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Home , Floater, Stargardt disease

Mystery 2018: Interactive Discussion of Challenging Cases

William F Mieler, MD Lee M Jampol, MD Chicago, IL Chicago, IL

Jerry A Shields, MD Richard F Spaide, MD Philadelphia, PA New York, NY

Carol L Shields, MD K Bailey Freund, MD Philadelphia, PA New York, NY

David Sarraf, MD SriniVas Sadda, MD Los Angeles, CA Los Angeles, CA

AAO Instruction Course # 240 Sunday, October 28th (2:00 – 4:15 PM) Chicago, IL

For the past 22 years, we have presented our “Mystery Retina-Interactive Discussion of Challenging Cases” instruction course at the American Academy of annual meeting. Each year, we present and discuss approximately 20 to 25 new and challenging cases.

At the completion of the instruction course, we provide access to an electronic handout for the attendees, though only at the conclusion of the course, as otherwise, the cases would not be presented as “mysteries”. We like to have an interactive course, with the faculty and the audience actively engaging in the presentations and discussions. So, now that the course has been completed, our handout has been made available to all attendees on the www.uic.edu/com/eye website. The handout includes a brief summary of each case, representative images, and pertinent references. Once you have accessed the handout, you can either print it out or download it to your computer.

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Case DZ William F Mieler, MD, Chicago, IL

A 28 year-old Caucasian female underwent a CT scan of her head for assessment of migraine headaches. The brain scan was negative, though a possible mass was noted in the left eye. Upon referral, VA was 20/20 OD, and 20/60 OS. Five diopters of asymmetry was noted in the (left eye was hyperopic). The left eye also had chronic open . The workup revealed diffuse choroidal thickening OS on echography, and a review of past medical history was significant for a left sided facial hemangioma (eradicated with laser therapy, and covered with cosmetics)

Diagnosis Diffuse choroidal hemangioma (Sturge-Weber syndrome)

References

1) Sullivan TJ, Clarke MP, Morin JD. The ocular manifestations of the Sturge-Weber syndrome. J Pediatr Ophthalmol 1992;29:349- 56 2) Madreperla S, Hungerford J, Plowman N, et al. Choroidal hemangiomas visual and anatomical results of treated by photo- coagulation or radiation therapy. Ophthalmol 1997;104: 1773–9 3) Bains HS, Cirino AC, Ticho BH, et al. Photodynamic therapy using verteporfin for a diffuse choroidal hemangioma in Sturge-Weber syndrome. Retina 2004;24:152-5 4) Sagong M, Lee J, Chang W. Application of intravitreal bevacizumab for circumscribed choroidal hemangioma. Korean J Ophthalmol 2009;23:127- 31 5) Chao AN, Shields CL, Shields JA, et al. Plaque radiotherapy for choroidal hemangioma with total and neovascularization. Retina 2001;21:682–4 6) Murthy R, Hanovar SG, Nalik M, et al. Ruthenium-106 plaque brachytherapy for treatment of diffuse choroidal hemangioma in Sturge Weber Syndrome. Indian J Ophthalmol 2005;53:274–5 7) Kubicka-Trzaska A, Kobylarz J, Romanowska-Dixon B. Ruthenium-106 plaque therapy for diffuse choroidal hemangioma in Sturge Weber Syndrome. Case Rep Ophthalmol Med 2011;2011:1–3 8) Zografos L, Bercher L, Chamot L, et al. Cobalt-60 treatment of choroidal hemangiomas. Am J Ophthalmol 1996;121: 190–9

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Case DB William F Mieler, MD, Chicago, IL

A 62 year old African American female was assessed for visual blurring OU, with VA of 20/30 OD and OS. There was a history of antiphospholipid syndrome (APL) with repetitive positive antibodies. Past history was significant for deep venous thrombosis. She had been on low-dose aspirin and warfarin in the past, though 2 years ago was started on hydroxychloroquine therapy at 800 mg/day (13 mg/kg/day). During this short two-year timeframe the patient developed evidence of toxicity based on SD-OCT, FAF, 10-2 HVF, and multi-focal ERG findings. The medication was discontinued, and the patient is being monitored for possible progression of findings

Diagnosis

Hydroxychloroquine toxicity in a patient with antiphospholipid (APL) syndrome

References

1) Rand JH, Wu XX, Quinn AS, Chen PP, Hathcock JJ, Taatjes DJ: Hydroxychloroquine directly reduces the binding of antiphospholipid antibody-B2-glycoprotein I complexes to phospholipid bilayers. Blood 2008;112:1687-95 2) Broder A, Putterman C: Hydroxychloroquine use is associated with lower odds of persistently positive antiphospholipid antibodies and/or lupus anticoagulant in systemic lupus erythematosus. J Rheumatol 2013;40:30- 3 3) Schmidt-Tanguy A, Voswinkel J, Henriion D, et al: Antithrombotic effects of hydroxychloroquine in primary antiphospholipid syndrome patients. J Thrombosis Hameostasis 2013;11:1927-9 4) Schreiber K, Sciascia S, de Groot PG, et al: Antiphospholipid syndrome. Nat Rev Dis Primers 2018;11:4:1710 5) Marmor MF, Kellner U, Lai TYY, Melles RB, Mieler WF, for the American Academy of Ophthalmology: Recommendations on screening for chloroquine and hydroxychloroquine (2016 revision). Ophthalmol 2016;123:1386-94

