis of retinal disease. Regions of loss are easily recognized in their fundus location. Ring ratios based upon response amplitudes all have a normal value of 1.0 which simplifies analysis. A case of early hydroxychloroquine retinopathy demonstrates the use of this Stanford display.CONCLUSIONS: Recognition of these recording and display options may help mfERG users to maximize the value of the test. Proper scaling of the mfERG stimulus array facilitates localization of retinal disease and simplifies ring response analysis. Different laboratories will have different priorities for signal analysis, but mfERG displays should always indicate the eccentricity of responses, and the use of a retina or field view.

  View details for PubMedID 30030672

• Sharp decline in hydroxychloroquine dosing-analysis of 17,797 initiators from 2007 to 2016 CLINICAL RHEUMATOLOGY Melles, R. B., Jorge, A. M., Marmor, M. F., Zhang, Y., Choi, H. K. 2018; 37 (7): 1853–59

  Abstract

  We aimed to assess the impact of ophthalmology weight-based hydroxychloroquine (HCQ) dosing guidelines on prescribing patterns. We examined initial HCQ prescription dosing between 2007 and 2016 and determined independent predictors for HCQ dosing above the previous (2011) recommended ≤ 6.5 mg/kg of ideal body weight (IBW)/day and the latest (2016) recommended ≤ 5.0 mg/kg of actual body weight (ABW)/day using logistic regression. Among 17,797 patients (82% female), the proportion of 400 mg prescribed daily dosing declined sharply from 80% in 2007-2011 to nearly 40% in 2014, whereas the proportions of 200- and 300-mg daily doses showed the opposite trends during the same periods. Accordingly, the risk of HCQ dosing above the guideline recommendations declined by more than 60%. While 36% of normal body mass index (BMI) individuals were classified as dosing above the IBW-based guideline, 66% would have received dosing above the latest ABW-based guideline. The risk of excess dosing was associated with female patients and dermatology prescribers (adjusted odds ratios ≥ 2 according to IBW- or ABW-based guidelines). There has been a sharp decline in HCQ dosing following ophthalmology weight-based guidelines in recent years. While this trend is likely helpful in reducing the risk of retinopathy, its potential impact on HCQ efficacy remains to be clarified.

  View details for PubMedID 29696437

• Hydroxychloroquine During Cancer Therapy. Retinal cases & brief reports Marmor, M. F. 2018

  View details for PubMedID 29781868

• DIFFUSE CHORIORETINOPATHY WITHOUT SEROUS DETACHMENT ASSOCIATED WITH CARDIAC TRANSPLANTATION. Retinal cases & brief reports Marmor, M. F. 2018

  Abstract

  PURPOSE: To analyze an unusual case of widespread chorioretinopathy after cardiac transplantation for its potential etiology and clinical significance.METHODS: Clinical examinations included widefield and macular color and fundus autofluorescence photography, spectral domain optical coherence tomography, fluorescein angiography and indocyanine green angiography, full-field electroretinography, and Goldmann visual fields.PATIENT: A 44-year-old Hispanic woman was referred to rule out retinitis pigmentosa. Medical history revealed cardiac transplantation 6 months previously for idiopathic cardiomyopathy.RESULTS: Visual acuity was 20/20 in both eyes. The fundi showed widespread gray mottling and little pigmentation, but fundus autofluorescence revealed black speckling broadly across the fundus, and geographic retinal pigment epithelium loss in the nasal midperiphery of the left eye. Spectral domain optical coherence tomography showed normal inner retina, and surprising preservation of outer nuclear layer, but the ellipsoid zone line was fragmented, and the interdigitation zone line was replaced with irregular debris. Retinal pigment epithelium was very thin with occasional excrescences. Electroretinography showed mild loss of both rods and cones, with mild flicker peak delay only in the left eye. Fluorescein angiography showed no leakage, but a reticular pigment pattern in the macula. Indocyanine green angiography showed irregular arteriolar remodeling, and few large arteries.DISCUSSION AND CONCLUSION: Serous retinopathy is well known after organ transplantations, but this patient had retinal pigment epithelium and retinal damage well into the periphery and no leakage. Retinal dystrophy was deemed unlikely given the relatively good electroretinography. The indocyanine green vascular changes raise the possibility of a transient choroidal ischemic event during or shortly after cardiac surgery. The event altered retinal pigment epithelium diffusely, but allowed for enough regeneration to sustain retinal function. Diffuse transplant chorioretinopathy may be discovered if postcardiac transplant patients get peripheral retinal examinations.

  View details for PubMedID 29342012

• A Novel Heterozygous Missense Mutation in GNAT1 Leads to Autosomal Dominant Riggs Type of Congenital Stationary Night Blindness BIOMED RESEARCH INTERNATIONAL Zeitz, C., Mejecase, C., Stevenard, M., Michiels, C., Audo, I., Marmor, M. F. 2018: 7694801

  Abstract

  Autosomal dominant congenital stationary night blindness (adCSNB) is rare and results from altered phototransduction giving a Riggs type of electroretinogram (ERG) with loss of the rod a-wave and small b-waves. These patients usually have normal vision in light. Only few mutations in genes coding for proteins of the phototransduction cascade lead to this condition; most of these gene defects cause progressive rod-cone dystrophy. Mutation analysis of an adCSNB family with a Riggs-type ERG revealed a novel variant (c.155T>A p.Ile52Asn) in GNAT1 coding for the α-subunit of transducin, cosegregating with the phenotype. Domain predictions and 3D-modelling suggest that the variant does not affect the GTP-binding site as other GNAT1 adCSNB mutations do. It affects a predicted nuclear localization signal and a part of the first α-helix, which is distant from the GTP-binding site. The subcellular protein localization of this and other mutant GNAT1 proteins implicated in CSNB are unaltered in mammalian GNAT1 overexpressing cells. Our findings add a third GNAT1 mutation causing adCSNB and suggest that different pathogenic mechanisms may cause this condition.

  View details for PubMedID 29850563

  View details for PubMedCentralID PMC5937575

• Modern management of antimalarial usage and retinopathy. Journal of current ophthalmology Marmor, M. F. 2017; 29 (3): 143–44

  View details for PubMedID 28913503

• Modern management of antimalarial usage and retinopathy JOURNAL OF CURRENT OPHTHALMOLOGY Marmor, M. F. 2017; 29 (3): 143–44

  View details for DOI 10.1016/j.joco.2017.07.001

  View details for Web of Science ID 000442812900001

• ERG and other discriminators between advanced hydroxychloroquine retinopathy and retinitis pigmentosa DOCUMENTA OPHTHALMOLOGICA Nair, A. A., Marmor, M. F. 2017; 134 (3): 175-183

  Abstract

  To study whether the ERG and other clinical findings help to distinguish between advanced hydroxychloroquine (HCQ) retinopathy and pericentral or diffuse retinitis pigmentosa (RP) with similar fundus appearance.We conducted a retrospective analysis of patients with advanced HCQ retinopathy (n = 11), pericentral RP (n = 8) and diffuse RP (n = 8). Pericentral RP was defined as having limited fundus damage and relatively normal flicker ERG time-to-peak. Diffuse RP had typical loss of the rod ERG and flicker timing delay. All patients showed reduced amplitude of the ISCEV responses in the full-field electroretinogram (ERG). Aspects of history, visual field results, fundus appearance, fundus autofluorescence and ocular coherence tomography were also compared.Relative to pericentral RP, patients with HCQ toxicity showed delayed flicker ERG time-to-peak and lower ERG amplitudes, particularly combined rod-cone responses. Relative to diffuse RP, most HCQ toxicity patients had some preserved rod ERG response, and there was no obvious predilection for rod over cone damage. In addition, patients with HCQ toxicity usually lacked markers of long-standing degeneration such as bone spicule figures or severe loss of peripheral field. History of familial disease and long-standing night blindness were specific to RP.While the early signs of HCQ damage are typically regional in the posterior pole, advanced disease is characteristically diffuse (unlike pericentral RP). This is appropriate for a systemic toxin, as is the finding that rods and cones were both affected in the ERG to a similar degree (unlike genetic rod-cone dystrophies). For patients with severe HCQ exposure and some of our discriminatory findings, and no family history or prior night blindness, HCQ toxicity is a sufficient diagnosis without invoking a second rare disease (Occam's razor).

  View details for DOI 10.1007/s10633-017-9588-8

  View details for PubMedID 28451987

• Re: Marmor et al.: American Academy of Ophthalmology Statement: Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 Revision). (Ophthalmology 2016;123:1386-1394) Reply OPHTHALMOLOGY Marmor, M. F., Lai, T. Y., Kellner, U., Melles, R. B., Mieler, W. F. 2017; 124 (3): E29–E30

  View details for PubMedID 28219514

• Hydroxychloroquine Screening Alert: Change is in the Wind OPHTHALMIC SURGERY LASERS & IMAGING RETINA Marmor, M. F. 2017; 48 (2): 96–98

  Abstract

  Recent studies have changed the management of hydroxychloroquine retinopathy. This editorial outlines a new standard. Estimate dose by real weight, staying below 5 mg/kg. Asian patients may show initial damage outside the parafovea. Renal disease, maculopathy, and tamoxifen are major risk factors. Proper screening allows long usage and avoids bull's eye retinopathy.

  View details for DOI 10.3928/23258160-20170130-01

  View details for Web of Science ID 000397235600001

  View details for PubMedID 28195610

• The Demise of the Bull's Eye (Screening for Hydroxychloroquine Retinopathy) RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES Marmor, M. F. 2016; 36 (10): 1803–5

  View details for PubMedID 27388736

• The Prevalence of Hydroxychloroquine Retinopathy and Toxic Dosing, and the Role of the Ophthalmologist in Reducing Both AMERICAN JOURNAL OF OPHTHALMOLOGY Melles, R. B., Marmor, M. F. 2016; 170: 240

  View details for DOI 10.1016/j.ajo.2016.06.045

  View details for Web of Science ID 000385900300035

  View details for PubMedID 27544039

• Retinal remodeling in human retinitis pigmentosa EXPERIMENTAL EYE RESEARCH Jones, B. W., Pfeiffer, R. L., Ferrell, W. D., Watt, C. B., Marmor, M., Marc, R. E. 2016; 150: 149-165

  Abstract

  Retinitis Pigmentosa (RP) in the human is a progressive, currently irreversible neural degenerative disease usually caused by gene defects that disrupt the function or architecture of the photoreceptors. While RP can initially be a disease of photoreceptors, there is increasing evidence that the inner retina becomes progressively disorganized as the outer retina degenerates. These alterations have been extensively described in animal models, but remodeling in humans has not been as well characterized. This study, using computational molecular phenotyping (CMP) seeks to advance our understanding of the retinal remodeling process in humans. We describe cone mediated preservation of overall topology, retinal reprogramming in the earliest stages of the disease in retinal bipolar cells, and alterations in both small molecule and protein signatures of neurons and glia. Furthermore, while Müller glia appear to be some of the last cells left in the degenerate retina, they are also one of the first cell classes in the neural retina to respond to stress which may reveal mechanisms related to remodeling and cell death in other retinal cell classes. Also fundamentally important is the finding that retinal network topologies are altered. Our results suggest interventions that presume substantial preservation of the neural retina will likely fail in late stages of the disease. Even early intervention offers no guarantee that the interventions will be immune to progressive remodeling. Fundamental work in the biology and mechanisms of disease progression are needed to support vision rescue strategies.

  View details for DOI 10.1016/j.exer.2016.03.018

  View details for Web of Science ID 000384395300013

  View details for PubMedID 27020758

  View details for PubMedCentralID PMC5031517

• Update on Screening Recommendations for Hydroxychloroquine Retinopathy JAMA OPHTHALMOLOGY Kim, J. E., Marmor, M. F. 2016; 134 (7): 849

  View details for PubMedID 27258704

• Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy (2016 Revision) OPHTHALMOLOGY Marmor, M. F., Kellner, U., Lai, T. Y., Melles, R. B., Mieler, W. F. 2016; 123 (6): 1386-1394

  Abstract

  The American Academy of Ophthalmology recommendations on screening for chloroquine (CQ) and hydroxychloroquine (HCQ) retinopathy are revised in light of new information about the prevalence of toxicity, risk factors, fundus distribution, and effectiveness of screening tools.Although the locus of toxic damage is parafoveal in many eyes, Asian patients often show an extramacular pattern of damage. DOSE: We recommend a maximum daily HCQ use of ≤5.0 mg/kg real weight, which correlates better with risk than ideal weight. There are no similar demographic data for CQ, but dose comparisons in older literature suggest using ≤2.3 mg/kg real weight.The risk of toxicity is dependent on daily dose and duration of use. At recommended doses, the risk of toxicity up to 5 years is under 1% and up to 10 years is under 2%, but it rises to almost 20% after 20 years. However, even after 20 years, a patient without toxicity has only a 4% risk of converting in the subsequent year.High dose and long duration of use are the most significant risks. Other major factors are concomitant renal disease, or use of tamoxifen.A baseline fundus examination should be performed to rule out preexisting maculopathy. Begin annual screening after 5 years for patients on acceptable doses and without major risk factors.The primary screening tests are automated visual fields plus spectral-domain optical coherence tomography (SD OCT). These should look beyond the central macula in Asian patients. The multifocal electroretinogram (mfERG) can provide objective corroboration for visual fields, and fundus autofluorescence (FAF) can show damage topographically. Modern screening should detect retinopathy before it is visible in the fundus.Retinopathy is not reversible, and there is no present therapy. Recognition at an early stage (before any RPE loss) is important to prevent central visual loss. However, questionable test results should be repeated or validated with additional procedures to avoid unnecessary cessation of valuable medication.Patients (and prescribing physicians) should be informed about risk of toxicity, proper dose levels, and the importance of regular annual screening.

  View details for DOI 10.1016/j.ophtha.2016.01.058

  View details for PubMedID 26992838

• Analysis of Inner and Outer Retinal Thickness in Patients Using Hydroxychloroquine Prior to Development of Retinopathy JAMA OPHTHALMOLOGY de Sisternes, L., Hu, J., Rubin, D. L., Marmor, M. F. 2016; 134 (5): 511-519

  View details for DOI 10.1001/jamaophthalmol.2016.0155

  View details for Web of Science ID 000375796100011

• Analysis of Inner and Outer Retinal Thickness in Patients Using Hydroxychloroquine Prior to Development of Retinopathy. JAMA ophthalmology de Sisternes, L., Hu, J., Rubin, D. L., Marmor, M. F. 2016; 134 (5): 511-519

  Abstract

  Retinopathy is a known risk of long-term use of hydroxychloroquine sulfate. However, whether the inner as well as outer retina are involved before retinopathy develops and whether changes in the retina might signal impending toxic effects during screening remain unknown.To determine the degree of inner and outer retinal involvement in short- and long-term use of hydroxychloroquine before the development of retinopathy.This retrospective medical record review of spectral-domain optical coherence tomography (SD-OCT) findings was performed at an academic medical center. Thirty-two patients without retinopathy and with high-quality SD-OCT images were studied. Twenty-seven patients were age matched (49-65 years old) for comparison of retinal layers among patients who used the drug less than 5 years (n = 12) or longer than 15 years (n = 15) at the initial visit. Populations were also defined (without age limitation) for comparison of change during 25 to 52 months of follow-up among patients with initial use of less than 5 years (n = 7) or longer than 15 years (n = 8). Data were collected from 2010 to 2015.Measurements of inner and outer retinal thickness in SD-OCT images using commercial software and a Stanford pixel-by-pixel segmentation software that also provided topographic maps of thickness dimensions and change.Thirty-two patients (5 men and 27 women) were included in the analysis. Measurements of inner retinal thickness between short- and long-term hydroxychloroquine users (n = 27) in different retinal regions, and during a median 39 months of follow-up (n = 15), showed no statistically significant differences or change. Similarly, no significant differences or changes were identified in outer retinal thickness except for the final visit of 1 patient who developed focal parafoveal thinning, a toxic effect of hydroxychloroquine use. Cirrus ganglion cell analysis measurements were inaccurate in the presence of outer retinal damage.The inner retina appears not to be involved in hydroxychloroquine-induced retinopathy to any clinically relevant degree within the limitations of our sample size. No clinically apparent warning of outer retinal damage was seen in the SD-OCT images of long-term hydroxychloroquine users until the actual appearance of focal retinopathy. Early detection of hydroxychloroquine-induced retinopathy is known to prevent visual acuity loss and serious progression after the therapy is stopped, and these data suggest that screening should seek distinct new areas of retinopathy (shown by topographic thickness maps) rather than long-term progressive thinning.

