Acta Ophthalmologica 2011

Treatment of congenital esotropia with botulinum toxin type A

vard Magnus Arnljot2 Kirsten Baggesen1 and Ha
1

Department of Ophthalmology, Aarhus University Hospital, Aalborg Sygehus, Denmark 2 Hospital, Sweden Eye Department, Solleftea

ABSTRACT. Purpose: To examine the effect of botulinum toxin type A injections given transconjunctivally into the medial recti muscles in patients with congenital esotropia. Methods: Eighty-two patients with congenital esotropia were treated with botulinum toxin type A transconjunctival injections into the medial recti muscles. Results: A KaplanMeier curve shows a 24-month success rate of 87% (n = 53) with alignment within 20 prism dioptres (PD) of the 80 patients who were seen at least 1 year following the last injection. Seven of the 80 patients underwent standard monocular surgery with recession of the medial rectus and resection of the lateral rectus muscle. Two patients were lost during follow-up. Conclusion: Botulinum toxin type A injections into the medial recti muscles are a valuable alternative to conventional strabismus surgery.
Key words: Botox botulinum toxin type A congenital esotropia strabismus convergence treatment

Acta Ophthalmol. 2011: 89: 484488

2009 The Authors Journal compilation 2009 Acta Ophthalmol

doi: 10.1111/j.1755-3768.2009.01737.x

congenital esotropia surgery. The Eye Department at Aalborg Hospital is the primary centre for strabismus surgery in the region. Congenital esotropia patients, dened as having esotropia present since birth, were seen by a physician before 6 months of age. All patients and their parents received a thorough explanation of both standard surgical procedure and BTX-A injections and were consulted about the risks and benets of the different methods. All patients were offered a routine surgical treatment if BTX-A injections were not cosmetically satisfactory. Based on this information, all patients and parents decided to have BTX-A treatment rather than a conventional operation. All patients were examined carefully and, when indicated, treated before injections as follows: (1) Patients with presumed amblyopia underwent full amblyopia treatment prior to the injection. None of the patients showed amblyopia of more than two lines in visual acuity at the time of the rst injection. Throughout the study, amblyopia treatment was reinstated if indicated. (2) Adequate correction of refractive errors was measured and adjusted throughout the study. (3) Surgical correction of oblique muscles (myectomia of the inferior oblique muscle) was performed prior to BTX-A treatment when indicated. (1) Criteria of inclusion: (i) Constant congenital esotropia of 20 prism dioptres (PD) or more. (2) Criteria of exclusion:

Introduction
In the last decade, several articles have been published on the use of botulinum toxin type A (BTX-A) in strabismus treatment. The studies have been performed on mixed types of strabismus using varying methods and different follow-up times. The outcomes have been diverse. In Scandinavia this has resulted in a defensive approach whereby BTX-A is used sparsely in strabismic treatment, namely at the end of surgery and in special cases preoperatively to predict postoperative outcomes. Only a few surgeons have used BTX-A as a routine treatment, meaning that there

are very few publications examining a Scandinavian population. In this study, all patients had a congenital condition whereby esotropia was present from very early childhood either as a mono-symptomatic esotropia or as an esotropia syndrome (essential infantile esotropia) with overacting inferior oblique muscles, latent nystagmus and dissociated vertical deviation (DVD).

