Corneal Pathology and Systemic Disease

A vast spectrum of conditions may be associated with corneal pathology ( Box 1-2 ). Associated inflammatory diseases include rheumatoid arthritis, Reiter’s syndrome, Behçet’s syndrome, and sarcoidosis. Connective tissue disorders such as ankylosing spondylosis, scleroderma, Sjögren’s syndrome, and Wegener’s granulomatosis have been associated with corneal disturbances. Associated metabolic diseases include cystinosis, disorders of carbohydrate metabolism, gout, hyperlipidemia, and Wilson’s disease. Also, such conditions as Graves’ hyperthyroid disease, leprosy, chronic renal failure, and tuberculosis may have associated corneal disease. Even skin diseases such as erythema multiforme and pemphigus have corneal manifestations (see Chapter 10 ). Finally, mandibulo-oculofacial dyscephaly (Hallermann-Streiff syndrome) is of interest to anesthesiologists because of anticipated difficulty with intubation.

Lens Pathology and Systemic Disease

A cataract is defined as a clouding of the normally clear crystalline lens of the eye. The different types of cataracts include nuclear-sclerotic, cortical, posterior subcapsular, and mixed. Each type has its own location in the lens and risk factors for development, with nuclear-sclerotic cataracts being the most common type of age-related cataract. The leading cause of blindness worldwide, cataracts affect more than 6 million individuals annually. Indeed, cataract surgery is the most frequently performed surgical procedure in the United States, with more than 1.5 million operations annually. More than half the population older than 65 develop age-related cataracts with associated visual disability. Despite extensive research into the pathogenesis and pharmacologic prevention of cataracts, however, there are no proven means to prevent age-related cataracts.

Although age-related cataracts are most frequently encountered, cataracts may be associated with dermatologic diseases such as incontinentia pigmenti, exogenous substances, genetic diseases, hematologic diseases, infections, and metabolic perturbations ( Box 1-3 ).

Exogenous substances that can trigger cataracts include corticosteroids, phenothiazines, naphthalene, ergot, parachlorobenzene, and alcohol. Metabolic conditions associated with cataracts include diabetes mellitus, Fabry’s disease, galactosemia, hepatolenticular degeneration (Wilson’s disease), hypoparathyroidism, hypothyroidism, phenylketonuria, Refsum’s disease, and xanthomatosis. Another metabolic disorder important in the differential diagnosis of congenital cataracts is Lowe’s (oculocerebrorenal) syndrome. In this X-linked disorder, cataract is frequently the presenting sign, with other abnormalities appearing later. These anomalies include mental and growth retardation, hypotonia, renal acidosis, aminoaciduria, proteinuria, and renal rickets, requiring calcium and vitamin D therapy. Other concomitants include osteoporosis and a distinctive facies (long with frontal bossing). Although lens changes may also be seen in heterozygous female children, affected male children usually have obvious, dense, bilateral cataracts at birth. They may also be afflicted with associated glaucoma. Interestingly, carrier females in their second decade of life have significantly higher numbers of lens opacities than age-related controls; however, absence of opacities is no guarantee that an individual is not a carrier. Anesthetic management includes careful attention to acid-base balance and to serum levels of calcium and electrolytes. Renal involvement of oculocerebrorenal syndrome of Lowe comprises tubular dysfunction characterized by proteinuria and generalized aminoaciduria progressing to the renal Fanconi’s syndrome. Bicarbonate wasting and hyperkaluria result from a proximal tubule transport defect, with later glomerular disease. The administration of drugs excreted by the kidney should be observed carefully and nephrotoxins avoided. The patient with osteoporosis should be positioned on the operating table gently and carefully.

Infectious causes of cataracts include herpesvirus, influenza, mumps, polio, rubella, toxoplasmosis, vaccinia, and varicella-zoster virus. Chromosomal anomalies associated with cataracts include trisomy 13 (Patau’s syndrome), trisomy 18 (Edward’s syndrome), and trisomy 21 (Down syndrome). In Patau’s and Edward’s syndromes, congenital cataracts frequently occur in conjunction with other ocular anomalies, such as coloboma and microphthalmia. Cataracts have also been reported with Turner’s syndrome (XO).