  View details for DOI 10.1001/jamaophthalmol.2016.0155

  View details for PubMedID 26986043

• Vision, eye disease, and art: 2015 Keeler Lecture EYE Marmor, M. F. 2016; 30 (2): 287-303

  Abstract

  The purpose of this study was to examine normal vision and eye disease in relation to art. Ophthalmology cannot explain art, but vision is a tool for artists and its normal and abnormal characteristics may influence what an artist can do. The retina codes for contrast, and the impact of this is evident throughout art history from Asian brush painting, to Renaissance chiaroscuro, to Op Art. Art exists, and can portray day or night, only because of the way retina adjusts to light. Color processing is complex, but artists have exploited it to create shimmer (Seurat, Op Art), or to disconnect color from form (fauvists, expressionists, Andy Warhol). It is hazardous to diagnose eye disease from an artist's work, because artists have license to create as they wish. El Greco was not astigmatic; Monet was not myopic; Turner did not have cataracts. But when eye disease is documented, the effects can be analyzed. Color-blind artists limit their palette to ambers and blues, and avoid greens. Dense brown cataracts destroy color distinctions, and Monet's late canvases (before surgery) showed strange and intense uses of color. Degas had failing vision for 40 years, and his pastels grew coarser and coarser. He may have continued working because his blurred vision smoothed over the rough work. This paper can barely touch upon the complexity of either vision or art. However, it demonstrates some ways in which understanding vision and eye disease give insight into art, and thereby an appreciation of both art and ophthalmology.

  View details for DOI 10.1038/eye.2015.197

  View details for Web of Science ID 000370449500018

  View details for PubMedID 26563659

  View details for PubMedCentralID PMC4763116

• A Critical Review of the Effects of Hydroxychloroquine and Chloroquine on the Eye CLINICAL REVIEWS IN ALLERGY & IMMUNOLOGY Costedoat-Chalumeau, N., Dunogue, B., Leroux, G., Morel, N., Jallouli, M., Le Guern, V., Piette, J., Brezin, A. P., Melles, R. B., Marmor, M. F. 2015; 49 (3): 317-326

  Abstract

  Hydroxychloroquine (HCQ) and chloroquine have been used for more than 50 years to treat systemic lupus erythematosus (SLE) and other rheumatic diseases. In general, these drugs are well tolerated and rarely need to be discontinued because of an adverse systemic reaction. However, both medications can be irreversibly toxic to the retina. A new study indicates that toxicity is not as rare as once believed, but depends critically on daily dosage and duration of use, as well as other risk factors. With attention to dosage and other factors, and with proper screening for early signs of toxicity, HCQ can be prescribed with relative safety even over long periods of time.

  View details for DOI 10.1007/s12016-015-8469-8

  View details for PubMedID 25672591

• Rapid Onset of Retinal Toxicity From High-Dose Hydroxychloroquine Given for Cancer Therapy. American journal of ophthalmology Leung, L. B., Neal, J. W., Wakelee, H. A., Sequist, L. V., Marmor, M. F. 2015; 160 (4): 799-805 e1

  Abstract

  To report rapid onset of retinal toxicity in a series of patients followed on high-dose (1000 mg daily) hydroxychloroquine during an oncologic clinical trial studying hydroxychloroquine with erlotinib for non-small cell lung cancer.Retrospective observational case series.Ophthalmic surveillance was performed on patients in a multicenter clinical trial testing high-dose (1000 mg daily) hydroxychloroquine for advanced non-small cell lung cancer. The US Food & Drug Administration-recommended screening protocol included only visual acuity testing, dilated fundus examination, Amsler grid testing, and color vision testing. In patients seen at Stanford, additional sensitive screening procedures were added at the discretion of the retinal physician: high-resolution spectral-domain optical coherence tomography (OCT), fundus autofluorescence (FAF) imaging, Humphrey visual field (HVF) testing, and multifocal electroretinography (mfERG).Out of the 7 patients having exposure of at least 6 months, 2 developed retinal toxicity (at 11 and 17 months of exposure). Damage was identified by OCT imaging, mfERG testing, and, in 1 case, visual field testing. Fundus autofluorescence imaging remained normal. Neither patient had symptomatic visual acuity loss.These cases show that high doses of hydroxychloroquine can initiate the development of retinal toxicity within 1-2 years. Although synergy with erlotinib is theoretically possible, there are no prior reports of erlotinib-associated retinal toxicity despite over a decade of use in oncology. These results also suggest that sensitive retinal screening tests should be added to ongoing and future clinical trials involving high-dose hydroxychloroquine to improve safety monitoring and preservation of vision.

  View details for DOI 10.1016/j.ajo.2015.07.012

  View details for PubMedID 26189086

• Rapid Onset of Retinal Toxicity From High-Dose Hydroxychloroquine Given for Cancer Therapy. American journal of ophthalmology Leung, L. B., Neal, J. W., Wakelee, H. A., Sequist, L. V., Marmor, M. F. 2015; 160 (4): 799-805 e1

  View details for DOI 10.1016/j.ajo.2015.07.012

  View details for PubMedID 26189086

• Pericentral Hydroxychloroquine Retinopathy in Korean Patients OPHTHALMOLOGY Lee, D. H., Melles, R. B., Joe, S. G., Lee, J. Y., Kim, J., Lee, C., Yoo, B., Koo, B. S., Kim, J. T., Marmor, M. F., Yoon, Y. H. 2015; 122 (6): 1252-1256

  Abstract

  A pericentral pattern of hydroxychloroquine (HCQ) retinopathy recently has been recognized in the United States in patients of Asian heritage. We report on an investigation of this pericentral retinopathy within a Korean population.Retrospective, observational study.Patients taking HCQ who were referred to ophthalmology for screening of HCQ retinopathy.The medical records of patients were reviewed, including spectral domain optical coherence tomography, fundus autofluorescence, and visual fields.Frequency of pericentral pattern of HCQ retinopathy and features of progression.Among 218 patients referred, 9 (4.1%) were diagnosed with toxicity. Of these, 8 had a predominantly pericentral pattern of retinal change, whereas only 1 had the classic parafoveal distribution of retinal damage. Progression of retinopathy was documented in 3 patients followed more than 12 months while taking HCQ. No progression was seen in 2 patients without retinal pigment epithelial (RPE) damage who were followed for at least 12 months after discontinuation of HCQ.We found that a pericentral pattern of HCQ retinopathy was predominant among Korean patients, rather than the traditional (bull's eye) parafoveal pattern of damage. Retinopathy progressed while on the drug, but the progression stopped in patients with toxicity detected before RPE damage. These observations suggest the need for new approaches when screening for HCQ toxicity in Asian patients.

  View details for DOI 10.1016/j.ophtha.2015.01.014

  View details for PubMedID 25712474

• Topographic OCT Segmentation of Inner and Outer Retina in Progressive Hydroxychloroquine Retinopathy Marmor, M. F., de Sisternes, L., Hu, J., Rubin, D. L. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2015

  View details for Web of Science ID 000362882204236

• Localization of Damage in Progressive Hydroxychloroquine Retinopathy On and Off the Drug: Inner Versus Outer Retina, Parafovea Versus Peripheral Fovea INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE de Sisternes, L., Hu, J., Rubin, D. L., Marmor, M. F. 2015; 56 (5): 3415-3426

  Abstract

  To evaluate the relative involvement of inner and outer retina in hydroxychloroquine (HCQ) retinopathy while on the drug, and after drug cessation, using data from spectral-domain optical coherence tomography (SD-OCT).A total of 102 SD-OCT scans were obtained from 11 patients (classified as having early, moderate, or severe stages of toxicity) over a period of 4 years after cessation of HCQ. The inner and outer retina boundaries were identified automatically to measure thickness and characterize progression topographically.The segmentation of retinal layers was verified in SD-OCT cross-sections for all eyes and scans included in this study (a total of 102 scans). Topographic analysis showed that inner retina was not involved in HCQ toxicity to any meaningful degree, either between stages of retinopathy or after the drug is stopped. The characteristic bull's eye pattern of outer macula thinning appears when comparing moderate retinopathy (before any RPE damage) to the early stage. Later damage, as toxicity evolved to a severe stage, was diffuse across most of the macula. If the drug was stopped at an early or moderate stage, progression was limited to the first year and occurred diffusely without parafoveal localization.Hydroxychloroquine retinopathy primarily involves outer retina (photoreceptors). Outer retinal thinning while using HCQ initially involves the parafovea, but becomes diffuse across the macula as damage progresses or after drug cessation. When HCQ is stopped at an early or moderate stage (before RPE damage), progression seems to be limited to the first year.

  View details for DOI 10.1167/iovs.14-16345

  View details for PubMedID 26024126

• Hydroxychloroquine and the retina. JAMA Marmor, M. F., Melles, R. B. 2015; 313 (8): 847-848

  View details for DOI 10.1001/jama.2014.14558

  View details for PubMedID 25710661

• ISCEV Standard for full-field clinical electroretinography (2015 update) DOCUMENTA OPHTHALMOLOGICA McCulloch, D. L., Marmor, M. F., Brigell, M. G., Hamilton, R., Holder, G. E., Tzekov, R., Bach, M. 2015; 130 (1): 1-12

  Abstract

  This document, from the International Society for Clinical Electrophysiology of Vision (ISCEV), presents an updated and revised ISCEV Standard for full-field clinical electroretinography (ffERG or simply ERG). The parameters for Standard flash stimuli have been revised to accommodate a variety of light sources including gas discharge lamps and light emitting diodes. This ISCEV Standard for clinical ERGs specifies six responses based on the adaptation state of the eye and the flash strength: (1) Dark-adapted 0.01 ERG (rod ERG); (2) Dark-adapted 3 ERG (combined rod-cone standard flash ERG); (3) Dark-adapted 3 oscillatory potentials; (4) Dark-adapted 10 ERG (strong flash ERG); (5) Light-adapted 3 ERG (standard flash "cone" ERG); and (6) Light-adapted 30 Hz flicker ERG. ISCEV encourages the use of additional ERG protocols for testing beyond this minimum standard for clinical ERGs.

  View details for DOI 10.1007/s10633-014-9473-7

  View details for Web of Science ID 000348340800001

  View details for PubMedID 25502644

• Pericentral Retinopathy and Racial Differences in Hydroxychloroquine Toxicity OPHTHALMOLOGY Melles, R. B., Marmor, M. F. 2015; 122 (1): 110-116

  Abstract

  To describe patterns of hydroxychloroquine retinopathy distinct from the classic parafoveal (bull's eye) maculopathy.Retrospective case series.Patients from a large multi-provider group practice and a smaller university referral practice diagnosed with hydroxychloroquine retinopathy. Patients with widespread or "end-stage" retinopathy were excluded.Review of ophthalmic studies (fundus photography, spectral-domain optical coherence tomography, fundus autofluorescence, multifocal electroretinography, visual fields) and classification of retinopathy into 1 of 3 patterns: parafoveal (retinal changes 2°-6° from the fovea), pericentral (retinal changes ≥ 8° from the fovea), or mixed (retinal changes in both parafoveal and pericentral areas).Relative frequency of different patterns of hydroxychloroquine retinopathy and comparison of risk factors.Of 201 total patients (18% Asian) with hydroxychloroquine retinopathy, 153 (76%) had typical parafoveal changes, 24 (12%) also had a zone of pericentral damage, and 24 (12%) had pericentral retinopathy without any parafoveal damage. Pericentral retinopathy alone was seen in 50% of Asian patients but only in 2% of white patients. Patients with the pericentral pattern were taking hydroxychloroquine for a somewhat longer duration (19.5 vs. 15.0 years, P < 0.01) and took a larger cumulative dose (2186 vs. 1813 g, P = 0.02) than patients with the parafoveal pattern, but they were diagnosed at a more severe stage of toxicity.Hydroxychloroquine retinopathy does not always develop in a parafoveal (bull's eye) pattern, and a pericentral pattern of damage is especially prevalent among Asian patients. Screening practices may need to be adjusted to recognize pericentral and parafoveal hydroxychloroquine retinopathy.

  View details for DOI 10.1016/j.ophtha.2014.07.018

  View details for PubMedID 25182842

• The Risk of Toxic Retinopathy in Patients on Long-term Hydroxychloroquine Therapy JAMA OPHTHALMOLOGY Melles, R. B., Marmor, M. F. 2014; 132 (12): 1453-1460

  Abstract

  Hydroxychloroquine sulfate is widely used for the long-term treatment of autoimmune conditions but can cause irreversible toxic retinopathy. Prior estimations of risk were low but were based largely on short-term users or severe retinal toxicity (bull's eye maculopathy). The risk may be much higher because retinopathy can be detected earlier when using more sensitive screening techniques.To reassess the prevalence of and risk factors for hydroxychloroquine retinal toxicity and to determine dosage levels that facilitate safe use of the drug.Retrospective case-control study in an integrated health organization of approximately 3.4 million members among 2361 patients who had used hydroxychloroquine continuously for at least 5 years according to pharmacy records and who were evaluated with visual field testing or spectral-domain optical coherence tomography.Hydroxychloroquine use for at least 5 years.Retinal toxicity as determined by characteristic visual field loss or retinal thinning and photoreceptor damage, as well as statistical measures of risk factors and prevalence.Real body weight predicted risk better than ideal body weight and was used for all calculations. The overall prevalence of hydroxychloroquine retinopathy was 7.5% but varied with daily consumption (odds ratio, 5.67; 95% CI, 4.14-7.79 for >5.0 mg/kg) and with duration of use (odds ratio, 3.22; 95% CI, 2.20-4.70 for >10 years). For daily consumption of 4.0 to 5.0 mg/kg, the prevalence of retinal toxicity remained less than 2% within the first 10 years of use but rose to almost 20% after 20 years of use. Other major risk factors include kidney disease (odds ratio, 2.08; 95% CI, 1.44-3.01) and concurrent tamoxifen citrate therapy (odds ratio, 4.59; 95% CI, 2.05-10.27).These data suggest that hydroxychloroquine retinopathy is more common than previously recognized, especially at high dosages and long duration of use. While no completely safe dosage is identified from this study, daily consumption of 5.0 mg/kg of real body weight or less is associated with a low risk for up to 10 years. Knowledge of these data and risk factors should help physicians prescribe hydroxychloroquine in a manner that will minimize the likelihood of vision loss.

  View details for DOI 10.1001/jamaophthalmol.2014.3459

  View details for PubMedID 25275721

• Effect of Disease Stage on Progression of Hydroxychloroquine Retinopathy JAMA OPHTHALMOLOGY Marmor, M. F., Hu, J. 2014; 132 (9): 1105-1112

  Abstract

  Hydroxychloroquine sulfate retinopathy can progress after the drug is stopped. It is not clear how this relates to the stage of retinopathy or whether early screening with modern imaging technology can prevent progression and visual loss.To determine the relationship between progression of retinopathy and the severity of disease using objective data from optical coherence tomography and assess the value of early screening for the toxic effects of hydroxychloroquine.Clinical findings in patients with hydroxychloroquine retinopathy were monitored with repeated anatomical and functional examinations for 13 to 40 months after the drug was stopped in a referral practice in a university medical center. Eleven patients participated, with the severity of toxic effects categorized as early (patchy parafoveal damage shown on field or objective testing), moderate (a 50%-100% parafoveal ring of optical coherence tomography thinning but intact retinal pigment epithelium), and severe (visible bull's-eye damage).Visual acuity, white 10-2 visual field pattern density plots, fundus autofluorescence, spectral-density optical coherence tomography cross sections, thickness (from cube diagrams), and ellipsoid zone length.Visual acuity and visual fields showed no consistent change. Fundus autofluorescence showed little or no change except in severe cases in which the bull's-eye damage expanded progressively. Optical coherence tomography cross sections showed little visible change in early and moderate cases but progressive foveal thinning (approximately 7 μm/y) and loss of ellipsoid zone (in the range of 100 μm/y) in severe cases, which was confirmed by quantitative measurements. The measurements also showed some foveal thinning (approximately 4 μm/y) and deepening of parafoveal loss in moderate cases, but the breadth of the ellipsoid zone remained constant in both early and moderate cases. A few cases showed a suggestion of ellipsoid zone improvement.Patients with hydroxychloroquine retinopathy involving the retinal pigment epithelium demonstrated progressive damage on optical coherence tomography for at least 3 years after the drug was discontinued, including loss of foveal thickness and cone structure. Cases recognized before retinal pigment epithelium damage retained foveal architecture with little retinal thinning. Early recognition of hydroxychloroquine toxic effects before any fundus changes are visible, using visual fields and optical coherence tomography (along with fundus autofluorescence and multifocal electroretinography as indicated), will greatly minimize late progression and the risk of visual loss.

  View details for DOI 10.1001/jamaophthalmol.2014.1099

  View details for PubMedID 24922444

• Vision Loss and Hearing Loss in Painting and Musical Composition OPHTHALMOLOGY Marmor, M. F. 2014; 121 (7): 1480–85

  Abstract

  This article considers the impact of vision and hearing loss on great painters and musical composers. The visual work of Mary Cassatt, Georgia O'Keeffe, Edgar Degas, and Claude Monet all showed alterations as their vision failed. In contrast, Gabriel Fauré, Bedřich Smetana, and Ludwig von Beethoven wrote many of their best compositions while totally deaf, and Georg Friedrich Handel and Frederick Delius struggled to compose late in life when they lost their vision (although their hearing remained excellent). There are 2 major distinctions between the role of vision and hearing for these artistic disciplines. First, there is a surrogate means of "hearing" music, through the musical score, which allows composers to write and edit music while totally deaf. The greatest problem with deafness for a skilled composer is interference from internal noise (tinnitus). There is no surrogate for vision to allow a painter to work when the subject is a blur or the colors on the canvas cannot be distinguished. Second, although the appreciation of art is visual and that of music is auditory, the transcription of both art and musical composition is visual. Thus, visual loss does pose a problem for a composer accustomed to working with good sight, because it disrupts habitual methods of writing and editing music.

