In Memorium

Robert N Shaffer, MD

1912–2007

One of the world’s great physicians and glaucomatologists died on July 13, 2007. Robert N Shaffer, born in Meadville, PA in 1912, became one of the last century’s leading glaucoma experts, clinicians, teachers and researchers. After receiving his medical degree and residency in ophthalmology from Stanford University School of Medicine while it was still in San Francisco, he established a practice in San Francisco which ultimately evolved into a center for excellence in patient care. He dedicated his career to the understanding and managing of the glaucomas. His keen powers of observation led to many clinical gems that are still in use today, including the Van Herrick-Shaffer slit lamp estimation of angle depth and the Shaffer classification of gonioscopic angle appearance. One of his proudest creations was the fellowship in his office that gave highly personal training to many of the next generation of glaucoma specialists from around the world: over 40 world leaders in glaucoma served as fellows in his office.

He was a prolific writer. In addition to his dozens of peerreviewed articles in ophthalmic journals, he, together with Dr Bernard Becker, one of the other giants of glaucoma teaching and research of the last century, began what was to become one of the definitive textbooks on glaucoma – The Diagnosis and Therapy of the Glaucomas.This textbook, now named Becker-Shaffer’s Diagnosis and Therapy of the Glaucomas, is currently in its eighth edition. He also served on the American Board of Ophthalmology, becoming its chairman and ultimately its executive vice-president.

Together with his partners, Drs John Hetherington and Dunbar Hoskins, he founded the Glaucoma Research Foundation which is dedicated to glaucoma research and education. Its mission is to find a cure for glaucoma and toward that end it has funded many promising pilot research projects.

Bob was a consummate teacher. In addition to his fellows, he trained residents at the University of California San Francisco where he was on the clinical faculty for over thirty years. They rotated through his office, seeing first hand his very personal brand of care as well as his clinical and surgical approaches to glaucoma. He lectured around the USA and the world, always presenting his material in an unsensational, fair, and illuminative fashion. His childhood sweetheart and wife,Virginia Shaffer, truly a life partner in so many of his activities, had a hand in making his lectures so enjoyable and educational, as she was herself an expert in public speaking and helped educate many of his fellows and residents in that skill.

One of his most memorable characteristics was his courtly, quiet and unfailingly unflappable (except on the tennis court) manner. He was truly a gentleman in all the very best meanings of the term. Those of us who were privileged to know him were enriched by his presence. He and his style of patient-centered care, bedside teaching and diplomacy will be sorely missed.

Definitions

The concepts and definitions of glaucoma have evolved in the past 100 years,1 and still they remain imprecise and subject to technical qualifications. The word glaucoma originally meant ‘clouded’ in Greek; as such, it may have referred either to a mature cataract or to corneal edema that might result from chronic elevated pressure. Today the term does not refer to a single disease entity, but rather to a group of diseases that differ in their clinical presentation, pathophysiology, and treatment.These diseases are grouped together because they share certain features, including cupping and atrophy of the optic nerve head, which has attendant visual field loss and is frequently related to the level of intraocular pressure (IOP).

In this text, glaucoma is defined as a disturbance of the structural or functional integrity of the optic nerve that can usually be arrested or diminished by adequate lowering of IOP. An important distinction must be noted in the criteria currently used to define primary open-angle glaucoma (POAG), in contrast to all other forms of glaucoma. Primary open-angle glaucoma is explicitly characterized as a multifactorial optic neuropathy with ‘a characteristic acquired atrophy of the optic nerve and loss of retinal ganglion cells and their axons’2 developing in the presence of open anterior chamber angles, and manifesting characteristic visual field abnormalities. In contrast, all other types of glaucoma – invariably the secondary glaucomas, and historically even the primary angleclosure glaucomas2b – are defined first and foremost by the presence of elevated IOP, and not in reference to the optic neuropathy that follows sustained elevated IOPs.

Classically the primary glaucomas are not associated with known ocular or systemic disorders that account for the increased resistance to aqueous outflow; the primary diseases are usually bilateral and probably reflect genetic predispositions.3 Conversely, the secondary glaucomas are associated with ocular or systemic abnormalities responsible for elevated IOP; these diseases are often unilateral and acquired. Some have argued that the distinctions between ‘primary’ and ‘secondary’ simply reflect our imperfect understanding of pathophysiologic events that converge in the common final pathway of optic atrophy and visual field loss.4 Although many risk factors have been associated with the development of POAG (Table 1-1), elevated IOP remains the most prominent factor – shared among the primary and secondary glaucomas – and the only factor contemporary ophthalmic intervention can reliably affect.

