Strabismus, 2014; 22(4): 176181

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ISSN: 0927-3972 print / 1744-5132 online
DOI: 10.3109/09273972.2014.962750

RESEARCH REPORT

Efficacy of Botulinum Toxin in the treatment of

Intermittent Exotropia
Mohammad Etezad Razavi, MD1, Mohammad Sharifi, MD2, and Fateme Armanfar, MD3

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Associate Professor of Ophthalmology, Eye Research Center of Mashhad University of Medical Sciences,
Mashhad, Iran, 2Assistant Professor of Ophthalmology, Eye Research Center of Mashhad University of
Medical Sciences, Mashhad, Iran, and 3Resident of Ophthalmology, Eye Research Center of Mashhad
University of Medical Sciences, Mashhad, Iran

ABSTRACT
Background: Multiple surgical interventions are burden to patients with intermittent exotropia (IXT) due to a
high recurrence rate. This study was designed to evaluate the efficacy of botulinum toxin injection in the
treatment of intermittent exotropia (IXT).
Method: A total of 21 patients with IXT, who had a far deviation of less than 40 prism diopters (PD), were
enrolled. All cases were followed for at least 6 months with non-surgical management and had decremented
fusional control (increasing 3 or more scores in Newcastle Control Score [NCS]). Botulinum toxin was injected
(10 units Dysport) to both lateral rectus muscles. Fusional control, sensory and motor status were evaluated at
1 day, 1 week, and 1, 3, and 6 months after injection to compare with the pre-injection values.
Results: Fusional control (based on NCS) showed a significant improvement during 6-month follow-up. Mean
NCS was 4.4 0.8 SD before botulinum toxin injection and 1.4 0.4 SD after 6 months (p50.001). Evaluation of
sensorial status with Worth Four Dot Test (WFDT) also demonstrated an improvement of fusion (the percentage
of patients demonstrating fusion on WFDT were 10.5% before injection and 61.5% after 6 months). The mean far
and near deviations decreased during 6 months of follow-up examination. Satisfactory outcome (stable
binocular alignment of the eyes to an orthophoria + / 10 PD in primary position) for far distance was achieved
in 38.1% at 6 months. The percentage of satisfactory outcome at near was 86% at 6 months follow-up
examination.
Conclusion: Botulinum toxin injection to lateral rectus muscles seems to be a promising procedure in the
management of fusional control, far and near deviations in patients with intermittent exotropia in short time.
Keywords: Botulinum toxin, fusional control, intermittent exotropia, newcastle control score, stereopsis

threshold of tiredness and last longer.1 There are

several signs that indicate the progression of disease
including decrease in fusional control, increase in the
amount of deviation, and increased duration of tropic
phase proportionate to phoric phase. Therefore, the
level of deviation and fusional controls should be
assessed for the clinical evaluation.3
There are some methods for clinical evaluation of
intermittent exotropia including the subjective (home
control) and objective (office control) methods for the
disease control. The Newcastle Control Score (NCS)
was introduced by Haggerty et al.4 in 2004 to provide

INTRODUCTION
Intermittent exotropia (IXT) is one of the most
common forms of strabismus during childhood.1
The etiology of IXT is unknown and in majority of
cases it is sporadic, while familial cases have been also
occasionally reported.2 Moreover, IXT has two phases,
a phoric phase in which patients have binocular
fusion and stereopsis, and a tropic phase during
which strabismus and suppression manifest. In many
untreated patients, the disease is progressive in nature
and eventually tropic episodes manifest with a lower

Received 24 February 2014; Revised 12 June 2014; Accepted 16 July 2014; Published online 13 October 2014
Correspondence: Mohammad Sharifi. Tel/Fax: 00985117281400. E-mail: sharifim@mums.ac.ir

