Effectiveness of the addition of citicoline to patching in the treatment of amblyopia around visual maturity: a randomized controlled trial.

AIM: To study the effectiveness of the addition of citicoline to patching in the treatment of amblyopia in the age group of 4-13 years.
MATERIALS AND METHODS: A randomized controlled trial, which included patients who were randomly divided into two groups. Both the groups received patching therapy till plateau was achieved in phase 1 of the study. Then in phase 2, group I received citicoline plus patching and group II continued to receive only patching. OUTCOME MEASURES: Outcome was measured by the visual acuity in logMAR every month in phase 1 till plateau was achieved and then for 12 months in phase 2.
RESULTS: No significant difference was found in the mean visual acuities in these two groups in phase 1 till plateau was reached. In phase 2, for the initial four months, there was no significant difference in the visual acuities in these two groups, at the respective intervals. However, five months onward, up to 12 months, there was a significant difference in the visual acuities in these groups.The result was the same in younger patients (< seven years of age) as well as in older patients (> seven years of age). In phase 2, the mean proportional improvement in group I was significantly more than that in group II, at two months and onward, at the respective intervals.
CONCLUSION: The improvement in visual acuity with citicoline plus patching was significantly more than that with patching alone, in one year of treatment.

RCT Entities:   Population Interventions Outcomes

Amblyopia is the most common cause of monocular visual impairment in children, young, and middle-aged adults.[1]

There is a consensus that amblyopia can be effectively treated in young children.[234] Although there has been, in the past, a general belief that treatment beyond a certain age is ineffective, it has been conclusively proved that ‘age’ is no bar, for the success of the treatment of anisometropic amblyopia.[5] Some believe that a treatment response is unlikely after the age of six or seven years, while others consider the age of nine or ten years to be the upper age limit for successful treatment.[678910] However, there are many studies involving older children and adults with amblyopia, responding to treatment with patching.[1112131415161718192021222324]

Occlusion therapy with patching of the sound eye has been the conventional treatment. However, there are many studies stating the effectiveness of some pharmacological agents in the treatment of amblyopia — citicoline is one of them.[2526]

Citicoline (cytidine-5-diphosphocholine) activates the biosynthesis of structural phospholipids in the neuronal cell membranes, which results in increased levels of neurotransmitters, and thus, has neuroprotective effects.[27] It has also been shown to improve the learning and memory performance. There are few animal studies that have reported the enhancement of dopaminergic neurotransmission in the brain with citicoline (exogenous cytidine-5′-diphosphocholine). A study aimed at determining whether citicoline (50 mg/kg., twice daily) could influence retinal catecholamine levels in adult male Albino rabbits, has reported that, compared to vehicle-treated controls, citicoline-treated animals displayed a significantly higher retinal dopamine concentration and a tendency toward an increase in adrenaline concentration, while the noradrenaline concentration remained unchanged.[28]

Citicoline is an intermediate in the making of phosphatidylcholine, a phospholipid, in cell membranes. Citicoline activates the biosynthesis of structural phospholipids in the neuronal membranes, increases brain metabolism, and influences the levels of different neurotransmitters. It has been shown to increase acetylcholine, norepinephrine, and dopamine levels in the central nervous system. Citicoline is currently used in the treatment of Alzheimer's disease and stroke as a brain stimulator.

Citicoline is presently also tried in the treatment of amblyopia.[2930] To the best of our knowledge, studies to evaluate the effect of citicoline in amblyopia have not been conducted in India. Therefore, the present study was conducted to find out the effectiveness of the addition of citicoline to patching in the treatment of amblyopia, in the age group of four to thirteen years.

Materials and Methods

The present study was carried out at Department of Ophthalmology, Dr. Vasantrao Pawar Medical College Hospital and Research Centre, Nashik; and Manishankar eye hospital and institute, Nashik The study was conducted between January 2006 and December 2009. Ethical clearance was taken from the Institutional Ethical Committee before the start of the study.

The inclusion criteria were

Patients of amblyopia from four to thirteen years of age

Patients not suffering from any other ophthalmic morbidity

Patients/Parents willing to participate in the study.

Exclusion criteria in this study were

Patients in whom citicoline was contraindicated, such as hypersensitivity to citicoline, history of epilepsy

Not willing to participate in the study, after thorough discussion of treatment and its side effects with the family.