  View details for PubMedID 24565744

• RETINAL TOXICITIES OF CANCER THERAPY DRUGS Biologics, Small Molecule Inhibitors, and Chemotherapies RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES Liu, C. Y., Francis, J. H., Brodie, S. E., Marr, B., Pulido, J. S., Marmor, M. F., Abramson, D. H. 2014; 34 (7): 1261–80

  Abstract

  To review reported retinal side effects from current cancer therapy drugs.Retinal toxicities from ophthalmologic or oncologic case reports, case series, and clinical trials were identified by a systematic literature search using Lexicomp and PubMed.Four biologics, 8 small molecule inhibitors, and 17 traditional chemotherapy agents had reported retinal side effects. For biologics, interferon alpha 2b was associated with retinopathy, denileukin diftitiox with pigmentary retinopathy, ipilimumab with a Vogt-Koyanagi-Harada-like syndrome, and trastuzumab with retinal ischemia. For small molecule inhibitors, v-raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors were associated with uveitis, mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitors with pigment epithelium detachments, and tyrosine kinase inhibitors with macular edema. Steroid antagonists were associated with crystalline retinopathy and macular edema. Nitrosoureas, platinum analogs, and cytosine arabinoside were associated with retinal vascular occlusions. Antimicrotubular agents were associated with cystoid macular edema but without fluorescein leakage. Retinoic acid derivatives were associated with impaired night vision, and mitotane was associated with a pigmentary retinopathy and papilledema.Certain agents used in the treatment of systemic cancer are associated with ocular complications. Awareness of these complications will allow early detections and maybe reversal of some of the ocular problems.

  View details for PubMedID 24949716

• Disparity between Visual Fields and Optical Coherence Tomography in Hydroxychloroquine Retinopathy OPHTHALMOLOGY Marmor, M. F., Melles, R. B. 2014; 121 (6): 1257-1262

  Abstract

  American Academy of Ophthalmology recommendations for screening for hydroxychloroquine (HCQ) retinopathy advise objective measures, such as spectral-domain optical coherence tomography (SD-OCT) and multifocal electroretinography (mfERG) along with visual fields. However, the relative sensitivity and specificity of screening tests have not been fully resolved. We characterize a subset of patients with toxicity who show unusual disparity between fields and SD-OCT and thus have implications for screening practice.Review of charts and clinical data.Patients at Stanford and Kaiser Permanente who had used HCQ with greater than 1000 g cumulative exposure. There were more than 2000 such individuals, among whom 150 had clear evidence of toxicity.Patients were evaluated by visual fields (10-2 white Swedish Interactive Threshold Algorithm pattern deviation plots), SD-OCT, and sometimes mfERG or fundus autofluorescence.Relative findings on visual fields in comparison with SD-OCT.There were 11 patients among those with HCQ toxicity who had parafoveal ring scotomas but a normal-appearing SD-OCT. None had a history of macular disease or evidence for any other cause of bull's eye maculopathy. Conversely, all cases with a clear degree of parafoveal damage on SD-OCT showed at least some focal spots of parafoveal field loss.Approximately 10% of patients with early HCQ toxicity showed prominent ring scotomas on field testing without obvious SD-OCT abnormality. This should encourage the inclusion of visual fields as a key screening tool, even when SD-OCT (a more specific and objective test) also is performed. The combination of visual fields and SD-OCT gives both sensitivity and specificity while avoiding unnecessary stoppage of the drug.

  View details for DOI 10.1016/j.ophtha.2013.12.002

  View details for PubMedID 24439759

• The Progression of Hydroxychloroquine Retinopathy Depends on the Severity of Disease Marmor, M. F., Hu, J. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2014

  View details for Web of Science ID 000433205501111

• Automated Segmentation and Quantification of Retinal Layers in Patients with Hydroxychloroquine Toxicity de Sisternes, L., Marmor, M. F., Leng, T., Rubin, D. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2014

  View details for Web of Science ID 000433205501372

• Fundus Autofluorescence Is Not the Best Early Screen for Hydroxychloroquine Toxicity JAMA OPHTHALMOLOGY Marmor, M. F. 2013; 131 (11): 1487–88

  View details for DOI 10.1001/jamaophthalmol.2013.4835

  View details for Web of Science ID 000329848300023

  View details for PubMedID 24232086

• An Eye Chart for Edgar Degas JAMA OPHTHALMOLOGY Marmor, M. F. 2013; 131 (10): 1353-1355

  Abstract

  The French Impressionist painter Edgar Degas had progressive visual loss from a type of maculopathy during the last 40 years of his life. The effects of this visual failure are evident in a comparison of early and later pastels, which shows a loss of precision in outlining, shading, and detail over the years. A remarkable oil painting, Scene from the Steeplechase: The Fallen Jockey, provides on one canvas an historical record of his visual struggles. It was begun in 1866 and reworked in 1880 and 1897, during which his visual acuity fell from near normal to 20/200. Computer simulations show Degas' own view of this painting at each of these times and demonstrate how his style changed: details became rougher and larger in correspondence with his failing acuity. The painting is an eye chart of his career.

  View details for DOI 10.1001/jamaophthalmol.2013.1967

  View details for PubMedID 24114134

• Value of red targets and pattern deviation plots in visual field screening for hydroxychloroquine retinopathy. JAMA ophthalmology Marmor, M. F., Chien, F. Y., Johnson, M. W. 2013; 131 (4): 476-480

  Abstract

  To compare the value of red vs white 10-2 visual field testing in patients with different levels of hydroxychloroquine exposure and retinopathy in reference to recent American Academy of Ophthalmology recommendations on screening for hydroxychloroquine retinopathy that advised the use of 10-2 visual field testing with a white test object.We studied retrospectively 13 patients using hydroxychloroquine who had undergone both red (FASTPAC) and white (SITA) 10-2 automated visual field testing in the course of their management. On clinical grounds, they were judged to have no retinopathy, early retinopathy, or moderate or severe hydroxychloroquine retinopathy.White visual field diagrams were difficult to interpret, but pattern deviation plots consistently showed parafoveal sensitivity losses in early retinopathy. Red fields often showed more prominent scotomas in early retinopathy but sometimes showed irregular losses that were hard to evaluate. Either modality showed clear losses in moderate retinopathy. On repeated testing, the pattern deviation plots were somewhat more consistent than red fields in showing parafoveal damage.With white 10-2 visual field hydroxychloroquine screening, the use of pattern deviation plots should be standard practice. Red testing appears to be more sensitive for early retinopathy but may be slightly less specific or consistent. We believe the main application for red testing is in screening for the earliest signs of retinopathy. Either red or white fields should be acceptable for hydroxychloroquine screening, as long as the clinician is sensitive to the characteristic patterns of early parafoveal damage and is prepared to retest fields and add objective tests.

  View details for PubMedID 23710501

• Modulation of Transgene Expression in Retinal Gene Therapy by Selective Laser Treatment INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Lavinsky, D., Chalberg, T. W., Mandel, Y., Huie, P., Dalal, R., Marmor, M., Palanker, D. 2013; 54 (3): 1873-1880

  Abstract

  To develop a method for modulation of transgene expression in retinal pigment epithelium (RPE) using scanning laser that spares neurosensory retina.Fifteen pigmented rabbits received subretinal injection of recombinant adeno-associated virus (rAAV-2) encoding green fluorescent protein (GFP). GFP expression was measured using confocal scanning laser ophthalmoscopy (cSLO) fluorescence imaging and immunohistochemistry. To reduce the total expression in RPE by half, 50% of the transfected RPE cells were selectively destroyed by microsecond exposures to scanning laser with 50% pattern density. The selectivity of RPE destruction and its migration and proliferation were monitored using fluorescein angiography, spectral-domain optical coherence tomography (SD-OCT), and light, transmission, and scanning electron microscopy. 5-Bromo-2'-dioxyuridine (BrdU) assay was performed to evaluate proliferation of RPE cells.RPE cells were selectively destroyed by the line scanning laser with 15 μs exposures, without damage to the photoreceptors or Bruch's membrane. RPE cells started migrating after the first day, and in 1 week there was complete restoration of RPE monolayer. Selective laser treatment decreased the GFP fluorescence by 54% as compared to control areas; this was further decreased by an additional 48% following a second treatment 1 month later. BrdU assay demonstrated proliferation in approximately half of the RPE cells in treatment areas.Microsecond exposures produced by scanning laser destroyed RPE cells selectively, without damage to neural retina. Continuity of RPE layer is restored within days by migration and proliferation, but transgene not integrated into the nucleus is not replicated. Therefore, gene expression can be modulated in a precise manner by controlling the laser pattern density and further adjusted using repeated applications.

  View details for DOI 10.1167/iovs.12-10933

  View details for PubMedID 23422827

• Controversy Over the Etiology and Therapy of Retinal Detachment: The Struggles of Jules Gonin SURVEY OF OPHTHALMOLOGY Gloor, B. P., Marmor, M. F. 2013; 58 (2): 184–95

  Abstract

  Retinal tears were recognized as soon as ophthalmoscopy became available. They were initially considered to be secondary events, from choroidal exudation and pressure behind the detached retina. This led von Graefe and others to recommend cuts in the retina to drain subretinal fluid into the vitreous cavity. De Wecker (1875, 1879) and Leber (1882) first proposed that intrinsic tears within the retina are the cause of retinal detachment, but they faced extreme and long lasting opposition for this view. Surgical results at this time were uniformly disastrous, and therapeutic nihilism still prevailed when Dufour and Gonin became convinced around 1904-1906 that the retinal tear was indeed the origin of the detachment. It took ten years, however, before Gonin figured out how to close tears by exact placement of heat coagulation ("thermopuncture") and provide therapeutic evidence for his beliefs. When he first presented his results in 1921, colleagues jeered at him, especially Deutschmann and Sourdille who, like the other ophthalmic surgeons, denied the role of the tear (and still made "therapeutic" incisions through the detached retina). Recognition of Gonin's approach finally came at the International Congresses in Amsterdam 1928 and in Madrid in 1933. Sourdille modified his approach when his son Gabriel convinced him to change after 1930, but Deutschmann stuck to his horrific procedure until his death in 1935. Then a new generation of retinal surgeons took over, with subsequent discussion focused on finding the best methods to close the tears.

  View details for DOI 10.1016/j.survophthal.2012.09.002

  View details for Web of Science ID 000315323700007

  View details for PubMedID 23257154

• Efficient and Effective Screening for Hydroxychloroquine Toxicity AMERICAN JOURNAL OF OPHTHALMOLOGY Marmor, M. F. 2013; 155 (3): 413-414

  View details for DOI 10.1016/j.ajo.2012.10.020

  View details for Web of Science ID 000315426000001

  View details for PubMedID 23394729

• Simulating Degas' vision: implications for dating his sculpture SCULPTURE JOURNAL Marmor, M. F. 2013; 22 (2): 96-108

  View details for DOI 10.3828/sj.2013.20b

  View details for Web of Science ID 000331673500008

• FOVEAL CAVITATION AS AN OPTICAL COHERENCE TOMOGRAPHY FINDING IN CENTRAL CONE DYSFUNCTION RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES Leng, T., Marmor, M. F., Kellner, U., Thompson, D. A., Renner, A. B., Moore, W., Sowden, J. C. 2012; 32 (7): 1411-1419

  Abstract

  To describe a distinctive foveal cavitation as seen by spectral-domain optical coherence tomography in certain cone dysfunction syndromes.Observational case series. Patients were evaluated by dilated fundus examination, fundus photography, fundus autofluorescence, full-field electroretinogram, multifocal electroretinogram, spectral-domain optical coherence tomography, color vision testing, fluorescein angiography, Goldmann visual field testing, and molecular genetic analysis.We present eight patients with foveal cavitation in association with presumed cone dysfunction. This was characterized on spectral-domain optical coherence tomography by a gap in the subfoveal outer segment layer without more diffuse retinal thinning. There were 5 patients of age 10 years to 27 years and 3 patients of age 49 years to 52 years, with a 1.5- to 38-year history of bilateral visual loss. A small foveal oval-shaped area of reduced foveal fundus autofluorescence, surrounded by increased fundus autofluorescence, was seen in the younger patients, and a broad circle of increased fundus autofluorescence in the older patients. The multifocal electroretinogram always showed central amplitude reduction, but there were varying degrees of cone dysfunction on full-field electroretinogram. There were mild abnormalities on desaturated color vision testing. The family history was noncontributory in all cases. None of the cases were congenital. ABCA4 gene mutations were identified in three of five patients tested; CNGB3 testing was negative in these patients.Cone dysfunction syndromes typically show retinal thinning on optical coherence tomography imaging, although several case reports have noted focal outer retinal loss. Our case series shows that a distinctive optical coherence tomography finding, foveal cavitation, may be a clue to cone dysfunction syndromes, but is not specific to any one hereditary disorder or age group.

  View details for DOI 10.1097/IAE.0b013e318236e4ea

  View details for PubMedID 22466470

• Comparison of Screening Procedures in Hydroxychloroquine Toxicity ARCHIVES OF OPHTHALMOLOGY Marmor, M. F. 2012; 130 (4): 461-469

  Abstract

  To compare different screening procedures for hydroxychloroquine sulfate (Plaquenil) toxicity at different stages of damage.Ten patients were studied using 10-2 automated fields, multifocal electroretinography, spectral domain optical coherence tomography (SD-OCT), and fundus autofluorescence.All 10 patients used hydroxychloroquine for more than 6 years, and those with severe toxicity had been overdosed. Fundus examination findings were normal except for the patients with severe toxicity. All the patients showed parafoveal field loss, but this was sometimes subtle. Multifocal electroretinography demonstrated parafoveal weakness in the milder cases. The SD-OCT subfield thickness plots showed a ring of parafoveal thinning in all the patients. The SD-OCT cross-sections showed parafoveal loss of the inner segment-outer segment and cone outer segment tip lines at early stages of toxicity, progressing to parafoveal thinning of the outer nuclear layer and eventually to retinal pigment epithelium damage. There was a ring of autofluorescence in most patients.Overdosage with hydroxychloroquine seemed a significant risk factor for toxicity. Different individuals were more or less sensitive to different tests. Fields can be sensitive but only if read with a low threshold for change. Hydroxychloroquine causes early parafoveal loss of the outer segment lines on SD-OCT, with the first changes often evident in the inferotemporal quadrant. Parafoveal thinning of the outer nuclear layer follows, before retinal pigment epithelium damage is visible. Careful screening with multiple tests can detect toxic damage before prominent loss of the outer nuclear layer.

  View details for DOI 10.1001/archophthalmol.2011.371

  View details for PubMedID 22159170

• Longterm cultures of the aged human RPE do not maintain epithelial morphology and high transepithelial resistance GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY Stanzel, B. V., Blumenkranz, M. S., Binder, S., Marmor, M. F. 2012; 250 (2): 313-315

  View details for DOI 10.1007/s00417-011-1624-x

  View details for Web of Science ID 000300290600021

  View details for PubMedID 21279375

• ISCEV standard for clinical multifocal electroretinography (mfERG) (2011 edition) DOCUMENTA OPHTHALMOLOGICA Hood, D. C., Bach, M., Brigell, M., Keating, D., Kondo, M., Lyons, J. S., Marmor, M. F., McCulloch, D. L., Palmowski-Wolfe, A. M. 2012; 124 (1): 1-13

  Abstract

  The clinical multifocal electroretinogram (mfERG) is an electrophysiological test of local retinal function. With this technique, many local ERG responses are recorded quasi-simultaneously from the cone-driven retina under light-adapted conditions. This document, from the International Society for Clinical Electrophysiology of Vision (ISCEV: www.iscev.org ), replaces the ISCEV guidelines for the mfERG published in 2007. Standards for performance of the basic clinical mfERG test with a stimulus array of 61 or 103 hexagons, as well as for reporting the results, are specified.

  View details for DOI 10.1007/s10633-011-9296-8

  View details for Web of Science ID 000300158700001

  View details for PubMedID 22038576

• Fifty Years of Ophthalmic Laser Therapy ARCHIVES OF OPHTHALMOLOGY Palanker, D. V., Blumenkranz, M. S., Marmor, M. F. 2011; 129 (12): 1613-1619

  View details for Web of Science ID 000297995000016

  View details for PubMedID 22159684

• Fluorescein Angiography Insight and Serendipity a Half Century Ago ARCHIVES OF OPHTHALMOLOGY Marmor, M. F., Ravin, J. G. 2011; 129 (7): 943-948

  Abstract

  It has been 50 years since fluorescein angiography was developed as a clinical procedure by 2 medical students at Indiana University. The story of its discovery and the recognition of its value to ophthalmology involve a combination of insight and serendipity. Fluorescein had been in use clinically for more than half a century, but it took a pulmonary medicine laboratory to provide the stimulus for the development of flash and barrier filters that would make vascular photography practical. The first article was rejected by the ophthalmology literature, but several clinics heard about it and soon documented the enormous diagnostic value of the procedure.

