DEFINITIONS
The concepts and definitions of glaucoma have evolved in the past 100 years, 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’ 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 angle-closure glaucomas – 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. 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. 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.
| Factor | Quality of evidence | Remarks |
|---|---|---|
| Ocular risk factors | ||
| Intraocular pressure | Excellent | Most important |
| Thinner central corneal thickness | Excellent | Related to IOP and to optic nerve? |
| Myopia | Excellent | Related to IOP and to optic nerve? |
| Disc hemorrhage | Good | Prognostically important |
| Increased cup/disc ratio | Equivocal | May represent early POAG |
| Asymmetric cupping | Equivocal | May represent early POAG |
| Non-ocular risk factors | ||
| Age | Excellent | Causal mechanisms unknown |
| Race (e.g. African or Hispanic descent) | Excellent | Causal mechanisms unknown |
| Family history | Excellent | Multifactorial genetic factors |
| Adult onset diabetes | Equivocal | Elevated IOPs, but ‘protective’ of ganglion cells? |
| Diastolic perfusion pressure | Excellent | Biologically plausible |
| Migraine and peripheral vasospasm | Equivocal | More relevant in ‘low-tension’ disease? |
| Gender | Inadequate | Contradictory reports |
| Alcohol consumption | Inadequate | Requires confirmation |
| Cigarette smoking | Inadequate | Requires confirmation |
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.) Although there is no absolutely ‘safe’ pressure that guarantees to prevent progression of POAG, lowering IOP to the low-normal range usually arrests or slows the progress of glaucoma. 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 blindness worldwide, with a disproportional morbidity among women and Asians. Globally, POAG affects more people than angle-closure glaucoma (ACG) – with an approximate ratio of 3:1, and wide variations among populations. 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 intervention ; 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).
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. Among white and black populations in the US, POAG accounts for nearly two-thirds of all reported glaucoma cases. It is estimated that 2.25 million people in the US over the age of 40 years have POAG, half of whom are unaware of their disease despite demonstrable visual field loss. 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. 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.
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. 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.
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 central corneal thickness, age, and life expectancy for elaboration of treatment decisions. The EMGT study unequivocally demonstrated that early treatment delayed disease progression, in contrast to an untreated control population; and that disease progression correlated with the higher the presenting IOP.
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. 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.
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. A few basic clarifications are useful to bear in mind :
- 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 stage s, 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.
- 4.
Risk factors for disease incidence are not necessarily the same as those for disease progression, nor for response to therapeutics . Hypertension, for example, is not associated with developing glaucoma in young patients, but it is with older hypertensives (specifically as disordered diastolic perfusion pressure) ; 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. Of enormous public health import for predicting 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, there is considerable controversy and confusion about the heritable parameters of ‘ethnicity’ and ‘race,’ technically being devoid of distinctive genetic substrates. 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. 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. These patients are twice as likely to be blind as their white counterparts, and they have the disease nearly 27% longer. These facts reflect neither the supply of ophthalmologists nor the patient’s personal income. Even higher rates have been reported among some Caribbean populations, although there are lower and more variable prevalence rates among the genetically heterogeneous African populations from whom these New World populations descended.
With the basic medical resources available in the developed world, 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 inadequate ; and even when full testing is performed, it may not be cost-effective. 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.
CLASSIFICATION OF THE GLAUCOMAS
The most widely used classification system of the glaucomas separates angle-closure glaucoma from open-angle glaucoma. This fundamental distinction still holds, but with altered emphasis regarding the former condition. Historically, angle-closure disease has been variably defined in terms of pupillary block mechanisms (e.g., ‘miotic induced’), presenting signs and symptoms (e.g., ‘congestive’), or the presumptive time-course of the condition (e.g., ‘subacute’). The most contemporary approach continues to emphasize the final pathogenic pathway mechanism of irido-trabecular obstruction that results in functional angle closure. But abetted by technologies that allow direct visualization of angle, lens, and anterior ciliary body structures, the current classification is an amalgam of both a natural history scheme that emphasizes progressive stages of disease, and a mechanistic scheme focusing on discrete sites of dysfunction in the anterior segment ( Fig. 1-2 ).
