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Levodopa/Carbidopa for Childhood Amblyopia Lawrence E. Leguire,* Gary L. Rogers,* Don L. Bremer* Philip D. Walson,^ and Mary Lou McGregor* Purpose. To evaluate the efficacy and tolerance of two low doses of levodopa/carbidopa (25/ 6.25 mg, 50/12.5 mg) and placebo (Turns) in 20 children with amblyopia between the ages of 4 and 14 years. Methods. A double-masked placebo-controlled randomized 8-hour study was performed during which subjects received one of two doses of levodopa/carbidopa or placebo, combined with occlusion of the dominant eye. Visual acuity was measured at baseline and at 1 and 5 hours after capsule ingestion. Tolerance was assessed by questionnaire and physical examination. Results. Visual acuity significantly improved by one line, from an overall average of 20/121 to 20/96, in the amblyopic eyes of both groups that received levodopa/carbidopa. Visual acuity did not significantly change in the placebo group. Tolerance was similar among all three groups. Conclusion. Average dose levels of 0.95/0.24 mg/kg and 1.94/0.49 mg/kg of levodopa/carbidopa were found to be well tolerated and efficacious at temporarily improving visual acuity in amblyopic eyes of children. Invest Ophthalmol Vis Sci. 1993;34:3090-3095. JYecently, Gottlob and Stangler-Zuschrott 1 found that a 200 mg/50 mg dose of levodopa/benzerazide temporarily improved contrast sensitivity and decreased scotoma size in the amblyopic eyes of nine adults. Based on these initial findings, Leguire and colleagues2 undertook a single-dose pilot study of the effects of levodopa/carbidopa on visual function in five children with amblyopia between the ages of 7 and 12 years and in two normal adults. Dose was dependent on body weight and averaged 4 mg/kg for the amblyopic subjects. Leguire et al2 used several tests of visual function including Snellen visual acuity, which was measured at baseline and at 1 and 5 hours after drug ingestion. The results revealed that 1 hour after drug ingestion Snellen visual acuity in the amblyopic eyes improved by about 50% from a mean of 20/159 to 20/83. Snellen visual acuity decreased to 20/103 5 hours after drug ingestion. Snellen visual acuity remainded stable in the normal subjects. Unfortunately, three of five amblyopic children and one normal adult experienced one or two episodes of transient nausea and emesis as side effects. Although the Snellen visual acuity results of the pilot study were encouraging, the high prevalence of nausea and emesis would preclude the study dose as an initial therapeutic dose. The purpose of the current study is to determine whether a much smaller dose of levodopa/carbidopa, when combined with occlusion therapy, could be used, which would improve visual function yet minimize adverse side effects such as nausea and emesis. METHODS From the *Departmenl of Ophthalmology, and the f Division of Pharmacology/ Toxicology, Children's Hospital, Columbus, Ohio. Supported in part, by the Knights Templar Eye Foundation, Inc., the Ohio Lion 's Eye Research Foundation and Children's Hospital Research Foundation. Some of these results were presented to the Association for Research in Vision and Ophthalmology, Sarasota, FL, 1992. Submitted for publication November 2, 1992; accepted March 24, 1993. Proprietary interest category: N. Reprint requests: Lawrence E. Leguire, Department of Ophthalmology, Children's Hospital, 700 Children's Drive, Columbus, Ohio 43205 3090 Downloaded From: http://iovs.arvojournals.org/ on 06/11/2017 Subjects Twenty amblyopic children participated in the study. Detailed subject information is listed in Table 1. Two additional subjects were recruited for the study; however, because the subjects did not know the alphabet they could not complete the visual acuity test at base- Investigative Ophthalmology & Visual Science, October 1993, Vol. 34, No. 11 Copyright © Association for Research in Vision and Ophthalmology Levodopa/Carbidopa for Childhood Amblyopia TABLE l. Subject No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 3091 Detailed Subject Information Age (yr) Gender 6.85 14.92 9.70 6.50 10.67 4.67 12.25 5.75 6.50 9.00 12.92 5.85 9.85 7.85 8.33 8.50 5.42 13.20 10.25 6.92 F F F F F F M