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Symposium Autonomic Innervation and Microcirculation in the Eye - Implication for Glaucoma Pathophysiology

February 26-27, 1999 in Erlangen, Germany

Georg Michelson

Supported by Sonderforschungsbereich 539 "Glaukome, einschließlich PEX" of the "Deutsche Forschungsgemeinschaft" (DFG-German Research Foundation)

The purpose of the congress "Autonomic Innervation and Microcirculation of the Eye - Implications in Glaucoma Pathophysiology", held in the Department of Ophthalmology of the University Erlangen-Nürnberg at the 27^th january 1999 was to get an overview about the relationship between choroidal perfusion and glaucoma. The workshop addressed following points:

• Anatomy & pathophysiology of autonomic ocular innervation

• Comparative anatomy of autonomic ocular innervation

• Control of ocular microcirculation

• Animal models of ocular microcirculation control

• Implication for glaucoma and related diseases

Lütjen-Drecoll (Erlangen) spoke about the functional morphology of the primate choroid: "The vasculature of the primate choroid consists mainly of branches of the short ciliary arteries which in the suprachoroid run in parallel to the scleral surface and pass nearly perpendicularly through the choroid proper to supply the lobularly arranged choriocapillaris. The arteries are connected to an elastic network extending in the anterior-posterior direction between the ciliary muscle and the elastic fibers surrounding the optic nerve head and, in the radial direction between Bruch's membrane and the suprachoroid. An elaborated choroidal nerve fiber plexus innervates the choroidal vasculature. Within this plexus especially in the suprachoroidal layer numerous ganglion cells are found. Innervated smooth muscle cells connect the vessels with the elastic network. Numerous lymphatic-like spaces are present int he choroid proper surrounded by different kinds of mast cells and other kinds of free cells. Within the spaces Koganei-cells are found, which often are squeezing through the sclera into the orbit."

"The choroid of the human eye harbours up to 2000 intrinsic ganglion cells" explained Neuhuber (Erlangen) in his lecture about the comparative anatomy of choroidal gangloin cells. "Their targets, neuronal connectivity and transmitters are almost unexplored, as is their function. However, they probably play an important role in regulation of ocular perfusion and intraocular pressure. The aim of this study was to establish an animal model to investigate the functional anatomy of choroidal ganglion cells using experimental morphological techniques. Data obtained in this model species should provide a basis for further elucidation of the intrinsic innervation of the human choroid. Intrinsic choroidal neurons innervate, besides choroidal blood vessels, non-vascular smooth muscle, are mechanically coupled to non-vascular smooth muscle fibers, and receive synaptic input from sympathetic, trigeminal afferent and probably also other intrinsic neurons. Available data suggest close similarities to intrinsic neurons in the human choroid. Choroidal neurons may function as motor to vascular and non-vascular smooth muscle, mechanosensors and integrators of synaptic input from various sources. The duck eye may provide a valuable model for the study of the functional role of choroidal ganglion cells, and for getting insights in their possible involvement in glaucoma pathogenesis."

Fitzgerald from Staten Island, NY USA gave an overview about the muscarinic and nitrergic regulation of choroidal blood flow by the ciliary gangloin in birds. She told that "both cholinergic and nitrergic mechanisms have been implicated in parasympathetic control of blood flow. Choroidal vasodilation in response to CG activation in bird is likely to occur via M3-mediated cholinergic stimulation of endothelial NO formation. NO released by preganglionic endings on choroidal neurons also may contribute to the choroidal response to EW activation."

De Stefano (Roma) spoke about the lymphatic vessels in the avian chorid. She described the choroid in avians. "The avian choroid contains a large system of thin-walled lacunae similar in their fine structure to lymphatic vessels. While terminating blindly among the blood vessels of the choriocapillaris facing the Bruch's membrane, in the suprachoroidea the lymphatic capillaries merge to form larger lacuanae, extending toward the posterior portion of the bulb. Numerous small- and medium-sized lacunae aggregate in correspondence of the large vortex veins that leave the eye bulb, and small branches are seen entering the sclera and abutting the muscular wall of the large scleral veins. Characteristic cellular plugs protrude as villi in the veins' lumina and are penetrated by the small branches of the lymphatic lacunae, suggesting these structures represent sites of communication between lymphatics and scleral veins. Experiments showing engorgement of the lymphatic lacunae with blood cells after lowering the intraocular pressure (IOP) by paracentesis of the anterior eye chamber further support this hypothesis. Although lacking a muscular tunica, the thin endothelial lining of the large lacunae is often abutted by short appendages of stromal smooth muscle cells, which are richly innervated and may control the patency of the lymphatic vessels and contribute to pump the lymph into the scleral veins. We propose that lymphatic lacunae in the avian choroid represent a true lymphatic system involved in removing transretinal and local fluids, in draining part of the ciliary processes-born aqueous humor, and in controlling IOP. Moreover, thickening of the suprachoroidea during recovery from experimental myopia in chicks, a mechanism that moves the retina forward and compensates for the defocus, suggest a choroidal role in controlling normal and abnormal eye growth. Despite reports of the presence of lymphatic capillaries in monkey and human choroid, no such extensive system of lymphatic vessels occupying large part of the choroid and connecting to the scleral veins has been described, suggesting important differences in the functional involvement of the choroid in pathologies concerning ocular fluids imbalance as glaucoma."

