Strabismus, Early Online, 1–6, 2015 ! Informa Healthcare USA, Inc. ISSN: 0927-3972 print / 1744-5132 online DOI: 10.3109/09273972.2014.999798
Clinical Outcomes of Botulinum Toxin Injection in Patients with Cerebral Palsy and Esotropia* Ahmad Ameri, MD1, Arash Mirmohammadsadeghi, MD2, Ali Makateb, Fatemeh Bazvand, MD2, and Simindokht Hosseini, MD3
Strabismus Downloaded from informahealthcare.com by Kainan University on 04/08/15 For personal use only.
1
MD
3
,
Associate Professor of Ophthalmology, 2Assistant Professor of Ophthalmology, and 3Ophthalmologist, Tehran University of Medical Science
ABSTRACT Purpose: To assess the efficacy of botulinum toxin (Novotox) injection in patients with cerebral palsy (CP) and esotropia. Patients and methods: In a non-comparative, prospective interventional case series botulinum toxin injection was done in 44 patients with CP and esotropia. A single dose of botulinum toxin was injected in both medial rectus muscles of all patients and was repeated in 12 patients. Angle of deviation within 10 prism diopters (PD) of orthotropia was defined as a successful outcome. Result: Forty-four patients (21 males) with the mean age of 47.56 ± 35.86 months were included in the study. The mean esotropia in all patients was 52.27 ± 18.40 PD (25–123 PD). The range of follow-up was 12–24 months. Thirty patients (68.18%) were treated successfully one year after surgery. The rates of success, consecutive exotropia, and residual esotropia were 61.4%, 13.63%, and 25% in the last follow-up, respectively. The logistic regression showed statistically significant results between success result and lower age, higher pre-injection deviation, one month post-injection deviation, and severe ptosis. Complications included subconjunctival hemorrhage and ptosis. Conclusion: Botulinum toxin injection is reasonably less invasive with light anesthesia, scar free, and a therapeutic alternative for the patient with esotropia and CP. Therefore, it can provide more possible surgical options in future. Keywords: Botulinum toxin, cerebral palsy, esotropia
overcorrection and undercorrection.2 These difficulties may lead to multiple reoperations to achieve the least angle of deviation. These reoperations may cause so many complications such as scarring and restrictions of globe movement. These complications are not acceptable, especially in children, and may interact with their possible treatment in future.3 There were some studies raising suspicion of the optimistic view of the high success rate of surgery in these children. Overcorrection or undercorrection was more common in these children when compared with developmentally intact children.2,4–6 Considering associated problems in these children, the use of a simple and less invasive method to correct
INTRODUCTION Cerebral palsy (CP) is characterized by muscle spasticity most often attributable to prematurity and it is also secondary to periventricular leukomalacia, etc.1 This disorder is associated with higher incidence of ocular deviation compared with the normal population.2 Surgical correction was identified as the main treatment option for clinically significant ocular misalignment in these patients, but success of the surgery may be low due to the unpredictable postoperative results. The customized standard nomogram and modified nomogram in these patients give rise to
*This manuscript data has been applied with taking informed consent from patients. Received 6 March 2014; Accepted 1 December 2014; Published online 14 January 2015 Correspondence: Fatemeh Bazvand, MD, Eye Research Center, Farabi Eye Hospital, South Kargar St, Tehran, Iran. Tel: +98-912-617-9214; Fax: +98-21-8824-3708. E-mail: [email protected]
1
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2
A. Ameri et al.
ocular misalignment could be useful. It is known that one of the present alternative treatments of esotropia in children with CP is botulinum toxin. Botulinum toxin injection has been shown to be effective in some types of strabismus, including mild to moderate esotropia and exotropia, eliminating diplopia in the acute phase of paralytic deviations, complementary treatment of residual deviation after extraocular muscle surgery, etc.3,7,8 It is reported that surgery was more effective than botulinum toxin injection in infantile esotropia with large angle deviations, but in mild to moderate deviation, the results of both procedures were comparable.7 There have been limited studies9–11 of botulinum toxin injection for correction of ocular misalignment in patients with CP with encouraging results, and the necessity of evaluating efficacy of this option in further studies is undeniable. In this study, the clinical outcome of botulinum toxin injection in correction of esotropia in the patients with CP was evaluated.
PATIENTS AND METHODS This non–comparative, prospective, interventional case series was done in the strabismus department of Farabi Eye Hospital, Tehran, between the years 2011 and 2014. Informed consent was obtained from all parents. All surgical procedures were performed by one surgeon (AA). Tenets of the Helsinki Declaration were followed and institutional review board of Tehran University of Medical Sciences approval was obtained. The children with CP and a non-accommodative, non-paralytic esotropia with onset before 12 months were included in the study. CP diagnosis and its etiology were confirmed by a child neurologist. Positive forced duction test (FDT) more than + 1 and any history of ocular surgery were considered as exclusion criteria of study. The age of the patients was not considered as exclusion criteria. Complete ophthalmologic examinations, including cyclo-refraction and ocular motility examination, were done for each patient. The amount of primary deviation was measured by alternate prism cover test, if patient was cooperative; otherwise we used Krimsky test or prism reflection test. All pre- and postoperative measurements were done by a trained orthoptist who was blinded to the purpose of the study. All patients were followed for at least one year after the first injection (range of 12–24 months follow up). At follow-up visits the measurement of deviation, amount of limitation in ocular motility, and surgical complication were assessed. Ptosis was further classified as mild, moderate, or severe. Marginal reflex distance (MRD) between 2 and 4 mm, less than 2 mm, and greater than 4 mm was identified as mild,
moderate, and severe ptosis, respectively. The successful treatment was defined as orthotropia ± 10 prism diopters (PD). We divided patients in 2 groups: group 1 included patients with esotropia 50 PD and group 2 included patients with esotropia 450 PD.