All the patients suffering from amblyopia were primarily screened for inclusion in the study. Subjects who fulfilled the inclusion criteria were selected for the study. The patients were randomly divided into two groups. The study was divided into two phases. In Phase 1, a complete history of the included patients was elicited including family, personal, and birth history. Visual acuity was tested with the Snellens chart. Dry retinoscopy and Wet retinoscopy were conducted followed by acceptance and prescription of the required glasses. Ophthalmic examination and slit lamp examination were performed for anterior segment examination. Dilated fundoscopy was carried out to rule out any retinal pathology.

The following tests were conducted:

Complete refractive status of both eyes

Binocular single vision by stereo charts and Worth four-dot test

Cover test/uncover test for the amount of squint and type of squint, added vertical or oblique deviation

Alternate cover test

Extraocular movements

Prism cover test

Forced duction test as per the case, local or general anesthesia

Dilated fundoscopy for the macular shift in cases of oblique overaction or eccentric fixation

Direct ophthalmocopy for eccentric fixation in strabismic amblyopia

Observation of result on initial patching therapy in strabismic cases.

Color vision testing.

Following this, the patching therapy was started in both groups. The patients were followed at one month intervals and visual acuity was recorded. If there was no improvement in the visual acuity for three consecutive followups, then a plateau was considered. It was approximately corresponding to the maximum correction that could be achieved with patching. Once a plateau was achieved, the patient entered phase 2 of the study.

In phase 2, group I received citicoline in addition to continued patching. The doses of citicoline were 250 mg OD (for patients below five years) and 500 mg OD (for patients above five years). Group II continued to receive only patching. In both groups, the respective treatment was continued for six months in phase 2. At the end of this period citicoline was gradually tapered by giving half the dose daily for two months, half the dose on alternate days for another two months, and then discontinued. Patching was continued for 12 months in both groups.

The patients were followed at one month intervals for 12 months in phase 2. The visual acuity was recorded in every followup visit. Visual acuity was converted into the Logarithm of the minimum angle of resolution (LogMAR). The mean LogMAR visual acuity was calculated in both the groups. Proportional improvement in the visual acuity, adjusted for fellow eyes, was calculated using the following formula, suggested by Stewart C E et al.[31]

Proportional improvement = (VAas – VAae)/(VAas – VAfe)

Where VAas is the LogMAR visual acuity of an amblyopic eye at the start of the study (baseline); VAae is the LogMAR visual acuity of the amblyopic eye at the end of the respective interval; and, VAfe is the LogMAR visual acuity of the fellow eye at the end of the respective interval.

Age: 1, (maximum 6:1) schedule was followed for patching. For example, for a patient of five years, 5:1 schedule was followed (five days full-time patching for the better eye and one-day patching for the worse eye). For a patient of 10 years, 6:1 schedule was followed.

The analysis of variance (ANOVA) was used to test the significant difference between the mean LogMAR values. Differences in the proportional improvements were tested with a non-parametric test like the Mann Whitney U test. Other tests like Chi-square test and Z-test were also used at appropriate places. Analysis was done using SPSS 16.

Results

In the study period 165 patients were primarily screened for inclusion in the trial. Out of them, 134 patients were finally selected for inclusion in the study. Out of these, we could follow up 84 patients for one year in phase 2.

The distribution of the study subjects is shown in Table 1.

Table 1

Distribution of the study subjects in the two groups

There was no significant difference in the baseline characteristics of patients in the two groups. The mean ages were 6.78 ± 1.53 and 6.68 ± 1.89 (P = 0.81). The mean visual acuity (LogMAR) in the amblyopic eyes were 0.78 ± 0.36 and 0.77 ± 0.35 (P = 0.90).

Table 2 shows the mean visual acuity at various intervals during treatment. In phase 1, both the groups received only the patching therapy. Therefore, no significant difference was found in the mean visual acuities in these two groups till the plateau was reached. The mean time taken to reach the plateau (no improvement in three consecutive assessments) was 8.28 months ± 1.09 in group I and 8.40 months ± 1.15 in group II. The range was seven to ten months in both the groups.

Table 2

Mean visual acuity (LogMAR) in both the groups during follow up

In phase 2, for the initial four months, there was no significant difference in the visual acuities in these two groups, in the respective intervals. However, at five months and onward, up to 12 months, there was a significant difference in the visual acuities in these two groups at the respective intervals. Thus, addition of citicoline showed a significant improvement in the mean visual acuities after five months. Group II, which received continued patching, showed some deterioration from the plateau, in the mean visual acuity, although marginal and statistically insignificant, after 12 months.