F M M F M F M M F M F M M Type of Amblyopia AA SA ASA SA AA AA SA AA DA AA SA AA AA SA AA AA ASA ASA SA SA Weight (kg) 25 55 27 23.6 22 15.9 66.1 20 20.9 22.9 52.3 24.8 30.2 23 23.4 26.4 17.1 48.9 45.2 24.1 AA: Anisometropic; SA: strabismic; ASA: anisometropic with strabismus; DA: deprivational. line and were dropped from the study. The subjects were considered either stable amblyopes (subjects who did not respond to occlusion or penalization therapy because of age) or difncult-to-treat amblyopes (younger than 9 years but did not comply with occlusion or penalization). Because of concern and limited available knowledge about the side effects and tolerance of levodopa/carbidopa in children, the number of subjects in the current study was determined to be the minimum required to reach statistical significance (0.05) of a change in visual acuity. The tenets of the Declaration of Helsinki were followed. The study protocol was approved by the Human Subjects Committee at Children's Hospital, Columbus, Ohio. Fully informed signed consent was obtained from at least one parent and assent was obtained from each child before the start of the study. Design and Procedures Each subject was instructed to have an empty stomach when they arrived at the Eye Clinic at Children's Hospital, Columbus, Ohio at 8:00 AM; however, fruit juice was allowed. In the current study we chose to measure visual acuity because in a pilot study2 it was found that levodopa/carbidopa had a greater effect on visual acuity than on contrast sensitivity, pattern visual evoked responses or stereoacuity. Following baseline visual acuity (described later), the subject's dominant eye was occluded throughout the study except for the vision tests. The subjects and parents were taken to the Clinical Study Center where a study nurse obtained base- Downloaded From: http://iovs.arvojournals.org/ on 06/11/2017 line information including blood pressure, heart rate, and respiration, and the subject was asked how he/she felt. Some of the subjects volunteered for a pharmacokinetic portion of the study, which was undertaken as previously described.2 However, the pharmacokinetic profiles have not been undertaken to date and will be reported elsewhere. After all baseline measures were taken the subject was given a capsule to take by mouth that contained one of two doses (25 mg or 50 mg) of levodopa (Sinemet; Merck, Sharp and Dohme, West Point, PA) with 25% carbidopa (6.25 mg or 12.5 mg, respectively) or placebo (1/4 tab of Turns, [Smith Kline Beecham, Philadelphia, PA]). The capsules were filled and randomized by pharmacy department personnel thus masking all study/test personnel and all subjects as to the contents of each capsule. For a few of the youngest subjects the capsule had to be crushed to be swallowed; however, because the placebo (Turns) and levodopa/carbidopa were the same color the crushing of the capsule did not unmask the study nurse. Tolerance information was collected at baseline and every half hour for the first 3 hours after capsule ingestion and every hour thereafter until the end of the 8-hour study. Two hours after capsule ingestion the subject was given a low-protein meal that typically included clear soup, salad, fruit, fruit juice, and cake or pie. At the end of the study the subject was required to consume 8 ounces of Sustacal (Bristol-Myers Squibb Co., Evansville, IN), a high protein drink, which theoretically3 would reduce further uptake of the levodopa/carbidopa into the brain. The next day a study nurse called the family to check on any side effects experienced after the subject left the study center. None were reported. Visual Acuity Visual acuity, as designated by log Snellen fraction, was measured with full optical correction at baseline and at one and five hours after capsule ingestion. Visual acuity was measured with three different Early Treatment Diabetic Retinopathy Study (ETDRS) acuity charts4 at a viewing distance of 6 m. The acuity chart was illuminated by a Kodak carousel projector and had a mean luminance of 216.7 cd/m2. A different chart was used for each of the three test sessions under forced choice conditions; therefore, memorization of letters from test session to test session was not possible. The