Method of Surgery The procedure was performed under general anesthesia without electromyography (EMG) guide. To find target medial rectus (MR) muscle through pale conjunctiva and also perform fundoscopy at the end of procedure for evaluation of possible retinal injury, eye drop of phenylephrine 2.5% was applied twice within 5-minute intervals. Then the FDT in horizontal plane was done. The globe was extremely abducted using 8–0 toothed forceps. The injection was performed in this position after grasping the MR with a 27-gauge needle. Novotox (China) was the botulinum toxin used in this study. The 50-unit vial of Novotox was diluted with 1.4 cc normal saline. So, the dose of Novatox was 3.5 IU/0.1 ml in each patient and was independent to the amount of deviation. A cotton applicator was pressured lightly on the site of injection for 30 seconds. Patients were placed in semi-sitting position after injection, avoiding possible wide spread of botulinum toxin into the levator muscle and decreasing its subsequent ptosis. Fundoscopy was done at the end of procedure in all patients to check nasal quadrants of retina for possible penetrating injury.
STATISTICAL ANALYSIS The data were analyzed by SPSS version 16.00. The descriptive data were reported as mean ± SD. Chisquare test was used to compare success rate. The logistic regression was used to model success rate as a function of age, deviation in different visits, and ptosis. For chi square, p50.05, and for logistic regression, p50.1, were considered significant.
RESULTS Forty-four children (21 [47.7%] males) with concurrent CP and esotropia were recruited in this investigation with a mean age of 47.56 ± 30.86 months (range: 5 to 124 months). The etiology CP was diagnosed as periventricular leukomalacia, hypoxic ischemic damage during delivery and sub-ependymal hemorrhage during neonatal period. The mean spherical equivalent of cyclorefraction of patients was 2.16 ± 2.01 (from 2.25 to + 6.38) and 2.08 ± 2.05 (from 4.50 to +8.00) diopters, respectively, in right and left eyes. The amount of deviations in different visits and the results Strabismus
Botulinum Toxin in Esotropia in Cerebral Palsy
3
TABLE 1. Amount of deviation in various visits in patients with esotropia and cerebral palsy.
Pre-injection deviation 1 month deviation 2 months deviation 6 months deviation 12 months deviation 18 months deviation 24 months deviation last F/U deviation
Mean ± SD
Median
52.27 ± 18.40 PD ET 13.75 ± 21.46 PD XT 8.20 ± 17.71 PD XT 3.87 ± 22.29 PD ET 6.05 ± 15.28 PD ET 6.95 ± 17.05 PD ET 6.50 ± 10.45 PD ET 7.06 ± 19.04 PD ET
50 PD ET 8 PD XT 0 PD 0 PD 0 PD 8 PD ET 0 PD 0 PD
Number of cases
Range 25–123 PD 70 PD XT 50 PD XT 50 PD XT 40 PD XT 30 PD XT 10 PD XT 30 PD XT
ET 30 PD 30 PD 87 PD 40 PD 40 PD 20 PD 40 PD
44 44 44 44 44 20 14 44
ET ET ET ET ET ET ET
PD: prism diopter; ET: esotropia; XT: exotropia; F/U: follow-up.
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TABLE 2. The result of botulinum injection in different follow-up visits in patients with esotropia and cerebral palsy. Success 1 month F/U 2 months F/U 6 months F/U 12 months F/U 18 months F/U 24 months F/U Last F/U
22 28 30 30 10 10 27
Consecutive XT
(50%) (63.63%) (68.18%) (68.18%) (50%) (71.42%) (61.4%)
19 (43.2%) 13 (29.54%) 6 (13.63%) 3 (6.8%) 3 (15%) 0 6 (13.63%)
Residual ET 3 3 8 11 7 4 11
(6.8%) (6.8%) (18.18%) (25%) (35%) (28.57%) (25%)
Number of cases 44 44 44 44 20 14 44
ET: esotropia; XT: exotropia; F/U: follow-up.
of botulinum toxin injection in all patients were shown in Tables 1 and 2. There was no significant difference between 2 groups of esotropia (450 PD and 50 PD) in success rates at 12 months (p = 0.808) and last follow-up (p = 0.125). The analysis of logistic regression was summarized in Table 3. The statistically significant result was obtained in age, pre-injection deviation, 1-month deviation, and ptosis. According to Table 3, the lower ages, pre-injection deviation larger than 50 PD, more residual esotropia in 1-month follow-up and severe ptosis were associated with a better result in the last follow-up. Three patients had a very large primary angle of esodeviation (470 PD), which resulted in a high amount of residual esodeviation (420 PD) that required repeated injection 2 months after the first injection. The injection was repeated due to an increase in esotropia in six patients at 12 months and three patients at 18 months after the first procedure. The complications of this procedure included subconjunctival hemorrhage and ptosis. Subconjunctival hemorrhage was occurred in 6 patients in first week after injection. Seventeen patients showed severe ptosis in first month after injection, but ptosis reduced significantly in all patients and only 2 patients had severe ptosis at the second month after injection !
2015 Informa Healthcare USA, Inc.
(Table 4). The tape was used in the patients with severe ptosis. Ptosis was completely improved after 6 months in all patients.
DISCUSSION Strabismus is one of the various common ophthalmic manifestations in patients with CP. Sanjay et al.12 reported that the most common ophthalmic disorder in these patients is refractive disorder (78%), followed by strabismus (36%), nystagmus, optic atrophy, and also some degree of visual cortex impairment. Early intervention may improve these children’s visual, behavioral, and physical development. Although the most common type of strabismus in these children is reported to be alternating exotropia, treatment of large angle esotropia is so challenging as it may prevent deep amblyopia in a high percentage of these children. Selection of the most appropriate intervention in these children has been controversial and indefinite existence of many confounding factors other than strabismus has made their post-intervention clinical course unpredictable. We preferred the procedure without EMG control and under general anesthesia because we believe that the procedure is safer under general anesthesia. There are multiple reported techniques for extra
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A. Ameri et al. TABLE 3. Data of regression analysis in the patients with esotropia and cerebral palsy.