Case BT William F Mieler, MD, Chicago, IL

A 49 year-old male presented with a history of visual loss in the past, which improved spontaneously. Pigment guttering extending inferiorly from the OD was noted, though there was no subretinal fluid. VA was 20/50 OD and 20/20 OS. The patient subsequently developed of unknown etiology. A systemic workup checking for a possible etiology was negative and he was started on systemic prednisone at 60 mg/day. The patient immediately noted a sharp decline in vision OD down to HM, and was found to have a bullous exudative RD OD. The prednisone was discontinued, and the situation rapidly improved.

12/28/17

Diagnosis Bullous central serous chorioretinopathy (exacerbated by systemic corticosteroids)

References

1) Balaratnasingam C, Freund KB, Tan AM, Mrejen S, Hunyor AP, Keegan DJ, Dansingani KK, Dayani PN, Barbazetto IA, Sarraf D, Jampol LM, Yannuzzi LA. Bullous Variant of Central Serous Chorioretinopathy: Expansion of Phenotypic Features Using Multimethod Imaging. Ophthalmology. 2016 Jul;123(7):1541-52. doi: 10.1016/j.ophtha.2016.03.017. Epub 2016 Apr 12. PubMed PMID: 27084564. 2) Salehi M, Wenick AS, Law HA, Evans JR, Gehlbach P. Interventions for central serous chorioretinopathy: a network meta-analysis. Cochrane Database Syst Rev 2015;22:CD011841. 3) Lim J et al. Collaborative retrospective macula society study of photodynamic therapy for chronic central serous chorioretinopathy. Ophthalmol 2014;121:1073-8

------Case 1 Carol L Shields, MD, Philadelphia, PA

History and findings A 67 year-old male optometrist noted over 1 month. He noted difficultly with the direct ophthalmoscope for 1 year. Previous visual acuity was 20/20 OU. He is an Ironman and competes frequently in the competition (2.4 mile swim, 112 mile bicycle, and 26.2 mile run). Keep in mind the eye complications from extreme athleticism include: central serous chorioretinopathy, dehydration retinopathy, high altitude retinopathy, Valsalva retinopathy, and Purtscher retinopathy. He was on Simvastatin for hyperlipidemia and enjoyed social alcohol use. There was no cigarette use.

On examination, visual acuity was 20/40 OD and 20/25 OS. IOPs were 16 mm Hg OU. Fundus findings showed a mass OD (see below) and was normal OS.

The differential diagnosis of this mass included: metastasis, melanoma, nevus, granuloma, or AMMPPE. OCT showed lumpy bumpy tumor surface and overlying SRF. There was a second tumor, strongly suggestive of metastatic

disease. Fine needle aspiration biopsy confirmed malignant cells and CT lung demonstrated pleural effusion with a 3 cm mass, suspect for lung cancer.

Diagnosis Choroidal metastasis from lung cancer in a non-smoker

Discussion Cancer is common and the lifetime risk for cancer in a US citizen is 1 of 2 for men and 1 of 3 for women. Lung cancer ranks #1 in death-related malignancy and #2 in new cases per year, based on the American Cancer Society. This patient never smoked and 20% of patients dying from lung cancer in USA have never smoked. Smoking is the leading cause of lung cancer, but other factors can lead to lung cancer including radon gas exposure, second-hand and third-hand smoke, and exposure to asbestos, diesel exhaust, and air pollution, and genetic mutations.

References 1. Shields CL, Welch RJ, Malik K, et al. Uveal metastasis: Clinical features and survival outcome of 2214 tumors in 1111 patients based on primary tumor origin. MEAJO 2018; in press. 2. Shields CL, Acaba-Berrocal LA, Selzer EB, et al. Uveal metastasis based on patient age in 1111 patients. Comparison of clinical features and outcomes per age category. Submitted for publication. 3. Welch RJ, Ang SM, Mayro E, Malik K, Newman J, Honig S Selzer E, Acaba- Berrocal L, McGarrey M, Graf AE, Considine SP, Shields JA, Shields CL. Uveal metastasis based on timing of primary cancer diagnosis: Interval to metastasis and overall survival in 1111 patients.

4. Shields CL, Shields JA, Gross N, et al. Survey of 520 eyes with uveal metastases. Ophthalmol 1997;104:1265-76. ------

Case 2 Carol L Shields, MD, Philadelphia, PA

History and findings A 64 year-old female noted painless blurred vision OU. She was thought to have uveitis

On examination, visual acuity was 20/50 OU. There were small (300 micron) deep choroidal “white dots” that appeared in a pattern of birdshot chorioretinopathy. HLA-A29 was negative.

