Imaging and Diagnostics

Imaging and Diagnostics Publications

Yamaguchi M, Nakao S, Kaizu Y, Kobayashi Y, Nakama T, Arima M, Yoshida S, Oshima Y, Takeda A, Ikeda Y, Mukai S, Ishibashi T, Sonoda K-H. High-Resolution Imaging by Adaptive Optics Scanning Laser Ophthalmoscopy Reveals Two Morphologically Distinct Types of Retinal Hard Exudates. Sci Rep 2016;6:33574.Abstract

Histological studies from autopsy specimens have characterized hard exudates as a composition of lipid-laden macrophages or noncellular materials including lipid and proteinaceous substances (hyaline substances). However, the characteristics of hard exudates in living patients have not been examined due to insufficient resolution of existing equipment. In this study, we used adaptive optics scanning laser ophthalmoscopy (AO-SLO) to examine the characteristics of hard exudates in patients with retinal vascular diseases. High resolution imaging using AO-SLO enables morphological classification of retinal hard exudates into two types, which could not be distinguished either on fundus examination or by spectral domain optical coherence tomography (SD-OCT). One, termed a round type, consisted of an accumulation of spherical particles (average diameter of particles: 26.9 ± 4.4 μm). The other, termed an irregular type, comprised an irregularly shaped hyper-reflective deposition. The retinal thickness in regions with round hard exudates was significantly greater than the thickness in regions with irregular hard exudates (P = 0.01 →0.02). This differentiation of retinal hard exudates in patients by AO-SLO may help in understanding the pathogenesis and clinical prognosis of retinal vascular diseases.

Evans KK, Haygood TM, Cooper J, Culpan A-M, Wolfe JM. A half-second glimpse often lets radiologists identify breast cancer cases even when viewing the mammogram of the opposite breast. Proc Natl Acad Sci U S A 2016;113(37):10292-7.Abstract

Humans are very adept at extracting the "gist" of a scene in a fraction of a second. We have found that radiologists can discriminate normal from abnormal mammograms at above-chance levels after a half-second viewing (d' ∼ 1) but are at chance in localizing the abnormality. This pattern of results suggests that they are detecting a global signal of abnormality. What are the stimulus properties that might support this ability? We investigated the nature of the gist signal in four experiments by asking radiologists to make detection and localization responses about briefly presented mammograms in which the spatial frequency, symmetry, and/or size of the images was manipulated. We show that the signal is stronger in the higher spatial frequencies. Performance does not depend on detection of breaks in the normal symmetry of left and right breasts. Moreover, above-chance classification is possible using images from the normal breast of a patient with overt signs of cancer only in the other breast. Some signal is present in the portions of the parenchyma (breast tissue) that do not contain a lesion or that are in the contralateral breast. This signal does not appear to be a simple assessment of breast density but rather the detection of the abnormal gist may be based on a widely distributed image statistic, learned by experts. The finding that a global signal, related to disease, can be detected in parenchyma that does not contain a lesion has implications for improving breast cancer detection.

Deiner MS, Lietman TM, McLeod SD, Chodosh J, Porco TC. Surveillance Tools Emerging From Search Engines and Social Media Data for Determining Eye Disease Patterns. JAMA Ophthalmol 2016;134(9):1024-30.Abstract

