Chapter 41
Special Topics
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Part 1: Drugs Affecting Blood
Part 2: Vitamins

Part 1: Drugs Affecting Blood


The use of heparin and oral anticoagulants for ocular disease is largely of historical interest. These agents were prescribed for prophylaxis of “impending” occlusions and to halt the progression of macular degeneration.1 They were also used to treat preexisting hemorrhages and infarcts. The results were disappointing.2–4 Retinal occlusions and macular hemorrhages have occurred in patients receiving anticoagulants for nonocular disease.5–7 Other negative aspects were the need for frequent coagulation studies (e.g., biweekly) and the occurrence, despite the most conscientious efforts, of uncontrolled bleeding. Complications included massive intraocular hemorrhage, epistaxis, hematuria, hemarthrosis, hypermenorrhea, and death from intracranial hemorrhage. Duff and co-workers treated 33 patients with occlusive retinal vascular disease for mean periods of 7 days (heparin) and 3 months (bishydroxycoumarin).2 Twenty-eight percent had unexpected bleeding.

Patients using coumadin have an increased risk of hyphema if intraocular surgery is performed.8 Short-term discontinuation of the drug may not prevent this problem, despite a normal laboratory prothrombin time. The reason is that the prothrombin time is dependent on either the prothrombin level or the factor VII level. The latter returns to normal before the former.

Heparin has been given intravenously or intravitreally during surgery to prevent postvitrectomy fibrin membranes.9 There was no significant effect using either an intravenous bolus of 10,000 IU heparin or an intravitreal infusion solution of 5 IU heparin/mL. An intravitreal solution containing 10 IU heparin/mL produced significantly less fibrin formation but significantly more bleeding. Overall, heparin appeared to be of little value.


Streptokinase, streptodornase, and urokinase are enzymes with little, if any, intrinsic thrombolytic activity. However, they cause the conversion of plasminogen (profibrinolysin) to plasmin (fibrinolysin). Plasmin breaks-up thrombi by cleaving fibrinogen. Streptokinase and streptodornase are derived from β-hemolytic streptococci. Urokinase is obtained from urine and is less antigenic; approximately 400 units/day are excreted by the adult male. Systemic administration frequently causes severe bleeding. γ-Aminocaproic acid is the specific antidote.

Kohner and co-workers studied patients with central vein occlusions presenting within 1 week of the onset of symptoms.10 Eighteen were treated with intravenous streptokinase, 600,000 units in 300 mL saline or dextrose. This was administered during a 30-minute interval and was followed by 100,000 units/hr for 72 hours. Sixty thousand units of heparin was given over the next 48 hours, and oral warfarin was begun and maintained for 6 months. A control group of 20 patients received no treatment. There was no significant difference in the visual acuities of the two groups at 1 year. Three treated patients had massive vitreous hemorrhages, two had severe allergic reactions to streptokinase consisting of fever, rash, and arthralgia, and one had neovascularization glaucoma.

Thrombolytic agents have been used with greater success in traumatic hyphemas. Sinskey and Krichesky injected blood into the anterior chambers of rabbits.11 One hour later, 50 μL of a solution containing streptokinase and streptodornase, 3125 units/mL, was injected into some of these eyes. Control rabbits received saline. During the next 48 hours, there was faster absorption of blood in the enzyme-treated eyes. Scheie and co-workers prepared plasmin by exposing human serum plasminogen to streptokinase.12 Anterior chamber clots were lysed. These authors stressed, as have others, that it was not necessary for all the clot to be removed.

Urokinase, 5000 units/mL, perfused onto rabbit corneal endothelium for 3 hours did not produce stromal swelling or alter endothelial cell appearance on scanning electron microscopy.13 Leet injected human blood into rabbit anterior chambers.14 Four to 6 hours later, urokinase, saline, or nothing was injected. Untreated eyes required up to 3 weeks for their hyphemas to clear. Urokinase-treated eyes cleared within 10 days. The length of time needed for saline-treated eyes to clear was intermediate. After traumatic hyphemas, anterior chamber clots in human eyes have been removed using urokinase. However, the visual results were often poor because of the nature of the injuries. Pierse and Le Grice were successful in removing the clots in eight human eyes.15 Rakusin reported 20 patients in whom saline irrigation of the anterior chamber failed.16 Progressive lysis of the clots was achieved using urokinase solutions of 2500 to 5000 units/mL water. The anterior chambers were slowly irrigated with 0.3 mL enzyme solution. After 3 minutes, the urokinase was washed out with saline. This sequence was repeated five times. If any clot remained after the last infusion, the enzyme was not irrigated out. No complications from therapy were noted, and all clots were removed within 48 hours. Because more than 60% of hyphemas will clear with saline, Rakusin suggested that urokinase be reserved for the failures.

Urokinase has been injected into the vitreous cavity in an attempt to clear longstanding vitreous hemorrhages.17–21 Two-tenths to 0.6 mL containing 2500 to 25,000 Ploug units have been used. The results, in general, have been disappointing, probably because fibrin clots and plasminogen were no longer present in the vitreous. However, Chapman-Smith and Crock found marked improvement in 10 of 27 patients treated.20 Transient complications were frequent. Sterile hypopyon, persisting up to 6 days, was common and occurred in up to 81% of eyes. Temporary elevations in intraocular pressure, reaching 36 mm Hg, reversible increases in central corneal thickness, by a mean 0.11 mm, and depressions in the electroretinogram, electrooculogram, and visual-evoked potential have occurred.

Tissue plasminogen activator (tPA) is an enzyme that converts plasminogen to plasmin. Plasminogen activators have been identified in human lacrimal fluid22 and aqueous humor23 and primate trabecular endothelium, corneal endothelium, and iris.24 Recombinant gene techniques have allowed commercial production of human tPA. This human tPA has several theoretical advantages over streptokinase and urokinase. Human tPA is markedly active in the presence of fibrin (i.e., in clots) and is relatively inactive in the presence of circulating fibrinogen. Major bleeding complications should therefore be less likely with tPA. Further, tPA could be injected intravenously, whereas streptokinase and urokinase should require threading a catheter into the vicinity of the clot to localize their activities. The time lost placing this catheter could be crucial. TPA has a shorter half-life, less than 10 minutes, which would allow a more rapid reversal of any bleeding complication. However, these potential advantages of tPA have not been convincingly demonstrated in acute myocardial infarction; tPA has not reduced the incidence of major bleeding complications, possibly because of concomitant use of heparin. Heparin is administered with all of the fibrinogen-lysing enzymes and could mask any advantage of tPA. The intracerebral hemorrhages reported with tPA use25,26 have been in patients receiving heparin. Meanwhile, systemic intravenous administration of streptokinase, without a catheter, has been shown effective and acceptably safe. The short half-life of tPA could be considered a therapeutic disadvantage that leads to re-occlusion, and tPA is far more expensive than the other thrombolytic agents.

In experimental animals, intracameral injections of tPA markedly reduced the time needed for total hyphemas to clear27 but increased the incidence of rebleeding.28 Laser-induced retinal arterial thrombi were effectively lysed by intravenous tPA.29 Intravitreal injection of the drug was somewhat effective in more rapidly clearing hyaloid blood but was associated with an increased incidence of retinal traction detachments.30 An as-yet unidentified excipient of the vehicle solution was retinotoxic.31

TPA has been used to clear subconjunctival clots after glaucoma-filtering surgery32 and to dissolve postvitrectomy fibrin pupillary blocks.33 Twenty-five micrograms of tPA injected into the anterior chambers or vitreous cavities of 23 eyes was associated with hyphema in two patients and with corneal thickening in two patients.34 Perfusing the posterior surfaces of human corneas in vitro with tPA did not produce endothelial cell damage.35

A reconstituted vial of tPA, 50 mg in 50 mL water, can be further diluted in sterile balanced saline, and, if stored at -70°C, will remain active for at least 1 year.36


Aspirin may be of value in reducing the frequency of amaurosis fugax, cerebral transient ischemic attacks, and retinal strokes caused by platelet-fibrin emboli from atherosclerotic carotid artery plaques. Aspirin is less effective than carotid endarterectomy, but the risks and complications of therapy are also reduced.