Differential diagnosis included birdshot chorioretinopathy, multifocal choroiditis, sarcoid, syphilis, Tb, lymphoma, or medication-related effect. OCT showed CME and shallow SRF with debris. IVFA showed no vasculitis, but there was mild optic disc staining OU and deep foveal leakage. ICG showed the dark choroidal defects without staining.

Further history revealed this patient had cutaneous melanoma and was on a checkpoint inhibitor, Pembrolizumab.

Diagnosis Birdshot-like chorioretinopathy from Pembrolizumab

Discussion Checkpoint inhibitors are a fairly new class of drugs directed to stimulate T cells to attack cancer, but inflammatory side effects are common, including dermatitis, hepatitis, gastritis, etc. Ocular side effects include dry eye, uveitis, and potential neurologic problems like myasthenia gravis that can be life threatening.

References Acaba Berrocal L, Lucio-Alvarez JA, Mashayekhi A, et al. Birdshot chorioretinopathy associated with pembrolizumab treatment. JAMA Ophthalmol 2018;in press. Dalvin LA, Shields CL, Orloff M, et al. Checkpoint inhibitor immune therapy. Systemic indications and ophthalmic side effects. Retina 2018 Apr 23 [Epub ahead of print] PMID: 29689030.

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Case 3 Carol L Shields, MD, Philadelphia, PA

History and findings A79 year-old male developed sudden painful and vision loss. He was found to have two pigmented choroidal tumors in his right eye.

On examination, visual acuity was 20/30 OD and 20/25 OS. The OS was normal. The OD showed mild and a dark brown choroidal mass superotemporally and inferonasally in the periphery (outlined in yellow).

The differential diagnosis included choroid melanoma multifocal, metastasis from cutaneous melanoma, lymphoma, effusion, hemorrhage, or suprachoroidal hemorrhage. OCT showed irregular choroid folds. IVFA and ICG revealed no retinal or choroidal mass, suggesting the process was suprachoroidal hemorrhage. Further history indicated that this patient had idiopathic thrombocytopenia purpura (ITP). Follow observation and management of his transient low platelets, the blood resolved.

Diagnosis Idiopathic thrombocytopenia purpura (ITP) with suprachoroidal hemorrhages simulating melanoma

Discussion ITP is an autoimmune hemorrhagic condition characterized by accelerated destruction and splenic sequestration of platelets from anti-platelet antibodies. In most cases, ITP is a relatively benign disease, commonly presenting with signs of mucocutaneous bleeding such as easy bruising, petechial and purpuric skin

rashes, epistaxis, gingival bleeding, and menorrhagia. Patients with mildly decreased platelet counts are often asymptomatic and diagnosed coincidentally, whereas severely affected patients with platelet counts less than 10,000/µL are at risk for serious bleeding complications, particularly intracranial or internal hemorrhagic episodes

References 1. Lambert MP, Gernsheimer TB. Clinical updates in adult immune thrombocytopenia. Blood 2017; 129:2829-35. 2. Honig SE, Srinivasan A, Shields CL. Choroidal hemorrhage simulating melanoma in idiopathic thrombocytopenia purpura (ITP). Oc Onc Pathol 2018;in press.

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Case 4 Carol L Shields, MD, Philadelphia, PA

History and findings A 58 year-old male noted declining vision. He was thought to have atypical CSCR or ARMD. He was borderline diabetic on Metformin, asthmatic on steroid inhaler, and hyperlipidemic on a statin. Visual acuity was 20/100 OD and 20/30 OS. Examination showed SRF OD and no SRF OS. Concern for steroid-related CSCR was raised and steroid inhalers were discontinued, but with no effect. Upon referral one month later, vision dropped to CF OD and 20/40 OS. Examination showed increased SRF OD and no SRF OS.

Autofluorescence and IVFA documented a “giraffe skin” mottled appearance to the RPE. OCT showed marked CME and moderate SRF OD, while OS showed only shallow SRF. The choroid was infiltrated with no visible vascular markings. Further history revealed previous rapid onset OU 6 months ago that were removed. Later, pulmonary embolism occurred. Investigation revealed lung cancer and Docetaxel was commenced.

Diagnosis Bilateral diffuse uveal melanocytic proliferation (BDUMP) in a patient with lung cancer

Discussion BDUMP is a paraneoplastic syndrome that can manifest with multifocal pigmented and nonpigmented choroidal tumors with RPE alterations simulating a “giraffe” pattern. Additional features include rapid onset cataract, conjunctival injection, IPE cysts, and pigmentation on mucous membranes. Diagnosis is established clinically and confirmed serologically with testing for CMEP. Treatment with plasmapheresis can be helpful.

References 1. Miles SL, Niles RM, Pittock S, et al. A factor found in the IgG fraction of serum of patients with paraneoplastic bilateral diffuse uveal melanocytic proliferation causes proliferation of cultured human melanocytes Retina 2012;9:1959-66. 2. Katz MSJ, Leder HA, Choudhury T. Successful treatment of bilateral diffuse uveal melanocytic proliferation with plasmapheresis. J VitreoRet Dis 2017; 6:420- 3

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Case 1 ?