amblyopic eye was always tested first and thus any changes evident in the amblyopic eye could not have been attributable to letter memorization within a session. Also, because all subjects were occluded throughout the study, changes in acuity in the amblyopic eye between groups could not be attributable to occlusion, per se. Each subject was required to read each letter on each line until a majority of the letters 3092 Investigative Ophthalmology & Visual Science, October 1993, Vol. 34, No. 11 on a given line were missed. The examiner held the tip of a yard stick below each letter to be read, and started approximately two lines above the subject's previously reported visual acuity level. In the event that the subject said that he could not see or identify the letter(s), the subject was instructed to give his best guess. Such forced choice procedures would minimize learning and criterion shifts within and between test sessions. In the event that the subject could not correctly identify all the letters on the top line at the viewing distance of 6 m, the chart was moved to a 3-m viewing distance for testing the amblyopic eye. Four subjects could not undertake the ETDRS acuity test because they did not know the whole alphabet and, instead, visual acuity was measured with the HOTV (Goodlite Co., Forrest Park, IL) visual acuity test at a viewing distance of 6 m under forced choice conditions. RESULTS Individual Visual Acuity Data Figures 1A to 1C depict log Snellen fractions for the dominant and amblyopic eyes for persons in the placebo (Fig. 1A), 25/6.25 mg (Fig. IB) and 50/12.5 mg (Fig. 1C) levodopa/carbidopa groups. For persons in all three groups, log Snellen fraction in the dominant eye appeared very stable at about 0.0 (20/20) during the three test trials. In the amblyopic eye, at baseline (trial 1) there was a wide range of log Snellen fractions for each group of subjects. In all three groups, after capsule ingestion, subjects exhibited various amounts of decrease (improvement) in log Snellen fraction in the amblyopic eye between baseline and the two follow-up trials. In the placebo group, the greatest improvement in log Snellen fraction, regardless of follow-up trial, was 0.15 (1.5 lines) and averaged 0.063 (SD = 0.073), which was not significantly different from 0 (1 sample t = 2.13, df = 5, P > 0.05). One subject in the placebo group did not exhibit a decrease in log Snellen fraction from baseline, in either follow-up trial, and had a minimum increase in log Snellen fraction of 0.06. In the 25/6.25 mg levodopa/carbidopa group, the greatest improvement in log Snellen fraction, regardless of follow-up trial, was 0.24 (2.4 lines) and averaged 0.143 (SD = 0.079), which was significantly different from 0 (1 sample t = 4.42, df = 5, P < 0.01). In the 50/12.5 mg levodopa/carbidopa group, the greatest improvement in log Snellen fraction, regardless of follow-up trial, was 0.38 (3.8 lines) and averaged 0.125 (SD = 0.124), which was significantly different from 0 (1 sample t = 2.85, df = 7, P < 0.03). Therefore, when comparing individual data among groups, there appears to be some evidence of a dose-response relationship with the largest improvement in the 50/12.5 mg levodopa/ carbidopa group and the smallest improvement in the Downloaded From: http://iovs.arvojournals.org/ on 06/11/2017 A. PLACEBO PLACEBO Dominant Eya Amblyoplo Eya 1.40 120 ' 1.00 oeo ' 0.6O ' 0.40 ' 020 ' 0.00 B. 26/6.26 mg »T Time 3 Trial 26/6.25 mg Dominant Eya Amblyoplo Eya 1.00 • 1.40 0.80 • 120 0.60 • 1.00 0.40 • oso 020 • 0.60 OXIO 0.40 • -020 • -0.40 sir Time 3 Trial «T Time 3 Trial C. 50/12.5 mg 60/12.5 mg Dominant Eya Amblyoplo Eya 1.00 • 0.80 • 0.60 • o 0.40 • o 1.40 e JO 120 • 1.00 ' OSO ' 020 • 0X10 -O20 • • = aeo' W 0.40 • O -0.40 Time Trial . 