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Effect of citicoline on visual acuity in amblyopia: Preliminary results

Article  in  Albrecht von Graæes Archiv für Ophthalmologie · June 1995

DOI: 10.1007/BF00177654 · Source: PubMed

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Graefe's Arch Clin Exp Ophthalmol (1995)
233:307-312 © Springer-Verlag 1995

Emilio C. Campos Effect of citicoline on visual acuity

Costantino Schiavi
Paola Benedetti in amblyopia: preliminary results
Roberto Bolzani
Vittorio Porciatti

Received: 28 October 1993 Abstract • Background: Citicoline to a treatment or placebo group

Revised version received:
21 February 1994
Accepted: 21 September 1994
E. C. Campos • C. Schiavi. P. Benedetti
R. Bolzani
Department of Ophthalmology,
University of Modena, Modena, Italy
E. C. Campos (Nil)
Clinica Oculistica dell' Universita,
via Massarenti, 9-I-40138 Bologna, Italy
Fax: +39-51-342516
V. Porciatti
Neurophysiology Institute, CNR, Pisa,
Italy
has been used to improve con-
sciousness levels in cerebral trauma
and as a complement for levodopa
in Parkinson's disease. It has also
been shown that severe glaucoma-
tous visual field deficits improve
for at least 4 months with the use
of citicoline. In this paper, prelimi-
nary results are presented of an
open and a double-blind study on
the effect of citicoline in ambly-
opia. • Methods: The open study
was started in 1991. Fifty patients
with amblyopia were treated with
citicoline (1000 mg i.m. daily for 15
days). They were selected from an
age group beyond the plastic peri-
od of the visual system. Occlusion
or other types of anti-amblyopic
treatment were never used at the
same time as citicoline. A double-
blind study was conducted on 10
more patients, randomly assigned
and followed for 6 months. A
statistical test for repeated mea-
sures was performed on all the re-
sults. • Results: A statistically sig-
nificant improvement in visual acu-
ity was found both for the ambly-
opic and the sound eye in 46 of the
50 patients (92%). The behaviour
was different for normal and am-
blyopic eyes. The improvement re-
mained stable for at least 4
months. These results have been
substantiated by the double-blind
study. No side effects were ob-
served. • Conclusion: Citicoline
improves visual acuity, at least
temporarily, in amblyopic patients
beyond the plastic period of the vi-
sual system. Our results suggest
that trials of citicoline as a medical
treatment of amblyopia are war-
ranted.

Introduction sound eye in monkeys beyond the plastic period of the

Much has been learnt on the pathophysiology of ambly-
opia in the past three decades, mainly by means of ani-
mal experimentation. It is now established that func-
tional and morphological changes occur in amblyopia
at the level of the lateral geniculate nucleus (LGN) and
the occipital striate cortex [12]. L G N changes have been
confirmed even in humans [14, 15]. Relevant experimen-
tal studies have also demonstrated that it is possible to
delay the plastic period of the visual system by means of
bicuculline, beta-blockers and nerve growth factor [4, 5,
7, 8]. Finally, it has been shown that enucleation of the
visual system causes a functional improvement of the
deprived amblyopic eye, because pre-existing synapses
are put back to work [6]. This body of information has
not been transferred yet to humans, for which occlusion
remains the most frequently used and most effective an-
ti-amblyopic treatment [13].
The possibility of influencing amblyopia with chemi-
cals has long been a dream of strabismologists. Nagel
was the first to use strychnine as a vasodilator in ambly-
opia [11]. Bietti showed in the 1950s that suppression
scotomata could be influenced by strychnine, oxygen
and nicotinic acid [1, 2]. These attempts at medical
308