Materials and Methods

Patients

All patients (n = 86) were recruited consecutively from our waiting list for

484

Acta Ophthalmologica 2011

(i) Horizontal muscle surgery performed prior to treatment. (ii) Persistent severe amblyopia in one eye ( 0.4). (iii) Other neurological symptoms. In total, 82 patients were included in this study. Sixty-seven (82%) patients were diagnosed with monosymptomatic esotropia at the time of the rst injection. Fifteen (18%) patients showed an essential infantile esotropia with a signicant overaction of the inferior oblique muscle, and underwent myectomia before treatment with BTX-A. The age range of the patients and follow-up time are listed in Table 1. As expected, most of the patients were hyperopic at the time of rst injection. The mean refractive error in the group was +2.59 D (range +8.0 to )0.25 D) in the right eye and +2.52 D (range +8.0 to )1.5 D) in the left eye. All signicant refractive errors (hyperopia +1.5 D or myopia )0.75 D) were treated with glasses for at least 3 months prior to injections. Two patients developed a signicant hyperopia during the study and were treated with glasses. No patients developed signicant myopia. Of the 86 patients who were offered BTX-A injections at the rst examination, three were excluded from this study because of Duanes syndrome and one because of persistent low visual acuity in one eye. At follow-up, all patients were examined 3 weeks after each injection and deviations were noted as aligned, divergent or convergent without measurement of the actual size of the angle. Complications were noted when present. All patients were re-examined 4 months after injection. If persistent esotropia of 20 PD or larger was present, the patients were offered a second or third injection, performed within 2 months. Follow-up regime was standardized for the rst, second and third injections. Patients who had a residual angle of < 20 PD and whose parents were satised at the 4-month post-injection examination were re-examined every 6 months for at least 12 months or until the age of 6 years. If fully aligned they were referred to the general ophthalmologist. Distance deviation, near deviation, visual acuity,

Table 1. Connection between age at injection and result of treatment. Age at 1st Age at 2nd Age at 3rd Date of 1st Date of last Patient injection (years) injection (years) injection (years) injection follow-up Status 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 1 2 2 4 4 1 6 3 4 10 7 4 5 4 1 4 4 6 6 6 6 7 7 2 3 2 1 6 3 2 5 4 2 4 7 2 2 5 6 5 1 1 10 5 3 3 4 5 5 8 3 4 7 11 1 1 5 4 3 6 2 5 4 3 1 3 3 4 1 6 09.10.02 13.11.02 16.02.02 16.01.02 25.05.05 14.05.03 14.08.02 18.02.04 12.02.03 16.01.02 28.05.03 29.08.01 08.01.03 08.05.02 13.08.03 17.03.04 22.10.03 13.04.05 12.02.03 09.10.02 04.09.02 17.12.04 08.05.02 14.09.05 25.05.05 04.09.02 09.06.04 25.05.05 16.03.05 20.09.06 10.10.01 09.04.03 29.08.01 21.11.01 12.02.03 11.10.06 20.03.02 09.06.04 17.12.04 20.03.02 12.05.04 15.03.06 04.09.02 17.07.02 20.09.06 15.02.06 25.05.05 24.04.02 28.05.03 18.02.04 15.02.06 12.05.04 20.03.02 18.08.04 17.05.06 09.06.04 11.10.06 12.05.04 11.10.06 14.05.03 28.05.03 13.04.05 02.11.05 10.10.01 23.01.07 10.01.08 27.01.05 09.08.07 01.04.08 07.06.07 21.07.08 12.02.08 02.12.04 20.02.07 23.09.04 16.07.02 17.11.05 13.11.07 13.03.08 10.10.06 01.04.08 12.12.08 25.07.07 04.01.05 12.03.08 10.10.07 20.04.05 22.08.07 03.10.07 30.08.05 09.01.08 01.05.07 02.01.08 06.02.08 23.01.07 11.04.07 25.09.07 16.08.05 25.11.04 01.10.07 29.01.08 12.05.07 09.08.07 22.01.04 12.12.08 13.03.08 04.09.03 09.05.07 08.01.09 09.10.07 09.01.08 20.08.03 19.07.07 03.07.07 08.01.09 29.01.08 08.08.07 01.04.08 06.09.07 19.12.07 25.03.08 21.06.06 31.01.08 02.06.09 03.11.05 26.04.06 02.08.07 09.10.02

3 5 2

10 4 5 4

L E

7 6 7 3 2 2 6 8

E E

4 5

4 5

6 2 5 4 6 6 8 3 4 7 11

5 8

L*

485

Acta Ophthalmologica 2011

Table 1. (Continued) Age at 1st Age at 2nd Age at 3rd Date of 1st Date of last Patient injection (years) injection (years) injection (years) injection follow-up Status 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 2 7 3 7 5 1 3 4 13 6 8 2 6 15 3 2 2 6 10.10.01 13.04.05 11.03.05 14.08.02 08.05.02 12.05.04 04.09.02 17.03.04 18.08.04 12.05.04 18.01.06 12.01.05 17.05.06 14.04.04 12.01.05 05.04.06 21.12.05 08.05.02 09.05.07 25.03.08 07.12.08 07.09.04 14.09.06 06.07.06 07.08.03 08.08.07 05.12.06 03.01.08 17.01.09 12.02.08 09.01.08 09.06.05 20.09.07 02.04.08 20.09.07 12.11.04