An additional type of lens abnormality that can be associated with major systemic disease is ectopia lentis ( Fig. 1-1 and Box 1-4 ). Displacement of the lens can be classified topographically as subluxation or luxation. Luxation denotes a lens that is dislocated either posteriorly into the vitreous cavity or, less often, anteriorly into the anterior chamber. In subluxation, some zonular attachments remain, and the lens stays in its plane posterior to the iris, but tilted. The most common cause of lens displacement is trauma, although ectopia lentis may also result from other ocular disease, such as intraocular tumor, congenital glaucoma, uveitis, aniridia, syphilis, or high myopia. Inherited defects and serious systemic diseases, such as Marfan’s syndrome, homocystinuria, Weill-Marchesani syndrome, hyperlysinemia, and sulfite oxidase deficiency, are also associated with ectopia lentis. Indeed, lens displacement occurs in approximately 80% of patients with Marfan’s syndrome (see later discussion).

Ectopia lentis.

Displaced lens of the eye is common in patients with Marfan’s syndrome.

(Courtesy American Academy of Ophthalmology, 2011, aao.org.)

Glaucoma and Systemic Disease

Glaucoma is a condition characterized by elevated intraocular pressure (IOP), resulting in impairment of capillary blood flow to the optic nerve and eventual loss of optic nerve tissue and function. Two different anatomic types of glaucoma exist: open-angle (or chronic simple) glaucoma and closed-angle (or acute) glaucoma. (Other variations of these processes occur but are not especially germane to anesthetic management. Glaucoma is actually many diseases, not one.)

With open-angle glaucoma, the elevated IOP exists in conjunction with an anatomically patent anterior chamber angle. Sclerosis of trabecular tissue is thought to produce impaired aqueous filtration and drainage. Treatment consists of medication to produce miosis and trabecular stretching. Common eyedrops include epinephrine, echothiophate iodide, timolol, dipivefrin, and betaxolol. Carbonic anhydrase inhibitors such as acetazolamide can also be administered by various routes to reduce IOP by interfering with the production of aqueous humor. All these drugs are systemically absorbed and thus can have anticipated side effects.

It is important to appreciate that maintenance of IOP is determined primarily by the rate of aqueous formation and the rate of aqueous outflow. The most important influence on formation of aqueous humor is the difference in osmotic pressure between aqueous and plasma, as illustrated by the following equation:

Fluctuations in aqueous outflow can also greatly change IOP. The primary factor controlling aqueous humor outflow is the diameter of Fontana’s spaces, as illustrated by the following equation:

The previous equation describing the volume of aqueous outflow per unit of time clearly underscores that outflow is exquisitely sensitive to fluctuations in venous pressure. Because an elevation in venous pressure results in an increased volume of ocular blood as well as decreased aqueous outflow, IOP increases considerably with any maneuver that increases venous pressure. Therefore, in addition to preoperative instillation of miotics, other anesthetic objectives for the patient with glaucoma include perioperative avoidance of venous congestion and of overhydration. Furthermore, hypotensive episodes should be avoided because these patients are purportedly vulnerable to retinal vascular thrombosis.

Although glaucoma usually occurs as an isolated disease, it may also be associated with such conditions as Sturge-Weber syndrome and von Recklinghausen’s disease (neurofibromatosis) ( Box 1-5 ). Ocular trauma, corticosteroid therapy, sarcoidosis, some forms of arthritis with uveitis, and pseudoexfoliation syndrome can also be associated with secondary glaucoma.