020 ' 0.00 ST Time 3 Trial FIGURE 1. Log Snellen fraction in the dominant (left) and amblyopic (right) eyes is plotted as a function of trial number and test time for individual subjects in the placebo (A), 25/ 6.25 mg (B), and 50/12.5 mg (C) levodopa/carbidopa groups. In each graph, a log Snellen fraction of 0.0 represents 20/20 Snellen visual acuity and 1.00 represents 20/ 200 Snellen visual acuity. Different symbols have been used to clarify each subject's change in log Snellen fraction over time. placebo group, with the 25/6.25 mg levodopa/carbidopa group falling between the two extremes. Grouped Visual Acuity Data Based on the results of the original pilot study2 we predicted that each levodopa/carbidopa group would exhibit an improvement in visual acuity in the amblyopic eye. Table 2 depicts the log Snellen fractions (means and standard deviations) for the three groups of subjects (placebo, 25/6.25 mg levodopa/carbidopa, 50/12.5 mg levodopa/carbidopa) at baseline and at 1 and 5 hours after capsule ingestion. Statistical probability levels are based on one- or two-tailed paired t Levodopa/Carbidopa for Childhood Amblyopia TABLE 3093 2. Grouped Visual Acuity Data Placebo 25/6.25 mg Baseline 1 hour 5 hours .83 (.24) .77 (.24) .83 (.26) 50/12.5 mg (n =•6) (n = 6) Ambly Dom Ambly .03 (.21) - . 0 1 (•21) - . 0 1 (.22) .89 (.14) .81 (.13) .79 (.16)* All Levodopa/Carbidopa Subjects 25/6.25 mg and 50/12.5 mg (n = 8) - . 0 5 (.15) .01 (.17)§ - . 0 5 (.20) (n = 14) Ambly Dom Ambly Dom .69 (.27) .64 (.29)* .60 (.24)* - . 0 4 (.15) - . 0 6 (.15) - . 0 8 (.16) .78 (.24) .71 (.24)f .68 (.23)t - . 0 5 (.14) - . 0 3 (.15) - . 0 7 (.17) Dom * P< .05 f P < .01 X P < .005 § P < .02 tests, dependent on the predictions derived from the pilot study. Note that the log Snellen fraction remained stable in the placebo group at about 0.83 (20/ 135) in the amblyopic eye and about 0.0 (20/20) in the dominant eye. In the 25/6.25 mg levodopa/carbidopa group, log Snellen fraction in the amblyopic eye improved by 0.1 (one line), from 0.89 (20/155) to 0.79 (20/123) (paired t = 2.68, df = 5, 1 tailed P < 0.05) 5 hours after capsule ingestion. In the 50/12.5 mg levodopa/carbidopa group, log Snellen fraction improved from 0.69 (20/98) to 0.64 (20/87) 1 hour after capsule ingestion (paired t = 2.12, df = 7, 1-tailed P < 0.05) and improved to 0.60 (20/80) 5 hours after capsule ingestion (paired t = 1.92, df = 7, 1-tailed P < 0.05). Therefore, in comparing the 25/6.25 mg and 50/12.5 mg groups it appears that a higher dose of levodopa/carbidopa yielded a more rapid change in visual acuity. When the subjects in the 25/6.25 mg and 50/12.5 mg levodopa/carbidopa groups were combined, the 14 subjects who received levodopa/carbidopa showed a significant improvement in log Snellen fraction in the amblyopic eye from 0.78 (20/121) to 0.71 (20/103) at 1 hour (paired t = 2.85, df = 13, 1-tailed P < 0.01) and to 0.68 (20/96) at 5 hours (paired t = 3.09, df = 13, 1-tailed P < 0.01) after capsule ingestion. The subjects who received levodopa/carbidopa included five children with strabismic amblyopia and seven children with anisometropic amblyopia (the other two included a combined anisometropic/strabismic amblyope and a deprivational amblyope). The children with strabismic amblyopia had a mean change in log Snellen fraction of 0.08 and the ones with anisometropic amblyopia had a mean change in log Snellen fraction of 0.16. Although the difference in change in log Snellen fraction was not statistically significant, there appears to be a clear trend toward the subjects with anisometropic amblyopia having a greater improvement in log Snellen fraction with levodopa/carbidopa. There was no significant correlation between the Downloaded From: http://iovs.arvojournals.org/ on 06/11/2017 subject's age and maximum amount of change in log Snellen fraction (R = 0.07) or between dose based on body weight (mg/kg) and maximum amount of change in log Snellen fraction (R = 0.23). The log Snellen fraction in the dominant eye of the subjects in the 50/12.5 mg levodopa/carbidopa group remained stable at about — 0.05 (20/18). However, the dominant eye of the subjects in the 25/6.25 mg levodopa/carbidopa group exhibited a small but significant increase in log Snellen fraction from — 0.05 (20/18) to 0.01 (20/20) 1 hour after capsule ingestion (paired t = 3.48, P < 0.02). The increase in log Snellen fraction was not present 5 hours after levodopa/carbidopa ingestion and was not evident in the combined data. Side Effects Table 3 depicts the number and percentage of reported symptoms from the three groups of subjects. The number and percentages are based on ten reporting periods multiplied by the number of subjects in the respective group. Therefore, the maximum number of reports would have been 60, 60, and 80 for the placebo, 25/6.25 mg, and 50/12.5 mg levodopa/carbidopa groups, respectively. Overall, the number of symptoms appeared similar among the three groups. One subject in the 50/ 12.5 mg levodopa/carbidopa group experienced two TABLE 3. Symptoms: Total Number (%) Placebo (n = 6) 25/6.25 mg (n = 6) 17(28%) 6 (9%) 3 (4%) 1 (1%) Irritable 10(17%) 2 (3%) 2 (3%) 3 (5%) Legs hurt Cold Tired/Sleepy Dizzy Nausea Headache Other * With emesis (X2). 