  View details for PubMedID 21746986

• Developmental or degenerative-NR2E3 gene mutations in two patients with enhanced S cone syndrome MOLECULAR VISION Udar, N., Small, K., Chalukya, M., Silva-Garcia, R., Marmor, M. 2011; 17 (59): 519–25

  Abstract

  Enhanced S Cone Syndrome is a rare autosomal recessive disorder characterized clinically by an absence of rod function, a replacement of most L and M cone function by S cone activity (Goldmann-Favre Syndrome) and by variable degrees of retinal degeneration in different families. The causative gene, nuclear receptor subfamily 2, group E, member 3 (NR2E3), controls the developmental sequence for rods and cones. The purpose of this study was to compare the nature and implications of mutations in two subjects with Enhanced S Cone Syndrome who have significantly different degrees of degenerative damage.A direct sequencing approach was used to identify the mutations. Genomic DNA was amplified from all the exons of NR2E3 and used as a template for sequencing. Of the two families studied, Case 1 is of Persian ethnicity while Case 2 is Brazilian. A total of six individuals within the two families were studied.Case 1 (original propositus of the syndrome) has the characteristic developmental rod/cone abnormality with large amplitude electroretinogram responses and no retinal degeneration. She was homozygous for a novel mutation, c.[del196-201del6] (p.G66-C67del), which lies entirely within the P-box for this gene. By comparison, Case 2 had Goldmann-Favre Syndrome with retinal degeneration and low electroretinogram signals. She was a compound heterozygote for c.[119-2A>C]+[del194-202del9] (p.N65-C67del), mutations that have been reported previously. Her second mutation overlaps that of Case 1 within the P-box.The novel in-frame homozygous deletion of Case 1, within the P-box motif of the DNA binding domain, caused a developmental abnormality without retinal degeneration. Case 2, with more traditional Goldmann-Favre Syndrome with retinal degeneration, was a compound heterozygote where one allele had a similar P-box deletion but the other was a splicing defect. Case 1 is the first reported homozygous deletion within the P-box. This is the first report of NR2E3 mutations in a Persian and a Brazilian family.

  View details for Web of Science ID 000288198700001

  View details for PubMedID 21364904

  View details for PubMedCentralID PMC3044695

• Revised Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy OPHTHALMOLOGY Marmor, M. F., Kellner, U., Lai, T. Y., Lyons, J. S., Mieler, W. F. 2011; 118 (2): 415-422

  Abstract

  The American Academy of Ophthalmology recommendations for screening of chloroquine (CQ) and hydroxychloroquine (HCQ) retinopathy were published in 2002, but improved screening tools and new knowledge about the prevalence of toxicity have appeared in the ensuing years. No treatment exists as yet for this disorder, so it is imperative that patients and their physicians be aware of the best practices for minimizing toxic damage. RISK OF TOXICITY: New data have shown that the risk of toxicity increases sharply toward 1% after 5 to 7 years of use, or a cumulative dose of 1000 g, of HCQ. The risk increases further with continued use of the drug. DOSAGE: The prior recommendation emphasized dosing by weight. However, most patients are routinely given 400 mg of HCQ daily (or 250 mg CQ). This dose is now considered acceptable, except for individuals of short stature, for whom the dose should be determined on the basis of ideal body weight to avoid overdosage. SCREENING SCHEDULE: A baseline examination is advised for patients starting these drugs to serve as a reference point and to rule out maculopathy, which might be a contraindication to their use. Annual screening should begin after 5 years (or sooner if there are unusual risk factors). SCREENING TESTS: Newer objective tests, such as multifocal electroretinogram (mfERG), spectral domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF), can be more sensitive than visual fields. It is now recommended that along with 10-2 automated fields, at least one of these procedures be used for routine screening where available. When fields are performed independently, even the most subtle 10-2 field changes should be taken seriously and are an indication for evaluation by objective testing. Because mfERG testing is an objective test that evaluates function, it may be used in place of visual fields. Amsler grid testing is no longer recommended. Fundus examinations are advised for documentation, but visible bull's-eye maculopathy is a late change, and the goal of screening is to recognize toxicity at an earlier stage. COUNSELING: Patients should be aware of the risk of toxicity and the rationale for screening (to detect early changes and minimize visual loss, not necessarily to prevent it). The drugs should be stopped if possible when toxicity is recognized or strongly suspected, but this is a decision to be made in conjunction with patients and their medical physicians.

  View details for DOI 10.1016/j.ophtha.2010.11.017

  View details for PubMedID 21292109

• Rates and Predictors of Hydroxychloroquine Retinal Toxicity in Patients With Rheumatoid Arthritis and Systemic Lupus Erythematosus ARTHRITIS CARE & RESEARCH Wolfe, F., Marmor, M. F. 2010; 62 (6): 775–84

  Abstract

  Hydroxychloroquine (HCQ) retinopathy is of concern because of the potential seriousness of visual loss and the medicolegal consequences of failure to detect toxicity. However, there have been limited demographic data on which to base recommendations for screening. We have studied the largest unselected series of patients to date to evaluate the risk of toxicity and the relevance of purported risk factors.We studied 3,995 patients with rheumatoid arthritis or systemic lupus erythematosus who had used HCQ, including 1,538 current users. We screened for self-reported toxicity, and followed up on positive cases with detailed interviews and specialist confirmation. We categorized cases as "definite or probable" if there was bull's eye maculopathy or visual field loss.Of the lifetime users of HCQ, 6.5% discontinued therapy because of an eye problem, including 1.8% who reported HCQ retinal problems. However, definite or probable toxicity was documented in only 0.65% (95% confidence interval 0.31-0.93). The risk of toxicity was low in the initial 7 years of exposure, and was approximately 5 times greater after 7 years of usage (or 1,000 gm total exposure). Toxicity was unrelated to age, weight, or daily dosage. Eye examinations were obtained annually by 50.5% and every 6 months by 40.4% of patients.HCQ toxicity remains uncommon, but increases markedly with the duration of therapy and exceeds 1% after 5-7 years. Toxicity was unassociated with age, daily dosage, or weight. These findings will aid the reformulation of screening guidelines.

  View details for DOI 10.1002/acr.20133

  View details for Web of Science ID 000280979800006

  View details for PubMedID 20535788

• Simulating vision with and without macular disease. Archives of ophthalmology Marmor, D. J., Marmor, M. F. 2010; 128 (1): 117-125

  Abstract

  Conventional photographs do not show how, at any moment of visual fixation, neural vision is clear only in the foveal center. We have developed new computer simulations to show both normal vision and vision with macular disease. These simulations show the nature of momentary vision for life tasks such as reading, facial recognition, and walking in the street. They also dramatically show the impact of macular disease (with scotomas and visual distortion), as there is no surrounding region of clarity. We hope these images will be instructive to both physicians and patients.

  View details for DOI 10.1001/archophthalmol.2009.366

  View details for PubMedID 20065228

• ERG evaluation of daily, high-dose sildenafil usage Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology Zoumalan, C. I., Zamanian, R. T., Doyle, R. L., Marmor, M. F. SPRINGER. 2009: 225–31

  Abstract

  Sildenafil can cause transient, mild ERG changes in healthy individuals taking large single doses. Although the drug was originally intended for intermittent use in erectile dysfunction, it has now been approved for chronic use in subjects with pulmonary arterial hypertension (PAH). The purpose of our study is to investigate possible ERG changes in subjects using large doses of sildenafil on a chronic daily basis.We examined five subjects with PAH taking sildenafil daily for 1-4 years. Full-field electroretinogram (ERG), multifocal ERG (mfERG), and color testing were performed. Three of the subjects returned on a later date for challenge off and on the medication.On chronic daily sildenafil, color vision testing was normal, and ERG and mfERG amplitudes were normal; however, cone implicit times on drug were modestly lengthened. There were no consistent full-field ERG changes when off the drug, but the mfERG showed a small amplitude increase and implicit time decrease, which returned 1 h after re-dosing.There was a modest lengthening of cone implicit time on chronic daily doses of sildenafil and a hint that some of these changes may be reversible in the short term. It does not appear that chronic sildenafil usage at these dosage levels is seriously toxic or threatening to vision.

  View details for DOI 10.1007/s10633-008-9148-3

  View details for PubMedID 18818963

• ISCEV Standard for full-field clinical electroretinography (2008 update) 45th ISCEV Symposium 2007 Marmor, M. F., Fulton, A. B., Holder, G. E., Miyake, Y., Brigell, M., Bach, M. SPRINGER. 2009: 69–77

  Abstract

  This document, from the International Society for Clinical Electrophysiology of Vision (ISCEV), presents an updated and revised ISCEV Standard for clinical electroretinography (ERG). The parameters for flash stimulation and background adaptation have been tightened, and responses renamed to indicate the flash strength (in cd x s x m(-2)). The ISCEV Standard specifies five responses: (1) Dark-adapted 0.01 ERG (rod response); (2) Dark-adapted 3.0 ERG (combined rod-cone response); (3) Dark-adapted 3.0 oscillatory potentials; (4) Light-adapted 3.0 ERG (cone response); (5) Light-adapted 3.0 flicker (30 Hz flicker). An additional Dark-adapted 10.0 ERG or Dark-adapted 30.0 ERG response is recommended.

  View details for DOI 10.1007/s10633-008-9155-4

  View details for Web of Science ID 000262650200007

  View details for PubMedID 19030905

• Effect of shape and coating of a subretinal prosthesis on its integration with the retina EXPERIMENTAL EYE RESEARCH Butterwick, A., Huie, P., Jones, B. W., Marc, R. E., Marmor, M., Palanker, D. 2009; 88 (1): 22-29

  Abstract

  Retinal stimulation with high spatial resolution requires close proximity of electrodes to target cells. This study examines the effects of material coatings and 3-dimensional geometries of subretinal prostheses on their integration with the retina. A trans-scleral implantation technique was developed to place microfabricated structures in the subretinal space of RCS rats. The effect of three coatings (silicon oxide, iridium oxide and parylene) and three geometries (flat, pillars and chambers) on the retinal integration was compared using passive implants. Retinal morphology was evaluated histologically 6 weeks after implantation. For 3-dimensional implants the retinal cell phenotype was also evaluated using Computational Molecular Phenotyping. Flat implants coated with parylene and iridium oxide were generally well tolerated in the subretinal space, inducing only a mild gliotic response. However, silicon-oxide coatings induced the formation of a significant fibrotic seal around the implants. Glial proliferation was observed at the base of the pillar electrode arrays and inside the chambers. The non-traumatic penetration of pillar tips into the retina provided uniform and stable proximity to the inner nuclear layer. Retinal cells migrated into chambers with apertures larger than 10 mum. Both pillars and chambers achieved better proximity to the inner retinal cells than flat implants. However, isolation of retinal cells inside the chamber arrays is likely to affect their long-term viability. Pillars demonstrated minimal alteration of the inner retinal architecture, and thus appear to be the most promising approach for maintaining close proximity between the retinal prosthetic electrodes and target neurons.

  View details for DOI 10.1016/j.exer.2008.09.018

  View details for Web of Science ID 000262395800004

  View details for PubMedID 18955050

• Healing of Retinal Photocoagulation Lesions INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Paulus, Y. M., Jain, A., Gariano, R. F., Stanzel, B. V., Marmor, M., Blumenkranz, M. S., Palanker, D. 2008; 49 (12): 5540-5545

  Abstract

  To systematically assess the changes in retinal morphology during the healing of retinal photocoagulation lesions of various clinical grades.Rabbits were irradiated with a 532-nm Nd:YAG laser with a beam diameter of 330 microm at the retinal surface, a power of 175 mW, and pulse durations between 5 and 100 ms. Retinal lesions were clinically graded 1 minute after placement as invisible, barely visible, light, moderate, intense, very intense, and rupture and were assessed histologically at six time points from 1 hour to 4 months.At all pulse durations, the width of the retinal lesions decreased over time. At clinical grades of light and more severe (pulse durations, 10-100 ms), retinal scarring stabilized at 1 month at approximately 35% of the initial lesion diameter. Lesions clinically categorized as barely visible and invisible (pulse durations of 7 and 5 ms) exhibited coagulation of the photoreceptor layer but did not result in permanent scarring. In these lesions, photoreceptors completely filled in the damaged areas by 4 months.The decreasing width of the retinal damage zone suggests that photoreceptors migrating from unaffected areas fill in the gap in the photoreceptor layer. Laser photocoagulation parameters can be specified to avoid not only the inner retinal damage, but also permanent disorganization and scarring in the photoreceptor layer. These data may facilitate studies to determine those aspects of laser treatment necessary for beneficial clinical response and those that result in extraneous retinal damage.

  View details for DOI 10.1167/iovs.08-1928

  View details for PubMedID 18757510

• Total rod ERG suppression with high dose compassionate Fenretinide usage DOCUMENTA OPHTHALMOLOGICA Marmor, M. F., Jain, A., Moshfeghi, D. 2008; 117 (3): 257-261

  Abstract

  Fenretinide is a synthetic retinoid that interferes with the attachment of retinol to retinol binding protein. It may inhibit accumulation of A2E and lipofuscin, and is proposed as therapy for Stargardt disease. It is currently used for cancer therapy, and mild depression of rod function and dark adaptation is a side effect at standard dosage. We studied two youngsters (aged between 12 and 13) receiving high doses as compassionate treatment for neuroblastoma: 800 mg daily for 1 out of every 3 weeks, for roughly 2 years. Goldmann-Weekers dark adaptometry, ISCEV standard ERG and mfERG were performed, and blood was analyzed for vitamin A. Neither child complained of night blindness or showed retinal fundus abnormalities. On initial exam, dark adaptation thresholds were elevated by 3 log units, and there were no detectable rod ERG responses. However, cone responses and mfERG were normal. Retesting one subject 3 months after stopping the drug revealed normal rod thresholds (slightly delayed) and low normal rod ERG responses. Serum vitamin A levels were normal from both subjects, but there is no record of whether the samples were drawn during cycles on or off drug. Our study demonstrates that high dose Fenretinide can suppress rod function quite completely, although serum vitamin A and rod function apparently return to normal or near normal levels rapidly once the drug is stopped. It is intriguing that cone function and access to vitamin A seems largely independent of Fenretinide effects on retinol availability.

  View details for DOI 10.1007/s10633-008-9132-y

  View details for PubMedID 18523815

• Visual insignificance of the foveal pit - Reassessment of foveal hypoplasia as fovea plana 30th Annual Meeting of the Macula-Society Marmor, M. F., Choi, S. S., Zawadzki, R. J., Werner, J. S. AMER MEDICAL ASSOC. 2008: 907–13

  Abstract

  To elucidate the visual significance of the foveal pit by measuring foveal architecture and function and to reassess use of the term foveal hypoplasia (as visual acuity can vary among patients who lack a pit).We describe 4 patients who lack a foveal pit. Visual acuities ranged from 20/20 to 20/50. Stratus and Cirrus (Carl Zeiss Meditec, Dublin, California) optical coherence tomographs (OCTs) and multifocal electroretinograms were obtained. High-resolution retinal imaging on 2 of the participants was obtained by using a high-resolution Fourier-domain OCT and an adaptive optics flood-illuminated fundus camera.No participants had a visible foveal pit with conventional OCT. Central widening of the outer nuclear layer and lengthening of cone outer segments were seen with high-resolution Fourier-domain OCT. Adaptive optics imaging showed normal cone diameters in the central 1 degrees to 2 degrees. Central multifocal electroretinogram responses were normal.We show that a foveal pit is not required for foveal cone specialization, anatomically or functionally. This helps to explain the potential for good acuity in the absence of a pit and raises questions about the visual role of the foveal pit. Because the term foveal hypoplasia commonly carries a negative functional implication, it may be more proper to call the anatomic lack of a pit fovea plana.

  View details for PubMedID 18625935

• Tadalafil 5 mg or sildenafil citrate 50 mg administered daily for up to 6 months does not affect visual safety Cordell, W. H., Maturi, R. K., Costigan, T. M., Marmor, M. F., Weleber, R. G., Coupland, S. G., Danis, R. P., McGettigan, J., Antoszyk, A. N., Klise, S. R., Sides, G. D. BLACKWELL PUBLISHING. 2008: 27

  View details for Web of Science ID 000252756000079

• Intrasession variability of the full-field ERG DOCUMENTA OPHTHALMOLOGICA Hochstein, G. D., Molnar, F. E., Marmor, M. F. 2007; 115 (2): 77-83

  Abstract

  (1) To document variability of the full-field ERG within single recording sessions under ISCEV standards. (2) To identify clinical factors contributing to the observed variability.Nine volunteer subjects were studied, aged 19-32 with no history of retinal disease. ISCEV standard ERGs were recorded. Dark-adapted "standard combined" and light-adapted "cone" b-wave amplitudes and implicit times were measured. Multiple flashes were presented at different interflash intervals and after different periods of dark and light adaptation. The stability of the stimulus flash was measured with a photometer.The statistical coefficient of variability was roughly 2.5% for the standard combined b-wave amplitude and 4.5% for the cone b-wave. B-wave implicit times showed a coefficient of variability of 2% for standard combined responses and 1.25% for cone responses. Variation in interflash interval, dark and light adaptation times, and sporadic unusual waveforms influenced measured b-wave amplitudes.Intrasession variability is much lower than previously reported values for intersession variability. Nonetheless, it represents a baseline of variability that will affect results and that may be minimized by recognition and control of contributing factors.

