On the other hand, several different mutations in the FOXC1 gene can produce the same clinical phenotype of Axenfeld-Rieger syndrome.139 Mice with PITX2 and FOXC1 mutations have become available so better understanding of the developmental steps that lead to these conditions should be just ahead.140 While mouse models may be helpful in improving our understanding, it is usually difficult to project findings from these models directly to humans; anatomy and chemistry are too different.

Aniridia

Aniridia is another condition associated with infantile, childhood, or young adult-onset glaucoma. Several studies from around the world point towards mutation in the PAX6 gene as the causative agent for this disease.141 PAX6 is a gene that regulates eye development in many species. One family with a single PAX6 mutation demonstrated wide variability in the degree of aniridia ranging from total to partial with variable expression of cataract, keratitis, foveal hypoplasia, and optic disc anomalies.142 As with other genes, mutations can produce variable penetrance suggesting that other independent influences play an important role. About 50% of these patients develop glaucoma usually during childhood or young adulthood. Abnormal trabecular meshwork and absence of Schlemm’s canal have been reported.143 A mutant mouse with a PAX6 mutation has been engineered. These mice show many of the characteristics of aniridia including hypoplastic iris, absent Schlemm’s canal, abnormal trabecular meshwork, and corneal opacities.144

Nail patella syndrome

Nail patella syndrome is an autosomal dominant condition characterized by dysplastic fingernails, absent, hypoplastic or dislocated patellae, kidney abnormalities, gastrointestinal symptoms, neurological and vasomotor instability. Glaucoma resembling the primary open-angle type occurs in about 10% (increasing with age) and elevated IOP in

about 8%.145 This condition has been associated with mutations in the transcription factor LMX1B at the 9q34 locus.146

Renal tubular acidosis

A rare form of infantile or childhood glaucoma is that associated with renal tubular acidosis. The syndrome is also associated with cataracts. This syndrome has been mapped to a specific genetric locus NBCe1.147 Some patients have been further characterized by a missense mutation that adversely affects Na /HCO3 metabolism in the kidney tubules, ciliary body, and lens.148

Summary

Genetic studies have shown that many familial types of glaucoma and some types not identified as familial may have a causative single mutated gene.This has been found especially true for the developmental glaucomas such as primary congenital glaucoma, AxenfeldRieger syndrome, aniridia, nail patella syndrome, and renal tubular acidosis. Juvenile-onset open-angle glaucoma and normal-tension glaucoma that have a strong familial character have also had mutations associated with them. However, the patients with glaucoma that have had genetic linkages only reach about 10% or so of the total number. While genetic studies may be helpful in identifying at-risk individuals in a single family with a strong tendency toward

open-angle, juvenile open-angle, or low-tension glaucoma, routine genetic screening cannot yet be recommended.149,150 The ability

to genetically engineer mice and other small mammals has given hope that we will be able to develop a better understanding of the tissue and molecular mechanisms by which glaucoma occurs and, perhaps, develop specific treatments that target these molecular mechanisms or processes that can interfere with the pathologic mechanisms.

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Despite the fact that there are many different types of glaucoma with different manifestations, diagnostic approaches, and treatment modalities, this chapter summarizes some of the generalizable concepts of glaucoma management.While there are probably as many approaches to glaucoma as there are different patients and different caregivers, the concepts presented here are the result of years of experience and are applicable to the extent that generalizations can be; however, they must be modified to the requirements of each patient and physician.

Symptoms and historical information related to the glaucomas

Many factors in the patient’s history bear on the diagnosis and treatment of glaucoma. Most patients with glaucoma, especially primary open-angle glaucoma (POAG), chronic angle-closure glaucoma, and other chronic forms of glaucoma, are asymptomatic until late in the course of the disease. However, certain patients may have symptoms such as pain, redness, halo vision, blurred vision, and a change in the appearance of the eye. Pain associated with glaucoma is related to the height of the intraocular pressure (IOP) and the rapidity with which it rises to that level. Conditions that cause rapid and sustained rises of IOP to high levels, such as acute angle-closure glaucoma, are often accompanied by pain. Conditions such as POAG that cause less dramatic changes in IOP are usually not associated with pain. Occasionally young patients with open-angle glaucoma (e.g., pigmentary glaucoma) may experience discomfort when IOP rises rapidly even to moderate levels. Other mechanisms for pain in glaucoma include inflammation, bullous keratopathy, and drug-induced side effects (e.g., mioticinduced ciliary and orbicularis muscle spasm). In angle-closure glaucoma or glaucoma associated with acute iritis, conjunctival injection may take the form of a ciliary flush. Other causes of red eyes in glaucoma patients include prostaglandin-like agents, other drug reactions, allergic conjunctivitis, endophthalmitis, neovascular glaucoma, hyphema, subconjunctival hemorrhage, bullous keratopathy, and increased episcleral venous pressure.

When IOP rises rapidly, the corneal endothelium may not be able to adequately pump fluid from the cornea – resulting in edema of the epithelium and, sometimes, the stroma. This condition may produce a visual sensation of colored halos around incandescent lights. Episodic blurring of vision is often noted when rapid elevations of IOP cause corneal edema. It is important to remember that many patients refer to uncolored semicircular or

radiating images as halos. This distortion in vision may be caused by opacities in the media, uncorrected refractive errors, and alterations in the tear film. In these latter conditions, the ophthalmologist can often elicit ‘halo’ vision in the office while the IOP is normal and the cornea is clear.

Glaucoma can alter vision in a number of other ways. Occasionally a patient may note a diminished visual field during some activity that requires monocular vision (e.g., aiming a rifle, looking through a camera). Patients with asymmetric vision loss may not be aware of their defect until they close the better eye. Loss of Snellen visual acuity usually occurs late in the course of glaucoma unless some other problem occurs, such as central retinal vein occlusion. However, loss of color perception, motion perception, contrast sensitivity, temporal contrast sensitivity, vernier acuity, and other visual functions may occur much earlier in the disease than previously thought; patients may be aware of these subtle changes and complain about them even when visual acuity and standard visual fields are normal.

A few patients may complain of a change in the appearance of the eye which may come from exophthalmos, haziness of the cornea, or an alteration in pupil size, shape, or position.

A careful medical history may provide important information related to glaucoma. The medical history should include the following points:

1.  Ocular history should include queries about amblyopia, trauma, inflammation, surgery, cataract, retinal detachment, and inflammation. If not questioned directly, patients may not remember a ‘trivial’ eye injury that may have occurred many years ago.

2.  General medical history should focus on obtaining information about vascular diseases (e.g., hypertension, diabetes, cardiac problems, hypotensive episodes) that might affect ocular perfusion, or other conditions that could mimic or aggravate glaucomatous visual field loss (e.g., demyelinating diseases, central nervous system tumors, or aneurysms). A history of migraine or other vasospastic disorders is important to elicit, particularly for ‘normalpressure’ glaucoma. The clinician must know about the patient’s general health before prescribing medication or considering surgery. For example, topical -blocker agents can exacerbate asthma or congestive heart failure.

3. The patient’s medication history and allergies should also be documented. Many drugs (e.g., corticosteroids or anticholinergic agents) can alter IOP and affect the course of glaucoma. Conversely, many ocular medications can induce or aggravate systemic medical problems. Frequent exchange of information between the ophthalmologist and the family physician is important. A history of sulfa allergy may make the use of carbonic anhydrase inhibitor therapy unwise unless no other alternative is available.