IMPORTANCE: Internet-based search engine and social media data may provide a novel complementary source for better understanding the epidemiologic factors of infectious eye diseases, which could better inform eye health care and disease prevention. OBJECTIVE: To assess whether data from internet-based social media and search engines are associated with objective clinic-based diagnoses of conjunctivitis. DESIGN, SETTING, AND PARTICIPANTS: Data from encounters of 4143 patients diagnosed with conjunctivitis from June 3, 2012, to April 26, 2014, at the University of California San Francisco (UCSF) Medical Center, were analyzed using Spearman rank correlation of each weekly observation to compare demographics and seasonality of nonallergic conjunctivitis with allergic conjunctivitis. Data for patient encounters with diagnoses for glaucoma and influenza were also obtained for the same period and compared with conjunctivitis. Temporal patterns of Twitter and Google web search data, geolocated to the United States and associated with these clinical diagnoses, were compared with the clinical encounters. The a priori hypothesis was that weekly internet-based searches and social media posts about conjunctivitis may reflect the true weekly clinical occurrence of conjunctivitis. MAIN OUTCOMES AND MEASURES: Weekly total clinical diagnoses at UCSF of nonallergic conjunctivitis, allergic conjunctivitis, glaucoma, and influenza were compared using Spearman rank correlation with equivalent weekly data on Tweets related to disease or disease-related keyword searches obtained from Google Trends. RESULTS: Seasonality of clinical diagnoses of nonallergic conjunctivitis among the 4143 patients (2364 females [57.1%] and 1776 males [42.9%]) with 5816 conjunctivitis encounters at UCSF correlated strongly with results of Google searches in the United States for the term pink eye (ρ, 0.68 [95% CI, 0.52 to 0.78]; P < .001) and correlated moderately with Twitter results about pink eye (ρ, 0.38 [95% CI, 0.16 to 0.56]; P < .001) and with clinical diagnosis of influenza (ρ, 0.33 [95% CI, 0.12 to 0.49]; P < .001), but did not significantly correlate with seasonality of clinical diagnoses of allergic conjunctivitis diagnosis at UCSF (ρ, 0.21 [95% CI, -0.02 to 0.42]; P = .06) or with results of Google searches in the United States for the term eye allergy (ρ, 0.13 [95% CI, -0.06 to 0.32]; P = .19). Seasonality of clinical diagnoses of allergic conjunctivitis at UCSF correlated strongly with results of Google searches in the United States for the term eye allergy (ρ, 0.44 [95% CI, 0.24 to 0.60]; P < .001) and eye drops (ρ, 0.47 [95% CI, 0.27 to 0.62]; P < .001). CONCLUSIONS AND RELEVANCE: Internet-based search engine and social media data may reflect the occurrence of clinically diagnosed conjunctivitis, suggesting that these data sources can be leveraged to better understand the epidemiologic factors of conjunctivitis.

García-Posadas L, Contreras-Ruiz L, Soriano-Romaní L, Dartt DA, Diebold Y. Conjunctival Goblet Cell Function: Effect of Contact Lens Wear and Cytokines. Eye Contact Lens 2016;42(2):83-90.Abstract

This review focuses on conjunctival goblet cells and their essential function in the maintenance of eye health. The main function of goblet cells is to produce and secrete mucins that lubricate the ocular surface. An excess or a defect in those mucins leads to several alterations that makes goblet cells central players in maintaining the proper mucin balance and ensuring the correct function of ocular surface tissues. A typical pathology that occurs with mucous deficiency is dry eye disease, whereas the classical example of mucous hyperproduction is allergic conjunctivitis. In this review, we analyze how goblet cell number and function can be altered in these diseases and in contact lens (CL) wearers. We found that most published studies focused exclusively on the goblet cell number. However, recent advances have demonstrated that, along with mucin secretion, goblet cells are also able to secrete cytokines and respond to them. We describe the effect of different cytokines on goblet cell proliferation and secretion. We conclude that it is important to further explore the effect of CL wear and cytokines on conjunctival goblet cell function.

Wen G, Aizenman A, Drew T, Wolfe JM, Haygood TM, Markey MK. Computational assessment of visual search strategies in volumetric medical images. J Med Imaging (Bellingham) 2016;3(1):015501.Abstract

When searching through volumetric images [e.g., computed tomography (CT)], radiologists appear to use two different search strategies: "drilling" (restrict eye movements to a small region of the image while quickly scrolling through slices), or "scanning" (search over large areas at a given depth before moving on to the next slice). To computationally identify the type of image information that is used in these two strategies, 23 naïve observers were instructed with either "drilling" or "scanning" when searching for target T's in 20 volumes of faux lung CTs. We computed saliency maps using both classical two-dimensional (2-D) saliency, and a three-dimensional (3-D) dynamic saliency that captures the characteristics of scrolling through slices. Comparing observers' gaze distributions with the saliency maps showed that search strategy alters the type of saliency that attracts fixations. Drillers' fixations aligned better with dynamic saliency and scanners with 2-D saliency. The computed saliency was greater for detected targets than for missed targets. Similar results were observed in data from 19 radiologists who searched five stacks of clinical chest CTs for lung nodules. Dynamic saliency may be superior to the 2-D saliency for detecting targets embedded in volumetric images, and thus "drilling" may be more efficient than "scanning."