  View details for DOI 10.1007/s10633-007-9057-x

  View details for PubMedID 17487544

• The dilemma of the late-onset "Dystrophy" DOCUMENTA OPHTHALMOLOGICA Marmor, M. F. 2007; 114 (2): 107-109

  Abstract

  A case of late-onset (age 51) visual loss and night-blindness is presented to illustrate the challenges of diagnosis. This patient had anti-enolase antibodies, and demonstrates the importance of auto-immune retinopathy as a potential cause of late-onset retinal "dystrophy."

  View details for DOI 10.1007/s10633-007-9046-0

  View details for PubMedID 17297602

• Ophthalmology and art: Simulation of Monet's cataracts and Degas' retinal disease ARCHIVES OF OPHTHALMOLOGY Marmor, M. F. 2006; 124 (12): 1764-1769

  View details for PubMedID 17159037

• The dilemma of hydroxychloroquine screening: New information from the multifocal ERG AMERICAN JOURNAL OF OPHTHALMOLOGY Marmor, M. F. 2005; 140 (5): 894-895

  View details for Web of Science ID 000233755600015

  View details for PubMedID 16310466

• Alcohol- and light-induced electro-oculographic responses in age-related macular degeneration & central serous chorioretinopathy. alcohol- and light-induced EOG responses in ARMD & CSC. Documenta ophthalmologica. Advances in ophthalmology Wu, K. H., Marmor, M. F. 2005; 110 (2-3): 237-46

  Abstract

  The non-photic electro-oculographic (EOG) response induced by alcohol has been proposed as an indicator of retinal pigment epithelial (RPE) integrity, and reported to be abnormal in age-related macular degeneration (ARMD). To evaluate this proposal, we have measured the alcohol-EOG as well as the ISCEV-standard EOG in patients with ARMD (n=11 patients, 4 eyes with drusen, 8 eyes with 'dry' and 7 eyes with 'wet' lesions) and central serous chorioretinopathy (CSC, n=11 patients, 7 eyes with active and 6 eyes with inactive lesions), compared with 29 normal controls. We recorded the alcohol-induced EOG response after a single oral administration of ethanol at 160 mg/kg, followed by an ISCEV-standard EOG. Blood alcohol levels were monitored with a breath analyzer. We found that neither the alcohol-EOG nor the light-induced EOG response showed any difference between either ARMD or CSC patients and normal controls. Nor was there difference among eyes of different ARMD or CSC subgroups. In addition, blood alcohol concentrations near the time of the alcohol-EOG peak showed no obvious relationship with peak/baseline ratios. These data suggest that neither the alcohol- nor the light-induced EOG is a sensitive indicator of these diseases.

  View details for DOI 10.1007/s10633-005-0649-z

  View details for PubMedID 16328932

• Alcohol- and light-induced electro-oculographic responses: variability and clinical utility DOCUMENTA OPHTHALMOLOGICA Marmor, M. F., Wu, K. H. 2005; 110 (2-3): 227-236

  Abstract

  The alcohol-induced electro-oculographic (EOG) response has been proposed by Arden as an indicator of retinal pigment epithelial (RPE) integrity. We have evaluated the consistency of the alcohol-EOG with respect to clinical applicability and compared this response to the ISCEV-standard EOG. We recorded, in a group of normal subjects (n=29, 14 men with mean age 42+/-11 years and 15 women with mean age 36+/-13 years), the alcohol response to a single oral dose of ethanol at 160 mg/kg (as 40 proof vodka, drunk in 15 s after 12 h of fasting), followed by an ISCEV-standard EOG 90 min after alcohol administration. Blood alcohol levels were monitored at regular intervals with a breath analyzer. We found a wide range of amplitudes in both light and alcohol responses among participants, from minimal to large values. Subjects had a wide range of blood alcohol concentrations from 0.02 to 0.10%; near the time of the response peak, but there was no relationship between alcohol levels and peak/baseline ratios. In addition, there was no relationship between alcohol peak/baseline ratio and the Arden ratio. Neither the alcohol nor the light response parameters showed any relationship with age or gender. Some of the inter-individual variability in the EOG response to alcohol may reflect variable absorption of oral alcohol. The alcohol-induced EOG has too broad a range of responses to be useful clinically for the one-time evaluation of individual patients. We have similar concerns regarding clinical applications of the standard light-induced EOG.

  View details for DOI 10.1007/s10633-005-0648-0

  View details for PubMedID 16328931

• Was Rembrandt stereoblind? NEW ENGLAND JOURNAL OF MEDICINE Marmor, M. F., Shaikh, S. 2005; 352 (6): 631–32

  View details for Web of Science ID 000226862100033

  View details for PubMedID 15703434

• Differential gene expression in anatomical compartments of the human eye GENOME BIOLOGY Diehn, J. J., Diehn, M., Marmor, M. F., Brown, P. O. 2005; 6 (9)

  Abstract

  The human eye is composed of multiple compartments, diverse in form, function, and embryologic origin, that work in concert to provide us with our sense of sight. We set out to systematically characterize the global gene expression patterns that specify the distinctive characteristics of the various eye compartments.We used DNA microarrays representing approximately 30,000 human genes to analyze gene expression in the cornea, lens, iris, ciliary body, retina, and optic nerve. The distinctive patterns of expression in each compartment could be interpreted in relation to the physiology and cellular composition of each tissue. Notably, the sets of genes selectively expressed in the retina and in the lens were particularly large and diverse. Genes with roles in immune defense, particularly complement components, were expressed at especially high levels in the anterior segment tissues. We also found consistent differences between the gene expression patterns of the macula and peripheral retina, paralleling the differences in cell layer densities between these regions. Based on the hypothesis that genes responsible for diseases that affect a particular eye compartment are likely to be selectively expressed in that compartment, we compared our gene expression signatures with genetic mapping studies to identify candidate genes for diseases affecting the cornea, lens, and retina.Through genome-scale gene expression profiling, we were able to discover distinct gene expression 'signatures' for each eye compartment and identified candidate disease genes that can serve as a reference database for investigating the physiology and pathophysiology of the eye.

  View details for DOI 10.1186/gb-2005-6-9-r74

  View details for PubMedID 16168081

• Migration of retinal cells through a perforated membrane: Implications for a high-resolution prosthesis INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Palanker, D., Huie, P., Vankov, A., Aramant, R., Seiler, M., Fishman, H., Marmor, M., Blumenkranz, M. 2004; 45 (9): 3266-3270

  Abstract

  One of the critical difficulties in design of a high-resolution retinal implant is the proximity of stimulating electrodes to the target cells. This is a report of a phenomenon of retinal cellular migration into a perforated membrane that may help to address this problem.Mylar membranes with an array of perforations (3-40 microm in diameter) were used as a substrate for in vitro retinal culture (chicken, rats) and were also transplanted into the subretinal space of adult RCS rats. A membrane was also constructed with a seal on one side to restrict the migration.Retinal tissue in vitro grew within 3 days through perforations of greater than 5 microm in diameter when the membranes were positioned on the photoreceptor side, but no migration occurred if the implant was placed on the inner retinal surface. Histology with light microscopy and transmission electron microscopy (TEM) demonstrated that migrating cells retain neuronal structures for signal transduction. Similar growth of RCS rat retinal cells occurred in vivo within 5 days of implantation. A basal seal kept the migrating tissue within a small membrane compartment.Retinal neurons migrate within a few days into perforations (> 5 microm in diameter) of a membrane placed into the subretinal space. This may provide a means of gaining close proximity between electrodes in a retinal prosthetic chip and target cells, and thus allow a greater density of stimulating elements to subserve higher resolution. Further studies are needed to explore the long-term stability of the retinal migration.

  View details for DOI 10.1167/iovs.03-1327

  View details for PubMedID 15326150

• Are circadian variations in the electroretinogram evident on routine testing? DOCUMENTA OPHTHALMOLOGICA Marcus, M., Cabael, L., Marmor, M. F. 2004; 108 (2): 165-169

  Abstract

  We sought to determine whether routine ERGs using ISCEV standard stimuli, would show a pattern of circadian variation. We examined ERGs from 40 successive normal subjects who were tested at different times during regular laboratory operating hours of 9 am to 4 pm, and also reviewed high intensity a-waves from a subgroup. There were no obvious associations of either ERG amplitude or implicit time with time of day. No statistically significant difference was found between average ISCEV ERG parameters or high-intensity a-wave parameters obtained in the morning (9 am to 1 pm) and afternoon (1 pm to 4 pm). We conclude that time of day is not critical for routine ERG recordings, although small, variable, circadian changes may well be present. We suggest that the time of day be noted on clinical recordings, in case this information becomes relevant for a particular patient.

  View details for PubMedID 15455799

• Standard for clinical electroretinography (2004 update) DOCUMENTA OPHTHALMOLOGICA Marmor, M. F., Holder, G. E., Seeliger, M. W., Yamamoto, S. 2004; 108 (2): 107-114

  View details for PubMedID 15455793

• Localized neurotransmitter release for use in a prototype retinal interface INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Peterman, M. C., Bloom, D. M., Lee, C., Bent, S. F., Marmor, M. E., Blumenkranz, M. S., Fishman, H. A. 2003; 44 (7): 3144-3149

  Abstract

  Current neural prostheses use electricity as the mode of stimulation, yet information transfer in neural circuitry is primarily through chemical transmitters. To address this disparity, this study was conducted to devise a prototype interface for a retinal prosthetic based on localized chemical delivery. The goal was to determine whether fluidic delivery through microfabricated apertures could be used to stimulate at single-cell dimensions.A drug delivery system was microfabricated based on a 5- or 10- microm aperture in a 500-nm thick silicon nitride membrane to localize and limit transmitter release. The aperture overlies a microfluidic delivery channel in a silicone elastomer. To demonstrate the effectiveness of this transmitter-based prosthesis, rat pheochromocytoma cells (PC12 cell line) were grown on the surface of the device to test the precision of stimulation, using bradykinin as a stimulant and measuring fluorescence from the calcium indicator, fluo-4.The extent of stimulation could be controlled accurately by varying the concentration of stimulant, from a single cell adjacent to the aperture to a broad area of cells. The stimulation radius was as small as 10 microm, corresponding to stimulation volumes as small as 2 pL. The relationship between the extent of stimulation and concentration was linear.The demonstration of localized chemical stimulation of excitable cells illustrates the potential of this technology for retinal prostheses. Although this is only a proof of concept of neurotransmitter stimulation for a retinal prosthesis, it is a significant first step toward mimicking neurotransmitter release during synaptic transmission.

  View details for DOI 10.1167/iovs.02-1097

  View details for PubMedID 12824264

• New American Academy of Ophthalmology recommendations on screening for hydroxychloroquine retinopathy ARTHRITIS AND RHEUMATISM Marmor, M. F. 2003; 48 (6): 1764

  View details for DOI 10.1002/art.10980

  View details for Web of Science ID 000183410300038

  View details for PubMedID 12794848

• Escher and the ophthalmologist SURVEY OF OPHTHALMOLOGY Marmor, M. F., Wagenaar, W. A. 2003; 48 (3): 356-361

  Abstract

  The Dutch graphic artist, Maurits C. Escher (1898-1972) is famous for intricate and sometimes illusory images which challenge our sensibility. Over many years, from the 1920s to the 1960s, he made designs with interlocking figures that confuse the distinction between object and background. His correspondence and writings suggest that these designs were largely self-created until the 1950s when fame brought him increasingly into contact with scholars from disciplines such as mathematics, crystallography, and psychology. One of these contacts was with an ophthalmologist, Johan W. Wagenaar (1911-), who had been using Escher's designs to illustrate lectures about vision during night driving. A correspondence began that extended for almost a decade and altered Escher's concept of his own work. It is an intriguing footnote to the career of this extraordinary artist.

  View details for DOI 10.1016/S0039-6257(03)00027-4

  View details for PubMedID 12745007

• Guidelines for basic multifocal electroretinography (mfERG) DOCUMENTA OPHTHALMOLOGICA Marmor, M. F., Hood, D. C., Keating, D., Kondo, M., Seeliger, M. W., Miyake, Y. 2003; 106 (2): 105-115

  View details for PubMedID 12678274

• Effects of sildenafil citrate (Viagra) on choroidal congestion OPHTHALMOLOGICA McCulley, T. J., Luu, J. K., Marmor, M. F., Feuer, W. J. 2002; 216 (6): 455–58

  Abstract

  This study evaluates the effect of sildenafil on choroidal vascular congestion and its correlation with visual effects. Thirteen healthy subjects were randomized to a sildenafil group (n = 7, 3 M, 4 F), who received 200 mg of sildenafil, and a control (n = 6, 5 F, 1 M) group, who received no drug. Measurements of choroidal thickness with ultrasonography, color vision with Desaturated Panel D-15 Test, and contrast sensitivity with CSV-1000e charts (Vector Vision) were performed at baseline and at 90 and 180 min. Mean choroidal thickness and contrast sensitivity did not change significantly relative to baseline in either group. However, the variance in differences between repeat and baseline measurements of choroidal thickness was significantly higher at 90 min (p = 0.003) in the sildenafil subjects. Color discrimination error scores increased after sildenafil but did not correlate with changes in choroidal thickness. An oral dose of 200 mg of sildenafil caused small inconsistent changes in choroidal thickness, which did not correlate with visual effects.

  View details for DOI 10.1159/000067549

  View details for Web of Science ID 000180619100013

  View details for PubMedID 12566892

• Pulsed Electron Avalanche Knife (PEAK) for intraocular surgery INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Palanker, D. V., MILLER, J. M., Marmor, M. F., Sanislo, S. R., Huie, P., Blumenkranz, M. S. 2001; 42 (11): 2673-2678

  Abstract

  To develop a better and more economical instrument for precise, tractionless, "cold" cutting during intraocular surgery. The use of highly localized electric fields rather than laser light as the means of tissue dissection was investigated.A high electric field at the tip of a fine wire can, like lasers, initiate plasma formation. Micrometer-length plasma streamers are generated when an insulated 25 micron (microm) wire, exposed to physiological medium at one end, is subjected to nanosecond electrical pulses between 1 and 8 kV in magnitude. The explosive evaporation of water in the vicinity of these streamers cuts soft tissue without heat deposition into surrounding material (cold cutting). Streamers of plasma and the dynamics of water evaporation were imaged using an inverted microscope and fast flash photography. Cutting effectiveness was evaluated on both polyacrylamide gels, on different tissues from excised bovine eyes, and in vivo on rabbit retina. Standard histology techniques were used to examine the tissue.Electric pulses with energies between 150 and 670 microJ produced plasma streamers in saline between 10 and 200 microm in length. Application of electric discharges to dense (10%) polyacrylamide gels resulted in fracturing of the gel without ejection of bulk material. In both dense and softer (6%) gels, layer by layer shaving was possible with pulse energy rather than number of pulses as the determinant of ultimate cutting depth. The instrument made precise partial or full-thickness cuts of retina, iris, lens, and lens capsule without any evidence of thermal damage. Because different tissues require distinct energies for dissection, tissue-selective cutting on complex structures can be performed if the appropriate pulse energies are used; for example, retina can be dissected without damage to the major retinal vessels.This instrument, called the Pulsed Electron Avalanche Knife (PEAK), can quickly and precisely cut intraocular tissues without traction. The small delivery probe and modest cost make it promising for many ophthalmic applications, including retinal, cataract, and glaucoma surgery. In addition, the instrument may be useful in nonophthalmic procedures such as intravascular surgery and neurosurgery.

  View details for Web of Science ID 000171433300037

  View details for PubMedID 11581215

• Double fault! Ocular hazards of a tennis sunglass ARCHIVES OF OPHTHALMOLOGY Marmor, M. F. 2001; 119 (7): 1064-1066

  View details for Web of Science ID 000169780200012

  View details for PubMedID 11448329

• The dilemma of color deficiency and art SURVEY OF OPHTHALMOLOGY Marmor, M. F., Lanthony, P. 2001; 45 (5): 407-415

  Abstract

  No "major" painter is known to be color deficient. Are there truly no color deficient artists, or have they not been recognized? The historical literature cites criteria for recognizing color deficiency in artists, but they are hard to apply without knowing the intentions of an artist. The work and commentary of a color-deficient artist who works currently in Paris are presented as an example. He uses a limited palette of colors, based on advice from colleagues as much as his own perceptions, and he uses colors in ways that do not always fit with expectations for color deficiency. Biographies of earlier painters suggest that there were a few whose color sense was poor, but these painters used assistants to help. The color sense of others, such as the English landscape painter John Constable (1776-1837), has been questioned because of a preponderance of suspicious color, such as murky green. However, there are good reasons to doubt that Constable was color deficient. It is instructive to know how proven color deficiency has influenced an artist's style. When medical information is unavailable, the best advice for the diagnostically-inclined observer is just to enjoy the art.

