Loren S. Jack

Ipilimumab-Associated Retinopathy

Ipilimumab is a novel immunotherapeutic agent that improves survival in patients diagnosed with metastatic melanoma. With the rising incidence of melanoma, the use of this pharmacologic agent is increasing. However, ipilimumab can be associated with rare but serious systemic adverse events. While the mechanism of these systemic adverse events is immune-related dysfunction, the index case highlights a possible direct ocular adverse event associated with ipilimumab infusion resulting in bilateral serous retinal detachment. Close observation of ocular findings using multimodal imaging analysis can provide insights into possible pathophysiology of the condition and guide further management.

Emixustat and Lampalizumab: Potential Therapeutic Options for Geographic Atrophy

Two novel classes of medications are currently under extensive investigation for the treatment of dry age-related macular degeneration (AMD). Emixustat, an orally administered visual cycle inhibitor, and lampalizumab, an intravitreally administered monoclonal body directed against complement factor D, have shown promise in phase 2 clinical trials in the treatment of nonneovascular (dry) AMD. Lampalizumab is currently being evaluated in a large, multicenter, phase 3 clinical trial for dry AMD - geographic atrophy.

Segmentation of Retinal Layers in Sjögren–Larsson Syndrome

In 1957, Sjogren and Larsson described an autosomal recessive syndrome in 28 individuals in northern Sweden who shared the clinical triad of congenital ichthyosis, intellectual disability, and spastic diplegia.1 Ichthyosis is the first sign of Sjogren–Larsson syndrome (SLS, MIM 270200) and prompts medical evaluation, but the diagnosis of SLS is rarely considered until neurologic features appear later in infancy. Macular crystalline inclusions, or “glistening dots,” are distinctive ophthalmic features that appear in infancy.2 Jagell et al3 suggested that glistening dots constitute a fourth major clinical sign. The macular crystals may be absent in young infants and increase with age.2 Although clinical symptoms present with variable severity, symptoms tend to stabilize by late childhood and remain stationary.4 Ophthalmologic evaluations may aid in distinguishing SLS from other neuroichthyotic syndromes. Sjogren–Larsson syndrome is rare and most reports are single cases that focus on the dermatologic or neurologic features. We studied 9 SLS patients to further characterize retinal findings in SLS. Mutations in the ALDH3A2 reduce enzyme activity of fatty aldehyde dehydrogenase (FALDH) resulting in accumulation of 16- and 18-carbon fatty aldehydes and alcohols thought to be responsible for the clinical symptoms. The FALDH oxidizes medium- and long-chain aliphatic aldehydes to fatty acids and is a critical component of the fatty alcohol nicotinamide adenine dinucleotide oxidoreductase complex of fatty alcohol metabolism. The diagnosis is made by measuring FALDH enzymatic activity in cultured fibroblasts and/or demonstrating pathogenic mutations in the ALDH3A2 gene. We designed and conducted a prospective, observational case series (NCT01971957, www.clinicaltrials.gov). The institutional review board at the University of Nebraska Medical Center approved the study, which conformed to the Declaration of Helsinki and complied with all federal and state laws and regulations. Informed consent followed Health Insurance Portability and Accountability Act guidelines and was obtained from the patient or appropriate legal guardian. Only persons with an ALDH3A2 mutation were enrolled. Exclusion criteria included patient or guardian failure to consent or inability to travel to the examination site. No patients met the exclusion criteria. Manual segmentation of the central 2 mm through the anatomic foveal center was performed by an author (M.A.S.) experienced with Heyex Explorer Version 5.2 (Heidelberg Engineering, Heidelberg, Germany) and Spectralis HRA-OCT (Heidelberg Engineering). Fourteen eyes were imaged with optical coherence tomography. The 2 eyes from the patient with the macular pseudocyst were excluded due to disruption of retinal layers. Eleven normal eyes (age range, 19–25 years; mean, 22.81) were used for controls. The nonparametric Mann–Whitney test was used to test significance since the data were not of a normal distribution. Statistical analysis was performed using Excel (Microsoft, Redmond, WA) and MiniTab 16 (MiniTab, State