Chapter 24
The Eye in Pulmonary Disorders
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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.

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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.

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1. Tso AY, Sinclair SH: Respiratory insufficiency. In Gold D, Weingesit TA (eds): The Eye in Systemic Disease. Philadelphia: JB Lippincott, 1990:491–495

2. Harris A, Arend O, Kopecky K et al: Physiological perturbation of ocular and cerebral blood flow as measured by scanning laser ophthalmoscopy and color doppler imaging. Surv Ophthalmol 38(Suppl):S81, 1994

3. Austen FK, Carmichael MW, Adams RD: Neurologic manifestations of chronic pulmonary insufficiency. N Engl J Med 257:579, 1957

4. Roff EJ, Harris A, Chung HS et al: Comprehensive assessment of retinal choroidal and retrobulbar haemodynamics during blood gas perturbation. Graefe's Arch Clin Exp Ophthalmol 237:984, 1999

5. Spalter HF, Bruce GM: Ocular changes in pulmonary insufficiency. Trans Am Acad Ophthalmol Otolaryngol 68:661, 1964

6. O'Halloran HS, Berger JR, Baker RS et al: Optic nerve edema as a consequence of respiratory disease. Neurology 53:2204, 1999

7. Marx JL: Cystic fibrosis gene is found. Science 245:923, 1989

8. Lemna WK, Feldman GL, Kerem BS et al: Mutational analysis for heterozygote detection and the prenatal diagnosis of cystic fibrosis. N Engl J Med 322:291, 1990

9. Stutts MJ, Boucher RC: Cystic fibrosis gene and functions of CFTR; implications of dysfunctional ion transport for pulmonary pathogenesis. In Yankaskas JR, Knowles MR (eds): Cystic Fibrosis in Adults. Philadelphia: Lippincott-Raven, 1999:3–25

10. Knowles MR, Friedman KJ, Silverman LM: Genetics, diagnosis, and clinical phenotype. In Yankaskas JR, Knowles MR (eds): Cystic Fibrosis in Adults. Philadelphia: Lippincott-Raven, 1999:27–42

11. Boat TF: Cystic fibrosis. In Behrman RE, Kliegman RM, Jenson HB (eds): Nelson Textbook of Pediatrics. 16th ed. Philadelphia: WB Saunders, 200:1315–1327

12. Rosenstein BJ, Cutting GR: The diagnosis of cystic fibrosis: A consensus statement. J Pediatr 132:589, 1998

13. Neugebauer MA, Vernon SA, Brimlow G et al: Nyctalopia and conjunctival xerosis indicating vitamin A deficiency in cystic fibrosis. Eye 2:360, 1989

14. Brooks HL, Driebe WT, Schemmer GG: Xerophthalmia and cystic fibrosis. Arch Ophthalmol 108:354, 1990

15. Sheppard JD, Orenstein DM, Chao CC et al: The ocular surface in cystic fibrosis. Ophthalmology 96:1624, 1989

16. McCannel CA, Scanlon PD, Thibodeau S et al: A study of aqueous humor formation in patients with cystic fibrosis. Invest Ophthalmol Vis Sci 33:160, 1992

17. Fama F, Castagna I, Palamara F et al: Cystic fibrosis and lens opacity. Ophthalmologica 212:178, 1998

18. Tomasi LG: Neurologic complications in cystic fibrosis. In Lloyd-Still JD (ed): Textbook of Cystic Fibrosis. New York: John Wright & Sons, 1983

19. Merz B: Capture of elusive cystic fibrosis gene prompts new approaches to treatment. JAMA 12:1567, 1989

20. Hanley RD, Huang NH, Marci CH et al: Optic neuritis and optic atrophy following chloramphenicol in cystic fibrosis patients. Trans Am Acad Ophthalmol Otolaryngol 74:1011, 1970

21. Spaide RF, Diamond G, D'Amico RA: Ocular findings in cystic fibrosis. Am J Ophthalmol 103:204, 1987

22. Leguire LE, Pappa KS, Kachmer ML et al: Loss of contrast sensitivity in cystic fibrosis. Am J Ophthalmol 111:427, 1991

23. Ansari EA, Sahni KS, Etherington C et al: Ocular signs and symptoms and vitamin A status in patients with cystic fibrosis treated with daily vitamin A supplements. Br J Ophthalmol 83:688, 1999

24. Sweet SC, Spray TL, Huddleston CB et al. Pediatric lung transplantation at St. Louis Children's Hospital 1990-1995. Am J Respir Crit Care Med 155:1027, 1997

25. Paradowski LJ, Egan TM: Lung transplantation for cystic fibrosis. In Yankaskas JR, Knowles MR (eds): Cystic Fibrosis in Adults. Philadelphia: Lippincott-Raven, 1999:195–219

26. Robinson CR: Is DNA destiny? A cure for cystic fibrosis. Clin Chest Med 19:527, 1998

27. Rubin BK: Emerging therapies for cystic fibrosis lung disease. Chest 115:1120, 1999

28. Caplen N, Alton E, Middleton P et al: Liposome-mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis. Nat Med 1:39, 1995

29. Crystal RG, McElvaney NG, Rosenfeld MA et al: Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis. Nat Genet 8:42, 1994

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