The first step in the formation of platelet emboli is platelet aggregation. Platelet aggregation is abnormally increased in patients with retinal artery occlusions.37 Aggregation is initiated by the release of the platelet-formed prostaglandin, thromboxane A2. Aspirin blocks thromboxane A2 synthesis.38 Aspirin also increases blood fibrinolytic activity.39 Unfortunately, aspirin inhibits the formation of another prostaglandin, prostacyclin.40 Prostacyclin (PGI2) is synthesized in blood vessel walls. Its release inhibits platelet aggregation.41 Both thromboxane A2 and prostacyclin synthesis are dependent on the activity of cyclo-oxygenase, an enzyme irreversibly inhibited by aspirin acetylation.

The Food and Drug Administration (FDA) has recommended 650 mg aspirin twice per day or 325 mg four times per day. However, because doses as low as 20 mg/day have been shown to effectively inhibit platelet prostaglandin synthesis,42 the FDA recommendation may be too high. The most effective aspirin administration may be enteric-coated preparations, one 325-mg tablet every other day.43–46 Not only is gastric irritation avoided but also are only small amounts of aspirin absorbed from the gastrointestinal tract. These small amounts of aspirin perfuse the portal circulation and permanently inactivate the cyclo-oxygenase of the platelets there but cannot escape beyond the liver into the peripheral circulation. This protects the peripheral vasculature endothelium cyclo-oxygenase from aspirin inactivation. The result is that platelet thromboxane synthesis is suppressed while peripheral arteriolar prostacyclin synthesis is not.

The Canadian cooperative study considered only stroke or death and not retinal artery occlusion.47 It found that men, but not women, benefited from aspirin therapy. An American study failed to show significant benefit from aspirin, 1300 mg/day, when the incidences of retinal infarction, continued ischemic attacks, stroke, and death were considered separately.48 However, when the data from all four categories were pooled, aspirin appeared to exert a significant beneficial effect. By the end of 6 months of therapy, the group receiving aspirin had a 19.2% incidence of “unfavorable outcome” and the placebo group had a 44.2% incidence. The need to pool different categories to reach significance has been criticized.49 A subsequent controlled study has indicated that in patients with amaurosis fugax and an ipsilateral partially occluded carotid artery, aspirin therapy was beneficial in decreasing the frequency of amaurotic attacks, retinal infarction, cerebral infarction, and death.50 Although heparin and coumadin may initially be more effective than enteric-coated aspirin in reducing the frequency of amaurotic attacks, they do not appear any more effective in preventing infarctions or death.51

Prostacyclin not only prevents platelet aggregation but also disperses, in vitro, platelets that have already aggregated. For this reason, Zygulska-Mach and co-workers treated three patients with partial central vein occlusions and vision of 20/200 (or 6/60 metric equivalent) or less with prostacyclin infusions, 5 ng/kg per minute for 72 hours.52 In one patient there was significant visual improvement to 20/40 (6/12). There was little change in the second patient, and the third patient became blind.

Aspirin and other cyclo-oxygenase inhibitors would appear contraindicated in the treatment of pain in patients with traumatic hyphema or in those undergoing ocular surgery. Rebleeding after traumatic hyphema has been reported to occur more frequently if aspirin had been ingested before or after the initial injury.53 Ganley and co-workers54 found that seven of 12 patients who took aspirin after the initial trauma had a recurrent hyphema, whereas only one of 13 patients who did not take aspirin rebled. However, when Marcus and co-workers55 performed a randomized, placebo-controlled prospective study of 51 patients, 23 of whom received aspirin, 1500 mg per day for 5 days, beginning when admitted for traumatic hyphema, there was no significant increase in rebleeding.

Acute retinal necrosis, a disease associated with infection by the herpes family of viruses, especially herpes zoster, has been reported to be associated with platelet hyperaggregation.56 Aspirin was found of some limited value in one report but not in another.57


Dobesilate (dihydrobenzenesulfonate) reduces blood vessel permeability. Grignolo and co-workers found fewer microaneurysms and reduced leakage in the iris angiograms of diabetic patients administered calcium dobesilate, 1 g/day, for 4 to 12 months.58 In 30 treated patients, improvement was found in 23% at 4 months and in 38% at 12 months. Ten percent showed progression, whereas in a control group of 18 untreated patients, 41% showed progression. However, Stamper and co-workers, in a well-controlled and masked study of diabetic patients with nonproliferative retinopathy given calcium dobesilate, 0.75 to 1.0 g/day for 6 to 12 months, found no benefit.59 Exudates, hemorrhages, microaneurysms, and leakage were evaluated using fluorescein angiography and fundus photography.



Recurrent hemorrhaging into the anterior chamber often occurs 2 to 5 days after the initial trauma. It has been attributed to resorption of the fibrin clots formed after the first episode. The antifibrinolytic drugs γ-aminocaproic acid (Amicar) and tranexamic acid have been used to prevent clot resorption. They are structurally related. γ-Aminocaproic acid is a carboxylic acid similar to lysine except that it lacks an amino group; tranexamic acid is a cyclic analog. Both act as competitive inhibitors of the blood components that convert plasminogen to plasmin. The latter lyses fibrin clots. These agents also lower blood plasminogen levels and inhibit the activity of formed plasmin. γ-Aminocaproic acid appears to be more toxic and has been associated with rhabdomyolysis and renal failure,60,61 inhibition of ejaculation,62 and delirium.63 Tranexamic acid is, on a weight basis, 18- to 20-times more potent than γ-aminocaproic acid. γ-Aminocaproic acid has peak antifibrinolytic activity 15 to 60 minutes after peak plasma concentrations are achieved after intravenous administration. Half the drug is eliminated within 5 hours, primarily by the kidneys.64 Continuous use of large doses may cause a paradoxical increased bleeding tendency, and a rebound increase in fibrinolytic activity can occur within 72 hours of discontinuing the drug.65 This latter phenomenon may explain why some patients with traumatic hyphemas exhibit rapid clot dissolution 1 to 4 days after γ-aminocaproic acid is discontinued.66 Significant amounts of γ-aminocaproic acid will penetrate the rabbit cornea if given topically in concentrated solutions containing polyvinyl alcohol or carboxypolymethylene, but the value of this observation has not been tested in humans.67 These agents have been used to prevent recurrent subarachnoid hemorrhages in patients with intracranial aneurysms. The results have been conflicting. Chandra68 and Kaste and Ramsay69 gave tranexamic acid, 6 g/day, for up to 3 weeks. The former found it of value, whereas the latter did not. Although tranexamic acid reduced rebleeding after subarachnoid hemorrhage, Vermeulen and co-workers70 did not find that the drug altered their mortality rate. There was an offsetting increase in ischemic cerebral infarctions. Tranexamic acid did reduce the mortality rate from acute upper gastrointestinal bleeding in a double-masked, randomized, placebo-controlled trial.71

Beneficial results have been reported in traumatic hyphemas. In a masked study, Crouch and Frenkel gave 32 patients oral γ-aminocaproic acid, 100 mg/kg, every 4 hours for 5 days, and 27 patients received a placebo.72 Three percent of the treated group rebled, whereas 33% of the placebo group had a recurrence. The initial clot remained in the anterior chamber a significantly longer time in the γ-aminocaproic acid group (4.0 vs 2.8 days). These authors stressed that treatment should start as soon as possible. Unfortunately, the visual outcome of the treated group was not significantly better than the placebo group, probably because of the severity of the original trauma. Two other prospective, randomized studies have confirmed the value of γ-aminocaproic acid in reducing the risk of rebleed after traumatic hyphema.73,74 An unfortunate side effect of the use of large (e.g., 100 mg/kg every 4 hours) oral doses of γ-aminocaproic acid is emesis. Vomiting should be avoided because it could lead to rebleeding. Unfortunately, reducing the dose of γ-aminocaproic acid in half, to 50 mg/kg, did not reduce the incidence of emesis, although this lower dose was still effective in preventing rebleeding.75

ε-Aminocaproic acid treatment was reported effective in terminating postdacryocystorhinostomy hemorrhage in a boy with thrombocytopenia from dyskeratosis congenita.76 The drug was also effective in preventing immediate postoperative vitreous hemorrhaging after vitrectomies in proliferative diabetic eyes. γ-Aminocaproic acid was begun 1 hour before surgery and continued for 4 days.77 However, this short-term treatment was not beneficial when eyes were examined 2 to 6 weeks after surgery. Treated and nontreated subjects had equally severe vitreous hemorrhages. This equalization was attributed to late bleeding in the treated group and spontaneous clearing of hemorrhage in the untreated group.