Richard F Spaide, MD, New York, NY

The case was a 60-year-old male with a 50-year history of diabetes, but essentially no diabetic retinopathy.

Seeing no retinopathy in a diabetic of such duration is unusual, and that is a clue to the diagnosis. Although the patient appears to have had laser, he really has many paving stone spots. These in turn have been theorized to result from poor choroidal perfusion. The phenotype suggests maternally inherited diabetes and deafness. He revealed a history of deafness and diabetes on his mother’s side of the family. The patient was tested and was found to have a m.3243A>G mutation, characteristic for MIDD. This mutation accounts for 1 – 2% of diabetes. This same mutation is also associated with MELAS, CPEO, hypertrophic cardiomyopathy and other disorders, even in the same family. The expression of disease is related to heteroplasmy levels. The explanation for varying heteroplasmy is not known, but analysis of how oocytes develop may give a clue. The primary oocyte starts with between 10 – 200 mitochondria. These undergo clonal expansion with development of the egg, which can have 100,000 to 600,000 mitochondria. It is possible that the limited sample size of mitochondria may cause significant variation in the proportion of mutated ones from one primary oocyte to another. The reason the patients with MIDD do not develop aggressive diabetic retinopathy is not known and is interesting to ponder.

Diagnosis Maternally Inherited Diabetes and Deafness (MIDD)

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Case 2: Not so Striking Macular

Richard F Spaide, MD, New York, NY

A 45-year -old male was struck in his left eyebrow with a golf ball and subsequently lost significant visual acuity. His maculas had a slightly reddish appearance. He has had an extensive work-up with the salient finding being central thinning of the outer nuclear layer and loss of the ellipsoid zone in the left eye. There were no apparent changes in the right eye. The vessels in the temporal juxtafoveal macula looked a bit larger than would be expected. Because of this the patient was evaluated with 1 test, macular pigment imaging. This showed a loss of macular pigment in the left eye and a nearly complete loss in the right. Loss of macular pigment is diagnostic of macular telangiectasia type 2, commonly known as MacTel2.

Loss of retinal transparency, crystalline deposits, telangiectasis, right angle venules, vascular invasion, atrophy, and neovascularization eventually appear, but earlier in the patient’s life the macula may look relatively normal. It is possible that the lack of xanthophyll pigment causes the macula to have a redder

appearance. Although anecdotal MacTel 2 may be more common in people from India and Bangladesh. There is no proven treatment, but ciliary neurotrophic factor being released by an implantable device is being investigated. Genetic evaluation of patients with MacTel2 have shown an association with common variants of genes associated with proline and serine. There is a one carbon pathway that is active in the retinal photoreceptors. This one-carbon pathway is used in cells using glycolysis. In the last century Otto Heinrich Warburg won the Nobel prize for the concept of aerobic glycolysis. Ordinarily in the presence of oxygen cells will use oxidative metabolism because of the increased ATP yield. Photoreceptors will also use extensive glycolysis in the presence of oxygen in a process called aerobic glycolysis or the Warburg effect. There may be more than one reason for this. Lactic acid is theorized to be a signaling mechanism from the photoreceptor to the retinal pigment epithelium. The photoreceptors need as much ATP as possible, so the mitochondria are going full-blast. The one-carbon pathway may release additional energy as well as regenerating NADPH, used in the synthesis of nucleotides, glutathione and is a regulator and sensor of cellular nutritional status. In MacTel2 there is depletion of Müller cells and eventual localized loss of photoreceptors. It is possible that in the present case the trauma accelerated the cell loss that would have occurred and ended up causing the loss of vision.

Diagnosis Traumatic loss of macular function from minimal ocular trauma in a patient with MacTel2

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Case 3: Transient Positive Richard F Spaide, MD, New York, NY

A 45-year-old healthy male with a long-term history of presented with a same day history of a small positive scotoma in the field of his left eye located below and slightly to the left of fixation. as illustrated by color and monochromatic fundus imaging showed no abnormalities. OCT angiography was performed, both to examine the vascular flow and to use the high density of the structural OCT. The OCT slab images through the inner nuclear layer showed a 175 µm area of increased reflectivity. The slab through this same region suggested a concomitant decrease in flow in the image from both devices, although certainty of this finding was limited by prominent artifacts. The patient returned 4 days later and stated there was a marked decrease in the severity of his symptoms. The increased reflectivity was less prominent. When examined two weeks after presentation there was no positive scotoma, no

regional increase in reflectivity, and no associated thinning of the inner nuclear layer.

