Drs. Dadeya, Vats, and Malik have disclosed no relevant financial relationships.
Presented in part at the Asia Pacific Academy of Ophthalmology meeting, Kula Lumpur, Malaysia, March 27–31, 2005. Supported by the Council of Scientific and Industrial Research, Government of India.
Address correspondence to Subhash Dadeya, MD, MNAMS, FIMSA, D-10, Mirdard Lane, Flat No. 13, Type 5 MAM, Maulana Azad Medical College, Delhi-2, India.
Amblyopia is a fairly common disorder affecting 1% to 2% of the population in most developed countries.1 Occlusion of the sound eye with an adhesive skin patch is perhaps the most effective means of therapy.2 However, it is associated with occlusion amblyopia, disruption in education, and deterrence to good compliance. Furthermore, the appearance of constant manifest deviation after occlusion in children who do not have strabismus is distressing. Additionally, occlusion of the child’s dominant eye is not an easy task and there is associated cosmetic blemish.
Levodopa is a precursor of dopamine, a neurotransmitter known to influence the visual system at both the retinal and cortical level.3 Animal amblyopic models have been shown to be deficient in dopamine.4 Carbidopa is a peripheral decarboxylase inhibitor that prevents the breakdown of levodopa at peripheral sites and allows more of it to cross the blood–retinal barrier. Levodopa has been shown to improve visual acuity in children and adults.5,6 However, it is not known how long the effect lasts or whether it is reversible. Tolerance of levodopa for treatment of long duration has not been studied. There are few studies in the literature regarding the use of levodopa in the treatment of strabismic amblyopia.7–14 Furthermore, whether the effect is greater in a younger age group or an older age group is also not known. This study examined whether levodopa/carbidopa facilitates occlusion therapy in the treatment of strabismic amblyopia and whether the effect is greater in a younger age group (3 to 7 years) or an older age group (8 to 12 years).
Patients and Methods
Thirty patients aged 3 to 12 years being treated for amblyopia between February 2000 and March 2004 were recruited in this double-blind randomized prospective clinical study. Amblyopia was defined as a difference of 2 or more lines of Snellen visual acuity as per Phelps criteria and patients were divided into two groups. Group A (levodopa group) received 0.50 mg of levodopa + 0.125 mg of carbidopa per kilogram of body weight three times daily after meals with a protein-rich drink. This dose was used because it has been found to be safe without any side effects by Leguire et al.5 Group B (placebo group) received placebo in the form of glucose.
Exclusion criteria included: children younger than 3 years, patients who had received prior amblyopia therapy in any form, patients having a contraindication to levodopa, and patients who did not return for follow-up for 6 months. Patients having anisometropia of more than 1.5 diopters were also excluded. Informed consent was obtained from the parents of patients prior to initiation of therapy.
A detailed history with onset, course, and treatment of amblyopia was obtained. To rule out systemic pathology, a comprehensive general physical examination was performed. Ophthalmologic evaluation included visual acuity, refraction under atropine, and fundus examination. Visual acuity was measured by children’s figure chart at the viewing distance of 6 meters under similar conditions all times. Both groups received full-time conventional occlusion as per the thumb age rule. Patients in each group were further divided into two groups—the younger age group was 3 to 7 years old and the older age group was 8 to 12 years old.
The drug was prepared as per body weight by a pharmacist who also held the key for coding. The patient picked up a paper slip to be allocated to a particular group. Neither the patients nor the physician were aware of the coding. The drug was dispensed in the form of powder. The parents were informed about the possible common side effects, such as tiredness, upset stomach, nausea, and vomiting. The patients were examined at 1 week, 2 weeks, 3 weeks, 1 month, 3 months, and 6 months. All parameters including body weight, temperature, pulse, respiration, heart rate, visual acuity, and refraction were recorded at each visit. Fundus examination was performed only once. However, levodopa was given for 3 months. Laboratory investigations were performed at initiation of therapy and at the end of the study.