50/12.5 mg (n = 8) 36 (45%) 1 (1%)* Hot (X2) Earache (X2) Sore throat 3094 Investigative Ophthalmology & Visual Science, October 1993, Vol. 34, No. 11 transient episodes of nausea and emesis. This subject received 2/0.5 mg/kg of levodopa/carbidopa while on average the group received 1.94/0.49 mg/kg (range: 0.76/0.19 to 3.14/0.49 mg/kg). However, these findings are complicated in that the subject's mother continually asked the subject if she was going to get sick, shortly after capsule ingestion and long before the subject experienced any symptoms. (Nausea and vomiting are listed as a possible side effects on the consent form.) The most prevalent side effect reported in the study was tiredness and sleepiness. This "side effect" of the study was probably the result of the length of the study. Most of the time the subjects and parents were waiting for the next test session or examination and they occupied their time by watching videotaped movies in the Clinical Study Center. The three groups of subjects had similar respiration, heart rate, and blood pressure at baseline and throughout the study session. In addition, the one subject who experienced nausea and emesis did not demonstrate any noticeable change in blood pressure, respiration, or heart rate associated with the emesis. DISCUSSION The current study revealed that 25/6.25 mg or 50/ 12.5 mg of levodopa/carbidopa significantly improved visual acuity by one line, from 20/121 to 20/ 96, in the amblyopic eyes of previously stable or difficult-to-treat children with amblyopia. Visual acuity did not change significantly in a similar group of amblyopic subjects who received placebo. In the original pilot study2 it was found that 100/25 mg to 200/50 mg of levodopa/carbidopa, depending on body weight and which averaged 4.0/1.0 mg/kg, improved visual acuity by about 0.3 log Snellen fractions or about 3 lines on the ETDRS acuity charts. In the pilot study a traditional Snellen visual acuity chart was used, with unequal letter size changes between lines, and on that chart there was a 1.5 line change in visual acuity. Therefore, some caution is noted in comparing the two studies. The combined results of the two studies, however, are suggestive of a dose-response relationship between levodopa/carbidopa and visual acuity; with a higher dose yielding a greater improvement in visual acuity. Also suggestive of a dose-response relationship was the finding that the greatest individual improvement in log Snellen fraction occurred in the 50/12.5 mg levodopa/carbidopa group (0.38), followed by 0.24 in the 25/6.25 mg levodopa/carbidopa group and 0.15 in the placebo group. A significant dose-response correlation was not found in the current study probably because of the relatively small difference in dose between levodopa/carbidopa Downloaded From: http://iovs.arvojournals.org/ on 06/11/2017 groups and because of the small change in visual acuity observed. The small change in visual acuity found with levodopa/carbidopa, however, was by design: our major aim was to find a low dose of levodopa/carbidopa that would minimize side effects yet reveal some improvement in vision. The current study doses of 25/6.25 mg and 50/ 12.5 mg reflect an average of 0.95/0.24 mg/kg and 1.94/0.49 mg/kg body weight, respectively. At these average single-dose levels one of 14 subjects experienced nausea with emesis, and that subject had received 2.0/.5 mg/kg of levodopa/carbidopa. In the original pilot study2 in which five amblyopic subjects received an average 4.0/1.0 mg/kg of levodopa/carbidopa, three subjects experienced nausea with emesis. Therefore, given the current results and those of the pilot study, it would seem reasonable in