Ferry JA, Klepeis V, Sohani AR, Harris NL, Preffer FI, Stone JH, Grove A, Deshpande V. IgG4-related Orbital Disease and Its Mimics in a Western Population. Am J Surg Pathol 2015;Abstract

Although chronic inflammatory disorders of the ocular adnexa are relatively common, their pathogenesis is in many cases poorly understood. Recent investigation suggests that many cases of sclerosing orbital inflammation are a manifestation of IgG4-related disease; however, most patients reported have been Asian, and it is not clear whether the results of studies from the Far East can be reliably extrapolated to draw conclusions about Western patients. We evaluated 38 cases previously diagnosed as orbital inflammatory pseudotumor or chronic dacryoadenitis to determine whether our cases fulfill the criteria for IgG4-RD (IgG4-related dacryoadenitis when involving the lacrimal gland, and IgG4-related sclerosing orbital inflammation when involving orbital soft tissue). Fifteen patients had IgG4-related dacryoadenitis or orbital inflammation. These patients included 9 men and 6 women, aged 24 to 77 years (median, 64 y). Lesions involved orbital soft tissue (8 cases), lacrimal gland (6 cases), and canthus (1 case). In 1 case, focal in situ follicular neoplasia was seen in a background of IgG4-RD. In another case, a clonal IGH gene rearrangement was detected. Four patients with IgG4-RD had evidence of IgG4-RD in other anatomic sites. Five patients, 1 man and 4 women, aged 26 to 74 years (median 50 y) had orbital lesions (2 involving lacrimal gland, 3 involving soft tissue) suspicious for, but not diagnostic of, IgG4-RD. Of 16 patients with IgG4-RD or probable IgG4-RD with information available regarding the course of their disease, 11 patients experienced recurrent or persistent orbital disease. However, no patient developed lymphoma, and no patient died of complications of IgG4-RD. Eighteen patients had lesions not representing IgG4-RD. They included 6 male and 12 female individuals aged 6 to 77 years (median, 47 y). These patients had a variety of diseases, including granulomatosis with polyangiitis (3 cases), Rosai-Dorfman disease (1 case), nonspecific chronic inflammation and fibrosis involving lacrimal gland or soft tissue (12 cases), and others. Clinical and pathologic findings among our patients with IgG4-RD involving the orbit are similar to those previously described in Asian patients. Careful evaluation of histologic and immunophenotypic features and clinical correlation are required to distinguish orbital IgG4-RD from other sclerosing inflammatory lesions in the orbit.

Sampson JF, Hasegawa E, Mulki L, Suryawanshi A, Jiang S, Chen W-S, Rabinovich GA, Connor KM, Panjwani N. Galectin-8 Ameliorates Murine Autoimmune Ocular Pathology and Promotes a Regulatory T Cell Response. PLoS One 2015;10(6):e0130772.Abstract

Galectins have emerged as potent immunoregulatory agents that control chronic inflammation through distinct mechanisms. Here, we report that treatment with Galectin-8 (Gal-8), a tandem-repeat member of the galectin family, reduces retinal pathology and prevents photoreceptor cell damage in a murine model of experimental autoimmune uveitis. Gal-8 treatment increased the number of regulatory T cells (Treg) in both the draining lymph node (dLN) and the inflamed retina. Moreover, a greater percentage of Treg cells in the dLN and retina of Gal-8 treated animals expressed the inhibitory coreceptor cytotoxic T lymphocyte antigen (CTLA)-4, the immunosuppressive cytokine IL-10, and the tissue-homing integrin CD103. Treg cells in the retina of Gal-8-treated mice were primarily inducible Treg cells that lack the expression of neuropilin-1. In addition, Gal-8 treatment blunted production of inflammatory cytokines by retinal T helper type (TH) 1 and TH17 cells. The effect of Gal-8 on T cell differentiation and/or function was specific for tissues undergoing an active immune response, as Gal-8 treatment had no effect on T cell populations in the spleen. Given the need for rational therapies for managing human uveitis, Gal-8 emerges as an attractive therapeutic candidate not only for treating retinal autoimmune diseases, but also for other TH1- and TH17-mediated inflammatory disorders.