treatment of amblyopia never found their way into clin- Table 1 The age and ocular condition of each of the 50 patients in
ical routine; their efficacy was questionable and their the open study
side effects relevant. Patient Age (years) Condition
Recently, it has been shown that levodopa improves
temporarily some visual functions in amblyopia [7, 10]. 1 13 Anisometropia
Duration of improvement is short, and side effects are 2 12 Anisometropia
not to be neglected. 3 9 Anisometropia
4 10 Strabismus
Cytidine-5-diphosphocholine (CDP-choline or citi- 5 9 Anisometropia
coline) has been used for many years to improve con- 6 14 Anisometropia
sciousness level in patients with post-traumatic cerebral 7 33 Strabismus
lesions and as a complement to levodopa in Parkinson's 8 9 Anisometropia
9 26 Anisometropia
disease patients. Even if animal experimental studies are 10 10 Deprivation
still unsufficient, it appears that citicoline improves 11 10 Anisometropia
membrane ATPase activity. It modulates the turnover 12 10 Deprivation
of catecholamines and serotonin. In particular, stimula- 13 12 Deprivation
tion of dopamine metabolism has been documented in 14 37 Strabismus
15 15 Anisometropia
the nigrostriatal dopaminergic system [18]. Citicoline 16 20 Anisometropia
absorption is increased in cerebral lesions. Citicoline 17 9 Deprivation
has been shown to ameliorate severe glaucomatous vi- 18 9 Anisometropia
sual field deficits for at least 4 months in about 60% of 19 17 Strabismus
20 18 Anisometropia
treated patients [16, 17]. We therefore started to use citi- 21 20 Anisometropia
coline in amblyopia in 1991 and have obtained encour- 22 22 Anisometropia
aging results [3]. Our preliminary findings are reported 23 12 Anisometropia
here. 24 14 Anisometropia
25 14 Strabismus
26 12 Deprivation
27 21 Anisometropla
Materials and methods 28 23 Anisometropla
29 17 Anisometropla
Sixty patients with amblyopia took part, 50 in an open study and
10 in a double-blind study. They were selected from among the 30 15 Anisometropla
31 13 Anisometropla
patients of the Pediatric Ophthalmology and Strabismus Service
32 16 Anisometropla
of the University of Modena and from the private practice of one
33 29 Anisometropla
of the authors (E.C.C). Their age was chosen to be beyond the
34 18 Anisometropla
plastic period of the visual system and ranged from 9 to 37 years
35 20 Anisometropla
(mean 16.6 years). All patients had previously been treated unsuc-
36 32 Strabismus
cessfully for amblyopia and were aware that they were participat-
37 16 Anisometropia
ing in an experimental study. A consent form was signed by the
38 21 Anisometropia
patient or, if applicable, by their parents. Of the 50 patients partic-
39 16 Deprivation
ipating in the open study, 32 had anisometropic, 12 strabismic and
40 15 Anisometropia
6 deprivation amblyopia (Table 1). Their visual acuity in the
41 28 Anisometropia
sound eye was 6/12 or better; that of the amblyopic eye ranged
42 12 Strabismus
from 6/60 to 6/6 (Table 2). Of the 10 patients in the random dou-
43 17 Strabismus
ble-blind study, 7 had anisometropic and 3 strabismic amblyopia
44 15 Anisometropia
(Table 3). Their visual acuity in the amblyopic eye ranged from
45 12 Strabismus
6/60 to 6/9; that of the sound eye was 6/6 or better (Table 4). 46 9 Strabismus
Visual acuity was always measured with the same charts in the 47 11 Anisometropia
same examining room. The upper measurable limit of visual acu- 48 18 Anisometropia
ity was 6/4.5 because of limitations of the charts. First, linear 49 20 Strabismus
acuity was measured with Snellen Es, separated by the same space 50 22 Strabismus
which included the letter of a given size (UEs). Then, separate Es
acuity was measured with letters projected on a screen (SEs). Visu-
al acuity measurements were repeated in all patients on 3 consec-
utive days before starting treatment, in order to exclude a training
effect. All patients had been exposed for many years to visual were all tested by P.B. and C.S., who were unaware of the content
acuity measurements because of their condition. They were all of the vials.
reliable observers. Visual acuity was tested in both eyes of all patients, starting 1
A daily dose of 1000 mg citicoline (Neuroton; Nuovo Con- week after the beginning of treatment and continuing at weekly
sorzio Sanitario Nazionale, Rome) i.m. for 15 days was prescribed intervals for 1 month and then on a monthly basis. Duration of
to the first group of patients. Five white unlabelled boxes with follow-up ranged from 6 to 18 months for the open study and was
three vials each, for a total of 15 vials, were given to the 10 patients restricted to 6 months for the double-blind study. A statistical
in the double-blind study. In five boxes the vials contained citico- analysis of variance for repeated measures was performed on the
line and in five they held physiological solution with additives. natural logarithms of the results of the open and the double-blind
The boxes were numbered by E.C.C., who knew the key. Patients studies. Specifically, differences in visual acuity before and 4
 309