Intraocular pressure is determined by the balance between the rate of aqueous humor production of the ciliary body, the resistance to aqueous outflow at the angle of the anterior chamber, and the level of episcleral venous pressure (Fig. 1-1). Elevated IOP is

usually caused by increased resistance to aqueous humor outflow. The optic nerve and visual field changes of glaucoma are determined by the resistance to damage of the optic nerve axons.

In most cases of glaucoma, progressive changes in the visual field and optic nerve are related to increased IOP; in some instances even ‘normal’ levels of IOP are too high for proper functioning of the optic nerve axons. (The concept of ‘normal’ must take into account both the range of IOPs for different ethnic groups as well as the correction factors for applanation tonometric measurements in the presence of thicker or thinner central corneal thicknesses.)5,20 Although there is no absolutely ‘safe’ pressure that guarantees to prevent progression of POAG,21 lowering IOP to

the low-normal range usually arrests or slows the progress of glau- coma.22–26 If the glaucoma continues to progress, it is postulated

that either (1) the IOP is not low enough or sufficiently free of fluctuations to stabilize the disease; or (2) the optic nerve and/or ganglion cells are so damaged that the cascade of deterioration persists, independently of IOP levels.

Epidemiologic and socioeconomic aspects of the glaucomas

Whether manifesting as POAG, primary angle-closure, or congenital disease, glaucoma is the second leading cause of blind-

ness worldwide, with a disproportional morbidity among women and Asians.27–30 Globally, POAG affects more people than angle-

closure glaucoma (ACG) – with an approximate ratio of 3:1, and wide variations among populations.29 Yet ACG manifests in a much more aggressive and debilitating course (especially among Asians) than was recognized a generation ago: its treatment usually requires more than iridotomy alone, frequent medical or surgical intervention31; and yet nevertheless ACG often leads to an appalling amount of morbidity (e.g., ACG accounts for less than

half of all glaucoma cases in China, but over 90% of its glaucoma blindness).32–36

In the United States, glaucoma of all types is the second leading cause of legal blindness, often despite the availability of excellent long-term management.37 Among white and black populations in

the US, POAG accounts for nearly two-thirds of all reported glaucoma cases.38–40 It is estimated that 2.25 million people in the US over the age of 40 years have POAG,41,42 half of whom are unaware

of their disease despite demonstrable visual field loss.43–45 Another 10 million Americans are estimated to have IOPs greater than 21, or other risk factors for developing the disease: approximately 10% of these eyes will convert to POAG over the course of a decade.46

The relationship between IOP and glaucomatous optic neuropathy is complex. On the one hand, the higher the IOP, the higher the risk of POAG; conversely, 1 out of 6 eyes with POAG never demonstrates IOP higher than the age-appropriate normal range.47,48

The complexity of the multiple parameters and variables converging in ‘glaucoma’ diagnosis and prognosis has led to a recent wealth of rigorously derived epidemiological data embracing the spectrum of early and advanced disease. Many of these studies are

known by their acronyms and address a wide range of risk factors, with a focus on clinical applicability.49–53 Although these

large, controlled studies were conducted in Western countries, their findings are directly applicable to addressing the management of glaucoma in the developing world as well.54

In brief: both the Ocular Hypertension Treatment Study (OHTS) and the Early Manifest Glaucoma Trial (EMGT) addressed the value in early detection and treatment of POAG. The OHTS study refined the parameters of predictive risk factors such as cen-

tral corneal thickness, age, and life expectancy for elaboration of treatment decisions.55–57 The EMGT study unequivocally demon-

strated that early treatment delayed disease progression, in contrast

to an untreated control population; and that disease progression correlated with the higher the presenting IOP.58,59

The effects and parameters of various interventions in eyes with established glaucomatous damage were addressed by the Collaborative Initial Glaucoma Treatment Study (CIGTS), the Advanced Glaucoma Intervention Study (AGIS), and the Collaborative Normal Tension Glaucoma Study (CNTGS). The CIGTS demonstrated that substantial IOP reductions (40–48% with medications or surgery, respectively) preserved visual function in most patients.60 The AGIS reports demonstrated the efficacy both of reduced IOP fluctuation and of subnormal IOPs (below

14 mmHg post-operatively, and reliably under 18 mmHg during 6 years’ follow-up) in stabilizing advanced visual field loss.60b,60c

Similarly the CNTGS, in randomizing ‘low-tension glaucoma’ patients with advanced field loss to aggressive treatment or not, found that a 30% IOP reduction stabilized most visual fields, although post-surgical cataract vision loss was frequent.61,62

Though the applicability of each particular study is discussed in greater detail in later chapters, it is worthwhile to discuss how our understanding of risk is evolving.