Primary closed-angle glaucoma is characterized by a shallow anterior chamber and a narrow iridocorneal angle that impedes the egress of aqueous humor from the eye because the trabecular meshwork is covered by the iris ( Box 1-6 ). Relative pupillary block is common in many angle-closure episodes in which iris-lens apposition or synechiae impede the flow of aqueous from the posterior chamber. In the United States, angle-closure glaucoma (ACG) is one-tenth as common as open-angle glaucoma ( Table 1-1 ). In acute ACG, if the pressure is not reduced promptly, permanent visual loss can ensue as a result of optic nerve damage. Because irreversible optic nerve injury can occur within 24 to 48 hours, treatment should be instituted immediately after making the diagnosis of acute ACG. Signs and symptoms include ocular pain (often excruciating), red eye, corneal edema, blurred vision, and a fixed, mid-dilated pupil. Consultation with an ophthalmologist should be sought immediately. Topical pilocarpine 2% is administered to cause miosis and pull the iris taut and away from the trabecular meshwork. A topical beta-adrenergic blocker (β-blocker) also should be considered. If a prompt reduction in IOP does not ensue, systemic therapy with an agent such as mannitol should be considered, but its potentially adverse hemodynamic effects should be weighed in a patient with cardiovascular disease.

If medical therapy is effective in reducing IOP to a safe level and the angle opens, an iridotomy/iridectomy can be performed immediately, or delayed until the corneal edema resolves and the iris becomes less hyperemic.

Retinal Complications of Systemic Disease

Retinal conditions such as vitreous hemorrhage and retinal detachment are most frequently associated with diabetes mellitus and hypertension ( Box 1-7 ), although patients with severe myopia (unaccompanied by any systemic disease) are vulnerable to retinal detachment. In addition, collagen disorders and connective tissue diseases, such as systemic lupus erythematosus, scleroderma, polyarteritis nodosa, Marfan’s syndrome, and Wagner-Stickler syndrome, are often associated with retinal pathology. Serious retinal complications have been reported with skin conditions (e.g., incontinentia pigmenti). Moreover, such conditions as sickle cell anemia, macroglobulinemia, Tay-Sachs disease, Niemann-Pick disease, and hyperlipidemia can result in vitreoretinal disorders. During the past three decades, cytomegalovirus retinitis has been reported in AIDS patients, sometimes causing retinal detachment.

Marfan’s Syndrome

Marfan’s syndrome is a disorder of connective tissue, involving primarily the cardiovascular, skeletal, and ocular systems. However, the skin, fascia, lungs, skeletal muscle, and adipose tissue may also be affected. The etiology is a mutation in FBNI, the gene that encodes fibrillin-1, a major component of extracellular microfibrils, which are the major components of elastic fibers that anchor the dermis, epidermis, and ocular zonules. Connective tissue in these patients has decreased tensile strength and elasticity. Marfan’s syndrome is inherited as an autosomal dominant trait with variable expression.

Ocular manifestations of Marfan’s syndrome include severe myopia, spontaneous retinal detachments, displaced lenses (see Fig. 1-1 ), and glaucoma. Cardiovascular manifestations include dilation of the ascending aorta and aortic insufficiency. The loss of elastic fibers in the media may also account for dilation of the pulmonary artery and mitral insufficiency resulting from extended chordae tendineae. Myocardial ischemia caused by medial necrosis of coronary arterioles as well as dysrhythmias and conduction disturbances have been well documented. Heart failure and dissecting aortic aneurysms or aortic rupture can occur.

Marfan’s patients are tall, with long, thin extremities and fingers (arachnodactyly). Joint ligaments are loose, resulting in frequent dislocations of the mandible and hip. Possible cervical spine laxity can also occur. Kyphoscoliosis and pectus excavatum can contribute to restrictive pulmonary disease. Lung cysts have also been described, increasing the risk of pneumothorax. A narrow, high-arched palate is typical.

The early manifestations of Marfan’s syndrome may be subtle, and therefore the patient presenting for initial surgery may be undiagnosed. The anesthesiologist, however, should have a high index of suspicion when a tall young patient with a heart murmur presents for repair of a spontaneously detached retina. These young patients should have a chest radiograph as well as an electrocardiogram (ECG) and echocardiogram before surgery. Antibiotics for subacute bacterial endocarditis prophylaxis should be considered, as well as β-blockers to mitigate increases in myocardial contractility and aortic wall tension (dP/dT).