Tranexamic acid has been used successfully to prevent rebleeding after traumatic hyphemas.78 The drug has long been in use in the Scandinavian countries. Varnek and co-workers reported favorable results in patients given oral tranexamic acid, 25 mg/kg, three times per day every other day for 6 days.79 Bramsen had used this same regimen in 72 patients and reported that only 1.4% rebled.79a The drug was first marketed in the United States in 1987. Unfortunately, the FDA-approved labeling emphasized potential ocular toxicity. These fears were based on retinal toxicity in laboratory animals fed doses three-times or more those that the patients would receive. Similar retinal degeneration had not been documented in the more than 4.5 million patients treated with tranexamic acid.80


Repeated edema of the eyelids can lead to blepharochalasis. There are two forms of recurrent angioedema, hereditary and idiopathic. Hereditary angioedema is associated with a deficiency of the enzyme that inhibits the activation of multiple blood factors (e.g., the first component of complement [C1 esterase], Hageman factor, kalli-krein, plasmin, and the coagulation component PTA).81 The antifibrinolytic drugs inhibit plasmin formation and plasmin activation of the first and/or second components of complement. The activated second component is a vasoactive substance that can produce angioedema when injected locally. γ-Aminocaproic acid and tranexamic acid are relatively effective in preventing and terminating attacks of hereditary angioedema. In daily doses of 1.5 to 3.0 g/day, tranexamic acid decreased their incidence in 12 of 15 patients. Only two patients became completely free of attacks.82 A more effective therapy is danazol, a weak androgen that induces synthesis of C1 esterase inhibitor.83

Idiopathic angioedema attacks respond to corticosteroids, antihistamines, and epinephrine. Tranexamic acid, 1 g orally three to four times per day initially and then tapered to 0.5 g twice per day has prophylactic value.84


Rabbit primary aqueous humor contains approximately 8% as much plasminogen as does serum.85 Systemic administration of γ-aminocaproic acid, 0.25 g/kg, inhibited anterior chamber fibrinolytic activity.86 In the human eye, fibrinolytic activity has been identified in the vessels of the ciliary body and iris and in the endothelium of the canal of Schlemm.87

It has been proposed that aqueous humor outflow is controlled by fibrinolytic activity. A reduction in fibrinolytic activity would allow fibrin to accumulate and block aqueous humor egress. Outflow resistance is reduced in monkey eyes when the anterior chambers are perfused with plasmin. However, urokinase is without effect.88,89 When patients were given tranexamic acid, there was no effect on intraocular pressure.90


Aqueous humor plasminogen may control the corneal endothelial pump. The mechanism by which it acts has not been stated. Hull and co-workers were unable to reverse in vitro swelling of rabbit corneas by perfusion with 1 mM or 10 mM tranexamic acid.91 However, a number of authors claim beneficial results in human studies. Central corneal thickness in Fuchs endothelial dystrophy92 and after cataract surgery93 was reduced after 1 g tranexamic acid three times per day in the former study and 25 mg/kg three times per day in the latter. Olsen and co-workers gave 10 normal subjects acetylsalicyclic acid or tranexamic acid, 1 g three times per day, in a masked, crossover study.94 Central corneal thickness increased in response to aspirin and decreased in response to tranexamic acid. However, Nissen and Ehlers95 were unable to show a corneal detergescent effect after cataract surgery and anterior chamber pseudophake implantation. Patients received one of three regimens: tranexamic acid, 1 g the night before surgery and 3 g daily for the next 5 days; an oral nonsteroidal antiinflammatory drug (naproxen); or both. There were no significant differences in the corneal thicknesses of the three groups.95


Thrombin, 100 units/mL infusion fluid, reduced intraocular bleeding time during vitreous surgery from a mean value of 180 ± 24 seconds to 27 ± 7 seconds (mean ± SD) without affecting corneal endothelial cell viability or producing lens opacities. ERG responses to light were slightly suppressed in treated eyes.96 These investigators then performed a prospective masked study in patients with diabetic retinopathy who were undergoing vitreous surgery.97 Use of 100 units/mL bovine thrombin infusion fluid significantly reduced bleeding time from 112 seconds to 12 seconds, but 20% of treated eyes had increased postoperative inflammation with hypopyon. A similar reduction in the duration, and quantity, of intraoperative bleeding during vitreous surgery was reported for eyes with stage V retinopathy of prematurity,98 without there being an associated increase in inflammation and hypopyon. This reduction of bleeding into the vitreous cavity facilitated surgery, but the commercially available thrombin preparations were made for topical, not ocular, use. As such, they may contain particulate contaminants and additives (e.g., glycine) that could be harmful to the eye.99

Packer and co-workers100,101 have found that instillation of 0.5 to 0.75 mL sodium hyaluronate into the vitreous cavity at the conclusion of vitrectomy reduced hemorrhage in the immediate postoperative period; 50% of eyes had clear media. However, in vitro studies showed that sodium hyaluronate both prolonged the prothrombin time and reduced platelet aggregation (i.e., had anticoagulant effects). Chondroitin sulfate also had an anticoagulant effect. Perhaps these drugs reduce bleeding in the clinical situation by acting as physical barriers.

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68. Chandra B: Treatment of subarachnoid hemorrhage from ruptured intracranial aneurysm with tranexamic acid: A double-bind clinical trial. Ann Neurol 3:502, 1978

69. Kaste M, Ramsay M: Tranexamic acid in subarachnoid hemorrhage: A double-bind study. Stroke 10:519, 1979

70. Vermeulen M, Lindsay KW, Murray GD, et al: Antifibrinolytic treatment in subarachnoid hemorrhage. N Engl J Med 311:432, 1984

71. Barer D, Ogilvie A, Henry D, et al: Cimetidine and tranexamic acid in the treatment of acute upper-gastrointestinal tract bleeding. N Engl J Med 308:1571, 1983

72. Crouch ER, Frenkel M: Aminocaproic acid in the treatment of traumatic hyphema. Am J Ophthalmol 81:355, 1976

73. McGetrick JJ, Jampol LM, Goldberg MF, et al: Aminocaproic acid decreases secondary hemorrhage after traumatic hyphema. Arch Ophthalmol 101:1031, 1983

74. Kutner B, Fourman S, Brein K, et al: Aminocaproic acid reduces the risk of secondary hemorrhage in patients with traumatic hyphema. Arch Ophthalmol 105:206, 1987

75. Palmer DJ, Goldberg MF, Frenkel M, et al: A comparison of two dose regimens of epsilon aminocaproic acid in the prevention and management of secondary traumatic hyphemas. Ophthalmology 93:102, 1986

76. Woog JJ, Dortzbach RK, Wexler SA, Shahidi NT: The role of aminocaproic acid in lacrimal surgery in dyskeratosis congenita. Am J Ophthalmol 100:728, 1985

77. deBustros S, Glaser BM, Michels RG, Aver C: Effect of γ-aminocaproic acid on postvitrectomy hemorrhage. Arch Ophthalmol 103:219, 1985

78. Uusitalo RJ, Ranta-Kemppainen L, Tarkkanen A: Management of traumatic hyphema in children: An analysis of 340 cases. Arch Ophthalmol 106:1207, 1988

79. Varnek L, Dalsgaard C, Hansen A, Klie F: The effect of tranexamic acid on secondary hemorrhage after traumatic hyphema. Acta Ophthalmol 58:787, 1980