Sex Age Esotropia 450 PD Pre–injection deviation 1 month deviation Ptosis 1 month
Wald
Significance
Odds ratio
95% CI
0.487 2.965 2.934 1.939 3.732 2.943
0.485 0.085 0.087 0.164 0.053 0.086
2.383 0.944 0.000 0.634 0.933 0.149
0.208–27.297 0.885–1.008 0.00–5.051 0.333–1.205 0.870–1.001 0.017–1.312
CI: confidence interval.
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TABLE 4. The rate of ptosis after botulinum toxin injection in the patients with esotropia and cerebral palsy. Amount of ptosis
No ptosis
Mild ptosis
Moderate ptosis
Severe ptosis
All patients 1 month 2 months 6 months
1 (2.3%) 27 (61.4%) 44 (100%)
7 (15.9%) 14 (31.8%) 0
19 (43.2%) 1 (2.3%) 0
17 (38.6%) 2 (4.5%) 0
TABLE 5. The result of botulinum toxin injection in patients with esotropia and cerebral palsy in various studies. Study
Year
Case
Number of cases
Duration of follow-up
Definition of success
Cronemberger et al.1.1 Harry Petrushkin et al.16
2006 2012
Infantile ET and CP Infantile ET and CP
17 3
6 months 2–10 months
10 PD
Marqurzata et al.9 This study
2013 2014
Infantile ET and CP ET and CP
7 44
12–24 months
10 PD 10 PD
Success rate 47.1% 2 cases ortho; 1 case 20 PD deviation 57.1% 61%
CP: cerebral palsy; ortho: orthotropia.
ocular muscle (EOM) injection such as electromyography (EMG)-guided transconjunctival or direct injection to muscle after conjunctival dissection.8,13–15 In other studies, no significant difference has been reported between doing the procedure with or without EMG guided control.8,13 In our study the procedure is usually done in a short duration and further re-injections may be required in near future. The anesthesia is provided by a facial mask and tetracaine eye drops instead of intubation. This method of anesthesia had fewer complications as compared with deep anesthesia for surgery especially for these children with additional cerebral problems. No complication or retinal perforation was observed in our patients. So, performing procedure with light anesthesia and without EMG monitoring might be a safe method for the injection of botulium toxin. In this investigation we found a 68.18% success rate with botulinum toxin injection in management of patients with CP and esotropia at 1 year after injection. The result of botulinum toxin injection in various studies was summarized in Table 5. The successful outcome of strabismus surgery was
reported from 56% to 77% in prior studies2,17,18 in patients with CP and esotropia, but high rate of overcorrection in these patients was observed in comparison with developmentally normal children with the same amount of correction.5 Thus, although we did not perform the comparative study, but the botulinum toxin injection might be at least as effective as surgery in the treatment of the patients with CP and esotropia. In our study, the rates of overcorrection and undercorrection were 43% and 6.8%, respectively, at one month and 6.8% and 25% after 12 months. Habot-Wilner et al.2 compared bimedial rectus recess outcomes between 2 groups of CP and developmentally intact children with esotropia. Only 56% of the patients in the CP group achieved successful outcome versus 94% in the normal group. Undercorrection was reported as the most common failure (86%) in the developmental delay patients.2 The etiology of unpredictable results following surgery is not so clear but it seems to be mainly related to the nature of their neurologic problems.19 Amount of deviation in these children is variable, which makes it Strabismus
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Botulinum Toxin in Esotropia in Cerebral Palsy difficult to obtain a precise measurement of the angle of deviation.19 The defect in binocular function and also the possible generalized muscle tone disorder may alter the final outcomes of these patients after a standard strabismus surgery when compared with developmentally intact children.2 This variable rate of response in different patients may be explained by prescription of equivalent dose of toxin in all patients independent to their angle of deviation. In our study, only 3 patients had undercorrection at the first injection session, possibly due to their primary large angle esotropia, and they achieved a better result after reinjection. The undercorrection increased from 6.8% to 25% during 12 months of follow-up, so the injection was repeated in 6 other patients. It was shown that the effect of injection waned over time. So, it may be possible to adjust the angle of deviation more precisely by re-injecting the muscle. In 1980, Scott20 studied botulinum toxin type A (BTX-A) for patients with strabismus, and he reported that the effect is totally dose dependent. The existence of precise dose-based nomogram may result in a higher rate of correction in these patients. So, with adjusting result of injection by exact nomogram, the botulinum toxin injection could be used as a safe and simple method for correction of deviation in patients with CP. The rate of overcorrection in the last follow-up was 13.63% in our study. The first experimental use of botulinum toxin was from Scott21 (1973) who reported that the exodeviation following botulinum toxin injection is persistent and the agonist/antagonist strength ratio of extraocular muscles altered permanently after injection. The sustained response following injection is explained by altered balance of agonist/ antagonist strength and muscle innervations in the affected muscles of the injected eye and also the contracture induced in the ipsilateral antagonist muscle during inactivity of the injected extraocular muscle.21,22 The permanent result of botulinum toxin injection for correction of deviation may be reproduced by repeated injection and it could be an accepted alternative to surgical correction in special cases of strabismus. However, this hypothesis requires further study with longer follow-up period. There was no major complication regarding botulinum injection in our patients. The complications after botulinum injection consist of vertical deviation and ptosis with different proportion between DysportÕ (24%) and BotoxÕ (52.17%–55.54%).23 The only complications were post-injection subconjunctival hemorrhage the following day after procedure and mild to severe ptosis (97%) at the first month postinjection visit due to spreading of toxin to the levator muscle. However severe ptosis, with covering pupil, was present in 38.6% (17) of our patients, which declined to 4.5% (2) at the second month of follow-up visit. Baggesen and Arnljot8 have reported that ptosis !