Graves’ Disease

Graves’ disease is the most common cause of both pediatric and adult hyperthyroidism. Graves’ disease encompasses hyperthyroidism, goiter, pretibial myxedema, and often but not inevitably, exophthalmos. The condition occurs in conjunction with the production of excess thyroid hormone and affects approximately 3 in 10,000 adults (usually women), typically age 25 to 50. Graves’ ophthalmopathy includes corneal ulcerations and exophthalmos that can be severe. Retro-orbital tissue and the extraocular muscles are infiltrated with lymphocytes, plasma cells, and mucopolysaccharides. The extraocular muscles often are swollen to 5 to 10 times their normal size. If proptosis secondary to infiltrative ophthalmopathy is severe and if muscle function or visual acuity deteriorates, corticosteroid therapy (usually prednisone, 20-40 mg/day for adults) is initiated, especially if retrobulbar neuritis develops. Patients who fail to respond to corticosteroid therapy require surgical intervention. Lateral (Krönlein’s) or supraorbital (Naffziger’s) decompression is performed.

Graves’ disease is thought to be autoimmune in origin, with thyroid-stimulating immunoglobulins directed against thyroid antigens that bind to thyroid-stimulating hormone (TSH, thyrotropin) receptors on the thyroid gland. Soft, multinodular, nonmalignant enlargement of the thyroid is typical. There is a strong hereditary component with Graves’ disease, and the condition is likely exacerbated by emotional stress. These patients may have other signs of autoimmune involvement, including myositis and occasionally myasthenia gravis. Symptoms include weakness, fatigue, weight loss, tremulousness, and increased tolerance to cold. Proptosis, diplopia or blurred vision, photophobia, conjunctival chemosis, and decreased visual acuity may be noted. Cardiac symptoms include a hyperdynamic precordium, tachycardia, and elevated systolic BP, decreased diastolic BP, and widened pulse pressure. Atrial fibrillation, palpitations, and dyspnea on exertion may also occur.

The differential diagnosis of Graves’ disease includes other causes of hyperthyroidism such as pregnancy that may be associated with the production of an ectopic TSH-like substance, autoimmune thyroiditis, thyroid adenoma, choriocarcinoma, a TSH-secreting pituitary adenoma, and surreptitious ingestion of tri-iodothyronine (T ₃ ) or thyroxine (T ₄ ). The goals of drug therapy in the hyperthyroid patient are to control the major manifestations of the thyrotoxic state and to render the patient euthyroid. The most frequently used agents are the thiourea derivatives propylthiouracil (PTU) and methimazole, which act by inhibiting synthesis of thyroid hormone. (PTU may also inhibit the conversion of T ₄ to T ₃ .) Because of the large glandular storage of hormone, 4 to 8 weeks is usually required to render a patient euthyroid with these drugs. Therapy typically lasts several months, after which thyroid reserve and suppressive response to thyroid hormone are re-evaluated. The major complication of this therapy is hypothyroidism, and the dosage is usually adjusted to the lowest possible once a euthyroid state is attained. Other side effects encountered in patients taking these antithyroid drugs include leukopenia, which may be therapy limiting, as well as agranulocytosis, hepatitis, rashes, and drug fever. Beta-receptor numbers are reportedly increased by hyperthyroidism, and β-blockers are used to control the effects of catecholamine stimulation rapidly, such as tachycardia, tremor, and diaphoresis.