  View details for Web of Science ID 000167810700003

  View details for PubMedID 11274694

• Multifocal electroretinogram abnormalities persist following resolution of central serous chorioretinopathy ARCHIVES OF OPHTHALMOLOGY Chappelow, A. V., Marmor, M. F. 2000; 118 (9): 1211-1215

  Abstract

  To examine results of the multifocal electroretinogram (MERG) after spontaneous resolution of central serous chorioretinopathy (CSC) detachments.Multifocal electroretinograms were recorded from both eyes of 5 recovered patients with CSC and 10 age-matched healthy subjects. All patients with CSC had bilaterally subnormal MERG amplitudes during a first attack of CSC occuring 7 to 23 months earlier.After recovery from CSC, MERG A-wave and B-wave amplitudes increased markedly where the detachment resolved, and moderately elsewhere in the posterior pole of both eyes. However, the signals from both eyes remained either subnormal or low-normal relative to controls. Multifocal electroretinogram B-wave latencies improved from prolonged to mid-normal values in both eyes.Both eyes of patients with active unilateral CSC exhibit diminished MERG amplitudes. Although MERG response amplitudes increased modestly after recovery from CSC, they remained statistically subnormal throughout the posterior pole of both eyes. These findings support the theory that subretinal fluid retention in CSC is secondary to diffuse pathologic changes in the choroid and/or retinal pigment epithelium. They also suggest that the underlying or predisposing abnormalities of CSC resolved only partially in our patients. Components of the MERG may have value as a prognostic tool for judging the risk of developing symptomatic CSC. Arch Ophthalmol. 2000;118:1211-1215

  View details for Web of Science ID 000089268300006

  View details for PubMedID 10980766

• A brief history of macular grids: From Thomas Reid to Edvard Munch and Marc Amsler SURVEY OF OPHTHALMOLOGY Marmor, M. F. 2000; 44 (4): 343-353

  Abstract

  Metamorphopsia is a symptom of retinal distortion from intrinsic retinal disease. It has undoubtedly been experienced for millennia, but its clinical significance has been appreciated only in modern times. The Norwegian painter Edvard Munch recognized scotomas and metamorphopsia after suffering an intraocular hemorrhage in his 60th year. Drawings made during this illness show his changing perceptions, and also his attempts to document them with a grid of lines. The Scottish philosopher Thomas Reid may have been the first to write about metamorphopsia. He described distortion of his vision in 1764, after an episode of sungazing, and recognized that the problem was probably of retinal origin. Lines or grids to document metamorphopsia have appeared in ophthalmology textbooks for more than 100 years, but testing for macular degeneration did not become routine until the dissemination of Amsler's grids in the middle of the 20th century. This is in large measure a result of developments in ophthalmology that made therapy for macular disease possible.

  View details for Web of Science ID 000085108000007

  View details for PubMedID 10667441

• Sildenafil (Viagra) and ophthalmology SURVEY OF OPHTHALMOLOGY Marmor, M. F., Kessler, R. 1999; 44 (2): 153-162

  Abstract

  Sildenafil citrate (Viagra) is a new oral medication that inhibits phosphodiesterase-5 (PDE5) in the corpus cavernosum to facilitate penile erection for the treatment of male impotence. The drug also has a mild inhibitory effect on PDE6, which controls the level of cyclic guanosine monophosphate in the retina, and it may cause a perception of bluish haze or increased light sensitivity in some patients. Long-term retinal damage has not been reported, but long-term electroretinographic studies have not been performed. Sildenafil causes a mild lowering of blood pressure and is absolutely contraindicated in patients taking any form of nitrate medication. A number of cardiovascular deaths and retinal vascular events in patients taking sildenafil have been reported, but so far the rate of these complications does not exceed expectation for an elderly population. Ophthalmologists should alert patients to the ocular side effects and potential risks of this new drug until further clinical experience has been obtained.

  View details for Web of Science ID 000083163900005

  View details for PubMedID 10541153

• The training of George K. Kambara, MD ARCHIVES OF OPHTHALMOLOGY Marmor, M. F. 1999; 117 (9): 1227-1235

  Abstract

  George K. Kambara has been a leader in ophthalmic education and practice on the West Coast. His choice of ophthalmology arose in part because of his experience running an eye, ear, nose, and throat clinic while interned as a Japanese American during World War II. His training took him from San Francisco, to the Tule Lake Relocation Center, to the Memphis Eye, Ear, Nose and Throat Hospital, to the University of Wisconsin, and eventually back to Los Angeles. He saw both sides of discrimination, as a Japanese American in California and as a "white" in the South. He was turned down for positions that he should have had based on his education, but he was also supported by many individuals who put aside public fears to help him. His story shows a triumph of the spirit, but is also a reminder of dark times that should not be forgotten.

  View details for Web of Science ID 000082513600015

  View details for PubMedID 10496396

• Topography of cone electrophysiology in the enhanced S cone syndrome INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Marmor, M. F., Tan, F., Sutter, E. E., Bearse, M. A. 1999; 40 (8): 1866-1873

  Abstract

  To investigate the topography of cone electroretinographic (ERG) responses in the enhanced S cone syndrome (ESCS).A 19-year-old female with ESCS who was one of the original cases defining the syndrome was studied. Full-field, focal (Maculoscope) and multifocal (VERIS) ERGs were performed using white light. Multifocal ERG responses were also generated with red and blue stimuli and with a slow m-sequence to elicit off-responses. Results were analyzed by averaging data in rings at increasing eccentricity from the fovea and compared to data recorded identically from a normal subject.The full-field ERG from this patient showed typ ical large slow photopic waveforms and was unchanged from recordings made 9 years earlier. The focal ERG showed signals of borderline low amplitude from the fovea with the multifocal ERG, the ESCS responses from the central macula had a relatively normal waveform, and those 9 degrees to 20 degrees from fixation showed the prolonged wave-form that characterizes the full-field ERG. Responses were larger to blue light than red light in ESCS in both center and periphery. The central ESCS responses were relatively normal in timing to both red and blue light, whereas the peripheral ESCS responses were markedly delayed to both. Off-responses were seen in ESCS only near the foveal center.The marked differences between central and peripheral ERG responses in ESCS suggest that there are different distributions of S, L, and M cones in these regions and that S cones may feed into different neural pathways in the center and periphery. It was postulated that in ESCS, S cones may partially replace L and M cones centrally and feed into the usual S cone pathways. In the periphery, however, there is little L and M cone b-wave activity in ESCS, and S cones may usurp both the space and neural pathways of the rods.

  View details for Web of Science ID 000081090300037

  View details for PubMedID 10393063

• Sildenafil (Viagra) and ophthalmology ARCHIVES OF OPHTHALMOLOGY Marmor, M. F. 1999; 117 (4): 518–19

  View details for Web of Science ID 000079672200012

  View details for PubMedID 10206581

• Mechanisms of fluid accumulation in retinal edema 2nd International Symposium on Macular Edema Marmor, M. F. SPRINGER. 1999: 239–49

  Abstract

  This paper reviews the anatomic and physiologic conditions which predispose to fluid accumulation within the retina. Retinal edema has its inception in disease that causes a breakdown of the blood-retinal barrier in retinal capillaries and/or the retinal pigment epithelium (RPE). Edema develops not only because protein and fluid enter the extracellular space, but because the external limiting membrane and the convoluted extracellular pathway within the retina limit the clearance of albumin and other large osmotically-active molecules. These molecules bind water to cause edema. Recognition of edema clinically is complicated by the facts that angiographic markers (fluorescein and ICG) do not match albumin in size, and that clinical leakage does not always correlate closely with tissue swelling or functional loss. Active water transport across the RPE is efficient at removing subretinal water, but the flow resistance of the retina limits RPE access to the water of retinal edema. Consideration of the pathophysiology of retinal edema may aid in the development of better strategies for managing retinal edema.

  View details for Web of Science ID 000087056700005

  View details for PubMedID 10896337

• Retinal Pigment Epithelium: Function and Disease. - Michael Marmor, TJ Wolfensberger 1998
• On the cause of serous detachments and acute central serous chorioretinopathy BRITISH JOURNAL OF OPHTHALMOLOGY Marmor, M. F. 1997; 81 (10): 812-813

  View details for Web of Science ID A1997YA15600003

  View details for PubMedID 9486016

  View details for PubMedCentralID PMC1722036

• The Eye of the Artist - Michael Marmor, JG Ravin 1997
• Pattern dystrophy of the retinal pigment epithelium and geographic atrophy of the macula AMERICAN JOURNAL OF OPHTHALMOLOGY Marmor, M. F., McNamara, J. A. 1996; 122 (3): 382-392

  Abstract

  Little information is available on the long-term course of pattern dystrophies, although some older individuals have been observed with macular atrophy. We sought to evaluate the evolution of symptoms, fundus changes, and physiologic findings by re-examining a family with pattern dystrophy after 20 years.Four patients of seven initially examined were reevaluated 20 years later; two additional affected family members over age 60 were studied for the first time. Patients' current ages ranged from 38 to 73 years. Comprehensive ophthalmic examinations were supplemented with fluorescein angiography, dark adaptometry, color vision, electroretinography, and electrooculography.During the 20-year interval, visual acuity remained stable and 20/40 or better in all patients. One 62-year-old patient developed paracentral scotomas. All fundi showed evolution of pigmentary changes and increasing atrophy of pigment epithelium and choriocapillaris in the macula. Electro-oculograms were originally subnormal in all patients and changed very little. Electroretinograms, initially normal in two patients, became borderline or mildly subnormal and slightly reduced in the two patients first examined after age 60.Pattern dystrophy in this family was associated with minimal diminution of visual function during a 20-year interval. However, there was electroretinographic evidence of mild diffuse photoreceptor damage in the older patients, and geographic macular atrophy was prominent (suggesting a risk of vision loss in old age). Some cases of atrophic, age-related macular degeneration may represent an evolution of pattern dystrophy.

  View details for Web of Science ID A1996VF62000010

  View details for PubMedID 8794711

• The source of fluid and protein in serous retinal detachments CURRENT EYE RESEARCH Takeuchi, A., Kricorian, G., Wolfensberger, T. J., Marmor, M. F. 1996; 15 (7): 764-767

  Abstract

  To investigate the source and protein content of sub-retinal fluid in self-forming experimental serous retinal detachments.Detachments were induced in Dutch rabbit eyes using rose bengal photosensitization to cause choriocapillaris injury and thrombosis. Serous detachments formed spontaneously within the next 24 h. Subretinal fluid was withdrawn 2, 8 and 24 hrs after photosensitization, and was analyzed for osmolality and albumin content by gel electrophoresis.The albumin concentration in the subretinal fluid of light-induced detachments was 68% of serum level at 3 h after light damage, and rose close to serum level by 24 h. The osmolality of subretinal fluid 24 h after light damage was essentially the same as serum and vitreous fluid.The subretinal protein and fluid in light-induced detachments in the central retina of the rabbit must come from the choroid, since there are no intrinsic retinal blood vessels in that region of the fundus. These data demonstrate that serous retinal detachments can form from choroidal fluid.

  View details for Web of Science ID A1996UZ34000010

  View details for PubMedID 8670785

• THE ERG IS ALIVE AND WELL ARCHIVES OF OPHTHALMOLOGY Marmor, M. F. 1995; 113 (11): 1371-1372

  View details for Web of Science ID A1995TD68000015

  View details for PubMedID 7487594

• THE INTERPHOTORECEPTOR MATRIX MEDIATES PRIMATE RETINAL ADHESION ARCHIVES OF OPHTHALMOLOGY Hageman, G. S., Marmor, M. F., Yao, X. Y., JOHNSON, L. V. 1995; 113 (5): 655-660

  Abstract

  To assess the participation of cone matrix sheaths, which are domains of the cone photoreceptor-associated interphotoreceptor matrix that extend from the neural retina to the surface of the retinal pigment epithelium (RPE), in retinal adhesion.Monkey and human retinas were partially peeled from the RPE, and the tissues were examined by lectin histochemistry to determine the effects of physical separation on the cone matrix sheath.A firm attachment of cone matrix sheaths to both the RPE and the neural retina that was strong enough to cause detachment of sheets of RPE cells from Bruch's membrane or tearing of the sheaths as a result of retinal peeling was observed. Cone matrix sheaths can stretch considerably and contract following tearing. Their integrity was compromised rapidly after the first postmortem minute.Cone matrix sheath glycoconjugates are likely to play a major role in mediating retinal adhesion by forming a molecular bridge between the neural retina and the RPE.

  View details for Web of Science ID A1995QY40700030

  View details for PubMedID 7748138

• THE METABOLIC DEPENDENCY OF RETINAL ADHESION IN RABBIT AND PRIMATE ARCHIVES OF OPHTHALMOLOGY Marmor, M. F., Yao, X. Y. 1995; 113 (2): 232-238

  Abstract

  To determine the oxygen and glucose dependency of retinal adhesion in primate and rabbit.Experiments were performed on Dutch rabbits and monkeys. Retinal adhesiveness was measured by peeling the retina from the retinal pigment epithelium in vitro, under different conditions of PO2 and glucose supply, and by observing the amount of adherent pigment. In vivo ischemia was produced by raising the intraocular pressure.Retinal adhesion failed quickly at low oxygen tensions, but a well-oxygenated solution preserved strong retinal adhesion in vitro for 15 to 20 minutes in rabbit tissue and up to 50 minutes in primate tissue. Ischemic adhesive failure was reversible on raising the PO2. Glucose levels did not affect adhesiveness. Ischemia in vivo for more than 1 minute caused rabbit retina to lose its adhesiveness.Retinal adhesion is continually and reversibly dependent on oxygenation, and probably on aerobic metabolism. Primate tissue is more resistant to metabolic adhesive failure than is rabbit tissue, but the metabolic requirements appear qualitatively similar.

  View details for Web of Science ID A1995QH04200033

  View details for PubMedID 7864758

• CONDITIONS NECESSARY FOR THE FORMATION SEROUS DETACHMENT - EXPERIMENTAL-EVIDENCE FROM THE CAT ARCHIVES OF OPHTHALMOLOGY Marmor, M. F., Yao, X. Y. 1994; 112 (6): 830-838

  Abstract

  To evaluate experimentally the conditions necessary for the formation of serous detachments.Selective injury to the retinal pigment epithelium (RPE) and choriocapillaris was produced in cats using weak laser burns and intense diffuse light, with or without photosensitization with rose bengal. The fundi were analyzed by observation, fluorescein angiography, and histologic examination.Injuring the RPE alone did not cause detachments. Focal injury to the RPE and choriocapillaris caused moderate detachment only when an area surrounding the focal leakage site had been subjected to light damage. Diffuse injury to the RPE and choriocapillaris caused broader detachments.Three conditions are necessary for serous detachments to form: (1) a source of fluid pressure, (2) a defect in the blood-retinal barrier (entry site), and (3) an area of impaired fluid transport beyond the site of leakage (if fluid is to accumulate over a broader area).

  View details for Web of Science ID A1994NQ99400029

  View details for PubMedID 8002843

• RETINAL ADHESIVENESS IN THE MONKEY INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Yao, X. Y., Hageman, G. S., Marmor, M. F. 1994; 35 (2): 744-748

  Abstract

  To determine factors that influence retinal adhesion in the primate and compare these with previous data from the rabbit.Retinal adhesiveness was studied in monkey eyes immediately after enucleation. The retina was peeled manually from the retinal pigment epithelium, and the amount of pigment that remained adherent to the retina was used as an index of adhesiveness.The rate of post mortem failure of retinal adhesiveness in the monkey was less than in the rabbit under similar conditions. However, as in the rabbit, adhesiveness was sensitive to temperature, pH, and the concentrations of calcium and magnesium, and subretinal injections of neuraminidase weakened adhesion beyond the injection sites.Mechanisms of retinal adhesion are similar in primates and rabbits.

  View details for Web of Science ID A1994MY95700053

  View details for PubMedID 8113025

• OXYGEN DEPENDENCY OF RETINAL ADHESION INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Kim, R. Y., Yao, X. Y., Marmor, M. F. 1993; 34 (6): 2074-2078

  Abstract

  Normal retina is firmly attached to the retinal pigment epithelium, but the force of this adhesion drops precipitously within the first 2-3 min after enucleation. The purpose was to study metabolic factors that might be relevant to this postmortem failure of adhesion.Dutch rabbit retina was manually peeled from the retinal pigment epithelium on strips of enucleated eyecup within a 37 degrees C bath. Retinal adhesiveness was measured by observing the amount of retinal pigment epithelium that remained adherent to the retina.Autologous whole blood in place of salt solution retarded the decrease in adhesiveness. A solution of hemoglobin alone was similarly effective, whereas methemoglobin solution failed to help the persistence of retinal adhesion. Bubbling oxygen into the salt solution and circulating it to avoid oxygen depletion at the tissue boundary also proved effective at sustaining retinal adhesiveness. Eyes made ischemic in vivo for 5 min or longer, by elevating intraocular pressure, showed virtually no retinal adhesion when enucleated immediately thereafter. However, eyes made ischemic for 10 min, but allowed to regain circulation for 5 min before enucleation, showed a return of retinal adhesiveness to 80% of normal.Oxidative metabolism is critical to the maintenance of retinal adhesiveness, and the effects of oxygen deprivation on adhesion are reversible within a certain time period.