176

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Efficacy ot botulinum toxin in intermittent exotropia

a scoring system to grade the severity of IXT and to
provide criteria for surgical intervention. The scoring
system is based on subjective (home control) and
objective (office control) items. Therapeutic modalities for IXT include surgical and non-surgical
methods. Surgical procedures include bilateral lateral
rectus recess and/or recess-resect procedure. High
recurrence rates, overcorrection, and known complications of strabismus surgery are major drawback
of such a surgery.3 The success rate for surgery was
different between studies and was between 43% and
61% depending on the definition of successful treatment.5 Nonsurgical methods such as minus glasses,
base-in prisms, correction of refractive error, patch
therapy, and orthoptic exercises are effective in IXT
patients with good control.5 Moreover, non-surgical
methods are effective in younger children for
whom the risk of overcorrection and development
of monofixational esotropia after surgery is a concern.3 In one review the success rates for nonsurgical
treatment were 28%, 28%, 37%, and 59% over minus,
prism, occlusion, and orthoptic vision therapy,
respectively.5
Another treatment option in the management of
IXT is the injection of botulinum toxin to the lateral
rectus muscles.6 The therapeutic principle of botulinum toxin in strabismus is to paralyze the injected
muscle. Side effects are known to be minimal, but it
may include globe perforation from the injection
needle, transient ptosis, and temporary adjacent
muscle paresis with induced vertical deviation. No
serious systemic side effects have been yet reported.7
In this study, we aimed to demonstrate the effect of
botulinum toxin in the amount of deviation and
fusional control state of IXT.

SUBJECTS AND METHODS

The present study was approved by the Ethics
Research Committee of Mashhad University of
Medical Sciences and performed in the strabismus
clinic of Khatam-al-anbia Hospital of Mashhad
University of Medical Sciences. The study conforms
to the Declaration of Helsinki. In addition, informed
consents were obtained from all the patients or their
parents/legal guardians.

Patient Characteristics
This prospective case series was performed on
21 patients (age ranged from 5 to 18 years), with
progression of IXT during a 6 months follow-up
examination. Only those with progression of IXT and
who agreed to have a botulinum toxin injection
enrolled in this study. Progression was documented
by a decrease in fusional control and an increase in
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177

NCS (score 3) in spite of nonsurgical treatment

(including patch therapy and/or minus glasses) at
the initial assessment versus at the end of 6 months
observation before enrollment. This means that the
cases were recruited over 6 months of time from the
ocular motility clinic and those whose clinic notes
suggested deterioration to a score of 3 or more were
included in the study population. These patients
had basic type IXT (less than 10 PD difference in
angle measurement at far-near distance) with an angle
of far deviation between 20 and 40 PD. Exclusion
criteria were: history of botulinum toxin injection into
extraocular muscles (EOM), history of previous surgery on EOM, anisometropic amblyopia, ametropic
amblyopia, other ocular deviations such as hypertropia and oblique muscles dysfunction, any concomitant ocular disease and retinal disorders, any central
nervous system and systemic disorders, and any
history of drug allergy.
The NCS for IXT was initially developed by
Haggerty,4 incorporating both subjective (home control) and objective (clinic control) criteria into a scale
to grade severity (Table 1). Important items in our
examinations include: uncorrected visual acuity
(UCVA), best corrected visual acuity (BCVA), full
cycloplegic refraction (FCR) if needed, sensorial
evaluation (fusion, stereopsis), motor evaluation (far
deviation before and after 1 hour monocular occlusion, near deviation), slit lamp examination, and
funduscopy (to rule out any concomitant ocular
disorders).
Because of the disruption that may be made by
motor tests, sensory tests were performed prior to the
motor evaluation. Among sensory examinations,
fusional control according to the NCS was performed
prior to other sensorial tests. Assessment of fusional
control was performed by two qualitative and quantitative techniques.

Assessment of Control
Quantitative measurement of fusion was performed
by NCS, which is a new grading system for the
severity of IXT (Table 1). This grading system is
applicable for the surgical management of IXT. We
have evaluated fusion according to the NCS in the
office (in near and far distances) and at home (by
asking questions of parents). Total NCS for each
patient was the summation of office control and home
control and ranged from 0 to 7.
Suppression and Stereopsis Assessment
Qualitative evaluation of fusion was done by Worth
4 dot test (WFDT), which was performed in a darkstate condition and at the distance of 4 m. Results
were reported as fusion, suppression, or diplopia.
Evaluation of near stereopsis was performed by

178 M. E. Razavi et al.

TABLE 1. Newcastle Control Scale (NCS) grading system.
Score

Component

Home control
0
Squint/monocular eye closure never noticed
1
Squint/monocular eye closure seen occasionally (550% of time child observed) for distance
2
Squint/monocular eye closure seen frequently (450% of time child observed) for distance
3
Squint/monocular eye closure seen for distance and near fixation
Clinic control near
0
Manifest only after cover test and resumes fusion without need for blink or refixation
1
Blink or refixate to control after CT
2
Manifest spontaneously or with any form of fusion disruption without recovery
Clinic control distance
0
Manifest only after cover test and resumes fusion without need for blink or refixation
1
Blink or refixate to control after CT
2
Manifest spontaneously or with any form of fusion disruption without recovery

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NCS total = Home + Clinic near + Clinic distance.