Homocystinuria

Although rare, homocystinuria is generally considered the second most common inborn error of amino acid metabolism (incidence ~1:200,000), after phenylketonuria (~1:25,000). An error of sulfur amino acid metabolism, homocystinuria is characterized by the excretion of a large amount of urinary homocystine, which can be detected by the cyanide-nitroprusside test. A host of assorted genetic aberrations may be linked with homocystinuria, but the most common is a deficiency of cystathionine β-synthase, with accumulation of methionine and homocystine. The disorder is autosomal recessive. Disease occurs in the homozygote, but the heterozygote is without risk of developing the potentially life-threatening complications of the condition. Although one third of homocystinuric patients have normal intelligence, most are mentally retarded.

Ectopia lentis occurs in at least 90% of persons with homocystinuria (see Fig. 1-1 ). Frequently there is subluxation of the lens into the anterior chamber, causing pupillary block glaucoma, necessitating surgical correction. Other ocular findings reported in homocystinuria include pale irides, retinoschisis, retinal detachment, optic atrophy, central retinal artery occlusion, and strabismus.

Because of abnormal connective tissue, the skeletal findings are similar to those of Marfan’s syndrome. Most homocystinuric patients have arachnodactyly, kyphoscoliosis, and sternal deformity. They also may have severe osteoporosis. Kyphoscoliosis and pectus excavatum may be associated with restrictive lung disease.

It is imperative to appreciate that patients with homocystinuria are extremely vulnerable to thrombotic complications associated with high mortality ( Box 1-10 ). An untreated homocystinuric patient may have a perioperative mortality rate as high as 50%. Elevated concentrations of homocystine irritate the vascular intima, promoting thrombolic nidus formation and presumably increasing the adhesiveness of platelets. Other possible causes of the thrombotic tendency include increased platelet aggregation, Hageman factor activation, and enhanced platelet consumption as a result of endothelial damage. Patients with homocystinuria are also at risk for hypoglycemic convulsions secondary to hyperinsulinemia, which is thought to be provoked by hypermethioninemia.

Preoperative measures include a low-methionine, high-cystine diet and vitamins B ₆ and B ₁₂ and folic acid to regulate homocystine levels, as well as acetylsalicylic acid (aspirin) and dipyridamole to prevent aberrant platelet function. Besides appropriate dietary and drug therapy, proper perioperative care involves prevention of hypoglycemia and maintenance of adequate circulation. Patients with osteoporosis must be carefully positioned on the operating table. Glucose levels should be monitored perioperatively. Low-flow, hypotensive states must be assiduously avoided. The patients must be kept well hydrated and well perfused. Anesthetic agents selected should promote high peripheral flow by reducing vascular resistance, maintain cardiac output, and foster rapid recovery and early ambulation. Postoperative vascular support stockings that prevent stasis thrombi in leg veins are indicated.

Hemoglobinopathies: Sickle Cell Disease

Hemoglobinopathies are inherited disorders of hemoglobin synthesis. There may be structural derangements of globin polypeptides or, as in thalassemia, abnormal synthesis of globin chains. In hemoglobin (Hb) S, for example, a single amino acid (valine) is substituted for glutamic acid in the β chain. This substitution has no effect on oxygen (O ₂ ) affinity or molecular stability. Nonetheless, in the setting of low O ₂ tension, it causes an intermolecular reaction, producing insoluble structures within the erythrocytes that result in sickling. These atypical red blood cells lodge in the microcirculation, causing painful vaso-occlusive crises, infarcts, and increased susceptibility to infection. Low O ₂ tension and acidic environments are major triggers and determinants of the degree of sickling. Sickled cells are thought to produce a rightward shift (P ₅₀ = 31 mm Hg) of the oxyhemoglobin dissociation curve to enhance O ₂ delivery.

Although ophthalmic pathology such as proliferative retinopathy can occur in all sickling diseases, it is more common in adults with Hb SC or Hb S thalassemia than in those with Hb SS. Proliferative retinopathy usually appears in the third or fourth decades of life and is the result of vascular occlusion. This occlusion of retinal vessels eventually produces ischemia, neovascularization, vitreous hemorrhage, fibrosis, traction, and retinal detachment or atrophy. Prophylactic laser photocoagulation has helped reduce the incidence of these conditions.