The paper "angioarchitecture and innervation of the primate anterior episclera" by Selbach (Erlangen) investigates the episcleral vasculature and its innervation. He points out, that "branches of the anterior ciliary arteries form the episcleral arterial circle. Branches of these arteries anastomose with the episcleral veins. In the monkey episclera 4-6/mm2 arteriovenous anastomoses (AVA) are found, in the human episclera only 0,5-1/mm2. These AVA are characterized by a narrow arteriolar segment and by a wider funnel-shaped venous segment. Numerous nerve endings staining for NADPHd and TH are found at the arteries and veins as well as at the venules of the episcleral plexus. Besides, nerve fibers staining for NPY, VIP, VACHT, CGRP and SP are found at the arteries and, however less numerous, at the veins. This innervation pattern is very similar at the AVA. In the episclera anterior to the vascular circle numerous free nerve endings staining for SP and CGRP are found. The AVA between branches of the anterior ciliary arteries and the aqueous draining episcleral veins, the extended episcleral venous plexus and their dense innervation probably allow a subtle modulation of blood flow and presumably of aqueous humor outflow."

Kiel from the Health Science Center at San Antonio determined the mechanism(s) responsible for the choroidal blood flow response to acute changes in mean arterial pressure (MAP). He suggested that "the choroidal blood flow response to acute changes in MAP in the anesthetized rabbit is mediated in part by a neural vasodilator system and by a dynamic interaction between locally generated NO and endothelin. In the conscious state or under pathologic conditions, these mechanisms are likely modulated by additional local and neurohumoral mechanisms."

Wildsoet from the New England College of Optometry in Boston spoke about a choroidal focusing mechanism. She gave the talk by a Internet-connection from Boston. "The choroid is traditionally thought of as a vascular tissue subserving the needs of inner ocular tissues in relation to thermoregulation and nutrition. However, recent research has uncovered a novel role for the choroid, that of refractive modulation. The purpose of this presentation is to provide some insight into the processes underlying this choroidal focusing (accommodation) mechanism. Taken together, these data suggests that both vascular and nonvascular (muscular and/or osmotic) mechanisms may contribute to choroidal accommodation which plays an important role in emmetropization."

Einar Stefansson from Reykjavik, Iceland studied the oxygen tension of the optic nerve. He found that "carbonic anhydrase inhibition by dorzolamide and acetazolamide raises oxygen tension of the optic nerve and this effect was dose dependent. These data demonstrate a direct effect by carbonic anhydrase inhibitors on the oxygen tension of the optic nerve."

Longo (Catania) reported on the effect of dark exposure on choroidal blood flow in the foveal area. He found that "the transition from light to darkness decreases choroidal blood flow in the foveal region of the human fundus. This effect is the result of a neural or metabolic process rather than a change in local choroidal temperature."

Michelson G (Erlangen) described a new provocation test to diagnose vasospastic reactions in LTG patients. He pointed out, that "the optic nerve atrophy in Low Tension Glaucoma (LTG) may be caused by a disorder of the autonomic nervous system producing vasospastic reactions in ocular vessels. The detection of ocular vasospasm in patients with LTG may help for the diagnose of LTG and may support a rational therapy with Ca++-antagonists. It is nessesary to detect vasospastic reactions in ocular vessels during cold provocation. We found that patients with LTG showed in 46% a significant decrease in elasticity of the ophthalmic artery during cold provocation. The "Ocular Cold Pressor Test" may be a new tool in the diagnostic approach in patients with Low Tension Glaucoma."

Jonas (Erlangen) described the morphologic findings in chronic high-pressure experimental glaucoma in rhesus monkeys and their implications for ocular perfusion. He evaluated parapapillary chorioretinal atrophy in chronic high-pressure glaucoma in rhesus monkeys, and effects of age and atherosclerosis and chronic arterial hypertension, in a prospective, planned study. They found that "in experimental chronic high-pressure glaucoma in monkeys, beta zone of parapapillary atrophy is positively correlated with glaucomatous optic nerve damage. In chronic experimental high-pressure glaucoma, neuroretinal rim loss and increase of beta zone may be independent of pre-existing parapapillary atrophy. Increase of beta zone may be independent of concomitant atherosclerosis-arterial hypertension."

K.-G. Schmidt (Giessen) found a reduced peripapillary hemodynamics in normal tension glaucoma. The optic nerve head, the area of primary damage in the glaucomas, is directly supplied by the peripapillary choroid and the short posterior ciliary arteries (SPCAs). He evaluted for choroidal and SPCA hemodynamics in high tension, normal tension, primary open angle glaucoma patients, and healthy controls .They suggested that " reduced hemodynamics in the choroid and in SPCAs of NTG patients may contribute to progression of this optic neuropathy in this subgroup of patients with normal intraocular pressures."

The parapapillary atrophy in the chronic open-angle glaucomas and their relation to intraocular pressure was examined by Budde (Erlangen-Nürnberg). He evaluated whether parapapillary atrophy varies among chronic open-angle glaucomas with different intraocular pressure levels. He found that "beta zone of parapapillary atrophy varies by a factor of more than 3 to 1 between the various types of chronic primary and secondary open-angle glaucomas. With exception of the focal normal-pressure glaucoma, it is inversely related with the level of the intraocular pressure."

The congress "Autonomic Innervation and Microcirculation of the Eye - Implications in Glaucoma Pathophysiology" was live-broadcoasted via Internet by the electronic journal "Online Journal of Ophthalmology" (www.onjoph.com). The original sound of the lectures was digitized by 8000 Hz and coded with 14 bit. Using the free software "Real-Audio-Player" the user could hear the speech of the lecturer in radio quality. Two live-pictures from two digital video cameras and the digitized slides were available at the screen within two frames. The congress was followed by 899 online- participants . 238 of 899 participants were able to hear the original sound. The lectures of this congress with sound and pictures and the abstracts are now available under the address http://www.onjoph.com/global/livewrk1/Default.htm