Joel S. Schuman, MD, FACS; Rachel L. Anderson, MD; and David L. Epstein, MD, MMM
THE PROBLEM
The study of glaucoma can be both clinically satisfying and intellectually stimulating. Yet, it is also the most humbling of disciplines, not only because of our clinical failures but also because of our lack of real understanding. If one considers the evolution of ophthalmic knowledge over the last century, amid the multitude of new medications, surgeries, and sophisticated measurement techniques, the field of glaucoma has shown the least progress.
Why is this? Chronic glaucomas are, in general, slowly progressive diseases. The longitudinal nature of the disease creates substantial difficulty in achieving meaningful clinical insight. One of the major motivations for this book is the notion that long-term clinical observations can provide a basis for meaningful knowledge. This is the true Chandler-Grant tradition.
Those caring for glaucoma patients bear the curse of long-term follow-up. However, the perspectives that long periods of clinical observation provide are important both for practical patient care and as a template for accumulating new knowledge. Experienced clinicians have a great deal to contribute to our knowledge of glaucoma.
OUR METHODS
Historically, our methods of information gathering in glaucoma have been crude and provided inadequate information. The measurement of intraocular pressure (IOP) is an inaccurate metric that provides information about just one instant in time. Myriad factors may contribute to IOP variation in a given patient. We know there is both a diurnal and seasonal variation in IOP.1 Patients often only take their antiglaucoma medication just before coming to the ophthalmologist’s office. We assume that each IOP measurement is representative of the patient’s IOP for the entire time interval since the last visit, though this is often not true.
This variation in IOP contributes to our imprecise understanding about primary open-angle glaucoma (POAG). Many population survey studies have demonstrated that patients with POAG-related field loss do not have elevated IOP at the time of sampling.2–4 This has led to postulation, particularly in the international glaucoma community, that IOP is not the pathophysiologic cause of glaucomatous optic neuropathy, even though most studies have shown that the risk for field loss in POAG increases linearly with the level of IOP.5 Though many investigators have dedicated time and effort to investigating the hypotheses regarding alternative pathophysiologic explanations for glaucoma and its progression, the same individuals have contemporaneously proposed early filtration surgery, an intervention that is presumed to achieve its efficacy through IOP reduction. A population study that required IOP measurement at multiple visits provided insight into a possible mechanism.6 A proportion of patients with normal IOP at the time of initial evaluation demonstrated an elevated IOP at a subsequent visit. This finding underscores the fact that, while IOP measurements may be accurate for a single time point, we are unable to capture additional vital data points that occur between clinic visits. Extrapolating continuous or summative approaches to data measurement used in internal medicine, such as Holter monitor or glycosylated hemoglobin, if possible, might revolutionize our understanding of the interplay between IOP and glaucoma and its progression. On the other hand, attempts such as the contact lens strain gauge (Sensimed Triggerfish) and implantable IOP sensors have failed to provide the hoped for benefits of continuous IOP data collection.
Long-term clinical observations have consistently demonstrated that optic nerve susceptibility to damage at a given IOP value is variable from patient to patient. The methods of clinical analysis currently employed to measure and analyze this damage are crude. Descriptions of optic discs, cup-to-disc ratios, and disc drawings are notoriously inaccurate. The best advice one could give the novice ophthalmology resident is to make drawings of optic nerves on all glaucoma patients and later compare these to actual disc photographs and imaging. When possible, stereo disc photographs should be obtained for all glaucoma patients, especially as a baseline. Although artifacts are inevitable if a true stereo image is not captured, state-of-the-art cameras can capture high-quality images reliably.7 A photograph, even if nonstereo, provides a permanent means for assessing the morphology of an optic nerve at one point in time, though it is vital to note that the assessment of this type of image remains subjective and vulnerable to bias and human error. It is essential to include quantitative, objective imaging of the retina and optic nerve, such as with optical coherence tomography, in our assessment of ocular structure in the glaucoma patient. The degree and pattern of optic nerve damage at a point in time can be accurately and reproducibly measured via advanced imaging techniques.8–19
Reliable and reproducible detection of change in the gross appearance of the optic nerve by clinicians remains a challenge. Current technology enables more precise and objective methods of anatomic ocular assessment than the previous approaches of direct, meticulous comparison by an individual physician of 2 photographs at different points in time or comparison of the current clinical examination against a baseline photograph. Computerized technologies now enable more rigorous measurement of progression. Optical coherence tomography is a validated method of measuring progressive structural change in glaucoma; techniques such as confocal scanning laser ophthalmoscopy and scanning laser polarimetry have mostly gone by the wayside.18–23
What of visual fields? Although great strides have been made in the reproducibility of data with modern automated perimetry machines, visual fields remain subjective tests that depend on a patient action in response to a stimulus. An objective visual field would yield more accurate and sensitive data; however, electrophysiology for this purpose has been disappointing to date.