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5
was seen in only 8.9% (19 of 214) of their patients following 2.5 IU BotoxÕ (Allergan) injection and only one patient had severe ptosis covering the pupil. Comparable to our study, Cronemberger et al.11 have reported subconjunctival hemorrhage (16.7%), transient vertical deviation (16.7%), and transient ptosis (91.7%) after 2–6 IU/2 ml (mean = 4 IU) of BotoxÕ in patients with CP and horizontal deviations. The relative high rate of ptosis in our patients may be explained by more tissue spreading side effect of the toxin that we used and its different product. In this study, the lower age, more ptosis, larger deviation pre-injection, and less deviation one month after injection were significantly were associated with better result in last follow-up. In the study of Levy et al.17, it has been also suggested that the age of surgery did not affect the final cosmetic and functional results in these patients.17 In our study, the association between lower age and more ptosis with success may be related to lack of contracture in lower age and more tissue spreading in severe ptosis, respectively. On the other hand, in the study by de Alba Campomanes3 on results of strabismus surgery and botulinum toxin and their comparison with each other, it was shown that in deviations larger than 30– 35 PD, surgery is superior to botulinum toxin with a 69% versus 36% success rate. Therefore, they proved that in deviations smaller than 30 PD there was no significant difference between those two groups and suggested botulinum injection as an alternative in patients with mild to moderate infantile esotropia. However they reported that with longer follow-up, more patients (up to 50%) may require additional surgeries. The difference between our study and this study may be explained by the population disparity of these two studies. On the other hand, this result about larger pre-injection deviation may be related to reinjection in our study. Subsequently, these factors (lower age, more ptosis, larger pre-injection deviation and less esotropia one month after injection) may be accounted as predictive factors for achieving better results. The wide age range age of patients could affect the response to botulinum toxin injection as well as absence of a control group were the limitations of our study. The lack of binocularity testing before and after botulinum toxin injection due to low age and neuro-developmental delay of these patients was the other drawback of this investigation.
CONCLUSION In conclusion, this procedure is a reasonably less invasive and scar-free procedure, providing more possible surgical options in the future for these children. Performing the procedure with light anesthesia and without EMG monitoring might be a safe
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and simple method for the injection of botulium toxin. Lower age, more ptosis, larger pre-injection deviation, and less esotropia one month after injection may be accounted as predictive factors for achieving better results. Future studies about the long-term follow-up of these children and the rate of subsequent surgeries in these patients are required.
DECLARATION OF INTEREST The authors have declared no conflicts of interest.
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REFERENCES 1. William B. Carey, ed. Developmental-behavioral pediatrics. 4th ed. Philadelphia, PA: Saunders/Elsevier; 2009:264. 2. Habot-Wilner Z, Spierer A, Glovinsky J, Wygnanski-Jaffe T. Bilateral medial rectus muscle recession: results in children with developmental delay compared with normally developed children. J AAPOS 2006;10:150–154. 3. de Alba Campomanes AG, Binenbaum G, Campomanes Eguiarte G. Comparison of botulinum toxin with surgery as primary treatment for infantile esotropia. J AAPOS 2010; 14:111–116. 4. Griffiths MI, Smith VH. Squint in relation to cerebral palsy: visual disorders and cerebral palsy. London: Medical Books Ltd; 1963:37. 5. Pickering JD, Simon JW, Lininger LL, et al. Exaggerated effect of bilateral medial rectus recession in developmentally delayed children. J Pediatr Ophthalmol Strabismus 1994; 31:374–377. 6. Holman RE, Merritt JC. Infantile esotropia: results in the neurologic impaired and ‘‘normal’’ child at MCNH (six years). J Pediatr Ophthalmol Strabismus 1986;23:41–44. 7. Raab EL, Aaby AA, Bloom JN, et al. Pediatric ophthalmology and strabismus. Section 6. In: 2011–2012 basic and clinical science course. San Francisco: American Academy of Ophthalmology, 2012 163–164.
8. Baggesen K, Arnljot HM. Treatment of congenital esotropia with botulinum toxin type A. Acta Ophthalmol 2011;89: 484–488. 9. Malgorzata M, Wojciech K, Alina BŁ, Artur B. Botulinum toxin injection as primary treatment for esotropia in patients with cerebral palsy. Klin Oczna 2013;115:13–14. 10. Petrushkin H, Oyewole K, Jain S. Botulinum toxin for the treatment of early-onset esotropia in children with cerebral palsy. J Pediatr Ophthalmol Strabismus 2012;49:125. 11. Cronemberger MF, Mendonca TS, Bicas HE. Botulinum toxin treatment for horizontal strabismus in children with cerebral palsy. Arq Bras Oftalmol 2006;69:523–529. 12. Marasini S, Paudel N, Adhikari P, Shrestha JB, Bowan MD. Ocular manifestations in children with cerebral palsy. Optometry & Vision Development 2011;42:178. 13. Benabent EC, Garcia Hermosa P, Arrazola MT, Alio y Sanz JL. Botulinum toxin injection without electromyographic assistance. J Pediatr Ophthalmol Strabismus 2002;39:231–234. 14. Elston JS. Is botulinum toxin helpful in squint management? Br J Ophthalmol 1998;82:105–106. 15. Scott AB, Magoon EH, McNeer KW, Stager DR. Botulinum treatment of childhood strabismus. Ophthalmology 1990;97: 1434–1438. 16. Harry P, Kehinde O, Saurabh J. Botulinum toxin for the treatment of early-onset esotropia in children with cerebral palsy. J Pediatr Ophthalmol Strabismus 2012;49:125. 17. Levy NS, Cassin B, Newman M. Strabismus in children with cerebral palsy. J Pediatr Ophthalmol 1976;13:72–74. 18. Hiles DA, Wallar PH, McFarlane F. Current concepts in the management of strabismus in children with cerebral palsy. Ann Ophthalmol 1975;7:789–798. 19. Pigassou–Albouy R, Fleming A. Amblyopia and strabismus in patients with cerebral palsy. Ann Ophthalmol 1975;7: 382–387. 20. Scott AB. Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. Ophthalmology 1980;87:1044–1049. 21. Scott AB, Rosenbaum AL, Collins CC. Pharmacologic weakening of extraocular muscles. Invest Ophthalmol 1973;12:924–927. 22. Elston JS, Lee JP, Powell CM, et al. Treatment of strabismus in adults with botulinum toxin A. Br J Ophthalmol 1985;69: 718–724. 23. Rowe FJ, Noonan CP. Botulinum toxin for the treatment of strabismus. Cochrane Database Syst Rev 2009;(2):CD006499.