College, PA). Fluorescein angiography, fundus autofluorescence, and color fundus photography were performed using the P-200Tx (Optos, Dunfermline, Scotland). Fundus photography was also performed using the Visucam (Zeiss, Jena, Germany). Full-field electroretinography was performed according to standard protocols from the International Society of Electrophysiology of Vision using the Espion Visual Electrophysiology System (Diagnosys, Lowell, MA). We studied 9 SLS patients (5 male, 4 female; age range, 3–23 years) with ALDH3A2 mutations who exhibited generalized ichthyosis and spastic diplegia (Table 1; available at www.aaojournal.org) All patients exhibited photophobia, ichthyosis of the upper eyelid skin, and macular crystals. Symmetric, moderate vision loss ranging from logarithm of the minimum angle of resolution 0.14 to 0.57 (mean, 0.44±0.15; Table 1) did not correlate with age (Pearson correlation coefficient of 0.11). Table 1 Clinical Exam Findings On examination and color fundus photography, macular crystals in our cohort were in a parafoveal distribution, varied in number and size, and were more evident on fundus photography than clinical examination, in part owing to photophobia and lack of cooperation (Fig 1; available at www.aaojournal.org). Retinal pigment epithelium atrophy was present in 10 of 18 eyes (56%; Fig 2; Table 1). One eye was found to have a pseudocyst (7.1%; Fig 2; Table 1). FIGURE 1 Representative fundus photos and fundus autofluorescence from patients with sjogren-Larsson Syndrome. (Top) Fundus photographs demonstrating macular glistening dots (arrows) and RPE changes (black arrowhead) in the central macula. (Bottom) Fundus ... Figure 2 Optical coherence tomography (OCT) through the fovea. Top left, Right eye demonstrating foveal retinal atrophy (white arrowheads). Top right, Right eye showing a foveal pseudocyst (asterisk) and macular glistening dots predominantly in the inner retinal ... Previous optical coherence tomography studies demonstrated macular crystals and pseudocysts.5 Intraretinal hyperreflective bodies corresponding to crystals were seen primarily in the macular and foveal outer plexiform layer and inner nuclear layers.5 We obtained optical coherence tomography in 14 eyes of 7 patients (Fig 2; Table 1). Although present in all layers, the vast majority of macular crystals localized to the inner nuclear and outer plexiform layers. Segmentation of retinal layers was performed on the full retinal thickness, on inner nuclear, and outer nuclear layers. These layers were selected because they were thought to better reflect the cellularity of the fovea. Also, histochemical studies indicate that FALDH is most active in the inner and outer nuclear and ganglion cell layers of the retina (Rizzo, unpublished observations, April, 2014). Full retinal thickness was reduced by 22% (P = 0.0015), the inner nuclear layer was reduced by 30% (P = 0.0023), and the outer nuclear layer was reduced by 40% (P = 0.0003). The SLS cohort displayed retinal thinning despite being compared with a slightly older reference cohort. Thinning seemed to be most pronounced in the umbo, where there is normally a paucity of rods and inner retinal layers. This thinning suggests that there is outer retinal injury in SLS, which could be a result of direct toxicity, changes in structural integrity, loss of trophic factors, or altered development. Inner nuclear layer, outer nuclear layer, and full-thickness retinal thinning suggest multiple cell types are likely affected in SLS. Fundus autofluorescence and fluorescein angiography showed retinal pigment epithelium atrophy. All 4 patients imaged using fundus autofluorescence demonstrated heterogeneous macular autofluorescence with crystals (Fig 1), which is consistent with a prior report describing reduced levels of central retinal macular pigment.4 All 4 eyes evaluated with fluorescein angiography were found to have window defects and crystals without the presence of leakage or an enlarged foveal avascular zone. In this study, we report the characterization of the retinal layers using retinal segmentation in SLS in the largest case series originating from the United States. Limitations of our study include low disease prevalence and the ability of young patients to complete examinations requiring patient attention and cooperation. Larger studies that include emerging imaging strategies may shed additional light on the retinal findings associated with this unique metabolic syndrome.

