In the preceding chapters, we have tried to summarize the important information known about glaucoma, its classification, diagnosis, and management. It should be readily apparent to the thinking reader that there are many holes in our knowledge and understanding of this disease. No longer can we just say: ‘Glaucoma is elevated intraocular pressure and if you bring the pressure into the ‘normal’ range, the patient will retain vision.’ Clearly, the glaucomas are optic neuropathies whose etiologies and pathophysiologies are still eluding us and represent a much more complex group of diseases than they have been given credit for in the past.
The decade since the last edition has seen some significant advances in pharmacologic and surgical management. Our understanding of the pathophysiology of plateau iris, pigmentary glaucoma, mechanisms of cell death, the genetics of juvenile glaucoma, epidemiology, the risk factors that presage future glaucoma in ocular hypertensives, and the efficacy of intraocular pressure lowering in preventing progression of the disease has been improved.
What follows is a wish list for the new millennium. Interestingly enough, despite some significant advances in our knowledge, the list does not differ terribly much from the one in the previous edition. So we may have come a long way but we still have a long way to go.
It has been thought that in most cases of primary open-angle glaucoma (POAG), the primary site of outflow obstruction resides in the juxtacanalicular region of Schlemm’s canal. Work in the last two decades suggests that this obstruction is related to a change in the extracellular ground substance, perhaps associated with increased glycosaminoglycan moieties. Recent evidence points to mutations in the myocilin (TIGR) gene as driving changes similar to those seen in POAG. Yet a myocilin mutation is only present in a very small percent of patients with POAG. Does this mean that there are mutations in other genes that need to come into play, or some combination of environmental and genetic factors? The number of genetic mutations associated with glaucoma grows but our understanding of how these mutations cause glaucoma has not. We need to identify the triggers and environmental factors that allow the genetic predispositions to be actualized. Once we do that, then lifestyle modification may have some effectiveness in the prevention and treatment of glaucoma.
The loss of vision in glaucoma is due to death of ganglion cells, but our understanding of the mechanism(s) by which ganglion cells die is rudimentary. Most of what we know is inferred from empirical clinical observations. We still don’t know exactly how the axons of the ganglion cells are injured or die in glaucoma, or what the triggers are or even if only one mechanism is involved, multiple mechanisms each working singly in different individuals, or different combinations in the same individual. Decreased optic nerve blood flow, mechanical deformation with blockage of axoplasmic transport, excitotoxicity from agents such as glutamate, autoimmune phenomena and apoptosis (programmed cell death) have all been indicted alone or in combination. As we learn more about each of these processes and develop the technology to measure and monitor them, we will probably find that all play some role – and to different degrees in different types of glaucoma and in different patients. Further studies in experimental models such as the lasered rat and mouse eyes, subhuman primate eyes and ‘knockout’ genetically altered small animals should better define the pathophysiological cascade that leads to ganglion cell death.
We are on the threshold of being able to assess blood flow to the optic nerve in humans. Although these tests are still primitive and only give us indirect measures of blood flow or direct measures of unkown circulations, new testing procedures should give us more and better insight into the role of blood flow in glaucomatous optic nerve damage. Further research should determine which of the noxious agents, ischemia, or axoplasmic blockage (or, again, some combination) serves as the trigger for apoptosis.
Of equally important promise in our comprehension of the dynamics of glaucomatous damage is the development of new technologies for measuring IOP in clinical and research settings. A revolutionary device would be a 24-hour IOP monitor with good ocular tolerability and capacity to assess weeks’ worth of momentary fluctuations, a phenomenon we can only crudely assess with our current technology. Such information could distinguish rates of disease progression, pharmacokinetics, and the precise effects of different glaucoma procedures on IOP control. Another technology of great value would be one that could sample the retro-bulbar pressures of the orbit, sub-arachnoid space, and CSF compartments. The centrality of the laminar cribrosa region in the pathogenesis of glaucomatous disease (see Chapter 12 ) makes the understanding of trans-laminar pressure gradients a compelling new line of research.
The pathophysiologic mechanisms of many of the secondary glaucomas remain elusive. What causes exfoliative syndrome? Why is it manifest in only one eye or quite asymmetrically even when we know from postmortem studies that it is a bilateral (and systemic) disease? Why do only some people with exfoliative syndrome develop glaucoma? What causes iridocorneal endothelial syndrome? Is it a virus, or some other infectious agent? That might explain why this type of glaucoma is so overwhelmingly unilateral. What about pigmentary glaucoma? If the elegant hydrodynamic hypothesis of ‘reverse pupillary block’ is operating, why doesn’t iridotomy seem to reverse the process? Do we treat too late? If so, how do we identify the relatively small percentage of people with pigmentary dispersion who will go on to actually develop glaucoma so we can prophylactically treat them in the early stages?