Ronald Mancini

Optical Coherence Tomography Measurement of Macular and Nerve Fiber Layer Thickness in Normal and Glaucomatous Human Eyes

PURPOSE To evaluate the hypothesis that macular thickness correlates with the diagnosis of glaucoma. DESIGN Cross-sectional study. PARTICIPANTS We studied 367 subjects (534 eyes), including 166 eyes of 109 normal subjects, 83 eyes of 58 glaucoma suspects, 196 eyes of 132 early glaucoma patients, and 89 eyes of 68 advanced glaucoma patients. METHODS We used optical coherence tomography (OCT) to measure macular and nerve fiber layer (NFL) thickness and to analyze their correlation with each other and with glaucoma status. We used both the commercial and prototype OCT units and evaluated correspondence between measurements performed on the same eyes on the same days. MAIN OUTCOME MEASURE Macular and NFL thickness as measured by OCT. RESULTS All NFL parameters both in prototype and commercial OCT units were statistically significantly different comparing normal subjects and either early or advanced glaucoma (P < 0.001). Inner ring, outer ring, and mean macular thickness both in prototype and commercial OCT devices were found to be significantly different between normal subjects and advanced glaucomatous eyes (P < 0.001). The outer ring was the only macular parameter that could significantly differentiate between normal and early glaucoma with either the prototype or commercial OCT unit (P = 0.003, P = 0.008, respectively). The area under the receiver operator characteristic (AROC) curves comparing mean NFL thickness between normal and advanced glaucomatous eyes was 1.00 for both the prototype and commercial OCT devices for eyes scanned on both machines on the same day. The AROC comparing mean macular thickness in normal and advanced glaucomatous eyes scanned on both machines on the same day was 0.88 for the prototype OCT device and 0.80 for the commercial OCT. CONCLUSIONS Both macular and NFL thickness as measured by OCT showed statistically significant correlations with glaucoma, although NFL thickness showed a stronger association than macular thickness. There was good correspondence between findings using both the prototype and commercial OCT units. Macular and NFL thickness measurements made with OCT may have usefulness in the clinical assessment of glaucoma.

Use of Hyaluronic Acid Gel in the Management of Paralytic Lagophthalmos: The Hyaluronic Acid Gel "Gold Weight"

Purpose: To evaluate the safety and efficacy of injecting hyaluronic acid gel in the upper eyelid as a nonsurgical alternative in the treatment of paralytic lagophthalmos. Methods: This is a retrospective study of 9 patients (10 eyelids) with paralytic lagophthalmos treated with hyaluronic acid gel in the prelevator aponeurosis region and/or pretarsal region of the paralytic upper eyelid. Pretreatment, posttreatment, and follow-up photographs were digitized, and overall outcomes assessed. Measurements of lagophthalmos were standardized and compared. Slit-lamp examination was used to evaluate the degree of exposure keratopathy. ImageJ was used for photographic analysis. Results: Ten eyelids (9 patients, 7 men; mean age 69.2 years; range, 31–90 years) with paralytic lagophthalmos were treated with hyaluronic acid gel. The average amount of injected hyaluronic acid gel was 0.9 ml (range, 0.2–1.2 ml). All patients demonstrated significant improvement in lagophthalmos and exposure keratopathy. The mean improvement in lagophthalmos was 4.8 mm (range, 0.9–11.9 mm; p = 0.001). Of the 5 patients with follow-up, the mean follow-up period was 3.6 months (range, 2–5 months). Of these, 2 had no change in lagophthalmos (both maintained 0 mm at 5 months), one had a slight decrease in lagophthalmos (4.8–4.6 mm at 2 months), one had a slight increase in lagophthalmos (0.3–0.5 mm at 2 months), and one had a more significant increase in lagophthalmos (1.9–4.3 mm at 4 months). The latter patient underwent a second treatment with further reduction of lagophthalmos to 0.4 mm. Overall, there was a decrease in margin reflex distance from the upper eyelid margin to the corneal light reflex (MRD1) but it was not statistically significant. Complications were minor and included transient ecchymosis, edema, and tenderness at the injection sites. Conclusions: On the basis of these preliminary results, hyaluronic acid gel shows promise as a safe and effective nonsurgical treatment for the management of paralytic lagophthalmos. This treatment may be particularly useful in patients who are poor surgical candidates and/or as a temporizing measure in patients in whom return of facial nerve function is anticipated, given the hyaluronic acid gel’s properties of slow resorption and reversibility with hyaluronidase.