Adaptive Optics Imaging of Retinal Photoreceptors Overlying Lesions in White Dot Syndrome and its Functional Correlation.

PURPOSE To quantify retinal photoreceptor density using adaptive optics (AO) imaging and correlate it with retinal tomography, fundus autofluorescence, and retinal sensitivity overlying lesions in various white dot syndromes (WDS). DESIGN Prospective cross-sectional study. METHODS setting: Stanley M. Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA. STUDY POPULATION Thirty-five lesions of WDS from 12 patients (19 eyes; mean age: 54.4 ± 15.8 years; 9 female) were analyzed. INTERVENTION Macular lesions (≤3 regions of interest/eye), at 2 fixed eccentric loci, were imaged using AO, spectral-domain optical coherence tomography, and fundus autofluorescence. In this study, lesions were defined as active if there was presence of hyperautofluorescence within the lesions. Photoreceptor density was calculated after manual correction and adjustment for axial length. Retinal sensitivity was assessed using microperimetry and correlated with photoreceptor density using Spearman rank correlation test. OUTCOME MEASURES Mean retinal sensitivity and photoreceptor density at the WDS lesions. RESULTS Mean photoreceptor density was 7331 ± 4628 cones/mm(2) overlying 16 active lesions and 6546 ± 3775 cones/mm(2) overlying 19 inactive lesions (P = .896). Mean retinal sensitivity (9.37 ± 5.34 dB) showed modest correlation with photoreceptor density (ρ = 0.42, P = .03). Retinal sensitivity over lesions with intact inner segment-outer segment (IS-OS) junction was 13.35 ± 3.75 dB and 6.33 ± 4.31 dB over lesions with disrupted IS-OS junction (P = .005). CONCLUSIONS AO imaging may allow high-resolution analysis of photoreceptor loss among lesions in WDS. Such microstructural changes may correlate with functional loss.

Combined systemic and ocular chemotherapy for anterior segment metastasis of systemic mantle cell lymphoma

BackgroundMantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin’s lymphoma that rarely metastasizes to the iris and the anterior segment. Blastic/pleomorphic morphology is thought to have an adverse effect on prognosis in MCL. MCL is resistant to conventional chemotherapeutic regimens with a tendency for multiple relapses. Management of anterior segment metastasis of systemic MCL has not been described in literature.FindingsA 58-year-old male presented with an aggressive, relapsing, metastatic, systemic blastic variant of MCL with ocular involvement. At the time of initial presentation, large tumor cells were visible in the anterior chamber (AC) along with hypopyon and fibrin. The AC cells stained positively for CD20. The iris was thickened and coated with lymphoma cells. Iris neovascularization was present. Given extensive systemic and ocular involvement, the patient was given combination chemotherapy with systemic ibrutinib and intravitreal injections of methotrexate and rituximab. The disease response was monitored using multimodal imaging, including anterior segment optical coherence tomography and ultrasound biomicroscopy. Following combination of systemic and intraocular chemotherapy, there was a marked decrease in the ocular tumor load and the systemic disease.ConclusionsCombination therapy with intravitreal injections of chemotherapeutic agents targeting monoclonal B-cell population and novel systemic agents may help to achieve remission in anterior segment metastasis of aggressive subtypes of NHL such as blastic variant of MCL. Multimodal imaging may assist in the management of these cases.

