| Chapter 24 The Eye in Pulmonary Disorders JOSEPH B. WALSH , RICHARD B. ROSEN and SETH W. MESKIN Table Of Contents |
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PULMONARY DISEASE CYSTIC FIBROSIS REFERENCES |
| PULMONARY DISEASE |
| Disorders of pulmonary gas exchange secondary to pulmonary disease most
commonly result in hypoxemia but may also cause hypercapnia or a combination
of both. Hypoxemia may be caused by numerous conditions including
pulmonary infection or edema, central nervous system depression of
respiration, restrictive lung diseases, and disorders of oxygen transport. Restrictive
disorders involve reduced oxygen-diffusing capacity
and include entities such as the pneumoconioses, idiopathic pulmonary
fibrosis, hypersensitivity pneumonitis, sarcoidosis, pulmonary alveolar
proteinosis, diffuse neoplasm, and connective tissue disorders. Oxygen
transport disorders include carbon monoxide poisoning, anemia, and
circulatory deficiencies. Chronic or intermittent retention of carbon
dioxide (hypercapnia) occurs in various forms of obstructive pulmonary
disease including asthma, pulmonary emphysema, pickwickian syndrome (sleep
apnea), cystic fibrosis, bronchiectasis, kyphoscoliotic lung disease, surgical
or traumatic loss of pulmonary substance, and tuberculosis
or other pulmonary infections. In the early phase of pulmonary disease, before the development of significant changes in blood gas constituents, there are no ocular findings. Initial manifestations of chronic pulmonary disease may vary, but when hypoxia occurs, the arterial oxygen desaturation (oxygen tension less than 75 mm Hg) may be reflected in the ocular vasculature as a darkening of the blood column in the conjunctiva and retinal vessels. The ocular tissues may take on the dusky color of cyanosis when the absolute concentration of desaturated hemoglobin exceeds 5 mg/ml.1 Retinal vascular flow increases markedly in response to diminished oxygen availability, although changes in vessel caliber cannot be easily appreciated ophthalmoscopically.2 As chronic lung disease progresses from dyspnea on exertion to dyspnea at rest, the increasing carbon dioxide levels, resulting from shunting of blood through the lungs, air trapping, or alveolar hypoventilation, further enhance retinal perfusion. Systemic signs that accompany these changes include cyanosis, clubbing of fingers and toes, and plethoric facies produced by secondary polycythemia. Obliteration of the pulmonary vascular bed in more advanced states results in increased pulmonary vascular resistance, which in turn may lead to pulmonary hypertension and right-sided heart failure. The clinical findings include increased venous pressure, peripheral edema, and hepatomegaly. As the inverting blood gas ratios continue to worsen, headaches, tremors, twitching of the extremities, and alterations in consciousness ensue.3 Cerebral and retinal vascular resistance decline, giving way to progressive vasodilation and increased blood flow.4 These changes along with increased serum viscosity, secondary polycythemia, and increased venous pressure produce the full clinical picture of chronic pulmonary failure. Because there is greater resistance in the retinal arterial walls than in the venous walls, the veins tend to dilate more than the arteries in response to the changes described earlier. The dilation tends to be segmental, as a result of the patchy fibrosis that replaces the normal elastic smooth muscle in the vessel walls of older patients. The result is pronounced irregularity of vessel caliber, which is especially evident at arteriovenous crossings, where the artery and vein share a common adventitial sheath. As pulmonary decompensation worsens, vascular configuration changes and hyperviscosity leads to occlusive and hemorrhagic events, resulting in retinal hemorrhages, macular edema, and optic disc edema.5,6 Visual acuity and visual fields may remain normal despite optic nerve swelling but often become severely compromised if macular hemorrhage and edema ensue. If the blood gas pattern can be normalized even at this stage, retinal and conjunctival vascular patterns may revert to normal. |
| CYSTIC FIBROSIS |
| Cystic fibrosis (fibrocystic disease of the pancreas or mucoviscidosis) was
first reported by Fanconi in Switzerland in 1936. In 1938, Anderson
defined this entity as a separate and distinct disorder. Tsui localized
the defective gene locus to the long arm of chromosome 7 in 1985 and
with Collins was then able to clone the gene in 1989.7 The manifestations of the disorder are protean, and the precise nature
of the defect is still under investigation.7–9 In the United States, the incidence of this disease is 1:3500 live white births and 1:15,300 live black infants.10 The disorder is most common in whites from Northern and Central European ancestry and less common in blacks and Asians. Inheritance of the cystic fibrosis (CF) gene is by an autosomal recessive pattern. Cystic fibrosis is the most frequent lethal recessive genetic disorder among whites. There are more than 750 gene mutations that may lead to cystic fibrosis. All of them occur at a single locus on the long arm of chromosome 7, with the most common being a three-base deletion resulting in the loss of a single phenylalanine residue at amino acid 508 (DeltaF508) in the gene's protein product. This mutation accounts for approximately 66% of the CF chromosomes reported worldwide. The CF gene codes for a protein called the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is found predominately in epithelial cells of airways, the gastrointestinal tract, the genitourinary system, and the sweat glands. It functions as a cyclic adenosine monophosphate (cAMP)-dependent membrane channel of chloride (Cl-) ions. Dysfunction of CFTR appears to prevent secretion of chloride (and secondarily water) into mucus thereby allowing mucous secretions to become more viscous and elastic and more difficult to clear by mucociliary and other mechanisms.11 Abnormalities of other epithelial ion channels or transporters (especially involving Na+ and K+), secondary to the absence of CFTR, are believed to occur and further participate in organ specific pathophysiology.9 Cystic fibrosis is usually recognized in children