Titmus Fly Stereo test and was reported in seconds

of arc."
Angle Measurement
The amount of deviation was measured in far (6 m)
and near (33 cm) distances. Far deviation was measured before and after patch test (one eye was patched
for 60 minutes) to overcome the tenacious proximal
fusion. The amount of deviation was measured with
cover test and alternate prism cover test (APCT). If
the patient was not cooperative, Hirschberg and
Krimsky tests were applied. Extraocular movement
was checked and individuals with any signs of
hypertropia or inferior oblique overaction were
excluded from the study population.
Botulinum Toxin Procedure
Bilateral injection of 10 units of botulinum toxin type
A (Dysport) (Ipsen, Medicis Pharmaceutical, United
States) (equivalent to 2.5 units Botox ) was done in
lateral rectus muscles without electromyography
guide. Dysport injection was done under inhalation
anesthesia (by anesthesiologist, without canulation).
Lid speculum was inserted, then lateral rectus muscle
was grasped by muscle forceps at 2 mm from its
insertion and 0.1 cc botulinum toxin type A was
injected to the muscle belly (8 mm distance from the
muscle insertion) with a hypodermic syringe needle
gauge 27. Injection was performed so that the bevel
of the needle had been toward the sclera and gentle
pressure was applied over the injection area.
Sensory and motor evaluations, the amount of
deviation, and fusional control were evaluated at
1 day, 1 week, 1 month, 3 months, and 6 months after
the procedure. Results were compared to the corresponding pre-injection values. All sensory, motor, and
fusional evaluations were performed by 2 optometrists under the ophthalmologists supervision.
Satisfactory outcome was defined as a primary position deviation between 0 and 10 PD eso- or

exophoria/-tropia in far and near distances at final

follow-up examination. We attributed a positive value
to XT and negative value to ET. All injections were
done by the same author (ME).

Statistical Analysis
Statistical testing was performed by using SPSS
Windows version 16 (SPSS, Inc., Chicago, Illinois).
Repeated measures analysis and McNemar tests were
used to compare the data before and after an injection.
In order to compare the means of dependent variables, Wilcoxon and Friedmans test were performed.
Differences were considered statistically significant
at a p value of 0.05 or less.

RESULTS
Twenty-one patients were enrolled in this study. A
total of 5 patients were male and 16 were female. A
six6month follow-up examination was done for all
patients. Mean age SD of patients was 7.1 3.5 years,
in the range of 5-18 years. Mean NCS difference
(between pre-injection and determined follow-up
period at 6 months) were 3.0 1.4. Improvement of
NCS was significant during follow-up period.
Mean SD of NCS at pre- and postinjection followup visits are represented in Table 2. Because of the
poor cooperation of patients, NCS were not measured
at first and seventh post-op days. As a good indicator
of fusional control, an NCS difference of 3 was
observed in 66.7% (14 of 21) in the 6-month follow-up
periods. Applying a Friedman test, the mean NCS
was compared between the first and final follow-up
examinations and the difference was statistically
significant (p50.001). According to the Wilcoxon
test, averages of NCS at 1 and 6 months after injection
were significantly different compared with the mean
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Efficacy ot botulinum toxin in intermittent exotropia

179

TABLE 2. Change in the control and amount of intermittent exotropia before and after treatment with botulinum toxin.

Pre-injection
1 day postinjection
1 week postinjection
1 month postinjection
3 months postinjection
6 months postinjection
p value

Number of
patient

NCS
(New Castle Control Score)

Far deviation
(prism diopter)

Near deviation
(prism diopter)

21
21
21
21
21
21

4.47 0.87

1.85 1.42

1.43 0.49
50.001 (Wilcoxon)

30.95 7.18
12.90 12.51
21.52 13.91
11.10 13.50
7.48 16.01
11.80 14.44
50.001 (Wilcoxon)

26.43 10.14
9.10 12.20
17.33 12.97
12.19 15.52
0.81 13.23
1.80 10.33
50.001 (Wilcoxon)

TABLE 3. Change in mean exodeviation following patch test before and after treatment with botulinum toxin.