When seen over a larger region of the macula, acutely increased reflectivity of the inner nuclear layer with visual symptoms is the hallmark of PAMM. This present patient had similar findings, but these were limited to a small area and he had no long-term anatomic or visual sequela. As such, this case may demonstrate what could be called “micro-PAMM”. With resolution, larger areas of PAMM are associated with decreases in the inner nuclear layer thickness. The smaller area involved in the present paper may be due to localized ischemia that resulted in damage, but not death of the involved cells. Oxygen diffusion in tissue may be successful in supporting tissue over small distances. Broader areas of poor perfusion, as is typically seen in PAMM, may lead to infarction of some of the affected cells, resulting in thinning of the inner nuclear layer in resolution. In cases with a limited affected zone, it is possible that some oxygen diffusion may occur from adjacent perfused areas. Given the 175 µm diameter, oxygen delivery from neighboring perfused areas of the retina may be able to supply enough oxygen to prevent significant cell loss. Complaints of transient positive scotomata include migraine, entopic phenomena, occipital lobe epilepsy, and psychogenic reasons. The findings in the present report are not visible by color fundus photography and may not necessarily be visible with conventional OCT if the scan density is low. The advantage of OCT angiography is the scan patterns used are quite dense with the spacing of the adjacent A-scans being closer than the spot size. This would increase the detection sensitivity for small lesions. Conventional OCT scanning using larger interscan separation may miss small lesions, potentially leading to an

unnecessary neurologic work-up of the patient. Previous reports have shown PAMM lesions that were not large, although they were larger than the lesion in the present report and they were visible by ophthalmoscopy. A high index of suspicion is required to diagnose the full-spectrum of PAMM lesions and the scan density of OCT angiographic examinations, or a comparable scan density with conventional OCT devices, would be required to image the associated pathologic changes in smaller lesions with a high degree of certainty.

Diagnosis Micro-PAMM

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Case 1 Jerry A Shields, MD, Philadelphia, PA

A 67 year old man developed blurred vision of 20/20 OD and 20/150 OS. He was found to have 2 amelanotic choroidal lesions with subretinal fluid. OCT showed the largest tumor to have a lumpy bumpy surface, suggestive of metastasis. Chest Xray was clear and he was a non-smoker. Further history revealed past BRCA2-related breast cancer in a MALE that was treated with mastectomy. There were no other metastatic foci. Fine needle aspiration biopsy confirmed breast cancer metastases. The tumors were treated with plaque radiotherapy and responded completely Keep in mind that 1% of all breast cancer occurs in MALES. Males with breast cancer tend to have more advanced disease and worse prognosis because the disease is more advanced due to lack of recognition. Males who carry BRCA1 or BRCA2 have a significantly higher risk for breast and prostate cancers compared to those without mutation. All females and males with family history of BRCA1 or

BRCA2 mutation should be tested and monitored for cancers. In fact, prophylactic mastectomy has been advised in some cases.

Reference Lam A, Shields CL, Shields JA Uveal metastases from breast carcinoma in three male patients. Ophthalmic Surg Lasers Imaging 2006;37:320-3. ------

Jerry A Shields, MD, Philadelphia, PA Case 2

A 14 year old girl developed painless blurred vision to 20/100 OD and 20/20 OS. She was found to have extensive ocular melanocytosis OD involving the entire eye. Posteriorly there was a diffuse mass of 3.5 mm thickness and 20 mm in basal diameter. The was pigmented too. There was concern for diffuse choroidal melanoma arising in an eye with ocular melanocytosis, posing risk for metastasis. Enucleation was performed. Histopathology revealed low grade melanocytic neoplasm of iris, , and choroid, with features most suggestive of extensive, massive melanocytoma and not melanoma. There was transcleral extension onto the surface of the . There was no mitotic activity. Most melanocytomas are small and reside in the optic disc or the iris. Extensive melanocytoma involving the entire is distinctly rare. Prognosis is anticipated to be favorable.

Reference Shields JA, Shields CL, Eagle RC Jr. Melanocytoma (hyperpigmented magnocellular nevus) of the uveal tract. The 34th G. Victor Simpson Lecture. Retina 2007. ------

Jerry A Shields, MD, Philadelphia, PA Case 3 A 28 year old Asian woman from China noted blurred vision OD but measured 20/20 OU. She was found to have a dilated retinal artery feeding into a pedunculated pigmented mass superiorly. She was referred to our service for management of presumed choroidal melanoma. On examination, the mass measured 12 mm basal diameter and 6 mm thickness. There was no hemorrhage, exudation, or subretinal fluid. The ultrasound demonstrated abruptly elevated intraocular mass with a derby-shaped configuration – this configuration can be seen with melanoma or RPE adenoma. Based on the features of feeder retinal artery, derby hat –shape, and Asian heritage, we were suspicious for RPE adenoma more than melanoma. Surgical resection of the mass was performed using a scleral flap with external removal.

Histopathology confirmed RPE adenoma with irregular cords and bands of pigmented epithelial cells. Long-term prognosis is anticipated to be favorable. On follow-up, visual acuity remained 20/20 OU.