A total of 33 cases of strabismic amblyopia were part of the study. Three patients did not return for follow-up because they had moved and were therefore excluded. The mean age was 8.3 years in the levodopa group and 8.7 years in the placebo group. There were 15 patients in each group. Both groups were matched for age and sex (Tables 1 and 2). In the levodopa group, 2 patients had a visual acuity of less than 6/60 (.10), 12 patients had a visual acuity ranging from 6/60 (.10) to 6/18 (.32), and 1 patient had a visual acuity of 6/12 (.50) at presentation.
Table 1: Age, Sex, and Changes in Visual Acuity in the Levodopa Group
Table 2: Age, Sex, and Changes in Visual Acuity in the Placebo Group
A good response to treatment was seen in all patients in the levodopa group, and 100% of patients had improvement of more than 2 lines of visual acuity at 3 months. This improvement was maintained in 87% of patients at 3 months and only 13% of patients had reversal of visual acuity at 6 months (Table 1). In the placebo group, 60% of patients had improvement in visual acuity at 3 months, and this improvement was maintained in 47% of patients at 6 months (Table 2).
One hundred percent of patients in the levodopa group had improvement in visual acuity, whereas only 60% of patients in the placebo group had improvement in visual acuity. This difference was found to be statistically significant (P < .005) (Tables 1 and 2). The chi-square test was used for statistical analysis.
Occlusion of the dominant eye has remained the mainstay of amblyopia therapy since 1722. There is neither a short cut nor a substitute for occlusion of the dominant eye in treatment of amblyopia. However, it is associated with disadvantages such as occlusion amblyopia, cosmetic blemish, and disruption in education. There is evidence that plasticity of the visual system during this sensitive period is dependent on inputs from nonadrenergic neurons and is subject to pharmacological manipulations. It has been thought that dopamine deficiency in the retina plays a part in amblyopia and levodopa therapy might help in reversing this condition, although the exact mechanism of action is not known.
Significant visual improvement in children with amblyopia with 3 weeks of therapy was reported by Leguire et al.15 A longer study of 7 weeks’ duration reported an increase in visual acuity of children with amblyopia with up to 5 weeks of therapy.5 Pandey et al.16 and Basmak et al.17 concluded that the effect of levodopa is transient and improvement in visual acuity decreased after cessation of therapy. Mohan et al.18 concluded that augmentation of levodopa with part-time or full-time occlusion does not enhance the recovery of vision in amblyopia. However, the addition of full-time occlusion to levodopa helps to maintain improved visual acuity longer compared to levodopa alone, and there is reversal of improved visual acuity in a significant number of patients.
There has been regression of visual acuity in children treated with levodopa.6,14,16–18 However, in our study, significant improvement in visual acuity was seen in both groups (levodopa group = 100% and placebo group = 60%). This improved visual acuity persisted until 6 months in 87% of the patients in the levodopa group and 47% of the patients in the placebo group. This difference in visual acuity at the end stage was significant, thereby implying that levodopa improves visual acuity in patients with amblyopia and maintains this improved visual acuity. In our study, we observed the patients for 3 months and found that only 13% of patients in each group had reversal of visual acuity at the end of 3 months. The latent period for significant change in vision was 1 week for occlusion + levodopa compared to 2 weeks for occlusion + placebo, implying that levodopa reduces the latent period of response to occlusion.
It has been reported that improvement in visual acuity is more frequently seen in younger patients. It is proposed that the visual system of young patients is more susceptible to levodopa than that of older patients. We divided the patients into two age groups: 3 to 7 years and 8 to 12 years. We found that improvement in visual acuity of more than 2 lines was seen in 100% of patients 3 to 7 years old versus 60% of patients 8 to 12 years old, thereby implying that levodopa is more effective in improving visual acuity in patients up to 8 years of age and the sensitive period probably extends up to 8 years of age.
Both levodopa and placebo were well tolerated. Side effects such as emesis, loss of appetite, nausea, paleness, irritability, and increased or decreased motor activity have been reported in the literature. However, in our study, a minor side effect in the form of nausea was observed in one patient only. This was perhaps due to the fact that we prescribed the minimum therapeutic dose with a protein-rich diet.
