33. Pharmacologis Vitreodynamics:
What Is It? – Why Is It Important?
Michael T. Trese (Royal Oak)
It is no secret that those who spend their time dealing with retinal and inherited diseases today
spend a great deal of time injecting drugs and genetic vectors into the vitreous cavity. These diseases
are seen as causing changes in the choroidal and retinal circulation manipulated in part by ischemia,
inflammation, and genetics, but it may be that these diseases and the usefulness of treatments are
affected by the vitreous composition and attachments.
Vitreoretinal surgeons have thought of retinal disease for decades as relating to vitreoretinal traction.
Vitreous surgery has been done to eliminate traction as much as possible to the resolution of
the operating microscope or indirect ophthalmoscope. This relief of traction has lead to variable surgical
results. This variability of results is often thought to be due to residual traction due to incomplete
relief of traction or vitreous schisis.
For many years, several authors have been proposing substances, enzymatic and non-enzymatic, to cleave the vitreoretinal juncture
or liquefy the central vitreous as an adjunct to vitreoretinal surgery or as a method to resolve vitreous traction or clear vitreous
opacity, such as vitreous hemorrhage, in a more rapid fashion. Plasmin and microplasmin have been shown to achieve both of
those goals without damage to the retina. (1,2,3,4,5) These substances can eliminate vitreoschisis and lead to a clean ILM as shown
in many animal studies and one human study. (6,7) This concept of lysing the vitreoretinal juncture and core vitreous has been
described as pharmacologic vitreolysis and describes in part the action of these agents. (8)
Vitreous surgery reduces vitreoretinal traction and actually removes at least the core vitreous and perhaps disrupts the anterior
hyaloid with the entry of surgical instruments. Vitreous surgery can also result in other lasting effects, such as altering ischemia
causing regression or quieting of retinopathy such as diabetic, and other neovascular processes such as can be seen in venous
occlusive disease. At first the effects were thought to be due to reduced traction, but now we know that vitreous surgery alters at
least oxygen concentration in the vitreous cavity and thus may reduce the VEGF drive and lead to lasting improvement of ischemia
driven retinal vascular disease. (9) We also have learned that increasing the vitreous cavity oxygen in adults can lead to advancing
nuclear sclerotic cataract and perhaps late glaucoma. (10)
As is now well known, ischemia is a major factor in elevating VEGF and today many VEGF driven diseases are treated with intravitreal
delivery of anti-VEGF-A drugs. These anti-VEGF-A drugs are most commonly given as every 4-6 week intravitreal injections.
Industry is working on the development of a variety of sustained release devices to bring anti-VEGF drug and other drugs to the
vitreous cavity without the time issue of frequent injections.
All Vitreous Cavities are not the Same
All vitreous cavities are not the same. Some have more liquefaction, some have less. The posterior hyaloid may or may not be
detached and the thickness and adherence of this posterior hyaloid may vary from location to location within an eye.
To date drug injection studies into the vitreous cavity have considered all vitreous cavities to be equal. Recently however, it has been
shown that oxygen flow across the vitreoretinal interface into the vitreous cavity and out of the vitreous cavity can be altered by
pharmacologic creation of PVD by microplasmin, which creates a PVD and liquefies the vitreous (11). This effect is not seen with
only liquefaction of the vitreous cavity. This change in oxygen molecular flux may be seen as a marker for behavior of other molecules
in the extracellular matrix of the vitreous cavity, particularly the vitreous cortex. In addition, variability in drug response may
in part be due to vitreous composition. Drug molecules may remain or leave the vitreous cavity reservoir more quickly or slowly
depending on vitreous cavity composition. It may even be that mild levels of vitreous traction or vitreous cortex remnants overlying
the maculae may lead to low levels of inflammation or local ischemia and that triggers a VEGF response that can lead to macular
edema or neovascularization of the retina and choroid. In no drug study of which I am aware has the vitreoretinal interface been
considered in the equation for efficacy and yet oxygen flow seems to be affected by the presence or absence of a complete PVD.
Could it be that larger molecules are even more affected by this clear collagen barrier?
As our profession of management of vitreoretinal disease has evolved, we have gone from gross observation to light microscopy to
transmission and scanning electron microscopy to molecular observation. Now we may be beginning to appreciate interactivity
between mechanical and biochemical changes in the vitreous cavity. These changes may be important in regard to retinal and
choroidal disease, lens clarity, development of glaucomlate, and efficacy of pharmacologic agents. It may be that understanding
and management of the vitreous cavity anatomy and biochemistry will become as important in adult vitreoretinal disease as it is in
inherited vitreoretinal dystrophies and pediatric retinal vascular disease.
As we understand more of the molecular flux in the vitreous cavity as it is determined by molecular weight and molecular charge,
molecular flux may also be manipulated by alteration of vitreous collagen. As we learn more of the pharmacological vitreodynamics
encompassing both the mechanical and biochemical changes in the vitreous cavity, I believe we will be able to better tailor
treatments for a variety of vitreoretinal diseases.
References
1. Trese MT, Williams GA, Hartzer MK. A new approach to stage 3 macular holes. Ophthalmology 2000; 107:1607-1611.
2. Margherio AR, Margherio RR, Hartzer M, Trese MT, Williams GA, Ferrone PJ. Plasmin enzyme-assisted vitrectomy in traumatic pediatric macular
holes. Ophthalmology 1998; 105:1617-1620.
3. Williams JG, Trese MT, Williams GA, Hartzer M. Autologous plasmin enzyme in the surgical management of diabetic retinopathy.
Ophthalmology 2001; 108:1902-1905.
4. Gandorfer A, Rohlender M, Sethi C et al. Posterior vitreous detachment induced by microplasmin.Invest Opthalmol Vis Sci 2004, 45:641-7
5. Kuppermann BD, Thomas EL, de Smet MD, Grillone LR: Vitrase for Vitreous Hemorrhage Study Groups. Pooled efficacy results from two multinational
randomized controlled clinical trials of a single intravitreous injection of highly purified ovine hyaluronidase (Vitrase) for the management
of vitreous hemorrhage. Am J Ophthalmol 2005; 140(4):573-84.
6. Verstraeten TC, Chapman C, Hartzer M, Winkler BS, Trese MT, Williams GA. Pharmacologic Induction of posterior vitreous detachment in the
rabbit. Arch Ophthalmol 111:849-854, 1993.
7. Asami T, Terasaki H, Kachi S, Nakamura M, Yamamura K, Nabeshima T, Miyake Y. Ultrastructure of internal limiting membrane removed during
plasmin-assisted vitrectomy from eyes with diabetic macular edema.
8. Sebag J. Pharmacologic vitreolysis. Retina 1998; 18(1):1-3 Review.
9. Stefansson E, Landers MB How does vitrectomy affect diabetic macular edema? Am J Ophthalmol. 2006, 141:984
10. Chang S. LXII Edward Jackson Lecture: Open Angle Glaucoma After Vitrectomy. Am J Ophthalmol 2006; 141(6):1033-1043.
11. Quiram PA, Leverenz V, Baker R, Dang L, Trese MT, Giblin FJ. Enzymatic manipulation of the vitreous cavity by microplasmin affects vitreous oxygen
levels in animal models. (Abstract 1486) Presented at the 2006 Annual Meeting of Association for Research in Vision and Ophthalmology.