2 4 14 7

16 3 3 3

16

L, lost to follow-up; E (event), indication for surgery. * The date of the last injection was also the date of last follow-up.

refractive errors, correction glasses and subjective degree of satisfaction were assessed at these visits. No binocularity was expected because all the patients had congenital esotropia and no assessments were carried out. All BTX-A injections plus pre-treatment and follow-up examinations were performed by the authors in collaboration with an orthoptist. A general ophthalmologist performed long-term follow-up in all patients who were discharged from the department, and readmitted the patients if the residual angle of deviation was more than 20 PD. However, only follow-up results performed at our department were included in this study.
Surgical method

and without successful identication of the muscle, the EMG recordings were abandoned in further treatments.
Statistical analysis

Statistics and KaplanMeier survival rates were calculated using the sas computer package (SAS Institute Inc., Cary, NC, USA).

Results
Eighty-two patients with a mean age of 4.4 years (range 116) were enrolled in this study. One-year follow-up of the BTX-A treatment included 80 of the 82 patients who originally entered the study. Two patients were lost to follow-up at this time. The result of the long-term followup is illustrated by the KaplanMeier survival curve in Fig. 1. The 24-month survival rate was 0.87 (n = 53), the

All patients where treated under general anaesthesia. A drop of Tetracain was added in each eye. An injection of 2.5 IU BTX-A (Botox; Allergan, Norden, Uppsala, Sweden ) was given through the conjunctiva into both medial recti muscles using a 23 G injection needle. At reinjections, the amount of BTX-A was increased from 2.5 to 4 IU in all cases. An electromyography recorder attached to the injection needle was used to identify the recti muscles in the rst 25 patients, with a success rate of 44% (11 25). Because results at 4-month follow-up were not signicantly different between patients with

48-month survival rate 0.82 (n = 18). At follow-up no consecutive exotropia was seen. Seven patients underwent standard monocular surgery with medial rectus muscle recession and lateral rectus muscle resection (surgical results were not included in this study). Two patients with indication for surgery declined this procedure. Both had pre-injection angles of 90 PD and post-injection angles of 40 and 45 PD, respectively, which was satisfactory for their parents. Pre- and post-injection angles are shown in Fig. 2. For the entire group the mean of pre-injection deviations was 48 PD (range 2590 PD). Bilateral injection of BTX-A in the medial recti muscles decreased the deviation to 11 PD (055 PD). The number of total treatments is shown in Table 2. Of the 82 patients 37 were aligned after one injection, 31 required two injections and 13 had three injections. One patient had four injections. If further treatment was necessary, standard surgical treatment was offered. The two patients who were lost to follow-up had two and three injections, respectively. The age of the patients at the time of the injections is listed in Table 1, together with the individual results. There was a trend towards better effect among the younger patients, but no signicant difference between age groups, probably because of the low number of teenagers. No pre-, intra- or persistent postoperative complications were recorded. A mild ptosis caused by spread to the levator muscle was seen in 19 of 214 (8.9%) injections. One of the patients experienced serious but temporary ptosis covering the pupil. No amblyopia was observed following this incident. Three patients showed a decreasing function of the superior oblique

Fig. 1. KaplanMeier survival curve following botulinum toxin type A injections.

486

Acta Ophthalmologica 2011

Pre-injeciton angle i prism diopters

100 90 80 70 60 50 40 30 20 10 0 Angle pre and post-injection

Fig. 2. Follow-up after treatment with botulinum toxin type A in prism dioptres: pre-injection angle; deviation at last follow-up.

muscle, resulting in a vertical squint, which in all cases disappeared after 4 months. One patient had signs of episcleritis 3 days post-injection on one eye. He had a previous history of episcleritis and was treated according to the department guidelines. Twoweeks later, his symptoms disappeared. During 2 years of follow-up no further complications were noted. All complications were reversible, and patients recovered fully until the examination at 4 months postinjection. None of the patients had DVD at entry; however, two patients (2%) developed DVD during the study period. Both patients had esotropia syndrome and had a myectomia performed on the inferior oblique muscle prior to treatment with BTXA. The DVD is thought to be part of the natural history of esotropia syndrome rather than a complication of BTX-A treatment.