Reference Shields JA, Shields CL, Gunduz K, Eagle RC. Neoplasms of the retinal pigment epithelium. The 1998 Albert Ruedemann Sr Memorial Lecture Part 2. Arch Ophthalmol 1999;111:601-8. ------

Jerry A Shields, MD, Philadelphia, PA Case 4

A 23 year old woman developed an abnormal appearance to her iris OS. Visual acuity was 20/20 OD and 20/200 OS. She was found to have a ciliary body mass with iris invasion. The mass measured 22 mm in basal diameter and 18 mm in thickness.

Fine needle aspiration biopsy revealed small round blue cells with necrosis and mitotic activity, suggestive of retinoblastoma – in this 23 year old person. Management options included enucleation followed by chemotherapy or chemotherapy alone with potential for enucleation later. She chose the latter. She was give 6 cycles of high dose vincristine, etoposide, and carboplatin with dramatic reduction of the tumor to a thickness of 3 mm. However, her follow-up was poor and she did not return for evaluation for 1 year. At that time, the tumor had recurred and measured 10 mm thickness. Enucleation was advised. Histopathology showed extensive recurrent tumor. Further chemotherapy was delivered.

Reference Shields CL, Shields JA, Shah P. Retinoblastoma in older children. Ophthalmol 1991;98:395-9 ------

SriniVas Sadda, MD, Pasadena, CA Case 1

A 67-year old female presented with complaints of diminishing over the past several years. Was referred from oculoplastics service after was excluded as a cause. Only previous ophthalmic history was in both eyes. Vision was 20/30 OD and 20/40 OS. Retinal exam revealed a peripheral ring of pigmentary alterations and atrophy with corresponding FAF changes. Diagnosis Autosomal Dominant Vitreoretinochoroidopathy (ADVIRC)

References Boulanger-Scemama E, Sahel JA, Mohand-Said S, Antonio A, Condroyer C, Zeitz C, Audo I. AUTOSOMAL DOMINANT VITREORETINOCHOROIDOPATHY: When Molecular Genetic Testing Helps Clinical Diagnosis. Retina. 2018 Jan 23. [Epub ahead of print] Burgess R, MacLaren RE, Davidson AE, Urquhart JE, Holder GE, Robson AG, Moore AT, Keefe RO, Black GC, Manson FD. ADVIRC is caused by distinct mutations in BEST1 that alter pre-mRNA splicing. J Med Genet. 2009 Sep;46:620-5.

Vincent A, McAlister C, Vandenhoven C, Héon E. BEST1-related autosomal dominant vitreoretinochoroidopathy: a with a range of developmental ocular anomalies. Eye (Lond). 2011 Jan;25:113-8. ------

SriniVas Sadda, MD, Pasadena, CA Case 2

A 28-year old female presented with a two month history of headaches, blurred vision, , shortness of breath, and right hand numbness. No previous ocular or medical history or family history. Vision was 20/20 OU. Retinal examination revealed scattered peripheral hemorrhages, some with white- centers. FA revealed innumerable tiny aneurysms in the retinal periphery with vessel staining. Systemic work-up including angiogram revealed thickening of the wall of the aortic arch, subclavian, and carotids.

Diagnosis Takayasu’s retinopathy

References Elizalde J, Capella MJ. Takayasu's retinopathy. Int Ophthalmol. 2011 Dec;31(6):533-7 Peter J, David S, Danda D, Peter JV, Horo S, Joseph G. Ocular manifestations of Takayasu arteritis: a cross-sectional study. Retina. 2011 Jun;31(6):1170-8. Sugiyama K, Ijiri S, Tagawa S, Shimizu K. Takayasu disease on the centenary of its discovery. Jpn J Ophthalmol. 2009 Mar;53(2):81-91. Bajgai P, Singh R. in Takayasu's Arteritis. N Engl J Med. 2018 May 24;378(21):e28. ------

SriniVas Sadda, MD, Pasadena, CA Case 3

A 67-year old female presented with complaints of metamorphopsia and diminishing central vision over 2-3 years. She was diagnosed elsewhere with age-related . several years. Vision was 20/25 OD and 20/30 OS. Retinal exam shows beaten bronze atrophy, albeit sparing the fovea with largely hyperfluorescent flecks. OCT shows the subretinal and intraretinal location of the flecks. Although RDS/peripherinopathy is in the differential diagnosis, genetic testing revealed compound heterozygotic mutations in ABCA4.

Diagnosis Late-onset Stargardt’s Macular Dystrophy

References 1) Westeneng-van Haaften SC, Boon CJ, Cremers FP, Hoefsloot LH, den Hollander AI, Hoyng CB. Clinical and genetic characteristics of late-onset Stargardt's disease. Ophthalmology. 2012 Jun;119(6):1199-210. 2) Huang WC, Cideciyan AV, Roman AJ, Sumaroka A, Sheplock R, Schwartz SB, Stone EM, Jacobson SG. Inner and outer retinal changes in retinal degenerations associated with ABCA4 mutations. Invest Ophthalmol Vis Sci. 2014 Mar 20;55(3):1810-22. 3) Querques G, Prato R, Coscas G, Soubrane G, Souied EH. In vivo visualization of photoreceptor layer and lipofuscin accumulation in Stargardt's disease and fundus flavimaculatus by high resolution spectral- domain optical coherence tomography. Clin Ophthalmol. 2009;3:693-9. 4) Latsenko AN, Shroyer NF, Lewis RA, Lupski JR. Late-onset is associated with missense mutations that map outside known functional regions of ABCR (ABCA4). Hum Genet. 2001 Apr;108(4):346- 55. ------