Table 2 The visual acuity of

the 50 patients in the open Patient Sound eye Amblyopic eye
study (SEs separated Es, UEs no.
unseparated Es) Before After 4 months Before After 4 months
SEs UEs SEs UEs SEs UEs SEs UEs
1 6/4.5 6/4.5 6/4 6/4 6/9 6/12 6/7.5 6/7.5
2 6/6 6/6 6/4.5 6/4.5 6/21 6/30 6/7.5 6/15
3 6/6 6/6 6/4 6/4 6/7.5 6/12 6/6 6/6
4 6/6 6/6 6/4.5 6/4.5 6/21 6/30 6/6 6/7.5
5 6/4.5 6/4.5 6/4 6/4 6/21 6/30 6/7.5 6/12
6 6/6 6/6 6/4.5 6 '4.5 6/9 6/12 6/6 6/6
7 6/6 6/6 6/4.5 6 '4.5 6/21 6/60 6/12 6/15
8 6/6 6/6 6/4 6 '4 6/7.5 6/9 6/4.5 6 '7.5
9 6/6 6/5 6/4 6'4 6/9 6/12 6/6 6'6
10 6/6 6/6 6/4.5 6 '4.5 6/7.5 6/9 6/6 6'9
11 6/4.5 6/4.5 6/4 6'4 6/7.5 6/9 6/6 6'9
12 6/4.5 6/4.5 6/4 6'4 6/24 6/37.5 6/12 6 '24
13 6/6 6/6 6/4.5 6 '4.5 6/12 6/15 6/9 6 '12
14 6/6 6/6 6/4.5 6 '4.5 6/60 6/60 6/15 6 '30
15 6/6 6/6 6 4.5 6 '4.5 6/12 6/15 6/9 6 '12
16 6/6 6/6 6 r4.5 6 '4.5 6/9 6/9 6/6 6'6
17 6/9 6/9 6 7.5 6 '7.5 6/9 6/12 6/9 6 '12
18 6/6 6/6 6 '4.5 6 '4.5 6/30 6/30 6/15 6 '24
19 6/4.5 6/4.5 6'4 6'4 6/12 6/12 6 7.5 6'9
20 6/6 6/6 6 '4.5 6 '4.5 6/9 6/12 66 6 '7.5
21 6/6 6/6 6 '4.5 6/4.5 6/12 6/12 6 r7.5 6/7.5
22 6/6 6/6 6 '4.5 6/4.5 6/21 6/21 6 r12 6/12
23 6/6 6/6 6 '4.5 6/4.5 6/9 6/9 6r6 6/6
24 6/9 6/9 6 '7.5 6/7.5 6/12 6/12 6'9 6/9
25 6/4.5 6/4.5 6'4 6/4 6/15 6/15 6 '7.5 6/7.5
26 6/12 6/12 6 '12 6/12 6/15 6/15 6 '15 6/15
27 6/5 6/5 6 '4.5 6/4.5 6/9 6/12 6'9 6/12
28 6/6 6/6 6 '4.5 6/4.5 6/9 6/12 6 '7.5 6/7.5
29 6/6 6/6 6 '4.5 6/4.5 6/6 6/7.5 6 '4.5 6/6
30 6/6 6/6 6 '4.5 6/4.5 6/12 6/24 6'9 6/12
31 6/4.5 6/4.5 6 '4 6/4 6/12 6/15 6 '7.5 6/9
32 6/4.5 6/4.5 6/4 6/4 6/7.5 6/9 6'6 6/7.5
33 6/4.5 6/4.5 6/4 6/4 6/7.5 6/9 6/6 6/9
34 6/6 6/6 6/4.5 6/4.5 6/15 6/18 6/12 6/18
35 6/6 6/6 6/4 6/4 6/24 6/60 6/12 6/24
36 6/6 6/6 6/4 6/4 6/12 6/15 6/7.5 6/9
37 6/6 6/6 6/4.5 6/4.5 6/9 6/12 6/7.5 6/6
38 6/6 6/6 6/4.5 6/4.5 6/7.5 6/9 6/6 6/7.5
39 6/12 6/12 6/7.5 6/7.5 6/9 6/12 6/6 6/7.5
40 6/4.5 6/4.5 6/4 6/4 6/12 6/12 6/7.5 6/7.5
41 6/6 6/6 6/4.5 6/4.5 6/9 6/12 6/7.5 6/9
42 6/6 6/6 6/4.5 6/4.5 6/15 6/15 6/15 6/15
43 6/6 6/6 6/4 6/4 6/12 6/15 6/9 6/12
44 6/6 6/6 6/4.5 6/4.5 6/7.5 6/9 6/6 6/7.5
45 6/6 6/6 6/4.5 6/4.5 6/9 6/15 6/7.5 6/12
46 6/6 6/6 6/4.5 6/4.5 6/15 6/30 6/9 6/12
47 6/6 6/6 6/6 6/6 6/9 6/12 6/6 6/9
48 6/6 6/6 6/6 6/6 6/12 6/12 6/7.5 6/9
49 6/6 6/6 6/6 6/6 6/21 6/60 6/12 6/21
50 6/6 6/6 6/4 6/4 6/30 6/60 6/15 6/60