Acute onset of fingolimod-associated macular edema

Purpose Fingolimod is among the first oral disease-modifying agents for the treatment of relapsing-remitting multiple sclerosis (MS). Despite its favorable safety profile, fingolimod may cause macular edema, a significant adverse event, which occurs within the first 4 months of therapy. Macular edema usually resolves upon discontinuation of fingolimod; however, the time required for resolution of this condition is unknown. Observations A 42-year-old white male with a history of relapsing-remitting MS presented with blurring of vision in his left eye 24 h after the first dose of fingolimod. Dilated fundus examination of the left eye revealed an increased retinal thickness and mild optic disc pallor. Spectral domain optical coherence tomography (SD-OCT) confirmed the diagnosis of cystoid macular edema. Topical nonsteroidal anti-inflammatory drug (NSAID) was initiated immediately after the diagnosis, and fingolimod therapy was discontinued shortly thereafter. Seven weeks after the initial presentation, intermediate uveitis was noted in the inferior periphery of the left eye, and SD-OCT revealed worsening of macular edema. Acetazolamide therapy was added to the topical NSAID to control the edema. Three weeks after initiation of acetazolamide, macular thickness reduced significantly. The patient then stopped all medications, and 3 weeks later macular edema rebounded. Systemic steroid was employed to control both the intermediate uveitis and macular edema. Conclusions and importance We report a case of acute and very rapid onset of fingolimod-associated macular edema (FAME). Acetazolamide may have a beneficial effect on macular edema secondary to fingolimod. It is unclear if intermediate uveitis is associated with the rapid development of FAME.

Emixustat und Lampalizumab: Potenzielle neue Therapieoptionen bei geographischer Atrophie

Zwei neuartige Wirkstoffklassen werden derzeit umfassend für die Behandlung der trockenen altersbedingten Makuladegeneration (AMD) untersucht. Emixustat, ein oral einzunehmender Sehzyklus-Inhibitor, und Lampalizumab, ein intravitreal zu verabreichendes monoklonales Antikörperfragment gegen Komplementfaktor D, haben in klinischen Studien der Phase 2 zur Behandlung der nichtneovaskulären (trockenen) AMD vielversprechende Ergebnisse gezeigt. Lampalizumab wird derzeit in einer großen multizentrischen klinischen Studie der Phase 3 zur trockenen AMD/geographischen Atrophie untersucht.

Möglichkeiten in der Anti-VEGF-A-Therapie

Die Neutralisation vom VEGF-A hat sich in der Behandlung der feuchten altersbedingten Makuladegeneration (AMD) durchgesetzt. Zur Verbesserung der Therapie werden antiVEGF-A-kombinierte Therapieansätze beforscht, die zusätzliche pathologische Mechanismen unterbinden. In klinischen Studien wie Fovista [1] oder ONYX [2] wird versucht, die Stabilität neuer Gefäße zu vermindern. Komplementfaktoren wären weitere mögliche effektive Targets. Die Bedeutung des Komplements zeigt sich am CD46, einem von fast jeder Zelle exprimierten Rezeptor, der verhindert, dass das Komplementsystem die eigenen Zellen angreift. In der Studie von Lyzogubov et al. zeigt eine CD46 Knock-out-Maus alle Symptome der AMD, vor allem geographische Atrophie. Wie ein Komplement das retinale Pigmentepithel (RPE) schädigt, konnten die Autoren Brandstetter et al. zeigen. Das Komplementprodukt C5a «primed» RPE Zellen zur Ausbildung eines Inflammasoms, das die RPE-Zellfunktionen in einem entzündlichen Phänotyp ändert. Änderungen der Zellfunktion durch Inflammasome sind durch einen Regulator des Zellmetabolismus, den mTOR (mammalian Target of Rapamycin) verknüpft. Tatsächlich konnten Ma et al. zeigen, dass mTOR-Hemmung die chorioidale Neovaskularisation im Mausmodell effektiv reduzieren kann. Fazit für Klinik ist, dass die Kombinationstherapie erhebliche Verbesserungen der bisherigen Anti-VEGF-A-Therapie ermöglicht, wie aktuelle klinische Studien zeigen. Untersuchungen zu Mechanismen der lokalen Komplement-Aktivierung zeigen neue Targets auf. Prof. Dr. Olaf Strauß olaf.strauss@charite.de