K. Bailey Freund, MD, New York, NY Case 1

An 84-year-old black female was referred for treatment of neovascular AMD in her left eye. She reported a gradual decrease in central vision in both eyes over several years. Her ocular history included bilateral cataract extraction. Medical history included hypertension and hypercholesterolemia. Medications were losartan, atorvastatin, and a daily aspirin (81mg). Visual acuity was 20/60 OU. Dilated funduscopic examination showed soft and cuticular drusen OU, with central macular atrophy OD. OCT showed unusual findings OU.

Diagnosis Cuticular drusen OU, plateau OD, PEVAC OD, and aperture OS

References 1. Balaratnasingam C, Cherepanoff S, Dolz-Marco R, Killingsworth M, Chen FK, Mendis R, Mrejen S, Too LK, Gal-Or O, Curcio CA, Freund KB. Cuticular drusen: clinical phenotypes and natural history defined using multimodal imaging. Ophthalmology. 2018 Jan 1;125(1):100-18. 2. Tan AC, Astroz P, Dansingani KK, Slakter JS, Yannuzzi LA, Curcio CA, Freund KB. The evolution of the plateau, an optical coherence tomography signature seen in . Invest Ophthalmol Vis Sci 2017;58:2349-58. 3. Querques G, Capuano V, Costanzo E, Corvi F, Querques L, Introini U, Souied EH, Bandello F. RETINAL PIGMENT EPITHELIUM APERTURE: a previously unreported finding in the evolution of avascular pigment epithelium detachment. Retina. 2016 Dec 1;36:S65-72. 4. Sacconi R, Freund KB, Yannuzzi LA, Dolz-Marco R, Souied E, Capuano V, Semoun O, Phasukkijwatana N, Sarraf D, Carnevali A, Querques L. The Expanded Spectrum of Perifoveal Exudative Vascular Anomalous Complex. Am J Ophthalmol 2017 Dec 1;184:137-46.

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K. Bailey Freund, MD, New York, NY Case 2

In 2010, a 70-year-old female was referred for an evaluation of a new disturbance in central vision in her left eye. She reported poor central vision in both eyes for more than 20 years due to an “autoimmune retinopathy”. The initial evaluation showed loss of the subfoveal ellipsoid zone OD (“optical gap”), type 1 anuerysmal neovascularization (PCV) OS with overlying subretinal fluid, and bilateral cuticular drusen. Full field ERG followed by whole exome genetic sequencing led to the detection of a heterozygous missense variant in the GUCA1A gene.

Diagnoses Cuticular drusen, aneurysmal type 1 NV (AT1/PCV), and an autosomal dominant cone dystrophy (GUCA1A gene)

References

1. Kelsell RE, Gregory-Evans K, Payne AM, Perrault I, Kaplan J, Yang RB, Garbers DL, Bird AC, Moore AT, Hunt DM. Mutations in the retinal guanylate cyclase (RETGC-1) gene in dominant cone-rod dystrophy. Human molecular genetics. 1998 Jul 1;7(7):1179-84. 2. Payne AM, Downes SM, Bessant DA, Taylor R, Holder GE, Warren MJ, Bird AC, Bhattacharya SS. A mutation in guanylate cyclase activator 1A (GUCA1A) in an autosomal dominant cone dystrophy pedigree mapping to a new locus on chromosome 6p21. 1. Human molecular genetics. 1998 Feb 1;7(2):273-7. 3. Kitiratschky VB, Behnen P, Kellner U, Heckenlively JR, Zrenner E, Jägle H, Kohl S, Wissinger B, Koch KW. Mutations in the GUCA1A gene involved in hereditary cone dystrophies impair calcium‐mediated regulation of guanylate cyclase. Human mutation. 2009 Aug;30(8): E782- 96. 4. Dansingani KK, Gal‐Or O, Sadda SR, Yannuzzi LA, Freund KB. Understanding aneurysmal type 1 neovascularization (polypoidal choroidal vasculopathy): a lesson in the taxonomy of ‘expanded spectra’–a review. Clinical & experimental ophthalmology. 2018 Mar;46(2):189-200. 5. Li M, Dolz-Marco R, Messinger JD, Sloan KR, Ferrara D, Curcio CA, Freund KB. Clinicopathologic correlation of aneurysmal type 1 neovascularization in age-related macular degeneration. Ophthalmology Retina. 2018 Sep 5.

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K. Bailey Freund, MD, New York, NY Case 3

A 71-year-old male was seen for routine monitoring of non-neovascular AMD. In both eyes he had experienced a spontaneous collapse of large drusenoid PEDs resulting in macular atrophy OD > OS. Visual acuity was 20/50 in his right eye and 20/400 in his left eye. Clinical examination showed a refractile yellow subretinal lesion in the nasal macula OD.