In open-angle glaucoma, there is relative impairment of flow of aqueous humor through the trabecular meshwork–Schlemm’s canal–venous system; yet on gonioscopy the angle appears to be open ( Fig. 1-3 ). But amidst all the details of classification, one must never lose sight of the ultimate final pathway in all glaucoma as manifest optic nerve damage and ganglion cell demise.
This basic classification scheme continues to be helpful because it clarifies pathogenetic mechanisms and therapeutic approaches. We propose to simplify glaucoma classification into three major divisions, which are subdivided into primary and secondary categories: (1) angle-closure glaucoma; (2) open-angle glaucoma; and (3) developmental glaucoma, in which some anomaly of the anterior segment manifests in the first years of life. The category of ‘combined-mechanism glaucoma’ historically referred to either sequential or coincidental presentations of entities from these three basic categories, and usually involved angle-closure mechanisms; hence we relegate these idiosyncratic cases among the secondary angle-closure glaucomas.
A similar classification system divides glaucoma into conditions that affect the internal flow, and conditions that affect the outflow of aqueous humor. Internal flow block is caused by such conditions as pupillary block or malignant glaucoma. Outflow block occurs with diseases of the trabecular meshwork (e.g., neovascularization) or that compromise Schlemm’s canal, collector channels, and the venous system (e.g., elevated episcleral venous pressure).
Alternative classification systems are based on other features of the diseases, including (1) the site of the outflow obstruction, which is divided into diseases that affect the pre-trabecular passage of aqueous humor (e.g., posterior synechiae to the lens after ocular inflammation), the trabecular flow (e.g., glaucoma after administration of α-chymotrypsin), and the post-trabecular movement of aqueous humor (e.g., increased episcleral venous pressure from a carotid-cavernous sinus fistula); (2) the tissue principally involved (e.g., glaucoma caused by diseases of the lens or diseases of the retina); (3) the proximal initial events (e.g., steroid glaucoma); and (4) the age of the patient (e.g., congenital, juvenile). Specific diseases have also been subclassified, such as POAG types, based on various appearances of the damaged optic nerve, or classification of disease stages by visual field damage; or the angle-closure glaucomas, based on IOP levels and gonioscopic configurations as correlated with ultrasonic biomicroscopy.
The reader is cautioned that all classification schemes are arbitrary and limited. Some cases do not fit neatly into one category or another. The classification that follows is not meant to be all- inclusive, but to be an aid in thinking about pathogenesis and treatment.
- I.
Angle-closure glaucoma
- A.
Primary angle-closure disease
Irido-trabecular contact is the final common pathway of angle closure disease, obstructing aqueous outflow; it can be conceptualized in two complimentary schemes:
- 1.
Natural history
- a.
Primary angle closure suspect
- b.
Primary angle closure
- c.
Primary angle-closure glaucoma
- a.
- 2.
Anterior segment mechanisms of closure
- a.
Iris-pupil obstruction (e.g., ‘pupillary block’)
- b.
Ciliary body anomalies (e.g., ‘plateau iris syndrome’)
- c.
Lens-pupil block (e.g., ‘phacomorphic block’ (swollen lens or microspherophakia))
- a.
- B.
Secondary angle-closures
- 1.
Anterior ‘pulling mechanism’
The iris is pulled forward by some process in the angle, often by the contraction of a membrane or peripheral anterior synechiae .
- a.
Neovascular glaucoma
- b.
Iridocorneal endothelial syndromes (e.g., Chandler’s syndrome)
- c.
Posterior polymorphous dystrophy
- d.
Epithelial downgrowth
- e.
Fibrous ingrowth
- f.
Flat anterior chamber
- g.
Inflammation
- h.
Penetrating keratoplasty
- i.
Aniridia
- a.
- 2.
Posterior ‘pushing mechanism’
The iris is pushed forward by some condition in the posterior segment. Often the ciliary body is rotated anteriorly, allowing the lens to come forward also.
- a.
Ciliary block glaucoma (malignant glaucoma)
- b.
Cysts of the iris and ciliary body
- c.
Intraocular tumors
- d.
Nanophthalmos
- e.
