Paul L. Kaufman

Effects of retinal ganglion cell loss on magno-, parvo-, koniocellular pathways in the lateral geniculate nucleus and visual cortex in glaucoma

Glaucoma is a leading cause of world blindness, and retinal ganglion cell death is its pathological hallmark. There is accumulating evidence that glaucomatous damage extends from retinal ganglion cells to vision centers in the brain. In an experimental primate model of unilateral glaucoma, degenerative changes are observed in magnocellular, parvocellular, and koniocellular pathways in the lateral geniculate nucleus, and these changes are presented in relation to intraocular pressure and the severity of optic nerve damage. Neuropathological findings are also present in lateral geniculate nucleus layers driven by the unaffected fellow eye. Finally, there is information on changes in the visual cortex in relation to varying degrees of retinal ganglion cell loss. The implications of these findings for refining concepts regarding the pathobiology of progression, and the detection and treatment of glaucoma, are discussed.

Prostaglandin F2α increases uveoscleral outflow in the cynomolgus monkey

Cynomolgus monkeys were treated topically in one eye twice daily with prostaglandin F2 alpha-l-isopropylester (PGF2 alpha-IE) for nine doses. On treatment day 4, 3 hr after the seventh dose, intraocular pressure (IOP) in the treated eye was reduced by 65% compared to the controls, to less than 5 mmHg. On treatment day 5, 3 hr after the ninth dose, total outflow facility was determined by two-level constant pressure perfusion of the anterior chamber. Immediately thereafter, uveoscleral outflow was determined by intracamerally infusing [125I]- or [131I]-albumin and fluoresceinated dextran, and calculating the volume of anterior chamber fluid required to have deposited the quantity of tracer recovered from the various ocular and periocular tissues. Simultaneously, trabecular outflow was determined by calculating the volume of anterior chamber fluid required to have deposited the quantity of tracer recovered from the general circulation. Total facility was approximately 50% higher in treated than in control eyes, but the effect was variable, of marginal statistical significance, and perhaps due to increased pseudofacility or uveoscleral facility. Uveoscleral outflow was approximately two to three-and-a-half times higher in treated than in control eyes, the magnitude of the effect being dependent upon the timing and pressure at which the perfusion was conducted. Trabecular outflow was reduced by approximately 75% in the treated eyes relative to control so that the proportion of total outflow comprised by trabecular outflow in the treated eyes was only one third that in the controls. Total aqueous flow was slightly (approximately 20%) but not significantly reduced in the treated eyes. The IOP lowering effect of PGF2 alpha in the cynomolgus monkey is due largely if not exclusively to an increase in uveoscleral outflow of aqueous humor, with aqueous outflow being redirected from the trabecular to the uveoscleral route.

The mechanism of accommodation in primates

OBJECTIVE To study the accommodative mechanism in primates using monkeys, in light of a recently proposed novel accommodative mechanism in primates and a concomitant controversial surgical procedure for the reversal of presbyopia, DESIGN Experimental study. METHODS Accommodation was induced by stimulation of an electrode surgically implanted in the midbrain and by topical ocular application of muscarinic agonists. Pharmacologic disaccommodation was achieved by topical application of a muscarinic antagonist. Movements of the lens equator and the ciliary body were imaged during accommodation and disaccommodation using ultrasound biomicroscopy and goniovideography, and the images were analyzed to determine the direction and the extent of the movements. RESULTS Despite the systematic eye movements occurring with electrical stimulation and the nonsystematic eye movements occurring with pharmacologic stimulation, in all instances the ciliary body and the lens equator moved away from the sclera during accommodation. CONCLUSIONS Movement of the accommodative structures is consistent with the classic mechanism of accommodation described by Helmholtz, and contrary to that recently proposed by Schachar.