  View details for PubMedID 8491557

• STANDARD FOR CLINICAL ELECTROOCULOGRAPHY ARCHIVES OF OPHTHALMOLOGY Marmor, M. F., Zrenner, E. 1993; 111 (5): 601-604

  Abstract

  The electro-oculogram is a widely used electrophysiological test, but recording techniques vary among different laboratories. This standard, approved by the International Society for Clinical Electrophysiology of Vision (ISCEV), describes simple technical procedures that will allow reproducible and comparable electro-oculograms to be recorded under a few defined conditions. The document is intended to improve the comparability of electro-oculographic data obtained throughout the world by guiding both clinicians and manufacturers, and the ISCEV recommends that future published reports indicate whether the recording technique meets the international standard.

  View details for Web of Science ID A1993LC12000020

  View details for PubMedID 8489436

• MANNITOL, DEXTROMETHORPHAN, AND CATALASE MINIMIZE ISCHEMIC DAMAGE TO RETINAL-PIGMENT EPITHELIUM AND RETINA ARCHIVES OF OPHTHALMOLOGY GUPTA, L. Y., Marmor, M. F. 1993; 111 (3): 384-388

  Abstract

  We studied the recovery of retinal pigment epithelium and retinal function after 80 minutes of pressure-induced ischemia in rabbits. Just before restoring circulation, we gave intravenous mannitol (an osmotic agent and free-radical scavenger), dextromethorphan (an N-methyl-D-aspartate receptor antagonist), or catalase (an antioxidant enzyme). Mannitol has not previously been shown to be protective for retinal or retinal pigment epithelial ischemia. At 24 hours after reperfusion, the electroretinogram b-wave was reduced to 37% of preischemic amplitude in untreated eyes, but it recovered to 67% to 80% after treatment with all three agents. The c-wave was replaced by a negative slow PIII response in control eyes and in seven of 12 catalase-treated eyes, but it recovered by 58% to 82% in the remaining catalase-treated eyes and all the mannitol- and dextromethorphan-treated eyes. Histologic examination confirmed that retinal pigment epithelium as well as retina had been damaged by the ischemia. The effects of mannitol seem of special interest, since the drug has a dual mechanism of action and is clinically available.

  View details for Web of Science ID A1993KR44600034

  View details for PubMedID 8447753

• RETINAL ADHESIVE FORCE IN LIVING RABBIT, CAT, AND MONKEY EYES - NORMATIVE DATA AND ENHANCEMENT BY MANNITOL AND ACETAZOLAMIDE INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Kita, M., Marmor, M. F. 1992; 33 (6): 1879-1882

  Abstract

  Small retinal detachments (blebs) were made in living eyes by injecting balanced salt solution into the subretinal space with a micropipette. A second micropipette, inserted into the same bleb, measured subretinal pressure using a resistance servonulling system. The adhesive force was calculated from the pressure difference across the retina according to Laplace's law. The retinal adhesive force in rabbit, cat, and monkey eyes averaged 1.0, 1.8, and 1.4 x 10(2) dyne/cm, respectively. In rabbit eyes, 2 hr after intravenous administration of 15 mg/kg acetazolamide, the retinal adhesive force was increased to 133%. In monkeys, this dose of acetazolamide increased retinal adhesion to 144% of control values. Mannitol (2 g/kg) increased retinal adhesion in the monkey to 153% of control values 90 min after intravenous injection (compared with an increase of 145% in previous experiments in the rabbit). Because both mannitol and acetazolamide enhance retinal adhesiveness in living primate eyes, it seems likely that they will have a similar effect in humans that they may be clinically useful.

  View details for Web of Science ID A1992HV58700008

  View details for PubMedID 1582792

• LOWERING THE CALCIUM-CONCENTRATION IN THE SUBRETINAL SPACE INVIVO LOOSENS RETINAL ADHESION INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Kita, M., Negi, A., Marmor, M. F. 1992; 33 (1): 23-29

  Abstract

  Retinal adhesiveness in vitro is reduced by lowering the external calcium (Ca2+) concentration. The effects of lowering subretinal Ca2+ concentration in living rabbit eyes was investigated by making experimental retinal detachments (blebs) filled with Ca(2+)-free disodium edetate solution. Unlike blebs made with Hanks' solution, these low-Ca2+ blebs enlarged progressively after they were formed, and they were surrounded by a wide whitish halo. This halo region had weak adhesion (shown by the rapid spread of fluorescein solution into the halo and by the measurement of local adhesiveness after enucleation). The retinal pigment epithelial microvilli in the halo appeared stretched toward the center of the blebs as if there had been retinal traction or movement. Measurements of retinal adhesiveness in vivo showed it to be decreased to about 30% of normal by use of this solution.

  View details for Web of Science ID A1992HA13700003

  View details for PubMedID 1730543

• Functional visual loss in Cambodian refugees: a study of cultural factors in ophthalmology. European journal of ophthalmology Drinnan, M. J., Marmor, M. F. 1991; 1 (3): 115-118

  Abstract

  South East (SE) Asians accounted for a disproportionate percentage of the functional visual loss (FVL) seen in our area between 1983 and 1987. Moreover, 94% of the SE Asian FVL patients were Cambodian, although Cambodians only represented 20-30% of the local SE Asian patient population. Cambodian refugees are, at present, generally from lower socio-economic classes than the Vietnamese, and a much larger percentage of them have a history of camp incarceration and previous trauma. The Cambodians presenting with FVL may have conversion hysteria influenced by their wartime experience and cultural background. This study demonstrates that the SE Asian refugees in California are not a homogenous group with respect to visual problems, and that an awareness of cultural or historical factors can be important to the management of ophthalmic symptoms in our multi-cultural societies.

  View details for PubMedID 1841666

• IS THIORIDAZINE RETINOPATHY PROGRESSIVE - RELATIONSHIP OF PIGMENTARY CHANGES TO VISUAL FUNCTION BRITISH JOURNAL OF OPHTHALMOLOGY Marmor, M. F. 1990; 74 (12): 739-742

  Abstract

  Thioridazine toxicity has been described as a 'progressive chorioretinopathy', but this designation can be misleading. During the first year after thioridazine exposure retinal pigmentation evolves from a granular to a patchy or nummular appearance. However, visual function and the electroretinogram typically improve during this period. Some cases may show chorioretinal atrophy and functional loss many years later, but there is little evidence for ongoing drug-related progression. Late atrophy may represent degeneration of cells that were injured subclinically at the time of initial drug exposure. Although thioridazine toxicity produces an evolving pigmentary disturbance, functional changes must be monitored independently of fundus appearance.

  View details for Web of Science ID A1990EL95200009

  View details for PubMedID 2275937

  View details for PubMedCentralID PMC1042279

• RETINAL ADHESIVENESS IS WEAKENED BY ENZYMATIC MODIFICATION OF THE INTERPHOTORECEPTOR MATRIX INVIVO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Yao, X. Y., Hageman, G. S., Marmor, M. F. 1990; 31 (10): 2051-2058

  Abstract

  The role of interphotoreceptor matrix (IPM) constituents in mediating adhesion between the retina and retinal pigment epithelium (RPE) was investigated by injecting specific enzymes into rabbit eyes either intravitreally or subretinally. Retinal adhesiveness was measured by peeling the retina from the pigment epithelium 1-3 days later and observing the amount of adherent pigment. Effects of enzymes on the IPM were monitored by observation of peanut agglutinin (PNA) binding to cone matrix sheaths; retinal and RPE toxicity was excluded by electroretinography and histology. Three enzymes that degrade glycosaminoglycans or saccharides known to be constituents of the IPM (chondroitinase ABC, neuraminidase, and testicular hyaluronidase) both weakened adhesion and altered PNA binding, although the effects on the cone matrix sheaths were different for each enzyme. An enzyme specific for hyaluronic acid (Streptomyces-derived hyaluronidase), which has not been identified as a major IPM constituent, had no effect on either adhesion or PNA binding. The authors conclude that IPM-associated glycoconjugates participate in retinal adhesion, although their precise composition, interaction with IPM components, and relationship to other mechanisms of adhesion remain to be determined.

  View details for Web of Science ID A1990ED60300018

  View details for PubMedID 2211002

• DIAGNOSTIC CLINICAL FINDINGS OF A NEW SYNDROME WITH NIGHT BLINDNESS, MACULOPATHY, AND ENHANCED S-CONE SENSITIVITY AMERICAN JOURNAL OF OPHTHALMOLOGY Marmor, M. F., Jacobson, S. G., Foerster, M. H., Kellner, U., Weleber, R. G. 1990; 110 (2): 124-134

  Abstract

  We studied eight patients who had night blindness, maculopathy (often cystoid), degenerative changes in the region of the vascular arcades, relatively mild visual field loss, and an unusual but characteristic electroretinogram. The dark-adapted electroretinogram showed no response to low-intensity stimuli that normally activate the rods, but large, slow responses to high-intensity stimuli. These large, slow waveforms persisted without change under light adaptation, and showed a striking mismatch to photopically balanced short and long wavelength stimuli (with sensitivity much greater to short than long wave-lengths). Since there is evidence from other studies that the electroretinogram and psychophysical responses represent hypersensitivity of short wavelength-sensitive (S or blue) cones, we propose that this disorder be called the enhanced S cone syndrome. There can be different degrees of severity in this syndrome, and progression appears to be slow.

  View details for Web of Science ID A1990DR57300003

  View details for PubMedID 2378376

• SWS (BLUE) CONE HYPERSENSITIVITY IN A NEWLY IDENTIFIED RETINAL DEGENERATION INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Jacobson, S. G., Marmor, M. F., Kemp, C. M., Knighton, R. W. 1990; 31 (5): 827-838

  Abstract

  Photoreceptor-mediated mechanisms were studied in patients with a recently identified retinopathy typified by night blindness, cystoid maculopathy, and similar scotopic and photopic electroretinograms (ERGs). Dark-adapted spectral sensitivity functions were only partly explained as composites of rod and cone curves shifted to lower sensitivities; there was unusually high sensitivity from 400-460 nm. A rod mechanism, reduced in sensitivity by at least 3 log units, was detectable with dark adaptometry. No measurable rhodopsin was found with fundus reflectometry. Light-adapted spectral sensitivities were subnormal for wavelengths greater than 500 nm but supernormal from 420-460 nm. On a yellow adapting field, the supernormal spectrum approximated that of the short-wavelength-sensitive (SWS) cone system. With spectral ERGs, two mechanisms were demonstrated. Dark- and light-adapted ERGs to green, orange-yellow, and red stimuli had similar waveforms and coincident intensity-response functions on a photopic intensity axis. ERGs to blue and blue-green stimuli were similar, and intensity-response functions coincided on a SWS cone intensity axis. Patients varied in the degree to which rod and midspectral cone function were decreased and SWS cone function was increased.

  View details for Web of Science ID A1990DD92100007

  View details for PubMedID 2335450

• LONG-TERM FOLLOW-UP OF THE PHYSIOLOGIC ABNORMALITIES AND FUNDUS CHANGES IN FUNDUS-ALBIPUNCTATUS OPHTHALMOLOGY Marmor, M. F. 1990; 97 (3): 380-384

  Abstract

  Fundus albipunctatus (FA) is considered to be a congenital stationary night-blinding disorder, but there has been no electrophysiologic or photographic documentation of long stability or change. This documentation is presented for two cases followed for 13 to 14 years. The physiologic (functional) deficits appeared to be stable, in support of the concept that FA is not a progressive dystrophy. However, the fundus lesions evolved in appearance from flecks in childhood to relatively permanent punctate dots that increase in number over the years.

  View details for Web of Science ID A1990CT25000028

  View details for PubMedID 2336278

• CONTROL OF SUBRETINAL FLUID - EXPERIMENTAL AND CLINICAL-STUDIES EYE Marmor, M. F. 1990; 4: 340-344

  Abstract

  Experimental work shows that subretinal fluid is removed both by active transport across the retinal pigment epithelium (RPE) and by passive hydrostatic and oncotic forces that work most effectively when the RPE barrier has been damaged. The retina will stay attached whether or not the RPE is intact--but retinal function requires the RPE barrier and thus active transport is the primary mechanism of subretinal fluid control. RPE fluid transport is normally limited by the retina (which resists water flow from the vitreous) but can be quite powerful when a reservoir of subretinal fluid is present. Clinical serous detachments are unlikely to form solely as a result of small RPE defects or leaks, since the active and passive transport systems for removing subretinal fluid are both so strong. It is suggested that the primary pathology in most serous retinopathy is a diffuse metabolic or vascular abnormality of RPE fluid transport, and that RPE defects or leaks are necessary but only secondary components of the disease. Several hypotheses for removing subretinal fluid therapeutically are considered in terms of their physiology. The subretinal space between the photoreceptors and the retinal pigment epithelium (RPE) is the remnant of the embryonic optic vesicle. In the developed eye the subretinal space is of minimal size, but no tissue junctions form across it and it can re-open under pathological conditions of retinal detachment. In a sense, the title of this paper is misleading since normally there should be no subretinal fluid to control. However, ocular mechanisms are necessary to prevent an accumulation of fluid, and to remove it under conditions of stress or disease.

  View details for Web of Science ID A1990DF65400013

  View details for PubMedID 2199242

• DEXTROMETHORPHAN PROTECTS RETINA AGAINST ISCHEMIC-INJURY INVIVO ARCHIVES OF OPHTHALMOLOGY Yoon, Y. H., Marmor, M. F. 1989; 107 (3): 409-411

  Abstract

  Retinal ischemia was induced in rabbits by increasing intraocular pressure above systolic blood pressure for 60 or 75 minutes, and retinal function was monitored by electroretinography. Pretreatment with intravenous dextromethorphan, a nonprescription antitussive and selective antagonist of N-methyl-D-aspartate receptors, enhanced greatly the post-ischemic recovery of b-wave amplitude. Dextromethorphan may prove to be useful clinically in the management of retinal ischemic disease.

  View details for Web of Science ID A1989T597500030

  View details for PubMedID 2923566

• PHOTOAVERSION IN RETINITIS PIGMENTOSA BRITISH JOURNAL OF OPHTHALMOLOGY Gawande, A. A., Donovan, W. J., Ginsburg, A. P., Marmor, M. F. 1989; 73 (2): 115-120

  Abstract

  Photoaversion, or light-induced interference with visual comfort and performance, has been a recognised but poorly documented symptom in retinitis pigmentosa (RP). We found that a majority of our RP patients complained of photoaversion even in the absence of significant cataract. RP patients had reduced contrast sensitivity relative to normal people, but the decrement in their visual performance as a result of glare or photostress was only slight. RP patients had raised short-term adaptation and increment threshold levels, but their rate of short-term or photopic adaptation was normal. Photoaversion in RP may result because a small interference with contrast sensitivity or adaptation can place patients in a range of functional disability, or it may derive from a combination of minor aberrations.

  View details for Web of Science ID A1989T330000008

  View details for PubMedID 2930757

  View details for PubMedCentralID PMC1041666

• NEW HYPOTHESES ON THE PATHOGENESIS AND TREATMENT OF SEROUS RETINAL-DETACHMENT GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY Marmor, M. F. 1988; 226 (6): 548-552

  Abstract

  Recent experimental work has shown that, under normal conditions, most subretinal fluid is absorbed rapidly by active transport across the retinal pigment epithelium (RPE). However, in the presence of damage to the RPE blood-retinal barrier, subretinal fluid is rapidly cleared by passive forces. Thus, it is apparent that RPE defects do not by themselves cause serous retinal detachment. A hypothesis is presented that some serous detachments occur because normal metabolic transport systems of the RPE have been damaged, while the blood-retinal barrier remains intact to prevent passive drainage of the subretinal space. Under these conditions, a focal RPE "leak" can overload the system so that the serous fluid accumulates and persists. Photocoagulation of a leaking point can facilitate resolution of the fluid, but as long as the underlying metabolic dysfunction of the RPE persists, recurrence is possible. Some forms of serous detachment may thus be viewed as diffuse rather than focal ocular disorders in which the transport capability of the RPE has been damaged; such damage can result from systemic pathology such as adrenergic stress (e.g., central serous chorioretinopathy) or vascular disease (e.g., hypertension).

  View details for Web of Science ID A1988R029400009

  View details for PubMedID 3209082

• ACUTE CHANGES IN RPE APICAL MORPHOLOGY AFTER RETINAL-DETACHMENT IN RABBIT - A SEM STUDY INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Immel, J., Negi, A., Marmor, M. F. 1986; 27 (12): 1770-1776

  Abstract

  The morphology of the apical surface of rabbit retinal pigment epithelium was studied by scanning electron microscopy from the first minute to several hours after making small nonrhegmatogenous retinal detachments (blebs). From 0 to 5 min, there were only slight changes in the homogeneous, dense mat of filamentous microvilli. From 5 to 30 min, filamentous microvilli retracted exposing larger processes. From 30 to 60 min blunt processes became completely exposed and sheet-like processes disappeared. At about 60 min, cone sheaths were no longer identifiable in most specimens. Between 60 min and the time of retinal reapposition (several hours), the apical surface became highly rounded. Colchicine and cytochalasin-D had no effect on the time required for fluid resorption, but colchicine greatly accelerated and enhanced cell rounding, while cytochalasin-D produced prominent apical tufts.