Suprachoroidal hemorrhage
- f.
Intravitreal air injection (e.g., retinal pneumopexy)
- g.
Ciliochoroidal effusions (e.g., panretinal photocoagulation)
- (a)
Inflammation (e.g., posterior scleritis)
- (b)
Central retinal vein occlusion
- (a)
- h.
Scleral buckling procedure
- i.
Retrolental fibroplasias
- a.
- 1.
- A.
- II.
Open-angle glaucoma
- A.
Primary open-angle glaucoma
- 1.
IOPs higher than ‘normal range’
- 2.
IOPs within ‘normal range’ (low-tension glaucoma)
- 1.
- B.
Secondary open-angle glaucoma
- 1.
Pigmentary glaucoma
- 2.
Pseudoexfoliation glaucoma
- 3.
Steroid glaucoma
- 4.
Lens-induced glaucoma
- a.
Phacolytic glaucoma
- b.
Lens-particle glaucoma
- c.
Phacoanaphylaxis
- a.
- 5.
Glaucoma after cataract surgery
- a.
α-Chymotrypsin glaucoma
- b.
Glaucoma with viscoelastics
- c.
Glaucoma with pigment dispersion and intraocular lens
- d.
UGH syndrome (uveitis + glaucoma + hyphema)
- e.
Glaucoma after neodymium:yttrium-aluminum-garnet (Nd:YAG) laser posterior capsulotomy
- f.
Glaucoma with vitreous in anterior chamber
- a.
- 6.
Glaucoma after trauma
- a.
Chemical burns
- b.
Electric shock
- c.
Radiation
- d.
Penetrating injury
- e.
Contusion injury
- a.
- 7.
Glaucoma associated with intraocular hemorrhage
- a.
Ghost cell glaucoma
- b.
Hemolytic glaucoma
- c.
Hemosiderosis
- a.
- 8.
Glaucoma associated with retinal detachment
- 9.
Glaucoma after vitrectomy
- a.
Intraocular gas
- b.
Intraocular silicone oil
- a.
- 10.
Glaucoma with uveitis
- a.
Fuchs’ heterochromic iridocyclitis
- b.
Glaucomatocyclitic crisis (Posner-Schlossman)
- c.
Precipitates on trabecular meshwork (trabeculitis)
- d.
Herpes simplex
- e.
Herpes zoster
- f.
Sarcoidosis
- g.
Juvenile rheumatoid arthritis
- h.
Syphilis
- i.
Human immunodeficiency virus (HIV) infection
- a.
- 11.
Glaucoma with intraocular tumors
- a.
Malignant melanoma
- b.
Metastatic lesions
- c.
Leukemia and lymphoma
- d.
Benign lesions (e.g., juvenile xanthogranuloma, neurofibromatosis)
- a.
- 12.
Amyloidosis
- 13.
Increased episcleral venous pressure
- a.
Obstruction of venous drainage (e.g., superior vena cava obstruction)
- b.
Arteriovenous fistula (e.g., carotid cavernous)
- c.
Ocular episcleral venous anomalies (e.g., Sturge-Weber syndrome)
- a.
- 1.
- A.
- III.
Developmental glaucoma
Anomalies of the anterior segment are present at birth. Glaucoma may be present at birth or may appear in the first decades of life (see Ch. 20 for detailed classification of pediatric glaucoma diseases).
- A.
Primary congenital (infantile) glaucoma
- 1.
Congenital glaucoma
- 2.
Autosomal dominant juvenile glaucoma
- 3.
Glaucoma associated with systemic abnormalities
- 4.
Glaucoma associated with ocular abnormalities
- 1.
- B.
Secondary glaucoma
- 1.
Traumatic glaucoma
- 2.
Glaucoma with intraocular neoplasm
- 3.
Uveitis glaucoma
- 4.
Lens-induced glaucoma
- 5.
Glaucoma after congenital cataract surgery
- 6.
Steroid-induced glaucoma
- 7.
Neovascular glaucoma
- 8.
Secondary angle-closure glaucoma
- 9.
Glaucoma with elevated episcleral venous pressure
- 10.
Glaucoma secondary to intraocular infection
- 1.
- A.
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