Table 3 shows the mean proportional improvement in the visual acuity, adjusted for fellow eye, with respect to the baseline values. In phase 1, there was no significant difference in the mean proportional improvements in these two groups. However, in phase 2 the mean proportional improvement in group I was significantly more than that in group II at two months, and onward up to 12 months, at the respective intervals. It showed that the mean proportional improvement even at the two- month interval was significantly more in group I (which received citicoline plus patching), as compared to Group II (which received patching alone).

Table 3

Mean proportional improvement in the visual acuity, adjusted for fellow eye, with respect to the baseline values

Table 4 shows the visual acuity–wise distribution of patients at the end of phase II.

Table 4

Visual acuity at the end of phase 2

To study the effect of age in the outcome, we have divided the study subjects in each group into two subgroups, one subgroup of young patients (age at start of phase 1 ≤ 7 years, Fig. 1) and the other of ‘old’ patients (age at start of phase 1 > 7 years, Fig. 2). At the end of the five months, in phase 2, the mean logMAR of the younger as well as older patients in group I was significantly less than that in Group II, showing significantly better improvement in the younger and older patients with citicoline along with patching (P < 0.05). This showed that the treatment of amblyopia with citicoline along with patching was equally effective in the seven-to-thirteen year age group.

Figure 1

Mean LogMAR of “young” patients during the study (age, at start of phase 1 ≤ 7 years)

Figure 2

Mean LogMAR of “Older” patients during study (age, at start of phase 1, >7)

No significant side effects, which could lead to withdrawal of the treatment, were recorded in both the groups. Only one patient in Group I had one episode of vomiting, which responded to the usual line of treatment.

Discussion

The present multicentric study was carried out to find out the effectiveness of the addition of citicoline to the conventional patching therapy for the treatment of amblyopia. This study has suggested that addition of citicoline, even after maximum improvement with conventional patching was achieved, can further improve the visual acuity.

Citicoline primarily acts by increasing the synthesis of phosphatidylcholine, the primary neuronal membrane phospholipid, thus enhancing the production of acetylcholine. Oral citicoline administration increases the plasma levels of choline and cytidine, the building blocks used to restore neuronal membrane integrity.[32] It is also postulated that citicoline facilitates the preservation of sphingomyelin, which promotes signal transduction in nerve cells.[33]

Citicoline may significantly impact the brain-remodeling activity. A study in rats has shown that citicoline treatment significantly increases the length and branch points of the dendrites, increasing the overall surface area occupied by neurons, which leads to an increased efficiency of sensory information processing. This mechanism of activity may potentially account for a significant portion of citicoline's neurorestorative functions.[34]

Campos et al.,[29] have also recorded that citicoline was effective in the treatment of amblyopia. They published the preliminary results of their study and stated that statistically significant improvement in visual acuity was found both for the amblyopic and sound eye in 46 of the 50 patients (92%). The behavior was different for normal and amblyopic eyes. The improvement remained stable for at least four months. Similarly Porciatti et al.,[35] recorded that visual acuity improved 1.4-1.5 lines in the amblyopic eyes and 0.4 lines in the normal eyes with citicoline. They also reported improvements in the contrast sensitivity and increase in the visually evoked potential. This study was conducted in adults with a mean age of 24.8 years. Ghosh S and Ghosh R, in a study on amblyopic patients, in the age group of 10 to 18 years, reported that 71% of the patients had shown visual improvement with citicoline.[36]

Our findings were in contrast with the findings of Michela Frenisa et al.,[30] who have reported that addition of CDP-choline to patching therapy was not found to be more effective than patching alone after a 30-day treatment. They have reported that adding CDP-choline to patching stabilized the effects obtained during the treatment period.

There are few limitations of this study, which must be documented. This was not a double-blind study rather it was an open study. This could have resulted in observer or investigator bias. Second, we have analyzed only those subjects whose follow-up data was available up to one year in phase 2. Therefore, there was a problem of attrition, which may have affected the results. No imputation methods have been used to fill the missing values. Nevertheless, this study has shown that the addition of citicoline to patching therapy can significantly improve the visual acuity in amblyopic patients.