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Pre-injection
6 months postinjection

Number of
patient

Before patch test

(prism diopter)

After patch test

(prism diopter)

p Value

21
21

30.9 7.1
11.8 14.4

36.1 8.7
13.3 14.5

0.001 (Wilcoxon)
0.043 (Wilcoxon)

of NCS pre-injection (p50.001 and p50.001,

respectively).
Sensorial condition was also assessed according to
the WFDT, frequency of suppression before toxin
injection and 6 months after injection were 89.4%
(17 of 19) and 29.4% (5 of 17), respectively. There was a
statistically significant difference between frequencies
of suppression before injection and 6 months postinjection (p = 0.0008), (McNemar Test). Frequency of
fusion was increased during follow-up visits, ie,
10.5% and 61.5% before injection and 6 months
afterward (p = 0.0008) (McNemar Test).
Equipment for measurement of far stereopsis was
not available, therefore, near stereopsis was evaluated
by Titmus Fly test. Mean SD of stereopsis was
224.6 278.9 seconds of arc before injection that
reached to 100 100.3 sec of arc 6 months after
injection. Wilcoxon test showed that near stereopsis
was statistically different before injection and 6
months after the injection (p = 0.005).
Mean SD of far deviation was 30.9 7.1 PD
exotropia before injection. It reached to the mean
of 11.8 14.4 PD exotropia 6 months later. There was a
statistically significant difference between mean far
deviation before and 6 months after an injection
(p50.001) (Wilcoxon test) (Table 2).
Near mean SD deviation was 26.4 10.1 PD IXT
before injection and reached to 1.8 10.3 PD IXT
6 months later. This difference was statistically
significant (p50.001) (Table 2).
Mean deviation was measured before and after
patch test, during 6 months follow-up examinations.
There was a statistically significant difference between
mean deviation before and after the patch test,
between pre-injection and 6 months postinjection
(Table 3). Frequency of patients that had satisfactory
outcome (orthophoria +/ 10 PD in primary position)
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for far and near were 38.1% (8 of 21)and 86% (18 of 21)
6 months after injection, respectively.

COMPLICATIONS
Abduction deficiency was observed in 42.8% (9 of 21)
at 1 week, 33.3% (7 of 21) at 1 month, and 4.8% (1 of 21)
at 6 months after an injection. It was graded as 4 to 0:
0 when full abduction was present, 4 when globe could
not pass the midline, 1 to 3 when abduction
limitations were 75%, 50%, or 25% of normal abduction
of the fellow eye.
Mild ptosis (52 mm) occurred in 42.8% (9 of 21) of
patients at 1 week and 1 month after injection. Ptosis
did not affect NSC measurement. There was no
patient with ptosis after that time.
Diplopia occurred in 4.7% (1 of 21), 52.4% (11 of 21),
14.3% (3 of 21), and 6.2% (1 of 16) of patients at preinjection, 1 week, 1 month, 3 months, and 6 months
after injection, respectively.
Subconjunctival hemorrhage occurred in 4.8%
(1 of 21) and 9.5% (2 of 21) of patients at 1 day and
1 week after injection, respectively.
Pupillary dilation occurred in one of our patients
and did not improve after 6 months; however the
above-mentioned patient did not have any relative
afferent papillary defect. His visual acuity was good
and did not show any changes compared to the preinjection assessment.
Asthenopia was found in 28.6% (6 of 21) of patients
before injection and was decreased to 4.8% (1 of 21)
6 months after injection. Astenopia was defined as an
eye strain after near work activities.
Esotropia (410 PD in primary position) occurred in
30% (7 of 21), 38% (8 of 21), 19.0% (4 of 21), and 6.3%
(1 of 16) of patients at 1 week, 1 month, 3 months, and

180 M. E. Razavi et al.

6 months after injection, respectively. Accommodative
esotropia was detected in one of our patients. FCR
(full cyclopelegic refraction) glasses were prescribed
for this patient.
Vertical deviation (44 PD in primary position)
occurred in 9.5% (2 of 21), 47.6% (10 of 21), 38%
(8 of 21), and 14.3% of patients at 1 day, 1 week,
1 month, and 6 months after injection, respectively.