Diagnosis Subretinal cholesterol crystals in non-neovascular AMD

References

1. Fleckenstein M, Issa PC, Helb HM, Schmitz-Valckenberg S, Finger RP, Scholl HP, Loeffler KU, Holz FG. High-resolution spectral domain-OCT imaging in geographic atrophy associated with age-related macular degeneration. Investigative ophthalmology & visual science. 2008 Sep 1;49(9):4137-44. 2. Moussa K, Lee JY, Stinnett SS, Jaffe GJ. Spectral Domain Optical Coherence Tomography–determined Morphologic Predictors of Age- related Macular Degeneration–associated Geographic Atrophy Progression. Retina. 2013 Sep 1;33(8):1590-9. 3. Querques G, Georges A, Moussa NB, Sterkers M, Souied EH. Appearance of regressing drusen on optical coherence tomography in age-related macular degeneration. Ophthalmology. 2014 Jan 1;121(1):173-9 4. Li M, Dolz-Marco R, Messinger JD, Sloan KR, Ferrara D, Curcio CA, Freund KB. Clinicopathologic correlation of aneurysmal type 1 neovascularization in age-related macular degeneration. Ophthalmology Retina. 2018 Sep 5. 5. Pang CE, Messinger JD, Zanzottera EC, Freund KB, Curcio CA. The onion sign in neovascular age-related macular degeneration represents cholesterol crystals. Ophthalmology. 2015 Nov 1;122(11):2316-26.

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David Sarraf, MD, Los Angeles, CA Case 1

A 47 year old female was referred for bilateral central vision loss. Visual acuity was 20/30 OD and 20/25 OS and retinal examination was unremarkable OU. Spectral domain OCT displayed subtle disruption of the central ellipsoid band OU. A similar OCT abnormality was also noted in the proband’s sister and mother. Full field ERG for the proband was remarkable for a cone rod dystrophy, and genetic testing was positive for heterozygous putative RP1LI mutations.

Diagnosis RP1L1 mutation (occult macular dystrophy)

PROBAND

SISTER

MOTHER

References Fujinami K et al. Novel RP1L1 Variants and Genotype-Photoreceptor Microstructural Phenotype Associations in Cohort of Japanese Patients With Occult Macular Dystrophy. Investigative Ophthalmology and Visual Science 2016; 57:4837-46 Agange N1, Sarraf D. Occult Macular Dystrophy With Mutations In The RP1L1 and KCNV2 Genes. Retinal Cases and Brief Reports 2017;11:S65-S67 ------

David Sarraf, MD, Los Angeles, CA Case 2 A 52 year old healthy male presented with a history of central serous chorioretinopathy and vision loss OS. Visual acuity was 20/20 OD and 20/25 OS and OCT displayed vitelliform pericentral OU with subretinal fluid OS. Peripapillary angioid streaks were detected OU but choroidal neovascularization was excluded in each eye. Dermatological consultation was obtained and the patient was diagnosed with . The patient returned with progressive vision loss OS and VA was noted to be 20/30 OS and repeat OCTA detected progressive CNV OS. AntiVEGF therapy was initiated and the patient responded well to a series of injections OS.

Diagnosis Pseudoxanthoma Elasticum

References Gal-Or O, Balaratnasingam C, Freund KB.Optical coherence tomography angiography findings of choroidal neovascularization in pseudoxanthoma elasticum. Int J Retina Vitreous. 7;1:11. 2015. Agarwal A, Patel P, Adkins T, Gass JD. Spectrum of pattern dystrophy in pseudoxanthoma elasticum. Arch Ophthalmol 2005;123:923-8 ------

David Sarraf, MD, Los Angeles, CA Case 3 A 77 year old healthy female presented with a history of neck pain, loss of consciousness and severe vision loss. Visual acuity was 20/400 OU. Retinal examination displayed retinal hemorrhage in each eye and spectral domain OCT illustrated characteristic hemorrhage at the level of the outer plexiform layer of Henle. Intracerebral angiogram was remarkable for an anterior communicating artery aneurysm and subarachnoid hemorrhage causing Terson’s syndrome. The mechanism of retinal hemorrhage in Terson’s syndrome may be related to increased central venous pressure causing hemorrhage from the deep retinal capillary plexus which has been shown to be a retinal capillary plexus specialized for retinal venous drainage.

Diagnosis Terson’s Syndrome and Henle Layer Hemorrhage

References Freund, Sarraf, Leong et al: Optical Coherence Tomography Angiography of Collaterals in Retinal Vein Occlusion Supports Major Venous Outflow through the Deep Vascular Complex. JAMA Ophthalmol (in press 2018) Garrity ST, Paques M, Gaudric A, Freund KB, Sarraf D: Considerations in the Understanding of Venous Outflow in the Retinal Capillary Plexus. Retina 2017;37:1809-12