Discussion
The traditional operation for esotropia with a recession resection procedure has certain inconveniences. Children with congenital esotropia require an average of 1.25 surgical procedures before acceptable alignment (Eye Department, Aarhus University Hospital, Aalborg Sygehus,

unpublished data). A certain number of patients with childhood surgery for esotropia develop consecutive exotropia and require further surgery later in life. Therefore, alternative treatment options for strabismus need to be explored. BTX-A injections require anaesthetics when children are treated, because movements of the eye and the risk of perforation if awake. The fact that the number of treatments is potentially higher for injection treatment than for traditional surgery should be taken into account when treatment modality is considered. In our study the injections were carried out with a mask anaesthetic of a very short duration and the patients were out of the clinic in < 4 hr. The children would be accepted in and t for day care the following day, which was convenient for the parents. The follow-up time of this study is too short to state that the amount of consecutive exotropia is less than in traditional surgery, but until now no patients have shown any sign of exotropia. For this question to be answered denitively, the patients would need to be followed up for 10 years or more. This study showed a 24-month success rate of 87% calculated in a KaplanMeier survival curve. Keeman &

Table 2. The number of injections needed for alignment. Mean in the group Number of injections 1 2 3 4 Number of patients 37 31 13 1 Preoperative angle (PD) 45.3 49.6 54.3 Postoperative angle (PD) 15.7 15.0 24.5

Willshaw (1992) published the results of squint surgery in 40 children with congenital esotropia and reported favourable outcome in 23 (57.5%) children. In a review article by Scheiman & Ciner (1987), 15 studies met the minimum criteria for analysis; the results showed overall cosmetic success rate of 43% following surgery in a mixed group of 1473 patients with acquired, comitant, non-accomodative or partially accommodative esotropia. The results following BTX-A injection in the present study were comparable to surgery with respect to favourable cosmetic outcomes. BTX-A was rst studied by Scott (1980, 1981), who discovered the benecial effect of temporary paralysis for strabismus treatment. His primary article describes the maximum time of paralysis to be 45 days following injection, gradually diminishing, depending on dose. He achieved a maximum of 40 PD strabismus correction. In the last decade, several articles have been published on the use of BTX-A in strabismic treatment. These studies have been performed on mixed types of strabismus, using different methods, different follow-up times and diverse outcomes (Lennerstrand et al. 1998). In Scandinavia this has resulted in a defensive approach whereby BTX-A is used sparingly in strabismic treatment, namely at the end of surgery and in special cases preoperatively to predict postoperative results. In this study all patients had a congenital condition with esotropia present from very early childhood either as a monosymptomatic esotropia or as esotropia syndrome (essential infantile esotropia) with overacting of the inferior oblique muscle, latent nystagmus and DVD. Several studies suggested slightly different injection techniques. Some surgeons open the conjunctiva and inject the BTX-A directly into the muscles. Another approach is to inject transconjunctivally with or without EMG control. In our study group the rst 25 patients were treated with transconjunctival injection under EMG control to obtain a signal when possible. We found no difference in results between patients where an EMG signal was found and the ones who were injected blindly. Benabent et al. (2002)showed high efcacy and

487

Acta Ophthalmologica 2011

low complication rate without EMG control in a series of 40 patients with essential infantile esotropia. Based on these results, we plan to perform injections without EMG control in the future. The original article by Scott (1980) stated a maximum correction of strabismus esotropia of 40 PD. Our study displays successful results in preinjection angles up to 90 PD. Following the rst injection, pre-injection angles were reduced by more than 50%. Maximum treatment was successful in two of the three patients with angles of 80 PD and above. Between 50% and 84% of patients operated for infantile esotropia were aligned effectively within 20 PD, which was dened as treatment success. In our study the overall success rate was 85% of patients aligned within this limit, which is slightly above that of surgical treatment. Two of our patients developed a signicant hyperopia ( +1.5 D) and were treated with glasses during the study period. Uretmen et al. (2008) described the risk of accommodative esotropia following infantile esotropia surgery to be 48.2% after 36 and 132 months follow-up. These children had early surgery and the mean age of accommodative esotropia onset was 8.8 months. In this study all patients were older than 12 months at the time of injection, which may explain the lower incidence of acquired hyperopia. The use of BTX-A avoids causing scar tissue and thus does not inuence surgical options at a later stage. All parents were offered a standard strabismus operation in case of post-injection angles of more than 20 PD and or subjective dissatisfaction. Overall, nine patients had indication for surgery following the three injections. Seven patients with post-injection angles of 20 PD or larger underwent a recession resection procedure following the BTX-A treatment. The results of this surgical intervention have not been included in this study because of a short followup at present. Despite a large residual angle, the parents of two patients