The severity of the anemia depends on the amount of Hb S present. In homozygous SS disease, the Hb S content is 85% to 90%, the remainder being Hb F. Sickle cell thalassemia (Hb SF) is characterized by an Hb S content of 67% to 82% and causes somewhat less severe problems. Indeed, patients with Hb SC and Hb S thalassemia typically have a much more benign course than those individuals with Hb SS and usually have only mild anemia and splenomegaly. Heterozygous persons with Hb SA (sickle trait) rarely have serious clinical problems. However, some increased risk of stroke and pulmonary emboli or infection has been suggested, but not well quantitated, after the stress of hypothermic, low-flow cardiopulmonary bypass in patients with sickle trait.

Sickle cell disease (Hb SS) is an autosomal recessive condition that occurs most frequently in individuals of African ancestry, although the gene for Hb S also occurs in persons with ancestors from areas endemic for falciparum malaria. From 8% to 10% of American blacks are heterozygous carriers of Hb S; approximately 0.5% of blacks are homozygous for Hb S disease. Patients with homozygous sickle cell disease have chronic hemolytic anemia ( Box 1-11 ). Organ damage results from vaso-occlusive ischemia because sickled cells are unable to traverse narrow capillary beds. Also, sickled cells tend to adhere to the endothelium and cause release of vasoactive substances. Chronic pulmonary disease gradually progresses as a result of recurrent pulmonary infection and infarction. Eventually, these individuals develop pulmonary hypertension, cardiomegaly, and heart failure, as well as renal failure.

Multiple problems place these patients at high perioperative risk, including anemia, underlying cardiopulmonary disease, and extreme vulnerability to dehydration, hypothermia, hypoxia, and acidosis. Preoperative management should include correction of anemia. In the past, controversy surrounded whether patients with sickle cell disease should receive a preoperative exchange transfusion with Hb A. Data now suggest, however, that preoperative transfusion to an Hb level of 10 g/dL, independent of the Hb S percentage, is equally effective in preventing perioperative complications as transfusion designed to establish a level of 10 g/dL and an Hb S level below 30%. Controversy also surrounds the issue of the relative risks of transfusion for simple, brief surgical procedures in patients who are minimally symptomatic and considered at low risk for intraoperative vaso-occlusive crises. Clearly, all blood transfusion in these patients carries a high risk of hemolytic transfusion reaction because of alloimmunization from previous exposure.

Acquired Immunodeficiency Syndrome (AIDS)

First described in the United States in 1981, the human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic is one of the most devastating to have afflicted humankind. Although ongoing research continues to improve the quality of life for the millions of people affected, there is still no cure. Thus, anesthesiologists must be prepared to manage the AIDS patient’s numerous and complex challenges.

Patients with AIDS frequently develop cytomegalovirus retinitis, a condition treated by the insertion of a slow-release antiviral drug packet into the vitreous. Occasionally, the retinitis will produce a retinal detachment that requires surgical correction.

Many patients with AIDS are extremely ill with cachexia, anemia, and residual respiratory insufficiency from previous episodes of Pneumocystis jiroveci (formerly P. carinii ) pneumonia, tuberculosis, or aspergillosis ( Box 1-12 ). In addition to reduced pulmonary reserve, these patients often have limited myocardial reserve because of the debilitating effects of their underlying disease. AIDS is strongly associated with the development of cardiomyopathy, hypertension, right ventricular dysfunction, myocarditis, pericardial effusion, and coronary artery disease. The preoperative assessment must reflect that AIDS is a complex, multiorgan disease requiring risk stratification. Disease severity may be staged by considering the peripheral blood CD4 counts and the clinical manifestations. CD4 cell counts range from relatively normal (>500/mm ) to severe depletion (<200/mm ). The clinical manifestations are typically placed in strata based on the level of immunologic dysfunction, ranging from “minimal” to “AIDS-defining” conditions. The presence of neurologic, pulmonary, cardiovascular, and hematologic abnormalities is of particular concern.

Box 1-12

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