Staurosporine-Induced Activation of Caspase-3 Is Potentiated by Presenilin 1 Familial Alzheimer's Disease Mutations in Human Neuroglioma Cells

Abstract : Familial Alzheimers disease (FAD) mutant forms of presenilin 1 (PS1) and 2 have been shown to sensitize cells to apoptotic cell death. Here we explore the effects of FAD mutant forms of PS1 on caspase activation during apoptosis. We show that caspase activation leads to increased generation of alternative C‐terminal fragments (CTFs) from mutant as compared to wild‐type (wt) PS1. For this purpose, very low expression levels of wt, A246E, L286V, and ΔE10 FAD mutant PS1 proteins in stably transfected human H4 neuroglioma cells were used to avoid artifactual induction of spontaneous apoptosis due to overexpression of PS1. Staurosporine treatment of these cells resulted in increased cell death and up to a 10‐fold increase in caspase‐3 activation in mutant versus wt PS1‐expressing cell lines. Correspondingly, relative levels of caspase‐cleaved PS1 CTFs were increased by five‐to sixfold in the FAD mutant versus wt PS1 cells. Elevated caspase activation and caspase cleavage of FAD mutant PS1 suggest the possibility of either a direct proapoptotic effect of mutant PS1 or interference of mutant PS1 with antiapoptotic effects of wt PS1.

Effects of Iron Ions, Protons and X Rays on Human Lens Cell Differentiation

Abstract Chang, P. Y., Bjornstad, K. A., Rosen, C. J., McNamara, M. P., Mancini, R., Goldstein, L. E., Chylack, L. T. and Blakely, E. A. Effects of Iron Ions, Protons and X Rays on Human Lens Cell Differentiation. Radiat. Res. 164, 531–539 (2005). We have investigated molecular changes in cultured differentiating human lens epithelial cells exposed to high-energy accelerated iron-ion beams as well as to protons and X rays. In this paper, we present results on the effects of radiation on gene families that include or are related to DNA damage, cell cycle regulators, cell adhesion molecules, and cell cytoskeletal function. A limited microarray survey with a panel of cell cycle-regulated genes illustrates that irradiation with protons altered the gene expression pattern of human lens epithelial cells. A focus of our work is CDKN1A (p21CIP1/WAF1), a protein that we demonstrate here has a role in several pathways functionally related to LET-responsive radiation damage. We quantitatively assessed RNA and protein expression in a time course before and after single 4-Gy radiation doses and demonstrated that transcription and translation of CDKN1A are both temporally regulated after exposure. Furthermore, we show qualitative differences in the distribution of CDKN1A immunofluorescence signals after exposure to X rays, protons or iron ions, suggesting that LET effects likely play a role in the misregulation of gene function in these cells. A model of molecular and cellular events is proposed to account for precataractous changes in the human lens after exposure to low- or high-LET radiations.

Nonsurgical Management of Congenital Eyelid Malpositions Using Hyaluronic Acid Gel

Purpose: To report our preliminary experience using hyaluronic acid gel fillers as a nonsurgical alternative in the management of congenital eyelid malpositions. Methods: In this retrospective interventional case series, 5 patients (10 eyes) with congenital eyelid malpositions, including eyelid retraction, ectropion, euryblepharon, epiblepharon, and abnormalities associated with a shallow orbit, with resultant lagophthalmos and/or keratopathy and tearing were evaluated before and after injection with hyaluronic acid gel (Restylane) in the pretarsal and/or septal regions of the affected eyelid(s). Pretreatment, posttreatment, and follow-up photographs were analyzed for eyelid position and degree of eyelid closure and lagophthalmos, and slit-lamp evaluation of the degree of keratopathy. Results: All 5 patients demonstrated significant improvement of eyelid position and degree of keratopathy. The mean improvement in lagophthalmos was 4.5 mm (range, 2–7 mm). The average volume of hyaluronic acid gel used was 0.5 ml per eyelid. Complications were minor, including transient edema and ecchymosis at the sites of injection. Of the 10 eyelids injected, only one had increased astigmatism after injection. Conclusions: Hyaluronic acid gel shows promise as a safe and effective nonsurgical treatment for the management of certain eyelid malpositions, disorders traditionally requiring surgical intervention if aggressive ocular lubrication fails. This treatment is particularly useful in such patients who are commonly premature with poor general health and serves as a temporizing measure by allowing the much needed tissue expansion to take effect over time.