Strabismus
Clinical Outcomes of Botulinum Toxin Injection in Patients with Cerebral Palsy and Esotropia* Ahmad Ameri, MD1, Arash Mirmohammadsadeghi, MD2, Ali Makateb, Fatemeh Bazvand, MD2, and Simindokht Hosseini, MD3
Strabismus Downloaded from informahealthcare.com by Kainan University on 04/08/15 For personal use only.
1
MD
3
,
Associate Professor of Ophthalmology, 2Assistant Professor of Ophthalmology, and 3Ophthalmologist, Tehran University of Medical Science
ABSTRACT Purpose: To assess the efficacy of botulinum toxin (Novotox) injection in patients with cerebral palsy (CP) and esotropia. Patients and methods: In a non-comparative, prospective interventional case series botulinum toxin injection was done in 44 patients with CP and esotropia. A single dose of botulinum toxin was injected in both medial rectus muscles of all patients and was repeated in 12 patients. Angle of deviation within 10 prism diopters (PD) of orthotropia was defined as a successful outcome. Result: Forty-four patients (21 males) with the mean age of 47.56 ± 35.86 months were included in the study. The mean esotropia in all patients was 52.27 ± 18.40 PD (25–123 PD). The range of follow-up was 12–24 months. Thirty patients (68.18%) were treated successfully one year after surgery. The rates of success, consecutive exotropia, and residual esotropia were 61.4%, 13.63%, and 25% in the last follow-up, respectively. The logistic regression showed statistically significant results between success result and lower age, higher pre-injection deviation, one month post-injection deviation, and severe ptosis. Complications included subconjunctival hemorrhage and ptosis. Conclusion: Botulinum toxin injection is reasonably less invasive with light anesthesia, scar free, and a therapeutic alternative for the patient with esotropia and CP. Therefore, it can provide more possible surgical options in future. Keywords: Botulinum toxin, cerebral palsy, esotropia
overcorrection and undercorrection.2 These difficulties may lead to multiple reoperations to achieve the least angle of deviation. These reoperations may cause so many complications such as scarring and restrictions of globe movement. These complications are not acceptable, especially in children, and may interact with their possible treatment in future.3 There were some studies raising suspicion of the optimistic view of the high success rate of surgery in these children. Overcorrection or undercorrection was more common in these children when compared with developmentally intact children.2,4–6 Considering associated problems in these children, the use of a simple and less invasive method to correct
INTRODUCTION Cerebral palsy (CP) is characterized by muscle spasticity most often attributable to prematurity and it is also secondary to periventricular leukomalacia, etc.1 This disorder is associated with higher incidence of ocular deviation compared with the normal population.2 Surgical correction was identified as the main treatment option for clinically significant ocular misalignment in these patients, but success of the surgery may be low due to the unpredictable postoperative results. The customized standard nomogram and modified nomogram in these patients give rise to
*This manuscript data has been applied with taking informed consent from patients. Received 6 March 2014; Accepted 1 December 2014; Published online 14 January 2015 Correspondence: Fatemeh Bazvand, MD, Eye Research Center, Farabi Eye Hospital, South Kargar St, Tehran, Iran. Tel: +98-912-617-9214; Fax: +98-21-8824-3708. E-mail: [email protected]
1
Strabismus Downloaded from informahealthcare.com by Kainan University on 04/08/15 For personal use only.
2
A. Ameri et al.
ocular misalignment could be useful. It is known that one of the present alternative treatments of esotropia in children with CP is botulinum toxin. Botulinum toxin injection has been shown to be effective in some types of strabismus, including mild to moderate esotropia and exotropia, eliminating diplopia in the acute phase of paralytic deviations, complementary treatment of residual deviation after extraocular muscle surgery, etc.3,7,8 It is reported that surgery was more effective than botulinum toxin injection in infantile esotropia with large angle deviations, but in mild to moderate deviation, the results of both procedures were comparable.7 There have been limited studies9–11 of botulinum toxin injection for correction of ocular misalignment in patients with CP with encouraging results, and the necessity of evaluating efficacy of this option in further studies is undeniable. In this study, the clinical outcome of botulinum toxin injection in correction of esotropia in the patients with CP was evaluated.
PATIENTS AND METHODS This non–comparative, prospective, interventional case series was done in the strabismus department of Farabi Eye Hospital, Tehran, between the years 2011 and 2014. Informed consent was obtained from all parents. All surgical procedures were performed by one surgeon (AA). Tenets of the Helsinki Declaration were followed and institutional review board of Tehran University of Medical Sciences approval was obtained. The children with CP and a non-accommodative, non-paralytic esotropia with onset before 12 months were included in the study. CP diagnosis and its etiology were confirmed by a child neurologist. Positive forced duction test (FDT) more than + 1 and any history of ocular surgery were considered as exclusion criteria of study. The age of the patients was not considered as exclusion criteria. Complete ophthalmologic examinations, including cyclo-refraction and ocular motility examination, were done for each patient. The amount of primary deviation was measured by alternate prism cover test, if patient was cooperative; otherwise we used Krimsky test or prism reflection test. All pre- and postoperative measurements were done by a trained orthoptist who was blinded to the purpose of the study. All patients were followed for at least one year after the first injection (range of 12–24 months follow up). At follow-up visits the measurement of deviation, amount of limitation in ocular motility, and surgical complication were assessed. Ptosis was further classified as mild, moderate, or severe. Marginal reflex distance (MRD) between 2 and 4 mm, less than 2 mm, and greater than 4 mm was identified as mild,
moderate, and severe ptosis, respectively. The successful treatment was defined as orthotropia ± 10 prism diopters (PD). We divided patients in 2 groups: group 1 included patients with esotropia 50 PD and group 2 included patients with esotropia 450 PD.