79a. Bramsen T: Traumatic hyphaema treated with the antifibrinolytic drug tranexamic acid. Acta Ophthalmol 54:250, 1976

80. Mindel JS: Problems in the use of tranexamic acid by ophthalmologists. Arch Ophthalmol 107:486, 1989

81. Ratnoff OD, Pensky J, Ogston D, Naff GB: The inhibition of plasmin, plasma kallikrein, plasma permeability factor and the C'1r component of the first compound of complement by serum C'1 esterase inhibitor. J Exp Med 129:315, 1969

82. Marasini B, Cicardi M, Martignoni GC, Agostoni A: Treatment of hereditary angioedema. Klin Wochenschr 56:819, 1978

83. Rosen FS, Austen KF: Androgen therapy in hereditary angioneurotic edema. N Engl J Med 295:1476, 1976

84. Thompson RA, Felix-Davies DD: Response of “idiopathic” recurrent angioneurotic oedema to tranexamic acid. Br Med J 2:608, 1978

85. Pandolfi M, Nilsson IM, Martinsson G: Coagulation and fibrinolytic components in primary and plasmoid aqueous humor of rabbit. Acta Ophthalmol 42:820, 1964

86. Pandolfi M, Nilsson IM, Nilehn JE: On intraocular fibrinolysis. Thromb Diath Haemorrh 15:161, 1966

87. Pandolfi M, Kwaan HC: Fibrinolysis in the anterior segment of the eye. Arch Ophthalmol 77:99, 1967

88. Pandolfi M: Fibrinolysis and outflow resistance in the eye. Am J Ophthalmol 64:1141, 1967

89. Saiduzzafar H: Tissue fibrinolytic activity in the anterior segment of the eye, as related to aqueous outflow. Exp Eye Res 10:297, 1970

90. Bramsen T: A double-blind study on the influence of tranexamic acid on the intraocular pressure and the central corneal thickness after trabeculectomy for glaucoma simplex. Acta Ophthalmol 56:998, 1978

91. Hull DS, Green K, Buyer JG: Tranexamic acid and corneal deturgescence. Acta Ophthalmol 57:252, 1979

92. Bramsen T, Ehlers N: Bullous keratopathy (Fuch's endothelial dystrophy) treated systemically with 4-transaminocyclohexano-carboxylic acid. Acta Ophthalmol 55:665, 1977

93. Bramsen T, Corydon L, Ehlers N: A double-blind study of the influence of tranexamic acid on the central corneal thickness after cataract extraction. Acta Ophthalmol 56:121, 1978

94. Olsen T, Ehlers N, Bramsen T: Influence of tranexamic acid and acetylsalicylic acid on the thickness of the normal cornea. Acta Ophthalmol 58:767, 1980

95. Nissen JN, Ehlers N: No additive effect of tranexamic acid and naproxen on corneal deswelling. Acta Ophthalmol 64:291, 1986

96. deBustros S, Glaser BM, Johnson MA: Thrombin infusion for the control of intraocular bleeding during vitreous surgery. Arch Ophthalmol 103:837, 1985

97. Thompson JT, Glaser BM, Michels RG, deBustros S: The use of intravitreal thrombin to control hemorrhage during vitrectomy. Ophthalmology 93:279, 1986

98. Blacharski PA, Charles ST: Thrombin infusion to control bleeding during vitrectomy for stage V retinopathy of prematurity. Arch Ophthalmol 105:203, 1989

99. McDermott ML, Edelhauser HF, Mannis MJ: Intracameral thrombin and the corneal endothelium. Am J Ophthalmol 106:414, 1988

100. Packer AJ, Folk JC, Weingeist TA, Goldsmith JC: Procoagulant effects of intraocular sodium hyaluronate. Am J Ophthalmol 100:479, 1985

101. Packer AJ, McCuen BW II, Hutton WL, Ramsay RC: Procoagulant effects of intraocular sodium hyaluronate (Healon) after phakic diabetic vitrectomy: A prospective, randomized study. Ophthalmology 96:1491, 1989

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Part 2: Vitamins


Vitamin A (retinol) is a fat-soluble alcohol important to corneal and retinal function. Humans ingest preformed vitamin A or its precursors, carotenoids. β-Carotene is the most common and most active of the carotenoids. One international unit (IU) of β-carotene is defined as having the same activity as 1 IU vitamin A; 0.600 μg trans-β-carotene equals 0.300 μg trans-β-retinol.

Vitamin A is absorbed from the intestine and stored in the liver in various ester forms (e.g., retinyl acetate). Vitamin A is normally transported in the blood bound to a specific protein; one molecule of retinol is bound to one molecule of retinol-binding protein. The pigment epithelium may store vitamin A.1 Human retina has two different receptors for vitamin A.2 Once in the retina, vitamin A aldehyde (retinal) is incorporated into the visual pigments. Its active form here is in the 11-cis configuration. When light strikes the retina, the 11-cis form is converted to the trans form and the latter is released by the photoreceptors to enter the pigment epithelium cells. Here it is reconverted to the cis form. This shuttling of vitamin A between photoreceptors and pigment epithelium occurs via a glycoprotein, interstitial retinol-binding protein, which is synthesized by the photoreceptors.3 Vitamin A aldehyde is irreversibly oxidized to vitamin A acid (retinoic acid). Different intracellular proteins bind retinol and retinoic acid, which suggests each has a different physiologic role. Retinoic acid can partially overcome systemic vitamin A deficiency, but it will not correct the retina's dysfunction. Bowling and Wald observed that vitamin A acid allowed rats to grow normally, except that their retinas continued to deteriorate.4

The suggested daily requirement for vitamin A has been revised downward because of the known toxicity of retinoids in early pregnancy. The recommended intake for adults is the equivalent of 1200 IU trans-β-carotene in men and 1000 IU trans-β-carotene in women.5


The lower limits of normal are approximately 65 IU/100 mL plasma and 135 IU/g liver. Night blindness usually occurs before xerophthalmia. In night blindness, there is a reduction in the electroretinogram and ultimately death of the photoreceptor cells. Vitamin A deficiency in the rat has been shown to decrease the rate of rod outer segment synthesis.6 The rate of recovery after vitamin A therapy is rapid. Brown and co-workers reported a 33-year-old man with night blindness after intestinal bypass surgery.7 Initially, his electroretinogram was markedly reduced and his visual field constricted to 10 degrees. Three days after beginning oral therapy with 25,000 IU vitamin A, four times per day, the patient's electroretinogram, dark adaptation curve, and visual fields were normal. However, it took 7 months from the time of receiving 500,000 units of vitamin A parenterally for a patient8 with a deficiency from intestinal bypass surgery to regain normal rod sensitivity, dark adaptation, and scotopic ERG responses.

Xerophthalmia, or dryness of the eye, can also lead to loss of vision. The dryness is caused by defective growth and differentiation of conjunctival and corneal epithelial cells. There is a marked decrease in the synthesis of glycoproteins and glycosaminoglycans.9 Keratinization and punctate epitheliopathy occur first, followed by stromal edema and keratomalacia. Vitamin A therapy results in an increased rate of glycosamine incorporation into glycoproteins.10,11 Mucus-secreting goblet cells are markedly reduced in number in xerophthalmia, but their absence may not be a key factor. The cornea begins to heal 1 to 4 days after starting systemic vitamin A therapy, even though conjunctional goblet cells cannot be found for more than 1 week.12

The British Medical Research Council found that 1330 IU of vitamin A restored scotopic vision in depleted subjects, but because the serum and liver vitamin A levels remained low, it suggested a minimum adult daily allowance of 2500 IU.13 When 200,000 IU (60 mg) vitamin A is given orally as a single dose every 6 months to children 1 to 4 years of age, satisfactory serum levels are obtained in areas where deficiency is prevalent.14