Characterization of Ocular Tissues Using Microindentation and Hertzian Viscoelastic Models

PURPOSE The authors applied a novel microindentation technique to characterize biomechanical properties of small ocular and orbital tissue specimens using the hertzian viscoelastic formulation, which defines material viscoelasticity in terms of the contact pressure required to maintain deformation by a harder body. METHODS They used a hard spherical indenter having 100 nm displacement and 100 μg force precision to impose small deformations on fresh bovine sclera, iris, crystalline lens, kidney fat, orbital pulley tissue, and orbital fatty tissue; normal human orbital fat, eyelid fat, and dermal fat; and orbital fat associated with thyroid eye disease. For each tissue, stress relaxation testing was performed using a range of ramp displacements. Results for single displacements were used to build quantitative hertzian models that were, in turn, compared with behavior for other displacements. Findings in orbital tissues were correlated with quantitative histology. RESULTS Viscoelastic properties of small specimens of orbital and ocular tissues were reliably characterized over a wide range of rates and displacements by microindentation using the hertzian formulation. Bovine and human orbital fatty tissues exhibited highly similar elastic and viscous behaviors, but all other orbital tissues exhibited a wide range of biomechanical properties. Stiffness of fatty tissues tissue depended strongly on the connective tissue content. CONCLUSIONS Relaxation testing by microindentation is a powerful method for characterization of time-dependent behaviors of a wide range of ocular and orbital tissues using small specimens, and provides data suitable to define finite element models of a wide range of tissue interactions.

Bilateral Lacrimal Gland Disease: Clinical Features of 97 Cases

OBJECTIVE Bilateral lacrimal gland (LG) disease is a unique presentation that can result from varied causes. We reviewed the diagnoses, clinical features, and outcomes of 97 patients with this entity. DESIGN Case series. PARTICIPANTS Ninety-seven patients with bilateral LG disease. METHODS Retrospective review and statistical analysis using analysis of variance and the Fisher exact test. MAIN OUTCOME MEASURES Patient demographics, clinical features, diagnostic testing, diagnosis, and treatment. RESULTS Patient age ranging from 8 to 84 years (mean, 46 years). The predominant gender was female (77%), and race included black (49%), white (38%), and Hispanic (12%) patients. Diagnoses fell into 4 categories: inflammatory (n = 51; 53%), structural (n = 20; 21%), lymphoproliferative (n = 19; 20%), and uncommon (n = 7; 7%) entities. The most common diagnoses included idiopathic orbital inflammation (IOI; n = 29; 30%), sarcoidosis (n = 19; 20%), prolapsed LG (n = 15; 15%), lymphoma (n = 11; 11%), lymphoid hyperplasia (n = 8; 8%), and dacryops (n = 5; 5%). Inflammatory conditions were more likely in younger patients (P<0.05) and in those with pain (P<0.001) and mechanical blepharoptosis (P<0.01) at presentation, whereas lymphoma was more common in older patients (P<0.001) without active signs of inflammation at presentation. Black patients were more likely to have sarcoidosis (P<0.01). Laboratory results showed high angiotensin converting enzyme level being significantly more likely in patients with sarcoidosis (P<0.05). However, sensitivity was limited to 45%, with 25% of patients diagnosed with IOI also demonstrating positive results. Corticosteroid therapy was the treatment of choice in 38 cases, corresponding to resolution of symptoms in 29% and improvement in an additional 32%. Overall, chronic underlying disease was found in 71% of patients, among whom 26% achieved a disease-free state, whereas 3% succumbed to their underlying disease. CONCLUSIONS The cause of bilateral lacrimal gland disease most commonly was inflammatory, followed by structural and lymphoproliferative. Patient characteristics and clinical presentations were key features distinguishing between competing possibilities. Despite local control with corticosteroids or radiotherapy, underlying disease continued in 71% of patients and led to death in 3%.