Changes in aqueous humor dynamics with age and glaucoma

Changes in aqueous humor dynamics with age and in glaucoma have been studied for several decades. More recently, techniques have been developed which confirm earlier studies showing that outflow facility decreases with age and in glaucoma and add the newer finding that uveoscleral outflow also decreases. Morphologic studies in aging and glaucoma eyes have shown an increase in accumulation of extracellular material in both the trabecular meshwork and ciliary muscle and a loss of trabecular meshwork cells, which contribute to this reduction in outflow and result in an increase in intraocular pressure. A reduction in hyaluronic acid and increases in fibronectin and thrombospondin contribute to the change in the extracellular environment. Imbalances in responses to age-related stresses such as oxidative damage to long-lived molecules, protein cross-linking and loss of elasticity could trigger excess production of factors such as transforming growth factor beta, interleukin-1 and CD44S that could stimulate pathways leading to increases in fibronectin, transformation of trabecular meshwork cells to a myoepithelial state and decrease the breakdown in extracellular matrix material, allowing excess to accumulate. Ultimately trabecular outflow and uveoscleral outflow are reduced and intraocular pressure becomes elevated, adding more stress and perpetuating the pathological condition. Future research to identify additional factors and clarify their roles in these processes could lead to alternative therapies for age and glaucoma related changes in the eye.

Accommodation and presbyopia in the human eye—aging of the anterior segment ☆

Ocular biometric parameters and accommodative amplitude were measured by various techniques in 100 normal emmetropic human subjects age 18-70 yr. Anterior chamber depth decreased and lens thickness increased linearly over the entire age group. Accommodative amplitude declined linearly until a stable nadir was reached at about age 50 yr. The respective slopes and intercepts of the age-dependent decline in anterior chamber depth were essentially the same for measurements made independently by optical pachmetry, A-scan ultrasonography, and slit-lamp Scheimpflug photography. The age-dependent increase in lens thickness differed in slope and intercept for measurements made by photography and ultrasonography if the generally accepted lenticular sound velocity was assumed for all subjects. However, if putative lenticular sound velocity was adjusted for age, the relationships given by the two techniques were essentially identical. Total anterior segment length (defined as the distance between the anterior corneal and posterior lens surfaces), vitreous cavity length (distance between the posterior lens and anterior retinal surfaces), and total globe length were all independent of age. This constellation of findings indicates that the human lens grows throughout adult life while the globe does not, that thickening of the lens completely accounts for shallowing of the anterior chamber with age, but that the posterior surface of the lens remains fixed in position relative to the cornea and retina.

Update on the Mechanism of Action of Topical Prostaglandins for Intraocular Pressure Reduction

A decade has passed since the first topical prostaglandin analog was prescribed to reduce intraocular pressure (IOP) for the treatment of glaucoma. Now four prostaglandin analogs are available for clinical use around the world and more are in development. The three most efficacious of these drugs are latanoprost, travoprost, and bimatoprost, and their effects on IOP and aqueous humor dynamics are similar. A consistent finding is a substantial increase in uveoscleral outflow and a less consistent finding is an increase in trabecular outflow facility. Aqueous flow appears to be slightly stimulated as well. Prostaglandin receptors and their associated mRNAs have been located in the trabecular meshwork, ciliary muscle, and sclera, providing evidence that endogenous prostaglandins have a functional role in aqueous humor drainage. Earlier evidence found that topical PG analogs release endogenous prostaglandins. One well-studied mechanism for the enhancement of outflow by prostaglandins is the regulation of matrix metalloproteinases and remodeling of extracellular matrix. Other proposed mechanisms include widening of the connective tissue-filled spaces and changes in the shape of cells. All of these mechanisms alter the permeability of tissues of the outflow pathways leading to changes in outflow resistance and/or outflow rates. This review summarizes recent (since 2000) animal and clinical studies of the effects of topical prostaglandin analogs on aqueous humor dynamics and recent cellular and molecular studies designed to clarify the outflow effects.

Effects of prostaglandins on the aqueous humor outflow pathways.