OUR BASIS OF UNDERSTANDING GLAUCOMA
What of glaucoma science? With the monumental progress in the understanding of diseases on a cellular and molecular level in mind, it is humbling to see how little true progress has been made in understanding glaucoma in the past few decades. Investigators struggle to form a consensus on which questions warrant study. There are many problems to be addressed by this small scientific field, which is fragmented both as to the anatomic areas of study (eg, trabecular meshwork [TM], ciliary body, optic nerve) and which hypotheses to test. The tissues involved are difficult to manipulate and assess because of their size and complexity. Animal models of the disease imperfectly reproduce human glaucoma. The competing, though valid, concepts of glaucoma as a disease of high IOP or as a primary optic neuropathy have added to the confusion.
A Concept
Given our current level of understanding, the chronic glaucomas may be defined as follows.
- In almost all cases, an abnormality in drainage of aqueous humor through the outflow pathway tissue, potentially at sites in the TM, leads to elevation of IOP and causes damage to the optic nerve end organ, which demonstrates varying susceptibility to different levels of IOP (including statistically normal IOP).
- The main scientific questions are as follows:
- In the open-angle glaucomas, what is the cause of obstruction to trabecular outflow, and how can this trabecular glaucoma be best treated?
- What is the cause of the optic nerve damage, particularly given the variation in susceptibility at a given IOP, and are there any specific mechanisms for preventing progression of this optic neuropathy beyond consistently lowering the IOP?
- In the open-angle glaucomas, what is the cause of obstruction to trabecular outflow, and how can this trabecular glaucoma be best treated?
Both of these questions are important. These schools of scientific inquiry should be complementary rather than competitive.
Clinical Implications of These Basic Concepts
For the student of glaucoma, framing these concepts is not only an academic exercise but also has clinical relevance. Students should strive to understand why IOP is elevated (why there is the obstruction to outflow), especially on comparative examinations, and why the optic nerve cupping is occurring at a specific IOP.
Elevated IOP is likely due to impaired drainage through the TM and is probably never due to abnormally high aqueous humor formation. During gonioscopy, the diseased tissue involved in the hydrodynamic component of glaucoma is visible. With a greater understanding of the nature of the abnormality in this tissue, advancement in diagnosis and treatment may be possible. For many patients with POAG, the angle may appear normal on clinical exam. A careful exam may provide unexpected insight. Are there occult inflammatory precipitates? Exfoliation material? Abnormal vessels? Partial angle closure? When a patient with open-angle glaucoma returns for follow-up and IOP is increased from the last visit, a thorough gonioscopic exam is warranted to search for a discrete, structural process that may be contributing to this change.
This tissue-oriented approach may also aid in understanding certain clinical phenomena. For example, the term steroid responder refers to a steroid-induced decrease in facility of aqueous humor drainage by the TM. Presence of such a response may portend latent POAG. In patients with acute uveitides, IOP elevation following initiation of a steroid regimen is likely secondary to the restoration of aqueous humor production via suppression of ciliary body inflammation rather than a steroid-induced decrease in TM function. From a clinical point of view, such patients should not be labeled as steroid responders. In fact, steroid discontinuation may not be warranted, and continued steroid therapy may actually improve any impairment in TM function caused by inflammation.
IOP alone is insufficient to explain the optic neuropathy of glaucoma. Which factors contribute to this varying susceptibility? Are they local or systemic? Could systemic medications increase the susceptibility of the optic nerve to glaucomatous cupping? When looking at the optic nerve of a patient who is progressing despite a generally tolerated IOP, step back, look at the whole patient, and consider whether there are any systemic or other local influences. At the present time, we do not have such understanding, but new connections are likely to stem from clinical observation by discerning ophthalmologists.
This possibility is what makes clinical glaucoma exciting and satisfying. It is a real clinical disease for which clinicians can make meaningful observations that, even in this high-tech era, can add value and spark new hypotheses for future investigation, both in the clinic and in the laboratory. Glaucoma doctors can be both clinicians and scientists, ultimately making a meaningful impact for patients with this chronic, progressive, and often devastating disease.
Glaucoma is a wonderful field for the young ophthalmologist. It is both an intellectual and a practical clinical challenge. We have gained much new knowledge and expect a great deal more in coming years. The new talent and evolving science will finally bring new methods of cellular and molecular inquiry to the discipline.
In some ways, the glaucoma field today is in both the worst and best of times.
GOAL OF THIS BOOK
The goal of this book is to provide practical clinical information about the management of all patients with glaucoma. We have tried to frame the current understanding in such a way as to stimulate the reader and the editors to ask the question, Why is this glaucoma occurring in this patient, and how might I be able to treat this better?
REFERENCES
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