Kenn A. Freedman

Beta-cyclodextrins enhance bioavailability of pilocarpine

Cyclodextrins have been used to improve drug solubility, stability and absorption for oral and parenteral administration. However, their potential for improving ocular drug delivery has received little attention. To evaluate the ability of hydroxypropyl-beta-cyclodextrins to improve ophthalmic drug bioavailability following topical administration, the miotic effect of topical solutions of pilocarpine was studied in New Zealand White rabbits. Pilocarpine varying in dose from 5 to 500 micrograms in the presence or absence of 5% cyclodextrin was administered (50 microliters) topically and the change in pupil diameter determined. These results demonstrated that pilocarpine alone or in the presence of cyclodextrin produces a dose-related reduction in pupil diameter. The addition of cyclodextrins produced a significant left-shift in the dose response curve, with an ED50 of 64 micrograms and 19 micrograms for pilocarpine and pilocarpine/5% cyclodextrin solutions, respectively. Studies in which the concentration of cyclodextrin was varied revealed that a one-to-one molar ratio of pilocarpine to cyclodextrin was sufficient to provide maximum increase in pilocarpine bioavailability. Electrophysiology and scanning electron microscopic studies demonstrated that cyclodextrin does not disrupt the normal ion transport currents, barrier properties or surface features of the corneal epithelium. Viscosity measurements indicated that difference in the viscosity of pilocarpine and pilocarpine/cyclodextrin solutions cannot account for increased bioavailability of pilocarpine. These data support the idea that the addition of cyclodextrin significantly improves the ocular bioavailability of pilocarpine. This enhanced bioavailability of pilocarpine does not appear to be due to a mechanism destructive to the epithelium or to an increase in vehicle viscosity.

Pupil size and the ablation zone in laser refractive surgery: considerations based on geometric optics

Purpose: To determine whether the currently accepted method of selecting a minimum ablation zone size for refractive surgery based on dark‐adapted pupil diameter is substantiated by geometric optical analysis. Setting: Department of Ophthalmology and Visual Sciences, Texas Tech University Health Sciences Center, Lubbock, Texas, USA. Methods: An optical model of the anterior segment was developed to calculate the effective corneal refractive diameter (ECRD), which is the diameter of the area of cornea that refracts all incident light rays arising from objects along the line of sight though the physical pupil (PP). The concept of the entrance pupil (EP) was reexamined and developed, and the ECRD was calculated over a range of corneal curvatures (K), anterior chamber depths (ACDs), and EP sizes. The model was generalized to include oblique light rays. Calculations were performed using MatLab Optimization Toolbox® software (The MathWorks). Results: For a given EP size, the ECRD was significantly influenced by K and slightly influenced by ACD. For objects on the line of sight, the ECRD was smaller than the EP in all cases. Regarding rays from objects in the periphery, the ECRD expanded rapidly as the angle of oblique incidence increased. Conclusions: For objects on the line of sight, the ECRD is always smaller than the clinically measured pupil (EP) because the EP is substantially magnified relative to the PP. Ablation zones larger than the EP should, in theory, prevent scattered or defocused light rays from contributing to the foveal image. When considering objects in the periphery, the increase in ECRD is sufficiently rapid that current refractive procedures cannot stop scattered light from these objects from contributing to the retinal image.

Topical apraclonidine in the diagnosis of suspected Horner syndrome.

Topical cocaine is used to confirm the clinical diagnosis of ocular sympathetic denervation, or Horner Syndrome (HS). Cocaine blocks re-uptake of norepinephrine (NE) by sympathetic nerve terminals in the iris dilator muscle, transiently increasing its concentration in the synaptic junction. Norepinephrine activates alpha1 receptors in the iris dilator to cause pupil dilation. In HS, cocaine fails to dilate the affected pupil as much as the unaffected pupil, but its indirect action makes it a weak dilator, and the test can give equivocal results. Cocaine is also a controlled substance and therefore difficult to obtain. A practical and reliable alternative to cocaine is apraclonidine, an ocular hypotensive agent that has a weak direct action on alpha1 receptors and therefore minimal to no clinical effect on the pupils of normal eyes. Patients with HS have denervation supersensitivity of the alpha1 receptors in the iris stroma of the affected eye, making the pupil dilator responsive to apraclonidine. In patients with HS, reversal of anisocoria occurs after bilateral instillation of apraclonidine 1% or 0.5%. Two cases that demonstrate this effect are reported. Apraclonidine should be considered a candidate to replace cocaine in the pharmacologic diagnosis of HS if a gold-standard comparison study confirms these results.