Therapy for night blindness and xerophthalmia usually begins with intramuscular administration of vitamin A, 100,000 IU (30 mg) per day for 1 or 2 days. Care must be taken to avoid inducing toxicity by overdosing. Intramuscular therapy has been preferred because of the fear that the diarrhea and low serum protein that often accompany this deficiency would impair oral absorption. The latter is caused by a generalized nutritional deficiency associated with hypovitaminosis A, and patients may have inadequate retinol-binding protein. Sommer and co-workers15 treated children with either 200,000 IU oil-miscible vitamin A orally or 100,000 IU water-miscible vitamin A intramuscularly; both groups received a second dose of 200,000 IU, orally, the next day. There was no difference in their responses even though the serum levels were significantly higher during each of the first 7 days after intramuscular treatment. With either treatment, there was improvement or recovery in 95% of corneas within 6 to 8 days. When children with diarrhea or hypoproteinemia, defined as less than 3 g albumin/100 mL serum, were analyzed, there was still no difference using either form of treatment. The reason appeared to be that only vitamin A bound to retinol-binding protein was therapeutic. Both oral and intramuscular treatment saturated the carrying capacity of this protein. A single, oral dose of 200,000 IU improved 40% of corneas within 3 days and produced complete resolution within 4 weeks.16 Those few eyes that had a delayed or transient response to vitamin A appeared to be in patients with severe generalized protein deficiency, irrespective of the serum retinol-binding protein level.17

Smaller doses are effective if given for a prolonged period. A patient with a serum vitamin A level of 20 IU/100 mL had a conjunctival biopsy demonstrating total absence of goblet cells. After 3 weeks of 25,000 IU/day oral therapy, his serum vitamin A level was 150 IU/100 mL. Goblet cells and reduced keratinization were evident in the conjunctival biopsy. After 8 weeks of treatment, his serum vitamin A level was 210 IU/100 mL and the epithelial structures had returned to normal.18 In the past, the presence and disappearance of Bitot's spots have been assumed to be synonymous with, respectively, the presence and correction of a vitamin A deficiency. However, occasionally, Bitot's spots represent a permanent alteration in the conjunctiva and, as such, do not correlate with the patient's vitamin A nutritional status.19,20

Because corneal disease may not respond for several days to systemic treatment, concomitant topical therapy has been investigated. Pirie treated rat xerophthalmia with topical retinoic acid and obtained good results.21 Sommer and Emran treated eight children unilaterally with up to 10 drops/day of 0.1% retinoic acid in arachis oil;22 the children also received systemic vitamin A therapy. Improvement was believed to occur more rapidly in the eyes receiving topical therapy. However, Bors and Fells reported minimal improvement in patients given vitamin A eye drops.23 For example, one patient with low-serum vitamin A (13 IU/100 ml), conjunctival xerosis, and corneal ulcers was given vitamin A eye drops, 150,000 IU/mL, every 2 hours for 2 days. Photophobia and ocular discomfort were reduced, but it was not until 3 to 4 days after receiving 200,000 IU vitamin A intramuscularly that dramatic improvement occurred.

Infants fed a diet deficient in vitamin A can develop hydrocephalus and a syndrome mimicking the pseudotumor cerebri of vitamin A toxicity.24,25 There is increased intracranial pressure, bulging of the fontanelles, and separation of the cranial sutures. Calves fed a diet deficient in vitamin A will also develop increased cerebrospinal fluid pressure.


Both vitamin A deficiency and retinitis pigmentosa produce a reduced electroretinogram and night blindness. A deficiency has been identified in the esterification of vitamin A in pigment epithelial cells of RCS rats with an inherited retinal dystrophy.27 Co-administration of vitamins A and E may retard the progression of the retinitis pigmentosa seen in abetalipoproteinemia.28 These facts suggest that abnormal retinoid metabolism may play a role in the cause of retinitis pigmentosa. However, vitamin A deficiency does not have the ophthalmoscopic picture of retinitis pigmentosa, although small defects in the pigment epithelium and retina have been reported.23,29 These lesions disappeared 2 to 3 months after therapy was begun. Patients with retinitis pigmentosa have vitamin A and β-carotene serum levels that are not significantly different from control groups.30,31 Raki had found small and probably not significant reductions in the retinol-binding protein levels of patients with retinitis pigmentosa.32 In a more exhaustive study of various genetic forms of retinitis pigmentosa (i.e., autosomal-recessive, autosomal-dominant, sex-linked recessive, Lawrence-Moon-Bardet-Biedl syndrome, Usher's syndrome, and Winkelman's syndrome), the levels of carrier protein were not significantly different from normal controls.33

In a masked study, Chatzinoff and co-workers concluded that vitamin A therapy was of no value in retinitis pigmentosa.34 Twenty-seven patients received 11-cis-vitamin A and 30 “control” patients received trans-vitamin A for 3 years. Both groups received twice per week intramuscular injections of 100,000 IU of their respective drugs. Seventy-eight percent of the group receiving 11-cis-vitamin A had an additional loss of vision of one or more lines and/or progressive visual field loss compared with 57% of the group receiving trans-vitamin A.

Gouras and co-workers found that two patients with abetalipoproteinemia had serum vitamin A deficiencies, with levels below 67 IU/100 mL, despite apparently normal diets.35 The electroretinogram and vision of both patients were impaired. A single oral dose of 200,000 IU to one patient and two doses to the other patient reversed these changes. Cone function recovered more rapidly than rod function.


Corneal epithelial healing occurred more rapidly in rabbits treated for 3 days with topical vitamin A acid ointment 0.1% or 1% twice per day.36 When herpes simplex keratitis was stimulated by subconjunctival injections of triamcinolone acetate, rabbits receiving multiple intraperitoneal injections of 100,000 IU vitamin A just before and up to 15 days after applying the virus had significantly less severe epithelial and stromal disease.37 Corneal endothelial cell migration also appeared to be stimulated by retinoic acid.38 Trans-retinoic acid appeared more effective than cis-retinoic acid.39

Based on these findings, topical all-trans-retinoic acid (tretinoin), 0.01% to 0.1% in arachnis oil or ointment, and retinol palmitate were tested in a variety of human disorders characterized by squamous metaplasia and keratinization of the conjunctival epithelium: keratoconjunctivitis sicca, ocular pemphigoid, radiation-induced sicca, superior limbic keratoconjunctivitis, Stevens-Johnson syndrome, and Bowen-like epithelial dysplasia 40–43 The initial reports were variably favorable. However, subsequent studies, including one that was multicentered and masked, failed to confirm the initially positive results.44,45


Excessive intake of vitamin A can produce toxicity. Evidence exists that the condition occurred in prehistoric man.46 Symptoms and findings include papilledema and paresis of the sixth cranial nerves from elevated intracranial pressure (pseudotumor cerebri); yellow skin with an erythematous eruption, scaling, and fissures; migratory bone pain; sparse hair; enlarged liver and spleen; exophthalmos; hypoprothrombinemia; irritability; and weight loss.

Work in rats suggested that excess vitamin A circulated in the serum as retinyl esters bound to lipoproteins instead of retinol bound to retinol-binding protein.47 The upper limit of normal in humans is less than 500 IU vitamin A/100 mL plasma. Less than 5% circulates as retinyl esters. Smith and Goodman found that patients with hypervitaminosis A had up to 67% circulating as retinyl esters.48 The concentrations of retinol-binding protein were normal.

Most toxicity occurs in adolescents ingesting vitamin A to prevent acne and in children given vitamin supplements by well-intentioned parents. Cutaneous absorption has been accused of causing hypervitaminosis A in infants.49 Eating chicken liver, polar bear liver, or shark liver can produce intoxication.50 Cases do occur in adults and one has been reported in a 62-year-old. The daily intake ranged from 25,000 IU for 2 years to 600,000 IU for shorter periods. Toxicity occurred in as little as 2 months when 200,000 to 275,000 IU was ingested daily. Serum vitamin A levels ranging from 320 to 6600 IU/100 mL have been reported.48,50–53

On discontinuing the drug, serum levels of vitamin A slowly declined. In one patient, the percent of vitamin A in the form of retinyl esters remained more than twice that normally found 9.5 months later.48 The papilledema may resolve relatively quickly (e.g., within 6 days) or may be prolonged (e.g., 4 to 6 months)52; this is probably dependent on the magnitude of storage in the liver and extrahepatic sites as well as the blood level.