Quiroz YT, Schultz AP, Chen K, Protas HD, Brickhouse M, Fleisher AS, Langbaum JB, Thiyyagura P, Fagan AM, Shah AR, Muniz M, Arboleda-Velasquez JF, Munoz C, Garcia G, Acosta-Baena N, Giraldo M, Tirado V, Ramírez DL, Tariot PN, Dickerson BC, Sperling RA, Lopera F, Reiman EM. Brain Imaging and Blood Biomarker Abnormalities in Children With Autosomal Dominant Alzheimer Disease: A Cross-Sectional Study. JAMA Neurol 2015;72(8):912-9.Abstract

IMPORTANCE: Brain imaging and fluid biomarkers are characterized in children at risk for autosomal dominant Alzheimer disease (ADAD). OBJECTIVE: To characterize and compare structural magnetic resonance imaging (MRI), resting-state and task-dependent functional MRI, and plasma amyloid-β (Aβ) measurements in presenilin 1 (PSEN1) E280A mutation-carrying and noncarrying children with ADAD. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional measures of structural and functional MRI and plasma Aβ assays were assessed in 18 PSEN1 E280A carriers and 19 noncarriers aged 9 to 17 years from a Colombian kindred with ADAD. Recruitment and data collection for this study were conducted at the University of Antioquia and the Hospital Pablo Tobon Uribe in Medellín, Colombia, between August 2011 and June 2012. MAIN OUTCOMES AND MEASURES: All participants had blood sampling, structural MRI, and functional MRI during associative memory encoding and resting-state and cognitive assessments. Outcome measures included plasma Aβ1-42 concentrations and Aβ1-42:Aβ1-40 ratios, memory encoding-dependent activation changes, resting-state connectivity, and regional gray matter volumes. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to AD. RESULTS: Similar to findings in adult mutation carriers, in the later preclinical and clinical stages of ADAD, mutation-carrying children were distinguished from control individuals by significantly higher plasma Aβ1-42 levels (mean [SD]: carriers, 18.8 [5.1] pg/mL and noncarriers, 13.1 [3.2] pg/mL; P < .001) and Aβ1-42:Aβ1-40 ratios (mean [SD]: carriers, 0.32 [0.06] and noncarriers, 0.21 [0.03]; P < .001), as well as less memory encoding task-related deactivation in parietal regions (eg, mean [SD] parameter estimates for the right precuneus were -0.590 [0.50] for noncarriers and -0.087 [0.38] for carriers; P < .005 uncorrected). Unlike carriers in the later stages, mutation-carrying children demonstrated increased functional connectivity of the posterior cingulate cortex with medial temporal lobe regions (mean [SD] parameter estimates were 0.038 [0.070] for noncarriers and 0.190 [0.057] for carriers), as well as greater gray matter volumes in temporal regions (eg, left parahippocampus; P < . 049, corrected for multiple comparisons). CONCLUSIONS AND RELEVANCE: Children at genetic risk for ADAD have functional and structural brain changes and abnormal levels of plasma Aβ1-42. The extent to which the underlying brain changes are either neurodegenerative or developmental remains to be determined. This study provides additional information about the earliest known biomarker changes associated with ADAD.

Islam R, Jackson C, Eidet JR, Messelt EB, Corraya RM, Lyberg T, Griffith M, Dartt DA, Utheim TP. Effect of Storage Temperature on Structure and Function of Cultured Human Oral Keratinocytes. PLoS One 2015;10(6):e0128306.Abstract

PURPOSE/AIMS: To assess the effect of storage temperature on the viability, phenotype, metabolism, and morphology of cultured human oral keratinocytes (HOK). MATERIALS AND METHODS: Cultured HOK cells were stored in HEPES- and sodium bicarbonate-buffered Minimum Essential Medium (MEM) at nine temperatures in approximately 4°C increments from 4°C to 37°C for seven days. Cells were characterized for viability by calcein fluorescence, phenotype retention by immunocytochemistry, metabolic parameters (pH, glucose, lactate, and O2) within the storage medium by blood gas analysis, and morphology by scanning electron microscopy and light microscopy. RESULTS: Relative to the cultured, but non-stored control cells, a high percentage of viable cells were retained only in the 12°C and 16°C storage groups (85%±13% and 68%±10%, respectively). Expression of ABCG2, Bmi1, C/EBPδ, PCNA, cytokeratin 18, and caspase-3 were preserved after storage in the 5 groups between 4°C and 20°C, compared to the non-stored control. Glucose, pH and pO2 in the storage medium declined, whereas lactate increased with increasing storage temperature. Morphology was best preserved following storage of the three groups between 12°C, 16°C, and 20°C. CONCLUSION: We conclude that storage temperatures of 12°C and 16°C were optimal for maintenance of cell viability, phenotype, and morphology of cultured HOK. The storage method described in the present study may be applicable for other cell types and tissues; thus its significance may extend beyond HOK and the field of ophthalmology.