declined surgery because they were subjectively very satised with the post-injection results. The toxin has been found to be safe and effective (McNeer 1989) when applied to the eye muscles. In our study we recorded no serious sideeffects. The most frequently described complication is ptosis, which occurred temporarily in 8.9% of our patients. Some authors suggest BTX-A treatment before the age of 1 year. However, at this age a total ptosis because of the treatment could lead to amblyopia and would require aggressive prevention. Thus, in very young children prophylactic treatment has to be considered. Lennerstrand (2007) has documented denervation atrophy in all muscle bre types of typical skeletal muscle following injection of BTX-A. When used on ocular muscles in the small doses used for strabismus correction, clinical examination shows no change in saccadic velocity and movement range. This may be explained by the velocity being subserved by other muscle bre types, which are unaffected by the low doses. Most authors assume that BTX-A remains at the synaptic terminal of the muscle, the injection site. Antonucci et al. (2008)demonstrated an axonal migration of BTX-A retrograde to the cerebral cortex in mice, which was not signicant. Clinically, the amount of BTX-A used for patients is small, and no severe systemic complications of the drug have been observed.

proves necessary over a longer followup period.

References
Antonucci F, Rossi C, Gianfraceschi L, Rossetto O & Celeo M (2008): Longdistance retrograde effects of botulinum neurotoxin A. J Neurosci 28: 36893696. Benabent EC, Garcia Hermosa P, Arrazola MT & Alio y Sanz JL (2002): Botulinum toxin injection without electromyographic assistance. J Pediatr Ophthalmol Strabismus 39: 231234. Keeman JM & Willshaw HE (1992): Outcome of strabismus surgery in congenital esotropia. Br J Ophthalmol 76: 342345. Lennerstrand G (2007): Strabismus and eye muscle function. Acta Ophthalmol Scand 85: 711723. Lennerstrand G, Nordbo OA, Tian S, Ericsson-Derouet B & Ali T (1998): Treatment of strabismus and nystagmus with Botulinum toxin type A. An evaluation of effects and complications. Acta Ophthalmol Scand 76: 2737. McNeer KW (1989): Botulinum toxin therapy of eye muscle disorders: safety and effectiveness. Ophthalmology 2: 3741. Scheiman M & Ciner E (1987): Surgical success rates in acquired, comitant, partially accommodative and nonaccommodative esotropia. J Am Optom Assoc 58: 556561. Scott AB (1980): Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. Ophthalmology 87: 10441049. Scott AB (1981): Botulinum toxin injection of eye muscles to correct strabismus. Trans Am Ophthalmol Soc 79: 734770. Uretmen O, Baturhan BC, Kose S, Yuce B & Egrilmez S (2008): Accommodative esotropia following surgical treatment of infantile esotropia: frequency and risk factors. Acta Ophthalmol 86: 279283.

Conclusions
BTX-A injection into the medial recti muscles is a safe procedure and offers a valuable alternative to strabismus surgery in congenital esotropia and esotropia syndrome patients. Because around half of the patients were aligned to the parents cosmetic satisfaction following one injection, the procedure should be offered for patients with congenital esotropia to avoid scaring in the conjunctiva and the muscles, which would allow for additional treatment later in life if it
Received on July 28th, 2008. Accepted on July 22nd, 2009. Correspondence: Kirsten Baggesen Department of Ophthalmology Aarhus University Hospital Aalborg Sygehus Hobrovej DK 9000 Aalborg Denmark Tel: + 45 9932 3299 Fax: + 45 9932 2456 Email: kirsten.baggesen@dadlnet.dk

488