We conclude that there is a significant increase in visual acuity with occlusion and levodopa, implying that augmentation with levodopa has a significant effect on final outcome in terms of vision and this effect is more pronounced in patients younger than 8 years compared to those older than 8 years. Levodopa is shown to dramatically reduce the latent period of response to occlusion. Improvement in visual acuity was maintained in 87% patients until 6 months and levodopa is safe in children up to 12 years of age in the prescribed dose.
- Flynn JT. Amblyopia revisited. 17th annual Frank Costenbader Lecture. J Pediatr Ophthalmol Strabismus. 1991;28:183–201.
- Iacobucci I. Patching program for treatment of amblyopia. J Pediatr Ophthalmol. 1977;14:7–11.
- Dyer RS, Howell WE, MacPhail RC. Dopamine depletion slows retinal transmission. Exp Neurol. 1981;71:326–340. doi:10.1016/0014-4886(81)90092-3 [CrossRef]
- Chino YM, Shansky MS, Hamaski DI. Development of receptive field properties of retinal ganglion cells in kittens raised with convergent squint. Exp Brain Res. 1980;39:313–320. doi:10.1007/BF00237120 [CrossRef]
- Leguire LE, Walson PD, Rogers GL, Bremer DL, McGregor ML. Levodopa /carbidopa treatment for amblyopia in older children. J Pediatr Ophthalmol Strabismus. 1995;32:143–151.
- Gottlob I, Wizov SS, Reinecke RD. Visual acuities and scotomas after 3 weeks’ levodopa administration in adult amblyopia. Graefes Arch Clin Exp Ophthalmol. 1995;233:407–413. doi:10.1007/BF00180943 [CrossRef]
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- Leguire LE, Walson PD, Rogers GL, Bremer DL, McGregor ML. Longitudinal study of levodopa/carbidopa for childhood amblyopia. J Pediatr Ophthalmol Strabismus. 1993;30:354–360.
- Leguire LE, Rogers GL, Walson PD, Bremer DL, McGregor ML. Occlusion and levodopacarbidopa treatment for childhood amblyopia. J AAPOS. 1998;2:1–7.
- Leguire LE, Komaromy KL, Nairus TM, Rogers GL. Long-term follow-up of L-dopa treatment in children with amblyopia. J Pediatr Ophthalmol Strabismus. 2002;39:326–330.
- Campos EC, Fresina M. Medical treatment of amblyopia: present state and perspectives. Strabismus. 2006;14:71–73. doi:10.1080/09273970600701044 [CrossRef]
- LaRoche GR. Detection, prevention, and rehabilitation of amblyopia. Curr Opin Ophthalmol. 2000;119:306–309. doi:10.1097/00055735-200010000-00003 [CrossRef]
- Chatzistefanou KI, Mills MD. The role of drug treatment in children with strabismus and amblyopia. Paediatric Drugs. 2000;2:91–100. doi:10.2165/00128072-200002020-00002 [CrossRef]
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- Pandey PK, Chaudhuri Z, Kumar M, Satyabala K, Sharma P. Effect of levodopa and carbidopa in human amblyopia. J Pediatr Ophthalmol Strabismus. 2002;39:81–89.
- Basmak H, Vilderem N, Erdine O, et al. . Effect of levodopa therapy, on visual evoked potentia, and visual acuity in amblyopia. Ophthalmologica. 1999;213:110–113.
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Age, Sex, and Changes in Visual Acuity in the Levodopa Group
|Patient No.||Age (Y)||Sex||Visual Acuity|
|At Start of Treatment||1st Week||2nd Week||3 Months||6 Months|
Age, Sex, and Changes in Visual Acuity in the Placebo Group
|Patient No.||Age (Y)||Sex||Visual Acuity|
|At Start of Treatment||1st Week||2nd Week||3 Months||6 Months|