Milman T, Kao AA, Chu D, Gorski M, Steiner A, Simon CZ, Shih C, Aldave AJ, Eagle RC, Jakobiec FA, Udell I. Paraproteinemic Keratopathy: The Expanding Diversity of Clinical and Pathologic Manifestations. Ophthalmology 2015;122(9):1748-56.Abstract

PURPOSE: To describe 7 patients with paraproteinemic keratopathy and to highlight the clinical and pathologic diversity of this rare entity and the importance of timely, systemic evaluation. DESIGN: Retrospective, multicenter collaborative case series. PARTICIPANTS: Seven patients with paraproteinemic keratopathy. METHODS: Clinical and pathologic records were reviewed to identify patients with well-documented corneal immunoglobulin deposits. Detailed ophthalmologic and medical histories were assembled. In 6 patients, corneal tissue was evaluated histochemically and immunohistochemically; in selected cases, corneal tissue was evaluated by in situ hybridization and ultrastructurally. MAIN OUTCOME MEASURES: Visual acuity and anterior segment examination at presentation and follow-up; local therapy; systemic diagnosis and management; and histopathologic, immunohistochemical, in situ hybridization, and ultrastructural findings. RESULTS: Seven patients were identified with corneal immunoglobulin deposition. In addition to previously reported crystalline, nummular, patch-like, and lattice-like corneal opacities, prominent corneal vascularization was present in 2 patients mimicking interstitial keratitis and limbal stem cell deficiency. All patients had evidence of paraproteinemia in a setting of monoclonal gammopathy of undetermined significance, smoldering plasma cell myeloma, or Waldenström macroglobulinemia. Corneal findings were the first manifestation of systemic disease in 4 patients, and the diagnosis was not suspected in 3 of these patients. Pathologic evaluation of biopsied corneal and conjunctival tissues demonstrated immunoglobulin deposits. Previously unreported ultrastructural patterns in the cornea were noted: large scroll-like immunotactoid deposits, immune complex-like deposits, and randomly arranged fibrils morphologically intermediate between amyloid and immunotactoid deposits. Surgical intervention to improve vision was performed in 4 patients, with recurrence of deposits in 3 patients. Three patients underwent systemic therapy with diminution of the deposits and improvement in vision in 1 patient. CONCLUSIONS: The clinical and pathologic expressions of corneal immunoglobulin deposits are protean and present a diagnostic challenge. Early recognition of this rare entity is important to address the potentially serious associated systemic disease.

Chen X, Jakobiec FA, Yadav P, Werdich XQ, Fay A. Melkersson-rosenthal syndrome with isolated unilateral eyelid edema: an immunopathologic study. Ophthal Plast Reconstr Surg 2015;31(3):e70-7.Abstract

Lymphedema is caused by defective drainage of the lymphatic system. In Melkersson-Rosenthal syndrome, involvement is predominantly of the lumens with blockage of lymphatic channels by histiocytic-epithelioid cell clusters accompanied by dermal granulomas and lymphocytes. It is a localized, painless, nonitching, and nonpitting form of lymphedema. Besides the eyelids, the disease can cause lip edema, facial palsy, and/or fissured tongue. It is rare and has received little attention in the ophthalmic literature, either in its complete triadic form, or more frequently, in its monosymptomatic forms. Pathogenesis is not well understood, and there is no effective therapy. The authors describe a case of Melkesson-Rosenthal syndrome in a 45-year-old Hispanic man with isolated unilateral upper eyelid edema. Histopathological and immunohistochemical evaluations of an eyelid biopsy specimen revealed intravascular and extravascular clusters of histiocytic-epithelioid cells that were CD68/163-positive. Variable numbers of mostly T-lymphocytes were found in the epidermis, dermis, and orbicularis muscle and by virtue of the associated granulomas established the diagnosis of Melkersson-Rosenthal syndrome. CD4 helper and CD8 suppressor T-lymphocytes were equally represented. CD20 B-lymphocytes were exceedingly sparse. Conspicuous CD1a-positive Langerhans' cells were present in the epidermis, sometimes formed subepithelial loose aggregates and were also incorporated in the granulomas. The differential diagnosis includes the far more common condition of acne rosacea. Management of Melkersson-Rosenthal syndrome, and of angioedema in general, is reviewed.