Vitamin B1 (thiamine) is a water-soluble heat labile vitamin. The recommended daily allowance is 0.3 to 0.5 mg in infants and 1.0 to 1.5 mg in adults. The therapeutic dose in cases of dietary deficiency is approximately 5 to 50 mg/day.


Optic nerve damage caused by poor nutrition is well established. However, it is not clear which specific deficiency is the cause of the condition (see vitamin B12). The importance of diet became apparent during the 1940s when prisoners of war and concentration camp internees developed centrocecal scotomas, reduced visual acuities, and pallor of the temporal optic nerve heads. Involvement was usually bilateral and often irreversible, depending on the degree of optic atrophy. For example, Bloom and co-workers fed prisoners of war with bilateral optic atrophy high-calorie diets supplemented by daily multivitamin capsules and vitamin B1 injections of 50 mg/day.54 Two months of therapy did not improve vision.

The evidence supporting a specific role for thiamine in human nutritional amblyopia is limited. Dreyfus demonstrated a reduced whole-blood transketolase activity in two patients with nutritional amblyopia.55 This enzyme is thiamine-dependent. Carroll supplemented the diets of patients with nutritional amblyopia with yeast, a rich source of thiamine, or with thiamine itself.56 Unfortunately, yeast contains small amounts, 1 ng/g dry weight, of vitamin B12.57 Because vitamin Bi2 deficiency causes amblyopia, the beneficial effects of yeast could not be attributed entirely to thiamine. The group fed thiamine itself consisted of only five patients. The initial visual acuities of their 10 eyes ranged from 20/20 (6/6 metric equivalent) to 20/200 (6/60 metric equivalent). After receiving 15 to 43 mg vitamin B1 daily for 3 to 6 weeks, four patients had 20/20 (6 eyes) or 20/30 (6/9) (2 eyes) acuities. Vision in each eye of the fifth patient improved from 20/200 to 20/70 (6/21 metric equivalent). However, when the entire B complex was given, it improved to 20/20. Seizure control in children occasionally requires a high-fat ketogenic diet. Two children, aged 5 and 7 years, developed centrocecal scotomas with normal-appearing discs while on this diet.58 Thiamine deficiency with a reduced serum transketolase activity was detected. It was attributed to the diarrhea that accompanied the diet and to the failure of the parents to give supplemental vitamins. The serum folic acid and vitamin B12 levels were normal. Thiamine and vitamin B supplements were begun. The visual acuities in one patient improved within 6 weeks from 20/80 (6/24 metric equivalent) to 20/40 (6/12 metric equivalent). In the other patient, they improved within 12 weeks from 20/120 (6/36 metric equivalent) for the right eye and 20/80 for the left eye to 20/15 (6/5 metric equivalent) for each eye. The centrocecal scotomas disappeared.

There has been little success in finding an appropriate animal model. Rats fed a thiamine-deficient diet for approximately 6 months developed optic atrophy.59 If the diet lacked all the vitamin B complex components, optic atrophy developed in 70 days.60 However, Leinfelder and Robbie could not produce optic atrophy in rats fed a vitamin B1-deficient diet for 5 months or a vitamin B complex-free diet for 70 days.61

If thiamine deficiency were sufficient to produce nutritional amblyopia, it is surprising that optic nerve dysfunction is so uncommon in the Wernicke-Korsakoff syndrome.


Leigh's disease (infantile necrotizing encephalomyopathy) is a fatal mitochondrial DNA inherited disease usually found in children.62 Feeding difficulties and psychomotor retardation progress to ophthalmoplegia, impaired pupillary light reflexes, unconsciousness, and respiratory death.63 Pathologically, the condition resembles Wernicke's encephalopathy except for the absence of degeneration in the mammillary bodies. Abnormalities have been reported in the metabolism of thiamine triphosphate. An endogenous inhibitor of the enzyme adenosine triphosphate, thiamine pyrophosphate phosphoryltransferase, has been identified in patients with Leigh's disease. This inhibitor prevents the synthesis of thiamine triphosphate. Increased cerebral thiamine diphosphate accumulates.64 Several investigators have treated patients with massive doses of thiamine propyl disulfide and thiamine tetrahydrofurfuryl disulfide. Initially, the patients often improve and the inhibitor cannot be demonstrated in the urine. Weeks later, the inhibitor reappears and the patients die despite continued therapy.65


Ophthalmoplegia and nystagmus are prominent findings in Wernicke's encephalopathy. It occurs from vitamin BI deficiency associated with chronic alcoholism, chronic malnutrition, or intravenous hyperalimentation when vitamins are not provided.66 Resolution begins within 24 hours of initiating therapy.


Weleber and co-workers, in a short-term study, gave vitamin B6 (pyridoxine) to four patients with gyrate atrophy of the retina.67 They received 18 to 750 mg/day, which is considerably more than the recommended daily dose of 1.6 to 2.5 mg. Three patients responded with a significant reduction in serum ornithine levels. The electroretinogram and electrooculogram responses improved. Pyridoxine may act by increasing the activity of the defective enzyme, ornithine aminotransferase, which converts ornithine to glutamic acid or proline. There may be several forms of the disease, which would explain why some but not all patients respond to pyridoxine treatment.68 The reduction in the serum ornithine level is only relative, and it remains abnormally high, so the disease progresses.69

A similar situation exists for homocystinuria, a disease producing ectopia lentis and caused by a defect in the enzyme cystathionine synthetase. Cystathionine synthetase requires pyridoxine, in the form of pyridoxal phosphate as a co-enzyme. Some cases of homocystinuria respond to large doses of vitamin B6 and some do not. Presumably, those that respond have a reduced affinity for pyridoxine that can be overcome by daily doses of 250 to 1500 mg. Responding cases can maintain normal levels of homocystine and the progression of the disease can be retarded.70,71



The recommended daily dietary allowance for vitamin B12 (cyanocobalamin) is 0.3 μg in infants and 2 μg in adults.72 Deficiency occurs despite adequate dietary intake if a glycoprotein called the intrinsic factor is not secreted by the gastric mucosa. This glycoprotein is necessary if the vitamin is to be absorbed in the small intestine.

Vitamin B12 deficiency results in inadequate myelin synthesis. The optic nerves, peripheral nerves, and spinal chord degenerate. The hematologic picture is one of a megaloblastic anemia. In approximately one-third of cases, visual difficulties precede the other neurologic and hematologic signs. An important reason for the absence of megaloblastic anemia at the time of progressive neurologic involvement relates to folic acid. Folic acid can reverse the hematologic, but not the neurologic, abnormalities of vitamin BJ2 deficiency. Folic acid may cause a more rapid progression of the neurologic symptoms. The optic nerve damage manifests itself as a centrocecal field defect and reduced visual acuity. If optic atrophy develops, the visual loss may be irreversible.

Monkeys fed a vitamin B12-deficient diet for 5 years developed vision loss.73 Between 33 and 45 months after starting the diet, five of nine rhesus monkeys had a gradual onset of vision impairment that, in two, progressed to blindness with loss of pupillary light reflexes and generalized optic atrophy. Temporal pallor occurred in the other three. Spastic paralysis of the limbs began 3 to 4 months after the visual impairment. Three of the remaining monkeys did not appear to have visual difficulties, but lesions were found at autopsy. Demyelinization and atrophy caused loss of 30% to 50% of the cross-sectional surfaces of the optic nerves, chiasms, and optic tracts. Similar results were reported by Chester and co-workers, who emphasized that the primate neurologic system was more susceptible than the hematologic system and that supplemental folic acid accelerated visual loss.74

Vitamin B12 deficiency with optic atrophy can result from prolonged ingestion of a vegetarian diet75 or from tapeworm infestation.76 In 102 tapeworm carriers, four were found with bilateral centrocecal scotomas, none of whom had megaloblastic anemia despite serum vitamin B12 levels far below normal. Prolonged exposure to the general anesthetic gas nitrous oxide can reduce vitamin B12 activity.77

If intrinsic factor is absent, oral vitamin Bi2 absorption is markedly reduced. Therapy in this situation requires either parenteral administration or very large oral doses daily (e.g., 100 μg or more).

