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Show Journal of Clinical Neuro- ophlhalmology 10( 1): 52- 55. 1990. Corneal Permeability in Patients with Tonic Pupil A Reevaluation of Its Cholinergic Supersensitivity Takashi Utsumi, M. D. © 1990 Raven Press, Ltd., New York Cholinergic supersensitivity of the iris sphincter helps to make the diagnosis of " tonic pupil." Because uncertain responses sometimes occur with mecholyl 2.5%, dilute solutions of pilocarpine are often used. There has always been some question as to whether individual variation in corneal permeability was one of the factors contributing to the variability in pupillary constriction to topical cholinergics in these patients. In this study, the degree of intraocular penetration of topical fluorescein was compared with the degree of pilocarpine- induced miosis in six tonic pupils and in seven age- matched normal controls. A noncontact fluorophotometer and a computerized videopupillogram were used. The patients showed a significant cholinergic supersensitivity in their affected tonic pupils and had normal intraocular penetration of fluorescein through the cornea in both eyes. It is concluded that the cholinergic supersensitivity of the iris in tonic pupils is not the result of increased corneal permeability but instead results from an increased sensitivity of the cholinergic receptors in iris sphincter muscles. Key Words: Tonic pupil- Cholinergic supersensitivityCorneal permeability- Fluorophotometry. From the Department of Ophthalmology, Osaka Medical College, Osaka, Japan. Address correspondence and reprint requests to Dr. Takashi Utsumi, Department of Ophthalmology, Osaka Medical College, 2- 7 Daigdku-,: h", T'k:. I', ukl, O, akJ ~ o9, Japan. 52 Adler and Scheie ( 1) recommended methacholine 2.5% ( mecholyl, Merck) to demonstrate cholinergic supersensitivity in patients with tonic pupil, but it was soon recognized that some tonic pupils failed to constrict to mecholyI2.5%. In 1966, Loewenfeld and Oono ( 2) showed that large interindividual variations in mecholyl sensitivity existed in normal subjects and suggested that this might be due to variations in corneal permeability. In 1977, Thompson ( 3) reported that the mecholyl 2.5% test was positive in only about two- thirds of patients with Adie's syndrome. In 1977, Purcell and colleagues ( 4) reported focal corneal insensitivity in patients with tonic pupils. Thompson ( 3) suggested in 1977 that despite the patchy numbness of the cornea in patients with Adie's syndrome, the corneal penetration of topical drugs appeared to be normal. He directly showed that adrenergic mydriatics and anticholinergic mydriatics dilated Adie's pupils without supersensitivity. Because of these uncertainties, I measured the corneal permeability in eyes with , tonic pupils using a recently developed fluorophotometer technique ( 5). SUBJECTS AND METHODS Six patients aged 40- 60 years ( mean 49 years) with unilateral tonic pupil were included in the study ( Table 1). Although their pupillary cholinergic supersensitivity was detected by topical instillation of a dilute solution of pilocarpine in the manner recommended by Pilley and Thompson ( 6), a weaker concentration was used ( 0.0313%) ( 7). This concentration was a little stronger than the minimum effective dose ( 0.022%) for Japanese irides ( 8). The patients had no neurologic disorder except tonic pupil. Seven age- matched normal CORNEAL PERMEABILITY IN TONIC PUPIL 53 TABLE 1. Data of tonic pupil patients Patient 1 23 4 56 Age ( yr)/ sex 40/ M 44/ F 46/ F 47/ F 57/ M 60/ F Affected side RL LRLR Pilocarpine miosis ( dB) Affected Sound eye eye - 5.82 - 0.98 - 3.38 - 0.81 - 2.20 - 0.20 - 2.96 - 0.79 - 6.66 - 1.02 - 2.66 - 0.25 TABLE 3. Log concentration of penetrated fluorescein in patients with tonic pupil Anterior chamber ( ng/ ml) Cornea ( ng/ ml) Affected Sound Affected Sound Patient eye eye eye eye 1 1.27 1.40 2.18 2.25 2 1.73 1.79 2.20 2.35 3 1.92 2.00 2.73 2.35 4 1.33 1.32 2.28 2.33 5 1.91 2.11 2.34 2.43 6 1.91 1.71 2.67 2.26 subjects aged 34-- 64 years ( mean 50.1 years) were examined as controls ( Table 2). We used a noncontact fluorophotometer ( Coherent FM- l, Fluorotron Master, Gherent, Palo Alto, CA) capable of automatically measuring the concentration of fluorescein in various parts of the eye by the strength of the emitted fluorescence. Before and 150 min after topical instillation of two 20-,. d drops of a 10% sodium fluorescein