months after treatment were evaluated separately for the sound
and the amblyopic eye.
Results
The effect of one course of 15 i.m. injections of citicoline
1000 mg improved visual acuity in 46 (92%) of 50 pa-
tients in the open study (Table 2). The improvement was
found both in the sound and in the amblyopic eye and
was statistically significant (P <0.001) (Fig. 1). The be-
haviour of normal and amblyopic eyes was different
(P<0.001). The amount of improvement could not be
correlated to the age of the patients. In the amblyopic
eye, the separate Es acuity varied widely. Details of the
responses are presented in Table 2. The separate letter
acuity was always better than the linear acuity in the
amblyopic eyes. A difference between separate and lin-
310

Table 3 The age and ocular condition of each of the 10 patients visual acuity expressed in 6/
in the double-blind study
Patient Age (years) Condition

I
1 14 Anisometropia
2 9 Anisometropia
3 11 Strabismus
4 22 Anisometropia
5 17 Anisometropia
6 15 Anisometropia 2 0
7 13 Strabismus
8 12 Strabismus
9 28 Anisometropia
10 19 Anisometropia 4 0

sound eye amblyopic eye

ear Es acuity was found only in the amblyopic eyes, as
shown by a significant interaction between type of acu-
ity and presence of amblyopia (P<0.001). The mean
linear acuity for the normal eyes was 6/6.04 before treat-
ment and 6/4.75 after treatment. The unseparated acuity
for the normal eyes was 6/6 before and 6/4.75 after treat-
ment. These improvements held up to logarithmic
transformation. In 46 patients the results were stable
Fig. 1 Mean visual acuity before and after treatment (vq separat-
ed Es before treatment, ~ unrepeated Es before treatment, 1~
separated Es after 4 months, m unseparated Es after 4 months)
Patient20 Age 18
6/4.5
..: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

after 4 months. The pattern of improvement is repre- Visual 6 / 6 /

Acuity
sented in the example depicted in Fig. 2. In 10 of the 30
patients followed up for 18 months, a deterioration took
6/7.5
/
place after 8 months. No deterioration was found be- 6/15
sides that detected at the 8-months check-up. A typical --- Amblyopic Eye SE
course in a patient who showed improvement and then 6/30 -- Amblyopic E y e U E
deterioration can be seen in Fig. 3. ....... Normal Eye
The double-blind study is summarized in Table 4. '2w3~
II,
The difference between patients treated with citicoline 1
and those treated with placebo was significant Time (months)
(P<O.O01).
Fig. 2 Visual acuity plotted against time for patient 20, with sep-
arated Es (SE) and unseparated Es (UE). Note that improvement
in visual acuity begins after the first week of treatment. Visual
Discussion acuity remained stable after 9 months of observation

In this preliminary study we have shown that visual

acuity in amblyopic patients can be influenced by citico-
line even beyond the plastic period of the visual system.