future studies to provide an upper limit in the initial dose of about 1.5/.38 mg/kg of levodopa/carbidopa to minimize nausea with emesis and yet yield an improvement in visual acuity. At the same time, however, it is important to note that the current and pilot studies were performed on subjects with an empty stomach. As a consequence, a higher initial dose could be considered if the levodopa/carbidopa is taken after the ingestion of food. The emphasis of the current endeavor is to determine the feasibility of augmenting occlusion therapy with levodopa/carbidopa. In this regard, in the current study all subjects were occluded throughout the 8-hour study. Because both the placebo and levodopa/carbidopa groups were occluded, the improvement in visual acuity seen in the levodopa/carbidopa group could not be attributable to occlusion, per se. The current results support the hypothesis that levodopa/carbidopa could be tolerated by children with amblyopia and support the possibility that levodopa/ carbidopa could be used to augment occlusion therapy. One reason it may be important to study the augmentation of occlusion therapy with levodopa/carbidopa is patient compliance with occlusion. When occlusion is first implemented on a child with active amblyopia, the success of occlusion therapy is dependent on compliance. And, from a clinical perspective, compliance depends on the child's initial visual acuity in the amblyopic eye. Children with deep amblyopia, say worse than 20/100, are less likely to comply with occlusion than children with mild amblyopia. When the child with deep amblyopia has his dominant eye occluded, he does not have functional vision with the amblyopic eye, finds it difficult to watch television, play games, or do class work or homework. If levodopa/carbidopa can be used to improve visual acuity such that functional vision can be achieved by the Levodopa/Carbidopa for Childhood Amblyopia amblyopic eye then compliance could be increased and the success of occlusion therapy might be improved. Thus an avenue for future research would be to undertake a systematic investigation into the influence of levodopa/carbidopa on occlusion compliance. Finally, it is important to note that many of the subjects in the current study were beyond the age where occlusion therapy is effective in amblyopia. Given that these older amblyopes also exhibited improved visual acuity with levodopa/carbidopa raises the possibility that older children and even adults could benefit from levodopa/carbidopa therapy. Indeed, preliminary evidence suggests that amblyopic adults could exhibit an improved and maintained visual acuity in the amblyopic eye following one week of levodopa therapy alone5. Likewise, our research group has found preliminary evidence that 3 weeks of part-time occlusion combined with levodopa/carbidopa can yield improved and maintained visual acuity and contrast sensitivity in the amblyopic eyes of older children (unpublished data). Overall, the improved visual function observed in amblyopic children26 and in amblyopic adults15 with levodopa therapy is very encouraging and warrants further study. Downloaded From: http://iovs.arvojournals.org/ on 06/11/2017 3095 Key Words amblyopia, levodopa, strabismus, anisometropia, sinemet References 1. Gottlob I, Stangler-Zuschrott E. Effect of levodopa on contrast sensitivity and scotomas in human amblyopia. Invest Ophthalmol Vis Sci. 1990;31:776-780. 2. Leguire LE, Rogers GL, Bremer DL, Walson P, Neff M. Levodopa and childhood amblyopia. J Ped Ophthalmol Strab. 1992;29:290-298. 3. Nutt JG, Woodward WR, Hammerstad JP, Carter JH, Anderson JL. The "on-off" phenomenon in Parkinson's disease: relation to levodopa absorption and transport. NEnglJMed. 1984;310:483-488. 4. Ferris FL, Kassoff A, Bresnick GH, Bailey I. New visual acuity charts for clinical research. AmJ Ophthalmol. 1982;94:91-96. 5. Gottlob I, Charlier J, Reinecke RD. Visual acuities and scotomas after one week of levodopa administration in amblyopic patients. Invest Ophthalmol Vis Sci. 1992;33:2722-2728. 6. Leguire LE, Rogers GL, Bremer DL, Walson P. Double masked placebo controlled randomized trial of levodopa for childhood amblyopia. Invest Ophthalmol Vis Sci Suppl. 1992;33(suppl):742.