Visual recovery, if it does occur, may take months. For example, one patient with centrocecal defects and 20/100 (6/30 metric equivalent) vision in the right eye and 20/80 vision in the left eye was given parenteral vitamin B12, 100 μg every 2 weeks for 2 months and then once per month. Eleven weeks after the first injection, vision was 20/60 (6/18 metric equivalent) in the right eye and 20/40 (6/12 metric equivalent) in the left eye; at 15 weeks, the acuities were 20/40 bilaterally.78 Stambolian and Behrens gave three injections of cyanocobalamin, 1 mg, during the first month of therapy and once per month injections of hydroxocobalamin, 1 mg, thereafter.79 Vision improved from 20/200 to 20/20 within 6 months. Occasionally, resolution is more rapid. Hamilton and co-workers reported improvement from 20/100 vision to 20/30 after intramuscular injection of 30-μg/day vitamin B12 for 4 days.80


The principal forms of serum cobalamin are methylcobalamin, hydroxocobalamin, and desoxyadenosylcobalamin.81 Cyanocobalamin comprises less than 5% of the total and may not occur at all in some people. However, cyanocobalamin was given the name vitamin B12 because the original isolation used a cyanide extraction technique that converted the cobalamin molecules to the cyano form.

Cyanide is a neurotoxin that has been implicated as the cause of tobacco amblyopia and tropical (West Indian, Jamaican, Nigerian) amblyopia. Cigar smoke and, to a lesser degree, cigarette smoke contain cyanogen.82 Cassava, a food staple in many tropical countries, contains the cyanoglycosides, linamarin and lotaustralin. When the cassava is crushed, the cyanoglycosides are brought into contact with the endogenous enzyme, linamarase, and these glycosides are hydrolyzed, releasing cyanide. Crushing and boiling the cassava before ingestion will prevent toxicity. The cobalamins may bind small quantities of cyanide and prevent toxicity. Cottrell and co-workers prevented nitroprusside-induced cyanide toxicity by injecting large doses of hydroxocobalamin.83 Patients with Nigerian amblyopia have abnormally high levels of cyanocobalamin and thiocyanate;84,85 these levels become normal when cassava is removed from the diet. Endogenous cyanide has been implicated in Leber's optic atrophy and dominant optic atrophy (e.g., Wilson found elevations of serum cyanocobalamin in these conditions86).

Cyanide may cause optic nerve damage by exceeding the binding capacity of cobalamin or by converting the more active forms of the vitamin (i.e., hydroxocobalamin and desoxyadenosylcobalamin) to a less active form (i.e., cyanocobalamin). Fouldes and co-workers reported two patients with pernicious anemia whose hematologic picture responded to cyanocobalamin, but vision remained poor despite prolonged parenteral therapy.87 When hydroxocabalamin, 1 mg twice per week, was substituted, the patients' visual acuities began to improve, although slowly. Nearly 10 months passed before their vision was 20/40 or better. Chisholm and co-workers allowed patients to continue smoking; there was a statistically significant better visual recovery in those treated with hydroxocobalamin than in those treated with cyanocobalamin.88 A third mechanism by which cyanide may produce amblyopia is by altering the relative distribution of cobalamins. Linnel and co-workers found that chronic cyanide administration elevated cobalamin blood levels in baboons, possibly at the expense of central nervous system stores.89

Despite the numerous theories linking cyanide and vision loss, many doubt that a causal relationship exists. Fouldes and co-workers found evidence of pernicious anemia in many patients with tobacco amblyopia.90 Forty percent had abnormally low serum vitamin B12 levels and 46% had abnormal Schilling tests. Heaton studied 14 patients with tobacco amblyopia.91 One had classic pernicious anemia, seven had histamine-fast achlorhydria, one had megaloblastic anemia, and one had subnormal vitamin B12 levels. Furthermore, some patients responded to parenteral cyanocobalamin while continuing to smoke.92 Montgomery and co-workers performed similar studies on patients with tropical amblyopia.93 Thirty percent of 147 patients had histamine-fast achlorhydria. However, their serum vitamin B12 levels and Schilling tests were normal and they did not respond to large doses of cyanocobalamin.


Vitamin C (ascorbic acid) is a water-soluble vitamin. The recommended daily dietary allowance in adults is 45 to 80 mg. Vitamin C is required for normal collagen and connective tissue synthesis. Ascorbate is actively transported into the eye. The normal aqueous humor level, 12 to 20 mg/100 mL, is approximately 25-times that of the plasma.


Vitamin C can lower the intraocular pressure. One well-established mechanism is by increasing serum osmolarity. Unfortunately, vitamin C penetrates the eye. This diminishes the duration and magnitude of its hypotensive effect. Subcutaneous or intravenous injections of 100 mg/kg doubled the rabbit aqueous humor level at 1 hour.94 At doses of 1.5 g/kg, rabbit ascorbate levels increased from a mean baseline value of 33 mg/100 mL aqueous humor to 114 mg/100 mL at 10 minutes and 124 mg/100 mL at 60 minutes.95 At this dose, the mean ocular pressures of hypertensive rabbits decreased from 55 to 39 mm Hg within 5 minutes.96 Patients given intravenous sodium ascorbate, 0.4 to 1.0 g/kg, obtained a maximum hypotensive effect 60 to 90 minutes after starting the infusion. Intraocular pressures did not return to baseline levels for more than 7 hours.

When the pH of ascorbate solutions is raised to 7.4 for parenteral administration, the vitamin C oxidizes relatively rapidly; solutions at this pH must be used within 48 hours. Oral vitamin C is effective if large amounts are given, but most patients develop diarrhea.97 Linner reported a negligible hypotensive effect with smaller doses (e.g., 1 g twice per day).98 When 0.5 g/kg was ingested as a 20% ascorbate solution, pH 2.1, there was a more pronounced effect. Maximum pressure reduction occurred 4 to 5 hours later and was maintained more than 8 hours in some patients. In patients with initial pressures of 50 to 69 mm Hg, the mean maximum reduction was 25 mm Hg; in those with initial pressures of 32 to 49 mm Hg, the mean maximum reduction was 19 mm Hg; and in those with initial pressures of 20 to 31 mm Hg, the mean maximum reduction was 6.5 mm Hg.

Virno and co-workers reported that the hematuria associated with the intravenous use of 30% glycerol, 0.25 to 2 g/kg, could be prevented if the patient simultaneously received sodium ascorbate, 0.5 to 1.5 g/kg.96

Ascorbate may also lower intraocular pressure by reacting with specific receptors. Buphthalmic rabbits have reduced levels of aqueous humor vitamin C. They may lack these receptors.99 Injection of 4 mg ascorbate directly into the anterior chambers of normotensive rabbits increases the facility of outflow; injection of up to 12 mg ascorbate has no effect on buphthalmic rabbits.100 Virno and co-workers reported that some glaucoma patients had a hypotensive response to oral ascorbate without an associated elevation in serum osmolarity.97 In three of 25 chronic simple glaucoma patients, the serum osmolarity was unchanged, and in three others it was reduced. Linner gave 14 subjects unilateral 10% ascorbic acid eye drops three times per day.101 On the third day of treatment, there was a small (1.2 mm Hg) but significant mean reduction in the ocular pressures of the eyes receiving vitamin C. Gnadinger and Willome found an effect of similar magnitude, but it was not statistically significant.102


In guinea pigs, lens extraction lowers corneal and aqueous humor vitamin C levels by 33% to 50%.103 Thermal burns of the corneal epithelium of these aphakic eyes heal more slowly and with more relapses. Phakic eyes require an average of 11 days to heal, whereas aphakic eyes require 17 days.