solution into the cul- de- sac of both eyes, the strength of the emitted fluorescence was measured by scanning through the eye. The maximum value in the cornea and the minimum value in the anterior chamber were obtained. The tissue autofluorescence before topical application of fluorescein was subtracted from the later measurements, and the concentration of fluorescein in the aqueous was determined. A degree of miosis caused by topical instillation of pilocarpine 0.0313% was obtained from the following equation as decibels ( dB): degree of miosis = 20 log ( PA post/ PA pre), where PA is the pupil area. Pupil area was measured by a computerized infrared videopupillogram ( HTV C- 301) which provided a digital output in square millimeters. After the fluorescein and pilocarpine tests, we estimated corneal sensitivity by touching the cornea with the twisted tip of cotton gauze and measured the basal tear volume by a phenol redimpregnated cotton thread, the crimped end of which was placed in the cul- de- sac for 15 s ( 9). TABLE 2. Data of normal subjects RESULTS The concentrations of penetrated fluorescein in the anterior chamber and in the cornea in patients with tonic pupil and in normal subjects are shown in Tables 3 and 4, respectively. Values were higher in the cornea than in the anterior chamber in both groups. Means and SD were computed for the patients' affected eyes, for the patients' unaffected eyes, and for the normal subjects. Mean values of the concentrations of each group were 1.68, 1.72, and 1.84 log ng/ ml in anterior chamber, and 2.35, 2.40 and 2.49 log ng/ ml in cornea, respectively ( Table 5). Because no statistically significant differences were found between the groups either in the anterior chamber or in the cornea, we concluded that both eyes of patients with unilateral tonic pupil had normal permeability. Correlation between the fluorescein concentration in the anterior chamber and in the cornea is shown in Fig. 1. Because all eyes in this study had the same concentration of fluorescein in the anterior chamber and another concentration in the cornea, all anterior chamber values were considered in a single group and all cornea values were considered in another group. The two groups are compared in Fig. 1. The significance of the linear correlation is evident. Cholinergic sensitivity to topical pilocarpine TABLE 4. Log concentration of penetrated fluorescein in normal subjects Subject 1 23 456 7 Age ( yr)/ sex 34/ F 40/ F 46/ M 52/ F 57/ M 58/ M 64/ F Pilocarpine miosis ( dB) Right eye Left eye - 1.15 - 1.42 - 0.43 - 0.70 - 0.08 - 0.51 - 0.46 - 0.55 - 6.22 - 5.85 - 1.56 - 0.50 - 5.22 - 4.13 Subject 1 23 4 56 7 Anterior chamber ( ng/ ml) Right eye Left eye 1.44 1.42 1.50 1.27 1.53 1.62 1.96 1.81 1.88 1.96 2.37 2.20 2.53 2.29 Cornea ( ng/ ml) Right eye Left eye 2.48 2.16 2.23 2.08 2.41 2.60 2.36 2.31 2.56 2.52 2.73 2.55 2.80 3.04 JClin Neuro- ophthalmol, Vol. 10, No. 1, 1990 54 T. UTSUMI DISCUSSION TABLE 5. Comparison of log concentration Opinion has varied regarding corneal permeability in tonic pupils ( 2,3). This study revealed that although patients with unilateral tonic pupil had a clearly higher sensitivity to topical pilocarpine than did normal controls in the affected eyes, penetration of fluorescein through the cornea appeared to be the same in both eyes. If there is no difference in corneal penetration of fluorescein between the two eyes, other drugs probably will not penetrate one cornea better than the other. Even though fluorescein penetrates the cornea through 0.313% as represented by the degree of miosis was obviously greater in the affected eyes than in the sound eyes in the tonic pupil patients ( Table 1), and the normal subjects had matched cholinergic supersensitivity in the two eyes. Figure 2 clearly shows that there was no statistically significant correlation between the concentration of penetrated fluorescein in the anterior chamber and the degree of miosis caused by topical pilocarpine. Corneal sensation was generally normal to touch, and basal tear volume was in the normal range ( 1~ 25 mm/ 15 s) in both eyes of all subjects. the intercellular spaces ( 10) whereas pilocarpine crosses cell membranes to enter the eye ( 11), our demonstration of parallel fluorescein penetration in the two eyes places the burden of proof on researchers who suggest that pilocarpine penetrates the cornea better in the eye with the tonic pupil. We assume that equal amounts of