Method of Surgery The procedure was performed under general anesthesia without electromyography (EMG) guide. To find target medial rectus (MR) muscle through pale conjunctiva and also perform fundoscopy at the end of procedure for evaluation of possible retinal injury, eye drop of phenylephrine 2.5% was applied twice within 5-minute intervals. Then the FDT in horizontal plane was done. The globe was extremely abducted using 8–0 toothed forceps. The injection was performed in this position after grasping the MR with a 27-gauge needle. Novotox (China) was the botulinum toxin used in this study. The 50-unit vial of Novotox was diluted with 1.4 cc normal saline. So, the dose of Novatox was 3.5 IU/0.1 ml in each patient and was independent to the amount of deviation. A cotton applicator was pressured lightly on the site of injection for 30 seconds. Patients were placed in semi-sitting position after injection, avoiding possible wide spread of botulinum toxin into the levator muscle and decreasing its subsequent ptosis. Fundoscopy was done at the end of procedure in all patients to check nasal quadrants of retina for possible penetrating injury.
STATISTICAL ANALYSIS The data were analyzed by SPSS version 16.00. The descriptive data were reported as mean ± SD. Chisquare test was used to compare success rate. The logistic regression was used to model success rate as a function of age, deviation in different visits, and ptosis. For chi square, p50.05, and for logistic regression, p50.1, were considered significant.
RESULTS Forty-four children (21 [47.7%] males) with concurrent CP and esotropia were recruited in this investigation with a mean age of 47.56 ± 30.86 months (range: 5 to 124 months). The etiology CP was diagnosed as periventricular leukomalacia, hypoxic ischemic damage during delivery and sub-ependymal hemorrhage during neonatal period. The mean spherical equivalent of cyclorefraction of patients was 2.16 ± 2.01 (from 2.25 to + 6.38) and 2.08 ± 2.05 (from 4.50 to +8.00) diopters, respectively, in right and left eyes. The amount of deviations in different visits and the results Strabismus
Botulinum Toxin in Esotropia in Cerebral Palsy
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TABLE 1. Amount of deviation in various visits in patients with esotropia and cerebral palsy.
Pre-injection deviation 1 month deviation 2 months deviation 6 months deviation 12 months deviation 18 months deviation 24 months deviation last F/U deviation
Mean ± SD
Median
52.27 ± 18.40 PD ET 13.75 ± 21.46 PD XT 8.20 ± 17.71 PD XT 3.87 ± 22.29 PD ET 6.05 ± 15.28 PD ET 6.95 ± 17.05 PD ET 6.50 ± 10.45 PD ET 7.06 ± 19.04 PD ET
50 PD ET 8 PD XT 0 PD 0 PD 0 PD 8 PD ET 0 PD 0 PD
Number of cases
Range 25–123 PD 70 PD XT 50 PD XT 50 PD XT 40 PD XT 30 PD XT 10 PD XT 30 PD XT
ET 30 PD 30 PD 87 PD 40 PD 40 PD 20 PD 40 PD
44 44 44 44 44 20 14 44
ET ET ET ET ET ET ET
PD: prism diopter; ET: esotropia; XT: exotropia; F/U: follow-up.
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TABLE 2. The result of botulinum injection in different follow-up visits in patients with esotropia and cerebral palsy. Success 1 month F/U 2 months F/U 6 months F/U 12 months F/U 18 months F/U 24 months F/U Last F/U
22 28 30 30 10 10 27
Consecutive XT
(50%) (63.63%) (68.18%) (68.18%) (50%) (71.42%) (61.4%)
19 (43.2%) 13 (29.54%) 6 (13.63%) 3 (6.8%) 3 (15%) 0 6 (13.63%)
Residual ET 3 3 8 11 7 4 11
(6.8%) (6.8%) (18.18%) (25%) (35%) (28.57%) (25%)
Number of cases 44 44 44 44 20 14 44
ET: esotropia; XT: exotropia; F/U: follow-up.
of botulinum toxin injection in all patients were shown in Tables 1 and 2. There was no significant difference between 2 groups of esotropia (450 PD and 50 PD) in success rates at 12 months (p = 0.808) and last follow-up (p = 0.125). The analysis of logistic regression was summarized in Table 3. The statistically significant result was obtained in age, pre-injection deviation, 1-month deviation, and ptosis. According to Table 3, the lower ages, pre-injection deviation larger than 50 PD, more residual esotropia in 1-month follow-up and severe ptosis were associated with a better result in the last follow-up. Three patients had a very large primary angle of esodeviation (470 PD), which resulted in a high amount of residual esodeviation (420 PD) that required repeated injection 2 months after the first injection. The injection was repeated due to an increase in esotropia in six patients at 12 months and three patients at 18 months after the first procedure. The complications of this procedure included subconjunctival hemorrhage and ptosis. Subconjunctival hemorrhage was occurred in 6 patients in first week after injection. Seventeen patients showed severe ptosis in first month after injection, but ptosis reduced significantly in all patients and only 2 patients had severe ptosis at the second month after injection !
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(Table 4). The tape was used in the patients with severe ptosis. Ptosis was completely improved after 6 months in all patients.
DISCUSSION Strabismus is one of the various common ophthalmic manifestations in patients with CP. Sanjay et al.12 reported that the most common ophthalmic disorder in these patients is refractive disorder (78%), followed by strabismus (36%), nystagmus, optic atrophy, and also some degree of visual cortex impairment. Early intervention may improve these children’s visual, behavioral, and physical development. Although the most common type of strabismus in these children is reported to be alternating exotropia, treatment of large angle esotropia is so challenging as it may prevent deep amblyopia in a high percentage of these children. Selection of the most appropriate intervention in these children has been controversial and indefinite existence of many confounding factors other than strabismus has made their post-intervention clinical course unpredictable. We preferred the procedure without EMG control and under general anesthesia because we believe that the procedure is safer under general anesthesia. There are multiple reported techniques for extra
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A. Ameri et al. TABLE 3. Data of regression analysis in the patients with esotropia and cerebral palsy.
Sex Age Esotropia 450 PD Pre–injection deviation 1 month deviation Ptosis 1 month
Wald
Significance
Odds ratio
95% CI
0.487 2.965 2.934 1.939 3.732 2.943
0.485 0.085 0.087 0.164 0.053 0.086
2.383 0.944 0.000 0.634 0.933 0.149
0.208–27.297 0.885–1.008 0.00–5.051 0.333–1.205 0.870–1.001 0.017–1.312
CI: confidence interval.