A Three-Dimensional Construct of the Aging Eyebrow: The Illusion of Volume Loss

BACKGROUND The eyebrows and eyebrow fat pads, key structures in upper facial aesthetics, are particularly vulnerable to age-related changes. OBJECTIVES In this study, the authors compare the impact of aging on the eyebrows and eyebrow fat pad volume in men and women through three-dimensional (3D) volumetric analysis. METHODS Electronic medical records of patients seen at the Jules Stein Eye Institute in the Division of Orbital and Ophthalmic Plastic Surgery between 2005 and 2010 were reviewed. Patients were included if they had undergone investigative imaging of the orbit for unilateral pathology. Computed tomography (CT) scans of patients with Graves disease diagnosis, extensive orbital trauma, and/or previous eyebrow surgery were excluded. A total of 52 CT scans (24 men and 28 women) were retained for analysis. A 3D reconstruction software was used to analyze the scans and calculate volumes of the retroorbicularis oculi fat (ROOF), galeal fat (ROOF and subcutaneous fat), and soft tissue muscles. RESULTS Galeal and brow fat volumes showed a significant positive trend toward enlargement in women (P values of .01 and .05, respectively). Although men showed a tendency toward fat enlargement with age, this was not statistically significant. Soft tissue-muscle volume decreased significantly in aging women (9.32 mm(3)/y) (P = .02). Data indicated that soft tissue volume in men tended to increase with age (3.92 mm(3)/y) but not significantly (P = .36). Neither total volume nor brow thickness appeared to change significantly in women (P = .56, P = .73). In men, total volume and brow thickness showed weak evidence of increasing with age (P = .12, P = .22). Linear regressions of Hertel measurements with and without sex interaction showed no statistically significant trend between the amount of proptosis and the galeal or brow fat. CONCLUSIONS Although overall eyebrow volume does not change with age, the relative contribution of fat and soft tissue to the total volume does seem to change. This pattern also differs between males and females. As women age, the fat volume increases and the soft tissue volume decreases. In men, the shift from soft tissue volume to fat volume is less pronounced. Although many clinicians have been drawn to the concept of fat volume deflation as a key element of facial aging, this study does not support this perspective in the eyebrow fat pad. An increasingly refined understanding of the dynamics of facial aging is mandatory for clinical diagnosis and will likely provide the framework from which to develop more innovative treatment options.

Orbital wall fracture repair using seprafilm

Purpose: Seprafilm is a hybrid product of carboxymethylcellulose and sodium hyaluronate that can act as an absorbable barrier to decrease the formation and severity of postoperative adhesions in abdominal, thoracic, and pelvic surgeries. The authors report their experience with use of Seprafilm in “trap door” orbital wall fracture repair. Methods: Retrospective case series of 4 consecutive patients with trap door orbital wall fractures secondary to blunt trauma with entrapped orbital soft tissue who underwent surgical repair with placement of Seprafilm implant in 2008. Orbitotomy was performed via standard transconjunctival and/or transcaruncular approaches with release of entrapped tissues, and placement of Seprafilm implant over the fracture site without fixation. Patients were followed for at least 6 months. Ophthalmic and orbital examinations, including ocular motility and Hertel exophthalmometry measurements, were recorded. Results: All 6 orbital wall fractures (4 floor, 2 medial wall) were successfully corrected with resolution of restrictive motility in the follow-up period (average 10 months; range 6 months to 1.5 years). Mean patient age was 13.5 years (range, 9–20 years). Two of the 4 patients had 2 separate fractures. There were no complications and no need for reoperation. Conclusions: Seprafilm may have a role in reconstruction of the “trap door” type of orbital wall fractures. The ease of use, lack of fixation, and absorbable properties without inflammation are encouraging for further study.

Conjunctiva-Sparing Posterior Ptosis Surgery: A Novel Approach.

Purpose: Müller’s muscle conjunctiva resection is a well-established means of correcting blepharoptosis. The primary objective of this prospective study was to determine if modifying Müller’s muscle conjunctiva resection by sparing the conjunctiva would accomplish successful repair while allowing patients to retain their conjunctiva. The potential advantages of preserving conjunctiva are significant and include: conservation of an anatomically normal tissue, retention of goblet cells, reduction of suture-related complications such as corneal irritation or abrasion as the conjunctiva covers the suture during postoperative healing, and preservation of conjunctiva for potential future surgical procedures critical to ocular health. Methods: This is a prospective study enrolling patients with mild to moderate ptosis. Results: The procedure has been performed in 18 patients and 30 eyelids. Follow up at 1 week revealed normal healing with expected postoperative edema and ecchymosis. Notably, all patients were free of any corneal abrasion or irritation. Follow up at 1 month and a minimum of 3 months (average 5.7 months) revealed that all patients had satisfactory correction of their blepharoptosis with Margin Reflex Distance 1 (MRD1) improvement to within 1 mm of the anticipated goal, preserved eyelid margin contour, and good symmetry (average 0.26 mm difference in MRD1 between the sides). Conclusion: These results show an effective correction of blepharoptosis with a favorable cosmetic outcome and low postoperative complication rate; all while preserving the conjunctiva.