  View details for Web of Science ID A1986F544700018

  View details for PubMedID 3793410

• PHARMACOLOGICAL MODIFICATION OF SUBRETINAL FLUID ABSORPTION IN THE RABBIT EYE ARCHIVES OF OPHTHALMOLOGY Marmor, M. F., Negi, A. 1986; 104 (11): 1674-1677

  Abstract

  We studied in the rabbit the effects of pharmacologic agents on the absorption of Hanks' solution from the subretinal space of experimental nonrhegmatogenous detachments. Intravenous acetazolamide had no effect at a clinical dose (15 mg/kg) but increased the rate of fluid absorption significantly at high doses (50 mg/kg). Acetazolamide causes systemic pH to fall, while PCO2 and PO2 increase; however, duplicating some of these effects by artificial respiration or breathing 95% O2 plus 5% CO2 did not alter the rate of fluid absorption. Adding cyclic AMP and related agents to the vitreous and subretinal space slowed down fluid absorption by 25%, whereas cyclic GMP analogues increased the rate of absorption by 33%.

  View details for Web of Science ID A1986E697200034

  View details for PubMedID 3778286

• MECHANISMS OF SUBRETINAL FLUID RESORPTION IN THE CAT EYE INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Negi, A., Marmor, M. F. 1986; 27 (11): 1560-1563

  Abstract

  Small, non-rhegmatogenous retinal detachments (blebs) were made in cat eyes by injecting fluid into the subretinal space, and the time course of fluid resorption was monitored. Blebs made with Hanks' solution over the pigmented RPE resorbed 22% faster than those over the tapetum. Blebs made with a non-ionic solution (isotonic sucrose) took 43% longer to resorb than those made with Hanks' solution, and blebs containing 3 X 10(-3) M sodium cyanide took 32% longer than controls. These results suggest that active ionic transport is involved in the absorption of subretinal fluid in the cat, as it is in the rabbit. Oncotic pressure in the choroid may also contribute to resorption, because blebs made with autologous serum took roughly 3 times longer to resorb than those made with non-proteinaceous Hanks' solution. The retinal vascular system does not appear to contribute, since the resorption time was similar for Hanks' blebs made under normal retina and those made under ischemic retina (produced by occluding retinal branch arteries with argon laser photocoagulation or endodiathermy).

  View details for Web of Science ID A1986E892800002

  View details for PubMedID 3771135

• QUANTITATIVE ESTIMATION OF METABOLIC TRANSPORT OF SUBRETINAL FLUID INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Negi, A., Marmor, M. F. 1986; 27 (11): 1564-1568

  Abstract

  A new technique to measure the ongoing rate of subretinal fluid resorption inside the living eye is described. Experimental non-rhegmatogenous detachments (blebs) were made in the posterior pole of rabbit eyes by injecting fluid directly into the subretinal space, and the height of these blebs was measured with a YAG laser focusing system utilizing dual He-Ne beams. The resorption rate for Hanks' balanced salt solution was relatively constant during the initial 2.5 hr, and averaged 0.12 +/- 0.04 microliter/mm2/hr. The resorption rate for blebs made with non-ionic solution (isotonic sucrose) was only 0.03 microliter/mm2/hr. The resorption rate for blebs made with Hanks' solution plus 1 mM DNP was 0.04 microliter/mm2/hr. These data support the concept that subretinal fluid is resorbed primarily across the retinal pigment epithelium, and suggests that 70% of this absorption is dependent upon active ionic transport. The remaining 30% is probably driven by the higher oncotic pressure of the choroid.

  View details for Web of Science ID A1986E892800003

  View details for PubMedID 3771136

• KINETICS OF MACROMOLECULES INJECTED INTO THE SUBRETINAL SPACE EXPERIMENTAL EYE RESEARCH Marmor, M. F., Negi, A., Maurice, D. M. 1985; 40 (5): 687-696

  Abstract

  Small, experimental, non-rhegmatogenous retinal detachments (blebs) in rabbit eyes resorbed 50% more slowly when filled with autologous serum than with Hanks' solution. To study the fate of large molecules in the subretinal space, carboxyfluorescein and several sizes of FITC-dextrans were injected into blebs and their movement followed by fluorophotometry. Carboxyfluorescein diffused quickly into the vitreous and was gone from the space after 8 hr. FITC-dextran 10-S (smaller than albumin) also diffused readily into the vitreous and took about 30 hr to be eliminated from the subretinal space. The diffusion of FITC-dextran 70-S and 150-S (both larger than albumin) was markedly slower, and roughly 80% of the 150-S was still present in the subretinal space after 3 days. Since the subretinal fluid in all of these blebs resorbed within 10 hr, the physiologic mechanisms for fluid resorption and elimination of large substances appear to be independent. Damaging the RPE barrier with sodium iodate allowed even the larger FITC-dextrans to exit from the subretinal space.

  View details for Web of Science ID A1985AKW8500005

  View details for PubMedID 2408910

• EFFECTS OF HYPOXIA AND HYPEROXIA ON THE HUMAN STANDING POTENTIAL DOCUMENTA OPHTHALMOLOGICA Marmor, M. F., Donovan, W. J., Gaba, D. M. 1985; 60 (4): 347-352

  Abstract

  We report that the human standing potential, measured by the EOG, rises slowly when oxygen saturation is lowered to near 80% by breathing a controlled oxygen-nitrogen mixture. The standing potential falls abruptly by 20-30% of its amplitude when the oxygen saturation returns to 100%. These changes can be generated reproducibly, with minimal discomfort, under conditions that could be adopted for clinical use. Animal experimental studies by Linsenmeier and Steinberg suggest that this hypoxia-hyperoxia response may be a delayed response to potassium concentration changes in the subretinal space. Since there is no requirement for light and no involvement of the Müller cells, the hypoxia-hyperoxia response may be more specific for pigment epithelial pathology than the c-wave.

  View details for Web of Science ID A1985AUA2000002

  View details for PubMedID 4064875

• HEALING OF PHOTOCOAGULATION LESIONS AFFECTS THE RATE OF SUBRETINAL FLUID RESORPTION OPHTHALMOLOGY Negi, A., Marmor, M. F. 1984; 91 (12): 1678-1683

  Abstract

  We have measured the rate of subretinal fluid resorption in rabbits by monitoring the collapse of small experimental retinal detachments (blebs) filled with either Hanks' solution (non-proteinaceous) or autologous serum. Blebs filled with Hanks' solution resorbed much more rapidly over freshly lasered RPE than normal RPE, but the effect disappeared over 10 to 14 days. This time course corresponds with angiographic and histologic evidence of RPE repair. In contrast, blebs filled with serum resorbed at nearly the same rate regardless of whether the RPE had been lasered or not. We conclude that photocoagulation destroys the RPE barrier acutely, and until the barrier heals non-proteinaceous subretinal fluid will be drawn out rapidly by the oncotic pressure of the choroid. This acute effect of photocoagulation is of uncertain benefit in clinical conditions because of protein in the subretinal fluid, and it seems more likely that photocoagulation works in serous retinopathy by arresting an active source of fluid.

  View details for Web of Science ID A1984TZ66100036

  View details for PubMedID 6542986

• VALIDATION OF A MODEL OF NON-RHEGMATOGENOUS RETINAL-DETACHMENT CURRENT EYE RESEARCH Marmor, M. F., Porteus, M., Negi, A., Immel, J. 1984; 3 (3): 515-518

  Abstract

  To study the movement of subretinal fluid, we have injected fluid into the subretinal space through a glass micropipette and monitored its resorption. This technique has been criticized as a model of non-rhegmatogenous detachment because the small retinal hole made by the micropipette might allow efflux of subretinal fluid into the vitreous. The present experiments answer this criticism: we found that sealing the micropipette hole with cyanoacrylate, mucilage or an air bubble had no effect on the rate of subretinal fluid resorption, and detachments with two to five micropipette holes did not resorb faster than those with only one.

  View details for Web of Science ID A1984SC67800016

  View details for PubMedID 6697753

• EXPERIMENTAL SEROUS RETINAL-DETACHMENT AND FOCAL PIGMENT EPITHELIAL DAMAGE ARCHIVES OF OPHTHALMOLOGY Negi, A., Marmor, M. F. 1984; 102 (3): 445-449

  Abstract

  We made small nonrhegmatogenous retinal detachments (blebs) in rabbits over regions of retinal pigment epithelium (RPE) that were damaged mechanically or by laser photocoagulation. Fluorescein diffused readily into blebs made over damaged RPE, but the subretinal fluid was resorbed more quickly than from blebs overlying normal RPE. Thus, focal damage appears to facilitate water movement from, rather than into, the subretinal space. We conclude from these data that central serous chorioretinopathy is not caused simply by a passive "leak" through the RPE barrier, and the effects of photocoagulation in this disease cannot be explained simply as sealing such a leak.

  View details for Web of Science ID A1984SG02800021

  View details for PubMedID 6703994

• THE RESORPTION OF SUBRETINAL FLUID AFTER DIFFUSE DAMAGE TO THE RETINAL-PIGMENT EPITHELIUM INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Negi, A., Marmor, M. F. 1983; 24 (11): 1475-1479

  Abstract

  We studied the role of the retinal pigment epithelium (RPE) in the resorption of different subretinal fluids from under small experimental retinal detachments (blebs) in the rabbit. Damaging the RPE with sodium iodate caused the resorption time, for blebs made with an ionic solution (Hanks'), to decrease from 2-6 hours to only about 30 minutes. Blebs made with sucrose also absorbed much more quickly after iodate. However, blebs made with autologous serum resorbed no faster after iodate. We conclude that iodate destroys the membrane barrier properties of the RPE, allowing subretinal fluid to cross freely according to oncotic pressure. We postulate that in the normal eye, where osmotic fluid movement is low because of the high resistance barrier, the RPE must transport fluid actively to keep the subretinal space dehydrated.

  View details for Web of Science ID A1983RS80800004

  View details for PubMedID 6642927

• RETINITIS PIGMENTOSA - A SYMPOSIUM ON TERMINOLOGY AND METHODS OF EXAMINATION OPHTHALMOLOGY Marmor, M. F., AGUIRRE, G., Arden, G., Berson, E., Birch, D. G., Boughman, J. A., Carr, R., CHATRIAN, G. E., Delmonte, M., Dowling, J., Enoch, J., Fishman, G. A., Fulton, A. B., Garcia, C. A., Gouras, P., Heckenlively, J., Hu, D. N., Lewis, R. A., Niemeyer, G., Parker, J. A., Perlman, I., Ripps, H., Sandberg, M. A., Siegel, I., Weleber, R. G., Wolf, M. L., Wu, L., Young, R. S. 1983; 90 (2): 126-131

  Abstract

  This report represents a summary of opinions expressed at a meeting of specialists interested in retinitis pigmentosa (RP) and allied diseases, at which an attempt was made to define some minimum guidelines for ocular evaluation of these disorders. The term RP would be reserved for a group of hereditary disorders that diffusely involve photoreceptor and pigment epithelial function, and should not be used when a secondary cause is suspected. RP may be classified by genetic type (single cases without known affected relatives should be termed isolated or simplex), by the topography of retinal involvement, and by the severity of disease (to identify subtypes with mild or localized disease). Patients should have at least one comprehensive examination that conforms to basic standards, preferable early in the course of the disease. The visual field examination should use both a small and a large test light. Electroretinographic testing should (1) use a full-field stimulus, and (2) routinely document three independent responses (cone, rod, and mixed cone-rod). Patients should be identifiable for future study or therapeutic trials. They should be counseled about the disease and followed regularly. No specific therapy exists at present for most of these diseases, but optical and night vision aids are available. Sunglasses for outdoor use are recommended until more is known about whether long-term exposure to bright sunlight alters the course of these diseases.

  View details for Web of Science ID A1983QH18300003

  View details for PubMedID 6856249

• THE C-WAVE OF THE RABBIT ELECTRORETINOGRAM DURING DARK-ADAPTATION AND THE STEADY-STATE ACTA OPHTHALMOLOGICA Wu, L., Lurie, M., Marmor, M. F. 1981; 59 (4): 603-608

  Abstract

  C-waves of the rabbit ERF under urethane anesthesia were elicited by a Grass photostimulator during dark adaptation and under steady-state conditions. After strong pre-adaptation with light, the amplitude and time-to-peak of the c-wave increased in parallel with the a- and b-waves, reaching a maximum of 90-130 min. In the dark-adapted steady-state, repetitive stimuli at intervals ranging from 15 sec to 5 min elicited a stable c-wave response except for a small dip in amplitude that occurred 2-6 min after initiating the shortest interval (15 sec) flashes. Although the changes in light and dark used in these experiments should have elicited shifts in the standing potential, no fluctuations of the c-wave amplitude were evident with a time course corresponding to a light response of the standing potential.

  View details for Web of Science ID A1981MF96500018

  View details for PubMedID 7315216

• SIMILARITIES BETWEEN THE C-WAVE AND SLOW PIII IN THE RABBIT EYE INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Lurie, M., Marmor, M. F. 1980; 19 (9): 1113-1116

  Abstract

  The c-wave of the electroretinogram was recorded from the eyes of Dutch rabbits and compared with the slow PIII response isolated by intravenous infection of sodium iodate and intravitreal injection of sodium aspartate. Although opposite in polarity, the waveforms of the two responses were remarkably similar over a wide range of stimulus intensities and durations. Plots of time-to-peak vs. log stimulus energy show that both responses follow the Bunsen-Roscoe law. Curves plotting the locus of all points for which the Bunsen-Roscoe law held were approximately parallel for the two responses, and the critical durations for each stimulus intensity were equivalent. The slow PIII peaked earlier than the c-wave, consistent with published observations that the time-to-peak of light-induced K+ changes is shorter near the photoreceptor inner segments than near the pigment epithelium. These data support the hypothesis that there is a common generator for the c-wave and slow PIII.

  View details for Web of Science ID A1980KH94300016

  View details for PubMedID 7410002

• ANALYSIS OF THE RESPONSE PROPERTIES AND LIGHT-INTEGRATING CHARACTERISTICS OF THE C-WAVE IN THE RABBIT EYE EXPERIMENTAL EYE RESEARCH Lurie, M., Marmor, M. F. 1980; 31 (3): 335-349

  View details for Web of Science ID A1980KW04200007

  View details for PubMedID 7428851

• The membrane of giant molluscan neurons: electrophysiologic properties and the origin of the resting potential. Progress in neurobiology Marmor, M. F. 1975; 5 (2): 167-195

  Abstract

  The molluscan neuron, because of its large size and accessibility, has been an important model for studying the electrophysiology of nerve cells. This review catalogs data about specific molluscan neurons, but the greater importance of this material is in the broad picture of how a neuronal membrane maintains internal potential and is responsive to changes in the environment. Electrical properties of the membrane. The mechanisms which contribute to the resting potential in molluscan neurons can be separated into ionic and metabolic components. When the electrogenic sodium pump is eliminated experimentally, the ionic component of the potential follows the constant field equation quite closely. Many of the "constants" and "parameters" which characterize the membrane of molluscan neurons are actually variables which depend upon temperature, ionic environment, and membrane potential. The evaluation of the electrical parameters is complicated by extensive infoldings of the somatic membrane, and by large axons which drain current from the soma. Most molluscan neurons have a very high specific membrane resistance and a correspondingly low potassium permeability. Membrane capacitance is close to the 1 microF/cm2 value which characterizes biological membranes. The current-voltage relation of molluscan neurons may be complicated by inward-going rectification, but if that is inhibited the I-V curve follows the prediction of either the constant field equation or a simple electrical model. Factors which modify membrane behavior. The resting potential of molluscan neurons is very sensitive to changes in temperature and Ko, through a combination of effects upon the electrogenic sodium pump, inward-going rectification, and the membrane "parameters". Inward-going rectification depends upon a rectifying K conductance, and can be eliminated by cold or the removal of Ko. Strong or prolonged currents have time-dependent effects upon the membrane, and excessive polarization leads to a "high conductance state". The underlying (non-rectifying) K permeability of the membrane is relatively insensitive to temperature and ionic changes, whereas the Na permeability increases with warming. Membrane resistance varies with both temperature and ions (because the I-V curve is sensitive to these conditions) but membrane capacitance is relatively insensitive to external factors. Electrogenic sodium transport. Sodium transport is electrogenic in molluscan neurons. It can be stimulated by warm temperatures and an excess of substrate (e.g. high Nai); it can be inhibited by cold, by an absence of substrate (e.g. low Ko), or by pharmacologic agents such as cyanide or ouabain.(ABSTRACT TRUNCATED AT 400 WORDS)

  View details for PubMedID 830083