Topical treatments with certain prostaglandins (PGs), including FP receptor agonists, lower intraocular pressure by increasing uveoscleral outflow. Although the precise mechanism for the increased uveoscleral outflow is not known, there appears to be activation of a molecular transduction cascade and an increase in the biosynthesis of certain metalloproteinases. This leads to reduction of extracellular matrix components within the ciliary muscle, iris root, and sclera. It is possible that this reduction of extracellular matrix present within portions of the uveoscleral pathway may contribute to the mechanism of increased uveoscleral outflow. Additional mechanisms that may contribute to the PG-mediated increase of uveoscleral outflow include relaxation of the ciliary muscle, cell shape changes, cytoskeletal alteration, or compaction of the extracellular matrix within the tissues of the uveoscleral outflow pathway. Future studies should clarify the importance of these various responses that may contribute to increased uveoscleral outflow. At present, there is no compelling evidence for a substantial facility-increasing effect on the trabecular meshwork outflow for any of these compounds.

Aging of the human crystalline lens and anterior segment

Changes in the unaccommodated human crystalline lens were characterized as a function of subject age for 100 normal emmetropes over the age range 18-70 yr by Scheimpflug slit-lamp photography. With increasing age, the lens becomes thicker sagittally, but since the distance from the cornea to the posterior lens surface remains unchanged, this indicates that the center of lens mass moves anteriorly and the anterior chamber becomes shallower. Sagittal nuclear thickness is independent of age, but both anterior and posterior cortical thicknesses increase with age, shifting the location of the nucleus and the central sulcus in the anterior direction. The amount of light scattered by the lens at high angles, as represented by normalized and integrated lens densities from the digitized images, increases with increasing age in an exponential fashion. Similar relationships to age are observed for the major anterior zone of discontinuity (maximum density) and the central sulcus (minimum density). The relationships of these results to accommodation and presbyopia are discussed.

Effects of topical PGF2α on aqueous humor dynamics in cynomolgus monkeys

Single topical applications of prostaglandin F2 alpha (PGF2 alpha) tromethamine salt to living cynomolgus monkey eyes reduced intraocular pressure (IOP). Twice daily topical application was far more effective, so that after the 7th 50 micrograms or 100 micrograms dose on day 4, IOP fell 40-50%, to 8-10 mm Hg. Following twice daily application of 50 or 100 micrograms for greater than 3 days: (1) no increase in total outflow facility could be demonstrated by 2-level constant pressure perfusion or Schiotz tonography; (2) no decrease in aqueous humor formation rate could be demonstrated by fluorophotometry--rather, aqueous flow may have increased; (3) anterior chamber aqueous humor protein concentration was unaltered, but entry of intravenously injected fluorescein into the cornea and anterior chamber tended to increase; (4) there was a weak but sometimes statistically significant miosis of up to approximately 0.5 mm. We conclude that in the cynomolgus monkey: (1) PGF2 alpha is a potent ocular hypotensive agent with only very weak miotic and blood-aqueous barrier-disrupting effects; (2) the ocular hypotensive action of PGF2 alpha is definitely not due to increased conventional outflow facility or decreased aqueous production, but probably to increased uveoscleral drainage of aqueous humor.

Follow-up of Angle-closure Glaucoma Suspects

One hundred twenty-nine patients thought to be at risk for developing angle-closure glaucoma underwent a baseline examination, which included gonioscopy, refraction, anterior chamber pachymetry, ultrasound biometry, and an angle-closure provocative test. Patients were then followed up with no treatment. Mean follow-up was 2.7 years with a range up to six years. Twenty-five patients developed angle closure in at least one eye during the follow-up period, but in most (17 of the 25 patients), the angle closure was nonacute (that is, no clinical signs or symptoms and no increase in intraocular pressure). None of the test factors studied showed a high sensitivity or positive predictive accuracy in detecting the eyes that later developed angle closure.