Risk factors

A brief review of epidemiological distinctions is required to help the clinician contextualize the bewildering array of well-designed

studies continuously appearing in the ophthalmic literature.63–67 A few basic clarifications are useful to bear in mind68,69:

1.  Causation is neither always linear nor applicable to individuals;‘risk factors’ are not synonymous with ‘causes’ of disease.

2.  Pathways of risk have multiple branches, sometimes converging or diverging: e.g., gender and ethnicity are static variables; IOP and blood pressure are dynamic variables (which may be either interactive or independent); different disease stages, whether early or advanced, may respond variably; and statistical strength of association may be more relevant to populations than to individuals.

3.  Some risk categories are an aggregate of unspecified variables. For example,‘age’ is frequently a surrogate for all time factors: aging of tissues; time of exposure to other risk factors; duration of disease; and it is variously presented as time since diagnosis, or length of

follow-up, or age of onset. Similarly ‘family history’ may reflect complex information about ethnicity, or multiple inherited factors which may or may not be independent: optic disc parameters; IOP levels; central corneal thickness; personal habits and attitudes towards disease risks and treatment; refractive errors; gene mutations, etc.

tics. Hypertension, for example, is not associated with developing glaucoma in young patients, but it is with older hypertensives (specifically as disordered diastolic perfusion pressure)6; and yet in established glaucoma, systemic hypertension is not a risk for disease progression. Currently there is great interest in elaborating ‘global

risk assessments’ for identifying ocular hypertensive patients converting into POAG.70,71,71b Of enormous public health import for pre-

dicting progression is determining those factors contributing not to the conversion into glaucoma, but which lead to blindness; such factors include advanced field loss at the time of presentation, African ethnicity, and clinical non-compliance. Less well studied are risk factors for therapeutic responsiveness, such as thicker corneas, male gender, and lower socioeconomic status.Table 1.1 lists those factors that have demonstrated, to a greater or lesser extent, statistical correlation with either the development or the progression of POAG.

In contrast to the precision inherent in the exploding field of ophthalmic genetics,72,73 there is considerable controversy and confusion about the heritable parameters of ‘ethnicity’ and ‘race,’ technically being devoid of distinctive genetic substrates.7,74 Besides the value of these categories as markers for patterns of risk or effect in larger populations, from which hopefully more precise mechanisms will one day be elucidated, they also highlight the importance of individualizing the care of each patient, sensitively attending to the impact of heredity and of culture for the specific patient at hand.

Yet much of the epidemiological literature of the past several decades deals explicitly with the categories of race and ethnic background, characterized by comprehensive population-based

studies with rigorous criteria for pressure measurements, angle evaluation, and disc and visual field assessment.8–10,75,76 These studies

consistently report a prevalence rate for POAG in 1–2% of white adults. However, significant racial differences exist. Among blacks, the prevalence is nearly 4 times higher.43 These patients are twice

as likely to be blind as their white counterparts, and they have the disease nearly 27% longer.39,77 These facts reflect neither the sup-

ply of ophthalmologists nor the patient’s personal income.78 Even

higher rates have been reported among some Caribbean populations,11,79,80 although there are lower and more variable prevalence

rates among the genetically heterogeneous African populations from whom these New World populations descended.81

With the basic medical resources available in the developed world,48 the ‘holy grail’ for clinicians is that all cases of blindness from glaucoma are preventable if the disease is detected early and proper treatment is implemented. Detection depends on education – educating the public about the importance of routine examinations, and training fellow health professionals to recognize the signs and symptoms of glaucoma. Screening strategies that rely only on IOP measures and that neglect disc and visual field assessment are inadequate82; and even when full testing is performed, it may not be cost-effective.83 Pending the widespread appearance of expanded and effective public health interventions, the individual clinician can be enormously successful in detecting undiagnosed glaucoma, simply by facilitating the ophthalmological examination of close relatives of existing glaucoma patients – especially siblings and older immediate family members.84,85