and adolescents. It is the most common cause of obstructive pulmonary disease and pancreatic insufficiency in the first three decades of life. The prognosis was once poor (80% died before age 20 years), but antibiotics and pulmonary physiotherapy have greatly lengthened life expectancy. Cystic fibrosis causes dysfunction of almost all exocrine, eccrine, and some endocrine glands. The resultant effect is an abnormal mucous secretion that causes obstruction of single mucin-producing cells. The pancreas secretes less enzyme (e.g., trypsin, lipase, and amylase), so malabsorption ensues with its attendant deficiency disorders. The islets of Langerhans are not directly affected, but their secondary ablation by exocrine gland cicatrization makes diabetes 25 times more common than in the general population. Ketoacidosis is rare, however, because necessary glucagon-producing cells are also destroyed by the fibrocystic changes. In the lungs, inspissated secretions cause blockage of the bronchioles with overinflation of alveolar spaces and secondary infection. Cirrhosis of the liver from biliary obstruction is present in 25% of autopsies. The abnormal eccrine glands lose excess sodium, potassium, and chloride in sweat and calcium and phosphorus in saliva. Most symptoms relate to pulmonary disease and to a lesser degree to pancreatic insufficiency. Pancreatic insufficiency causes malabsorption with steatorrhea and malnutrition. Pulmonary problems present clinically as frequent recurrent infections (bronchopneumonia, bronchiectasis, and lung abscess), particularly with Staphylococcus aureus and/or Pseudomonas aeruginosa. These chronic infections may lead to lobar atelectasis, pneumothorax, hemoptysis, and mediastinal and subcutaneous emphysema. In patients with severe or long-standing disease, cor pulmonale and pulmonary hypertension occur. The typical clinical pattern is one of a progressively, chronically ill, malnourished child with steatorrhea and recurrent pulmonary infections. If pulmonary insufficiency is severe, cyanosis and clubbing of the fingers and toes may occur. With improved treatments, most children now survive and are relatively healthy into adolescence or adulthood. Lung disease, however, eventually reaches disabling proportions. Median cumulative survival is approximately 30 years. The diagnosis is based on the presence of one or more characteristic phenotypic features (e.g., typical chronic obstructive pulmonary disease, documented exocrine pancreatic insufficiency, or nutritional abnormalities) or a positive family history plus laboratory evidence of CFTR dysfunction. Laboratory abnormalities include two elevated sweat chloride (greater than 60 mEq/L) concentrations obtained on separate days, identification of two CF gene mutations, or an abnormal potential difference measurement across nasal epithelium.10,12 Ocular signs and symptoms seem to correlate most closely with the severity and rapidity of the pulmonary insufficiency. The most significant factor appears to be retention of carbon dioxide (hypercapnia), although chronic ischemia and often diabetes mellitus play a significant part in retinal pathology. The most common findings are in the retina and include venous dilation and tortuosity and retinal hemorrhages (posterior pole). Papilledema may occur, and intraretinal edema at the posterior pole is occasionally found, perhaps as a result of vascular incompetence. It may lead to a cystic macula or even a lamellar macular hole. Except for these latter findings, the retinal changes are mostly reversible with improvement in the pulmonary status. Ocular surface changes are generally minimal, but abnormal tear function and a propensity for blepharitis have been demonstrated. Xerophthalmia and nyctalopia have occasionally been reported as sequelae to vitamin A deficiency.13,14 There is also some evidence to support abnormal corneal endothelial function, especially when aggravated by hyperglycemia.15 Cystic fibrosis does not appear to affect aqueous humor formation. A study investigating intraocular pressure and the circadian pattern of aqueous flow found no significant difference between cystic fibrosis patients and normal people.16 Decreased lens transparency has been demonstrated with the use of an opacity lens meter in cystic fibrosis patients who had otherwise normal visual acuities of 20/20 and normal slit lamp examinations.17 Associated vitamin and mineral deficiencies may contribute to this finding. Neuro-ophthalmic manifestations include retrobulbar neuritis and preganglionic oculosympathetic paresis.18 Optic nerve functional deficiencies manifested by decreased contrast sensitivity, abnormal visually evoked potentials, and dyschromatopsia have been reported in association with antibiotic use (especially chronic chloramphenicol).19–21 Vitamin and mineral (particularly vitamin A) deficiencies and hypoxia may also contribute to optic nerve compromise, although the complete effects of these factors remains unclear.22,23 Treatment of cystic fibrosis remains directed toward preventing progressive pulmonary destruction and supplementing pancreatic insufficiency. The former is accomplished through the use of antibiotics, anti-inflammatory agents, and pulmonary physiotherapy, whereas the latter is achieved through enzyme replacement, dietary adjustments, and vitamins A, D, E, and K supplementation. Bilateral lung transplantation is a final therapeutic option for patients with preterminal disease. Although there are many inherent risks (graft rejection, infection, and intraoperative and postoperative complications) and challenges (candidate selection and donor organ availability), this procedure has improved survival rates and quality of life.24,25 Because cystic fibrosis is an autosomal recessive single gene defect, it presents an attractive model for innovative genetic and pharmacologic therapies. Examples include the pharmacologically enhanced function of mutated CFTR or the use of modified adenovirus, retrovirus, or nonviral cationic liposome vectors to introduce DNA that encodes normal CFTR into airway epithelial cells.26–29 Continued exploration of genetic and pharmacologic therapies holds much promise for controlling and potentially curing cystic fibrosis. |