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DISCUSSION
This prospective case series evaluated the effect of
botulinum toxin on the fusional control of patients
with IXT who had not received any surgical therapy
before, and the disease progressed during a 6-month
period despite a nonsurgical management. Fusional
control of patients was evaluated in the present study
with NCS, which is a relatively new method for
grading the severity of IXT. The grading system was
introduced by Haggerty et al.4 not only as a score to
grade the severity of IXT but to decide about the
therapeutic intervention. They concluded that
patients with NCS 3 are more likely to need surgical
therapy. Buck et al.8 evaluated NCS in the management of IXT and they reported that the use of NCS as a
grading system for severity of IXT can be a useful
procedure to serially assess the clinical improvement
or deterioration of the disease. In another study by
Buck et al. satisfactory control (improvement in NCS)
was achieved in 65% following surgery for IXT.9 In the
current study, NCS changes showed improvement in
two-thirds, similar to the Buck et al. study. In our
patients, NCS difference was 3.0 1.4 during 6 months
after injection. Spencer et al.10 investigated the effectiveness of botulinun toxin injection in the treatment of
IXT. Stable orthophoria (10 PD) was achieved in 69%
of patients at final visit (1244 months). In our study,
NCS difference of 3, as an indicator of good fusional
control ability, was achieved in 66.7% (14 of 21) of
patients at 6 months after injection, which indicates
the efficacy of this treatment in fusional control.
Satisfactory outcome (orthophoria +/ 10 PD in
primary position) was low compared to the Spencer
et al. study (38% vs 69%), which might be due to the
single injection or injection without EMG guidance.
In patients with IXT, near deviation is usually less
than far deviation, partly because of the tenacious
proximal fusion. This mechanism is removed after
patch test and may help to differentiate it from
patients with high AC/A. We observed a statistically
significant difference between mean deviations before
and after the patch test, between pre-injection and at 6
months postinjection. This decrease in difference
between deviation before and after the patch test at
6 months post-injection could be considered as
another index for the fusional control ability of
patients.

Distance stereoacuity is an objective method to

evaluate the control of deviation and decide for
timing of the surgery in IXT.11 We did not have a
distance stereoacuity test available, therefore, we
evaluated near stereopsis with Titmus Fly, which
showed significant improvement at final follow-up
examination. Li et al.12 performed a clinical study in
60 children aged 4 to 12 years who were diagnosed
with intermittent exotropia. Patients were divided
into surgery and toxin injection groups. Alignment
and binocularity were evaluated 6 months after
treatment. Deviation was changed from 41.33 12
PD before injection to 6.23 9.80 PD after injection at final visit. Recovery rate was 77% and 90%
in the toxin and surgery groups, respectively;
however, this difference did not reach statistical
significance. Some patients were found to have
fusion and distance stereopsis rebuilt, while others
were found to have near stereopsis improvement in both groups. In our study, far deviation
changed from 30.9 7.1 PD exotropia before injection to 11.8 14.4 PD exotropia 6 months later.
Documented by an improvement of NCS, increased
frequency of patients with fusion in WFDT, decrease
in the amount of far and near deviation, and the
results of patch test, we suggest that botulinum
toxin injection might be a good therapeutic option
and alternative method for treatment of IXT patients
with progressive disease (change of NCS 3) in
short time.
The current study has some limitations that need
to be mentioned. First, similar to the Spencer study,
we have used the same dosage of Dysport for
all children with 40 PD IXT, but it may be better
to adjust the dosage according to the amount of
deviation to achieve better results and decrease the
rate of complications. Future investigation with larger
sample size, longer follow-up, and randomized clinical trials are necessary for this purpose.
Other limitations were lack of a control group and
relatively small sample size, which was a restriction to
categorizing patients in different age groups.
Therefore, we could not obtain precise information
about the effect of botulinum toxin in different age
groups. Relatively poor outcome at final visit may be
due to the single injection and/or injection without
using the electromyography. Finally, the follow-up
period was not long enough to evaluate the long-term
effects of botulinum toxin injection in IXT. If data at
12 months or longer were available, we could confirm
the conclusion, but patients did not return for followup visits.
In conclusion, botulinum toxin injection to lateral
rectus muscles seems to be a promising treatment in
the management of fusional control and far and
near deviation of patients with intermittent exotropia and could be considered as an alternative
option.
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Efficacy ot botulinum toxin in intermittent exotropia

ACKNOWLEDGMENTS
This work has been supported by a research grant
from the Research Deputy of Mashhad University of
Medical Sciences.

DECLARATION OF INTEREST
The authors declare no conflict of interest.

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