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TABLE 4. The rate of ptosis after botulinum toxin injection in the patients with esotropia and cerebral palsy. Amount of ptosis
No ptosis
Mild ptosis
Moderate ptosis
Severe ptosis
All patients 1 month 2 months 6 months
1 (2.3%) 27 (61.4%) 44 (100%)
7 (15.9%) 14 (31.8%) 0
19 (43.2%) 1 (2.3%) 0
17 (38.6%) 2 (4.5%) 0
TABLE 5. The result of botulinum toxin injection in patients with esotropia and cerebral palsy in various studies. Study
Year
Case
Number of cases
Duration of follow-up
Definition of success
Cronemberger et al.1.1 Harry Petrushkin et al.16
2006 2012
Infantile ET and CP Infantile ET and CP
17 3
6 months 2–10 months
10 PD
Marqurzata et al.9 This study
2013 2014
Infantile ET and CP ET and CP
7 44
12–24 months
10 PD 10 PD
Success rate 47.1% 2 cases ortho; 1 case 20 PD deviation 57.1% 61%
CP: cerebral palsy; ortho: orthotropia.
ocular muscle (EOM) injection such as electromyography (EMG)-guided transconjunctival or direct injection to muscle after conjunctival dissection.8,13–15 In other studies, no significant difference has been reported between doing the procedure with or without EMG guided control.8,13 In our study the procedure is usually done in a short duration and further re-injections may be required in near future. The anesthesia is provided by a facial mask and tetracaine eye drops instead of intubation. This method of anesthesia had fewer complications as compared with deep anesthesia for surgery especially for these children with additional cerebral problems. No complication or retinal perforation was observed in our patients. So, performing procedure with light anesthesia and without EMG monitoring might be a safe method for the injection of botulium toxin. In this investigation we found a 68.18% success rate with botulinum toxin injection in management of patients with CP and esotropia at 1 year after injection. The result of botulinum toxin injection in various studies was summarized in Table 5. The successful outcome of strabismus surgery was
reported from 56% to 77% in prior studies2,17,18 in patients with CP and esotropia, but high rate of overcorrection in these patients was observed in comparison with developmentally normal children with the same amount of correction.5 Thus, although we did not perform the comparative study, but the botulinum toxin injection might be at least as effective as surgery in the treatment of the patients with CP and esotropia. In our study, the rates of overcorrection and undercorrection were 43% and 6.8%, respectively, at one month and 6.8% and 25% after 12 months. Habot-Wilner et al.2 compared bimedial rectus recess outcomes between 2 groups of CP and developmentally intact children with esotropia. Only 56% of the patients in the CP group achieved successful outcome versus 94% in the normal group. Undercorrection was reported as the most common failure (86%) in the developmental delay patients.2 The etiology of unpredictable results following surgery is not so clear but it seems to be mainly related to the nature of their neurologic problems.19 Amount of deviation in these children is variable, which makes it Strabismus
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Botulinum Toxin in Esotropia in Cerebral Palsy difficult to obtain a precise measurement of the angle of deviation.19 The defect in binocular function and also the possible generalized muscle tone disorder may alter the final outcomes of these patients after a standard strabismus surgery when compared with developmentally intact children.2 This variable rate of response in different patients may be explained by prescription of equivalent dose of toxin in all patients independent to their angle of deviation. In our study, only 3 patients had undercorrection at the first injection session, possibly due to their primary large angle esotropia, and they achieved a better result after reinjection. The undercorrection increased from 6.8% to 25% during 12 months of follow-up, so the injection was repeated in 6 other patients. It was shown that the effect of injection waned over time. So, it may be possible to adjust the angle of deviation more precisely by re-injecting the muscle. In 1980, Scott20 studied botulinum toxin type A (BTX-A) for patients with strabismus, and he reported that the effect is totally dose dependent. The existence of precise dose-based nomogram may result in a higher rate of correction in these patients. So, with adjusting result of injection by exact nomogram, the botulinum toxin injection could be used as a safe and simple method for correction of deviation in patients with CP. The rate of overcorrection in the last follow-up was 13.63% in our study. The first experimental use of botulinum toxin was from Scott21 (1973) who reported that the exodeviation following botulinum toxin injection is persistent and the agonist/antagonist strength ratio of extraocular muscles altered permanently after injection. The sustained response following injection is explained by altered balance of agonist/ antagonist strength and muscle innervations in the affected muscles of the injected eye and also the contracture induced in the ipsilateral antagonist muscle during inactivity of the injected extraocular muscle.21,22 The permanent result of botulinum toxin injection for correction of deviation may be reproduced by repeated injection and it could be an accepted alternative to surgical correction in special cases of strabismus. However, this hypothesis requires further study with longer follow-up period. There was no major complication regarding botulinum injection in our patients. The complications after botulinum injection consist of vertical deviation and ptosis with different proportion between DysportÕ (24%) and BotoxÕ (52.17%–55.54%).23 The only complications were post-injection subconjunctival hemorrhage the following day after procedure and mild to severe ptosis (97%) at the first month postinjection visit due to spreading of toxin to the levator muscle. However severe ptosis, with covering pupil, was present in 38.6% (17) of our patients, which declined to 4.5% (2) at the second month of follow-up visit. Baggesen and Arnljot8 have reported that ptosis !