Effective corneal refractive diameter as a function of the object tangent angle in visual space

PURPOSE: To determine whether the currently accepted method of selecting a minimum optical zone diameter for laser refractive surgery that is equal to or slightly greater than the dark‐adapted pupil diameter provides a sufficient diameter of corneal surface to focus light arising from objects in the paracentral and peripheral visual field. SETTING: Department of Ophthalmology and Visual Sciences, Texas Tech University Health Sciences Center, Lubbock, Texas, USA. METHODS: An optical model of the anterior segment was developed to calculate the effective corneal refractive diameter (ECRD), which is the diameter of the area of cornea that refracts all incident light rays arising from an object through the physical pupil (PP). This model incorporates the patient variables of central anterior chamber depth (ACD), central corneal curvature (Kc), and the diameter of the apparent entrance pupil (EP). The model was expanded to incorporate distant objects off the line of sight (LOS), described by their angular displacement from the fixation object in visual space (the object tangent angle δob). Results were calculated for the 360 meridian degree visual field (ie, for all objects in visual space perceptually displaced from the fixation object by angle δob). The effect of the prolate nature of the cornea was also investigated. RESULTS: The ECRD expanded rapidly as a function of PP and δob but was minimally influenced by Kc. Beyond a critical object tangent angle δc, light rays striking the corneal vertex were not refracted through the PP, and the ECRD became an annular surface centered on the corneal vertex. The δc was not a function of K, but increased as the PP increased and decreased as the ACD increased. The prolate nature of the cornea had little influence on the ECRD, even for very peripheral light rays. CONCLUSIONS: The ECRD expands rapidly when considering distant objects only slightly displaced from the LOS. A patient treated with an optical zone equal to or slightly greater than the dark‐adapted pupil diameter may experience vision quality loss for paracentral and midperipheral objects even under conditions of ambient indoor lighting.

The effective corneal refractive surface as a function of a point in visual space: a three-dimensional analysis.

Purpose:  To develop a three‐dimensional optical model of the anterior segment which will provide a basis for understanding the effects of corneal and adnexal problems on vision.

Mucosa-associated lymphoid tissue lymphoma with intraocular and orbital involvement: case presentation and review of the literature

ABSTRACT Primary ocular lymphomas are typically confined to either the eye or the orbit. Rarely, in immune-competent patients, lymphomas affect both the eye and the orbit simultaneously. Mucosa-associated lymphoid tissue (MALT) lymphomas are the most common ocular lymphomas. They usually present primarily in the orbit but sometimes can present primarily in intraocular tissue. MALT lymphomas that occur initially in the uvea can sometimes spread to the adjacent orbit. We report a case of progressively enlarging MALT lymphoma in a 62-year-old immune-competent patient causing a severe mass effect in the orbit and simultaneously presenting with intraocular involvement. There was radiographic evidence of lymphoma confined to the orbit with intraocular involvement. The simultaneous presentation makes it difficult to determine if the lymphoma initially presented in the orbit or intraocular tissue, although the orbital component was more impressive. The case also includes a literature review of simultaneous orbital and intraocular MALT lymphomas. The patient responded to systemic chemotherapy with regression in size of the lymphoma, relief of the mass effect seen in the orbit, and the regression of the intraocular involvement.

Lacrimal gland enlargement as an early clinical or radiological sign in thyroid orbitopathy

Purpose Characteristic ophthalmic signs of Thyroid Orbitopathy (TO) include exophthalmos, eyelid retraction, eyelid edema, restrictive extraocular myopathy, and optic neuropathy. In addition lacrimal gland (LG) enlargement can be observed in these patients. However TO has not usually been considered in the differential diagnosis of cases of isolated LG enlargement. Observations A female patient at our institution (Texas Tech) was seen over a period from 2006 to 2012. This patient presented initially with LG enlargement as the primary clinical or radiologic sign of what later was diagnosed as TO. Computerized tomography and/or magnetic resonance imaging of the orbits were obtained and demonstrated isolated LG enlargement. Conclusions and importance This case represents, to our knowledge, the first report of LG enlargement as an initial presenting sign of TO. Further clinical and radiological studies looking at the natural history of TO would be useful to better understand the timing of LG involvement. In patients presenting with lacrimal gland enlargement, thyroid orbitopathy should be strongly considered in the differential diagnosis together with other causes of dacryoadenitis and LG tumors. This may save unnecessary and extensive diagnostic testing or even LG biopsies.