pilocarpine reach the cholinergic receptors of both iris sphincters. This suggests that the cholinergic supersensitivity of the pupil does not result from increased penetration of the pilocarpine through a relatively numb cornea but instead results from enhanced sensitivity of the denervated cholinergic receptors at the iris sphincter muscles. Furthermore, normal response to mydriatics of the pupil in tonic pupil patients as demonstrated by Thompson ( 3) 11 years ago suggested normal corneal permeability in patients with Adie's syndrome. The strong linear correlation between the concentration of fluorescein in the anterior chamber and in the cornea suggests that once the drugs penetrate the corneal epithelium they merely pass through the stroma and endothelium and are diffused into the aqueous humor in the anterior chamber according to the slope of the concentration. Abnormal corneal sensitivity in tonic pupils was carefully studied by Purcell and associates ( 4). These abnormalities suggest the possibility of an abnormality of corneal penetration. However, results obtained in this study suggest otherwise. On the other hand, because I did not map corneal sensitivity with the attention to detail used in the study by Purcell and associates ( 4), I may have missed some regional lowered sensitivity. Cornea ( ng/ ml) 2.35 0.18 2.40 0.19 2.49 0.26 0.30 0.32 0.40 1.68 1.72 1.84 Anterior chamber ( ng/ ml) Tonic pupils Affected eye ( 6) Sound eye ( 6) Normal controls ( 14) Subjects ( no. of eyes) 10 20 25 o Y = 1 13322 X- 0.996753 r = 0758955 ( P 0",) o o o . .. o o o 0 o. o o o o o , I , 20 2.5 30 CONCENTRATION OF PENETRATED FLUORESCEIN IN CORNEA ( LOG ng/ ml) zw U V1 W IrOE :-. JJ . c." LL<: J 8~ ~ ei Ir eo tJ~ z<! WI D.- U LLIr 00 Z cr 15 Q~ ~ z Ir<! tz- zw U z aU FIG. 1. Correlation between the fluorescein concentration in the anterior chamber and in the cornea. A linear regression curve is shown. Eyes of normal controls ( open circles); sound eyes of patients with tonic pupil ( open triangles); affected eyes of patients with tonic pupil ( closed triangles). /. 1'./ 1 CORNEAL PERMEABILITY IN TONIC PUPIL 55 1.0 2.5 20 do - do - go DEGREE OF MIOSIS CAUSED BY PL ( dB) FIG. 2. Relationship between the fluorescein concentration in the anterior chamber and the degree of miosis caused by topical pilocarpine. Statistically significant correlation is absent. Eyes of normal controls ( open circles); sound eyes of patients with tonic pupil ( open triangles); affected eyes of patients with tonic pupil ( closed triangles). o 0 0 0 .. .> 0 .. • • 0 • 0 0 .. • 0 0 0 .. .. 00 0 • o z W U < Jl W 0:: 0: 0 o E :: J~ -. J ~ LL.., 0° W;::! t: i: o:: o:: W t- CD W2 Z< t WI Q. U LLO:: 00 Z c:: 15 Q~ t: i: Z o::< t t- Z ZW UZo U Acknowledgment: I thank Dr. H. Stanley Thompson of the Department of Ophthalmology of the University of Iowa for reviewing a draft of this paper, and Dr. Shigetoshi Nagataki of the Department of Ophthalmology of the Ryukyu University for technical advice. I also thank Ritsuko Miyachi for secretarial assistance. REFERENCES 1. Adler FH, Scheie HG. The site of the disturbance in tonic pupilS. Trans Am Ophthalmol Soc 1940; 738: 18~ 92. 2. Loewenfeld IE, Oono S. The iris as a pharmacologic indicator: The supposed instability of mecholyl. Eye Ear Nose Throat Man 1966; 45: 69- 77. 3. Thompson HS. Adie's syndrome: Some new observations. Trans Am Ophthalmol Soc 1977; 75: 587- 626. 4. PurceU JJ Jr, Krachmer JH, Thompson HS. Corneal sensation in Adie's syndrome. Am J OphthalmoI1977; 84: 496- 500. 5. Maurice OM. New objective fluorophotometer. Exp Eye Res 1963; 2: 3~. 6. Pilley SF], Thompson HS. Cholinergic supersensitivity in Adie's syndrome: pilocarpine vs mecholyl. Am J Ophthalmol 1975; 80: 955. 7. Utsumi T. Pupillary light reflex under open- loop photic stimulus. A clinical application. Acta Soc Ophthalmol Jpn 1981; 85: 1497- 502. 8. Hashimoto T, Utsumi T, Onishi Y. Effect of topically administrated adrenergics and cholinergics on pupillary dynamics under open- loop condition. Folia Ophthalmol Jpn 1978; 29: 1138- 47. 9. Hamano H, Hori M, Hamano T, Mitsunaga S, et al. A new method for measuring tears. CLAO J 1983; 9: 281- 9. 10. Maurice OM. The use of fluorescein in ophthalmolOgical research. Invest Ophthalmol Vis Sci 1967; 6:~ 77. 11. Swan KC, White NG. Corneal permeability. 1: Factors affecting penetration of drugs into the cornea. Am J OphthalmoI1942; 25: 104~ 58. I Gin Neuro- ophthalmol, Vol. 10, No. 1, 1990 |