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was seen in only 8.9% (19 of 214) of their patients following 2.5 IU BotoxÕ (Allergan) injection and only one patient had severe ptosis covering the pupil. Comparable to our study, Cronemberger et al.11 have reported subconjunctival hemorrhage (16.7%), transient vertical deviation (16.7%), and transient ptosis (91.7%) after 2–6 IU/2 ml (mean = 4 IU) of BotoxÕ in patients with CP and horizontal deviations. The relative high rate of ptosis in our patients may be explained by more tissue spreading side effect of the toxin that we used and its different product. In this study, the lower age, more ptosis, larger deviation pre-injection, and less deviation one month after injection were significantly were associated with better result in last follow-up. In the study of Levy et al.17, it has been also suggested that the age of surgery did not affect the final cosmetic and functional results in these patients.17 In our study, the association between lower age and more ptosis with success may be related to lack of contracture in lower age and more tissue spreading in severe ptosis, respectively. On the other hand, in the study by de Alba Campomanes3 on results of strabismus surgery and botulinum toxin and their comparison with each other, it was shown that in deviations larger than 30– 35 PD, surgery is superior to botulinum toxin with a 69% versus 36% success rate. Therefore, they proved that in deviations smaller than 30 PD there was no significant difference between those two groups and suggested botulinum injection as an alternative in patients with mild to moderate infantile esotropia. However they reported that with longer follow-up, more patients (up to 50%) may require additional surgeries. The difference between our study and this study may be explained by the population disparity of these two studies. On the other hand, this result about larger pre-injection deviation may be related to reinjection in our study. Subsequently, these factors (lower age, more ptosis, larger pre-injection deviation and less esotropia one month after injection) may be accounted as predictive factors for achieving better results. The wide age range age of patients could affect the response to botulinum toxin injection as well as absence of a control group were the limitations of our study. The lack of binocularity testing before and after botulinum toxin injection due to low age and neuro-developmental delay of these patients was the other drawback of this investigation.
CONCLUSION In conclusion, this procedure is a reasonably less invasive and scar-free procedure, providing more possible surgical options in the future for these children. Performing the procedure with light anesthesia and without EMG monitoring might be a safe
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and simple method for the injection of botulium toxin. Lower age, more ptosis, larger pre-injection deviation, and less esotropia one month after injection may be accounted as predictive factors for achieving better results. Future studies about the long-term follow-up of these children and the rate of subsequent surgeries in these patients are required.
DECLARATION OF INTEREST The authors have declared no conflicts of interest.
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REFERENCES 1. William B. Carey, ed. Developmental-behavioral pediatrics. 4th ed. Philadelphia, PA: Saunders/Elsevier; 2009:264. 2. Habot-Wilner Z, Spierer A, Glovinsky J, Wygnanski-Jaffe T. Bilateral medial rectus muscle recession: results in children with developmental delay compared with normally developed children. J AAPOS 2006;10:150–154. 3. de Alba Campomanes AG, Binenbaum G, Campomanes Eguiarte G. Comparison of botulinum toxin with surgery as primary treatment for infantile esotropia. J AAPOS 2010; 14:111–116. 4. Griffiths MI, Smith VH. Squint in relation to cerebral palsy: visual disorders and cerebral palsy. London: Medical Books Ltd; 1963:37. 5. Pickering JD, Simon JW, Lininger LL, et al. Exaggerated effect of bilateral medial rectus recession in developmentally delayed children. J Pediatr Ophthalmol Strabismus 1994; 31:374–377. 6. Holman RE, Merritt JC. Infantile esotropia: results in the neurologic impaired and ‘‘normal’’ child at MCNH (six years). J Pediatr Ophthalmol Strabismus 1986;23:41–44. 7. Raab EL, Aaby AA, Bloom JN, et al. Pediatric ophthalmology and strabismus. Section 6. In: 2011–2012 basic and clinical science course. San Francisco: American Academy of Ophthalmology, 2012 163–164.
8. Baggesen K, Arnljot HM. Treatment of congenital esotropia with botulinum toxin type A. Acta Ophthalmol 2011;89: 484–488. 9. Malgorzata M, Wojciech K, Alina BŁ, Artur B. Botulinum toxin injection as primary treatment for esotropia in patients with cerebral palsy. Klin Oczna 2013;115:13–14. 10. Petrushkin H, Oyewole K, Jain S. Botulinum toxin for the treatment of early-onset esotropia in children with cerebral palsy. J Pediatr Ophthalmol Strabismus 2012;49:125. 11. Cronemberger MF, Mendonca TS, Bicas HE. Botulinum toxin treatment for horizontal strabismus in children with cerebral palsy. Arq Bras Oftalmol 2006;69:523–529. 12. Marasini S, Paudel N, Adhikari P, Shrestha JB, Bowan MD. Ocular manifestations in children with cerebral palsy. Optometry & Vision Development 2011;42:178. 13. Benabent EC, Garcia Hermosa P, Arrazola MT, Alio y Sanz JL. Botulinum toxin injection without electromyographic assistance. J Pediatr Ophthalmol Strabismus 2002;39:231–234. 14. Elston JS. Is botulinum toxin helpful in squint management? Br J Ophthalmol 1998;82:105–106. 15. Scott AB, Magoon EH, McNeer KW, Stager DR. Botulinum treatment of childhood strabismus. Ophthalmology 1990;97: 1434–1438. 16. Harry P, Kehinde O, Saurabh J. Botulinum toxin for the treatment of early-onset esotropia in children with cerebral palsy. J Pediatr Ophthalmol Strabismus 2012;49:125. 17. Levy NS, Cassin B, Newman M. Strabismus in children with cerebral palsy. J Pediatr Ophthalmol 1976;13:72–74. 18. Hiles DA, Wallar PH, McFarlane F. Current concepts in the management of strabismus in children with cerebral palsy. Ann Ophthalmol 1975;7:789–798. 19. Pigassou–Albouy R, Fleming A. Amblyopia and strabismus in patients with cerebral palsy. Ann Ophthalmol 1975;7: 382–387. 20. Scott AB. Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. Ophthalmology 1980;87:1044–1049. 21. Scott AB, Rosenbaum AL, Collins CC. Pharmacologic weakening of extraocular muscles. Invest Ophthalmol 1973;12:924–927. 22. Elston JS, Lee JP, Powell CM, et al. Treatment of strabismus in adults with botulinum toxin A. Br J Ophthalmol 1985;69: 718–724. 23. Rowe FJ, Noonan CP. Botulinum toxin for the treatment of strabismus. Cochrane Database Syst Rev 2009;(2):CD006499.
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