Table 4 The visual acuity

of the 10 patients in the Patient no. Sound Eye Amblyopic eye
double-blind study
Before After Be~re After
SEs UEs SEs UEs SEs UEs SEs UEs

1 (placebo) 6/6 6/6 6/6 6/6 6/60 6/60 6/60 6/60

2 6/6 6/6 6/4.5 6/6 6/12 6/15 6/9 6/12
3 (placebo) 6/4.5 6/6 6/4.5 6/6 6/15 6/18 6/15 6/18
4 (placebo) 6/4.5 6/6 6/4.5 6/6 6/30 6/60 6/30 6/60
5 6/6 6/6 6/4.5 6/6 6/12 6/24 6/9 6/12
6 (placebo) 6/6 6/6 6/6 6/6 6/15 6/30 6/15 6/30
7 6/6 6/9 6/6 6/6 6/12 6/15 6/7.5 6/9
8 6/6 6/6 6/4.5 6/6 6/24 6/60 6/12 6/24
9 (placebo) 6/4.5 6/6 6/4.5 6/6 6/9 6/12 6/9 6/12
10 6/6 6/6 6/45 6/6 6/24 6/30 6/15 6/24
 311

Patient 2 Age 12 One could speculate that many neural connections

exist in the visual system which are not normally used.
6/45 _ ...................................................................... ,........ ..........

Visual Citicoline may favour their utilization. Presumably, the

Acuity 6 / 6
inhibitory mechanisms such as suppression are un-
6/7.5
touched by citicoline, because patients continue to fix-
I
l ate with the sound eye and do not exhibit diplopia. The
6/15
visual acuity of the sound eye improves as well. In
6/30 J ---
--
Amblyopic Eye SE
Amblyopic Eye U E
essence, the general threshold of functioning of the sys-
tem is lowered.
........ Normal Eye It will also be interesting to find out whether repeated
6/60
'r :iv?, treatments with citicoline have an additive effect or
serve simply as maintenance. In a preliminary study [3],
T i m e (months) we found in some patients, though not all, that repeat-
ing once the administration of citicoline restores visual
Fig. 3 Course of visual acuity in patient 2. Deterioration was
detected at the 8-month check-up acuity to the level obtained after the first treatment.
Our research in this domain has just started. Many
more questions need to be answered. We have instigated
a study in which various visual functions are tested in
This is quite evident in the open study. Repeated mea- these patients during and after treatment. Furthermore,
sures of visual acuity before the beginning of treatment the mechanism of action of citicoline is still unknown, in
ensured that improvements could not be attributed to a spite of the fact that neurologists in various countries
learning effect. The results of the control double-blind have been using it for a number of years.
study, although it was performed with 6 months obser- Multi-centre randomized studies with a cross-over
vation only and with a low number of patients, also procedure are planed, in order to substantiate our pre-
suggest that the effect is due to citicoline. liminary results. We plan to use citicoline in amblyopic
It is noteworthy that visual acuity improves in both patients during the plastic period of the visual system
the sound and the amblyopic eye. This shows that the and ascertain whether its effect differs from that found in
substance acts generally on the visual cortex and not adults.
specifically on the neurons connected with the ambly- In conclusion, we have provided evidence in favour
opic eye. of citicoline's ability to improve visual acuity in adults
The effect of citicoline was stable in only 20 of the 30 with amblyopia. We are clearly not yet in a position to
patients followed up for 18 months. There is a tendency consider it a medical treatment of amblyopia. Much
of the effect to decay with time. However, no patient work remains to be done.
went back to his/her original visual acuity. This pilot Acknowledgements The authors thank Prof. Michele Virno, Chief
study was not designed to treat children, both for ethical of the Ocular Physio-Pharmacology Laboratory, Department of
reasons and because citicoline has to be administered by Ophthalmology, University La Sapienza, Rome, for suggesting
i.m. injection. the use of citicoline in amblyopia. Thanks are due to the "Nuovo
No side effects of citicoline were found in any pa- Consorzio Sanitario Nazionale", Rome, for providing the citicol-
ine used in this study. The authors have no propertary interest in
tients. They all stated that they could '° see better', pre- this substance. This work was supported in part by a grant of the
sumably because of the effect on the sound eye. MURST (60%) to E.C.C.

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