Severe acid or alkali burns inhibit the active transport of vitamin C into the anterior chamber. Aqueous humor ascorbate levels are lowered by approximately two-thirds.104 This may result in decreased corneal collagen synthesis and an increased incidence of perforation. Topical administration of 10% ascorbate drops, given hourly 14 times per day for 6 weeks, significantly reduces the incidence of corneal ulcers in rabbits with alkali burns from 47% to 6%.104 Subcutaneous injections of vitamin C are also effective.105,106 Although alkali burns are less likely to perforate if they have been treated with ascorbate drops,107 thermal burns have a poorer outcome if ascorbate is given.108 Ascorbate prevents light-induced damage to the lenses109 and retinas110 of rats. The presumed protective mechanism is an antioxidative effect.


Vitamin D (calciferol and cholecalciferol) may inhibit retinoblastoma growth. Human retinoblastoma cells have receptors for the active form of vitamin D, calcitriol.111 In mice,112 subcutaneous implants of human retinoblastoma cells showed increased necrosis and calcification after ergocalciferol injections five times per week for 5 weeks. Three times per week injections of calcitriol for 5 weeks inhibited tumor growth but did not increase calcification.113 The doses used, 2.8 and 7.8 mg ergocalciferol and 500 mg calcitriol per kg, were toxic, producing weight loss and an increased mortality rate.


The tocopherols comprise the fat-soluble vitamin E; the most active is α-tocopherol. Although a recommended daily dietary allowance exists (12 to 15 IU for adults), there is little evidence that vitamin E is a nutritional requirement in humans. Its physiologic role is uncertain. It has been proposed that tocopherols are antioxidants.

Adult serum levels of vitamin E are 0.7 to 2.0 mg/100 mL. Neonates with birth weights of less than 1500 g have serum levels in the 0.1 to 0.5 mg/100 mL range114 and retinal vitamin E levels 5% to 12% those found in mature newborns.115 Serum levels more than 3.0 mg/100 mL are associated with an increased incidence of sepsis and necrotizing enterocolitis.116 Oral administration of 50 mg and 100 mg/kg per day will raise the serum levels.117 The 100 mg/kg per day dose will result in 38% of premature infants having serum vitamin E levels equal to or greater than 3.5 mg/100 mL. The serum half-life of vitamin E after intramuscular injection is 44 hours.118 Daily parenteral tocopherol doses of 4.6 mg will bring serum levels to at least 0.5 mg/100 mL at 48 hours, but 31% will have serum levels at or above 3.5 mg/100 mL.119 Parenteral doses of 2.1 mg/day will not consistently maintain a serum level of 0.5 mg/100 mL.

Unlike humans, experimental animals exhibit multiple ocular abnormalities when fed a tocopherol-deficient diet. Monkeys tend to develop macular degeneration within 2 years.120 Keratoconus-like changes and lens opacities appear in the embryos of turkey hens.121 Albino rabbits develop cataracts122 and rats have increased lipofuscin in their pigment epithelium, choriocapillaris, and scleral veins.123,124

Oxygen may be toxic to the retinal vessels because it is an oxidant. If so, vitamin E might prevent retrolental fibroplasia by acting as an antioxidant. α-Tocopherol, 400 mg/kg, injected daily into adult rabbits did not prevent oxygen-induced rod and cone degeneration.125 However, in the newborn kitten, d,l-α-tocopherol acetate, 50 mg intramuscularly each day beginning at birth, reduced the severity and incidence of retinopathy.126,127 Before the causal relationship of oxygen to retrolental fibroplasia was known, Owens and Owens gave d,l-α-tocopherol orally to 11 premature infants who weighed less than 3 pounds.128 The mean serum tocopherol level in treated children was 4.12 mg/100 mL, whereas the mean serum tocopherol level in a control group was 0.25 mg/100 mL. None of these 11 treated children developed retrolental fibroplasia, whereas five of 15 control patients did. When the study was expanded to 23 treated infants, one did develop retrolental fibroplasia, but treatment of this child began on day 11. Kinsey and Chisholm studied 101 infants with birth weights of less than 4 pounds.129 Forty-six infants were divided into two groups. Some received no treatment, whereas others received 30 to 150 mg d,l-α-tocopherol acetate per day when the first signs of retrolental fibroplasia were observed. Another 55 infants were divided into two groups. Some received no treatment, whereas others received 50 mg three times per day beginning a few days after birth. Vitamin E was of neither prophylactic nor therapeutic value. However, Johnson and co-workers, studying premature infants with birth weights of less than 4 pounds, or gestational ages less than 38 weeks, found vitamin E of significant benefit if both the incidence and severity of retrolental fibroplasia were considered.130 They gave vitamin E, intramuscularly, 15 mg/kg, within 4 to 24 hours of birth. The same dose was given daily for 10 to 12 days thereafter, except during periods of exposure to high oxygen concentrations. At these times, the daily dose was increased to a maximum of 60 mg/ kg. A serum vitamin E level of 2 mg/100 mL serum was maintained and oral tocopherol, 50 mg per feeding, was substituted as soon as feasible.

The effectiveness of tocopherol treatment in preventing the retinopathy of prematurity remains controversial, but the weight of evidence favors the view that it is of little or no benefit. Hittner provided clinical and histologic evidence of vitamin E effectiveness.131–135 The initial morphologic event in the development of the disease was an increase in the gap junctions between adjacent retinal spindle cells, the precursors of the retinal capillaries. Elevated oxygen levels increased gap junction area and vitamin E prevented this phenomenon. Finer and co-workers136 were not able to demonstrate a significant benefit from intramuscular vitamin E in a prospective, randomized study of infants weighing less than 1500 g who were begun on therapy within 12 hours of birth. Nor could they show a benefit for infants in a prospective, nonrandomized study when oral vitamin E was begun 40 hours or more after birth. Only when infants treated within 12 hours of birth by intramuscular and oral therapy were lumped together was vitamin E treatment correlated with fewer instances of the more severe grades of retinopathy. But children developing severe retinopathy were also found to have been smaller at birth, required more mechanical ventilation and supplemental oxygen, and had more frequent elevated arterial and capillary PO2 readings. Three other larger prospective, randomized trials, of 100, 278, and 545 infants, also failed to show any benefit from vitamin E therapy.137–139 A higher incidence of retinal hemorrhages was reported in tocopherol-treated infants.140

Vitamin E deficiency produced by malabsorption, e.g., Crohn's disease, postoperative small bowel resection, and cholestasis, can be associated with a spinocerebellar degeneration and skeletal muscle atrophy. The concurrent ophthalmoplegias, nystagmus and retinopathy, respond to vitamin E therapy by either stabilizing or regressing.141–146 Vitamin E deficiency has also been associated with the retinopathy and neurologic deficits of abetalipoproteinemia; dietary supplementation with tocopherol (e.g., approximately 100 mg/kg per day, orally) and the other fat-soluble vitamins appeared to retard or prevent progression.147–149 The proposed mechanism by which vitamin E protects the retina has been the prevention of auto-oxidative reactions induced by visible light. This theory is appealing because it could also provide a therapeutic role for vitamin E in senile macular degeneration. In rats, vitamin E deficiency is associated with retinal pigment epithelium deposits of lipofuscin150 and with photoreceptor degeneration.151,152 However, light-induced photoreceptor damage in rats fed a normal vitamin E diet did not produce a reduction in retinal levels of vitamin E,153 nor did a diet rich in vitamin E protect the retina from bright light.154


Administration of vitamin K to pregnant women at term raises the prothrombin levels of their newborns.155 Maumanee and co-workers treated 50 women with 2 mg/day oral vitamin K for 4 or more days before delivery.156 Another 173 women received only a single dose, during labor. The incidence of retinal hemorrhages was 4% in the first group and 15% in the second group. The incidence in newborns of 233 untreated women was 25%. Pray and co-workers gave pregnant women menadione, 2 mg, three times per day for 3 days to 6 weeks before delivery.157 Another group received 10 or 20 mg during labor. A third group received no therapy. The incidence of retinal hemorrhages was significantly reduced in the first two groups, being 13% and 19%, respectively, whereas the untreated group had a 44% incidence.

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