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103BTXA in childhood strabismus
Correspondence andreprint requests to:J.P. LeeMoorfields Eye Hosp.City Road, London EC1V 2PDEngland, U.K.
Acknowledgements:This work was supported in part byIpsen, 1 Bath Road, Maidenhead,Berks, SL6 4UH, England, whomarket botulinum toxin under thetrade name Dysport.
Original paper
Strabismus 0927-3972/99/US$ 15.00
Strabismus – 1999, Vol. 7, No. 2,pp. 103-111© Æolus Press 1999
Accepted 12 March 1999
Botulinum toxin in childhood strabismus
S.A. Rayner FRCOphthE.J. Hollick
J.P. Lee
Moorfields Eye Hospital, London, U.K.
Abstract The use of botulinum toxin A (BTXA) in childhood stra-bismus is still a matter of debate. This study investigates the indica-tions for and outcome of BTXA therapy in children at our institution.From 1985 to 1995, 237 children up to and including 16 years of agewere treated with BTXA for strabismus. We undertook a retrospectivestudy of 163 (69%) children from this group. Factors considered wereage; anaesthesia; number of, indication for and outcome of injections;complications and follow-up. There were three major indications forthe use of BTXA in children: firstly to improve binocular function,secondly as a post-operative diplopia test or for cosmetic reasons, andthirdly in the investigation or treatment of paralytic and restrictive stra-bismus.
In the first group (54 children), BTXA produced improved binocularfunction in 54% of all patients treated and in 49% of those with aminimum follow-up of 12 months. In the second group (82 children),88% showed informative post-operative diplopia tests and 44% hadmore than one injection to maintain improved cosmetic alignment.
The third group comprised 27 children with a range of diagnoses,including 1 third nerve paresis, 12 unilateral or bilateral sixth nervepareses, 7 unilateral or bilateral Duane’s syndromes, 5 lost or fibrosedmuscles and 2 others. This group had a range of outcomes which arediscussed in the text. BTXA is useful in the treatment of a select groupof children with strabismus. If there is evidence of threatened or recent-ly lost binocularity, or risk of creating or worsening diplopia aftersurgery, it is a useful therapeutic tool. In children with strabismus ofunusual cause it has diagnostic value.
Key words Strabismus; children; botulinum toxin; diplopia
Introduction Alan Scott introduced the use of botulinum toxin Afor strabismus in 1979.1 The value of this agent for the management ofvarious types of adult strabismus is well established2 but relatively littlehas been reported regarding its use in children.3-7 This study retrospec-tively reviews our experience of the use of botulinum toxin in child-hood strabismus, with the aim of identifying the most appropriate in-
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dications for the use of this agent as an alternative to or in conjunctionwith strabismus surgery. We began the use of botulinum toxin therapyin 1982, initially in adults only, and treated our first child in 1985.
Materials and methods We obtained details from our ToxinClinic database of all patients treated with botulinum toxin for strabis-mus who were 16 years or under at the time of first injection. Therewere a total of 237 children, 163 (69%) of whose records were avail-able for review. A database of injections documented the total numberof children treated but some of the case notes were unavailable as theyhad been returned to the referring hospital or the child had not returnedafter BTXA injection for review. As assessed by comparison betweenthe injection database and the available case notes, the diagnoses, agedistribution and frequency of injection did not vary significantly be-tween the cases whose records were available and those whose recordscould not be obtained for review. The age distribution and sex ratio ofthe cases studied are shown in Fig. 1a. This shows a bimodal distribu-tion, with most children between 5 and 9 years or between 13 and 16years at first injection. Equal numbers of boys and girls were treated.
All injections were given under electromyographic control, using amonopolar injection electrode. The formulation of botulinum toxin usedthroughout was DYSPORTTM (Speywood Pharmaceuticals, England).A standard dose of 62.5 pg (2.5 UK units) was given in all cases.Older, co-operative children (9 to 16 years) were treated awake as foradult injection. Local anaesthesia was obtained with G Amethocaine1% (4 drops), and G Adrenaline 0.01% (one drop) was instilled justbefore injection to blanch the conjunctiva. Younger children (less than11 years) were sedated with intravenous ketamine (2 mg/kg) in addi-tion to topical anaesthesia. All patients were seen either one or twoweeks after injection to assess the therapeutic response.
indications for treatment Inspection of the data showed thatthe patients fell into three broad groups. Groups 1 and 2 consisted of
Fig. 1a. Age distribution of childrenincluded in this study. The totalnumber of children was 163.
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children with concomitant strabismus, and group 3 of children withincomitant strabismus.
The first group, comprising 54 children, had a history of recent dis-ruption of binocular vision, or difficulties with control of a heteropho-ria. Botulinum toxin was used to support or restore the pre-existingbinocular visual acuity, which was felt to be compromised.
The second group, of 82 children, had been assessed as having nopotential for binocular function. The reason for the choice of botulinumtoxin in this group was either the further investigation of a positive testwith prisms suggesting the likelihood of post-operative diplopia, or achoice of botulinum toxin as the preferred treatment modality to im-prove cosmetic appearance, for instance in consecutive exotropia withmultiple previous surgeries. A ‘cosmetic’ squint is defined here as anocular deviation where there is no residual binocular function; align-ment of the eyes will not achieve binocularity and hence the eyes willalways tend to deviate from the ‘straight’ position.
The third group, comprising 27 children with a miscellaneous groupof diagnoses, including paralytic strabismus and Duane’s syndrome,were treated for a mixture of diagnostic and therapeutic reasons.
Results The 163 patients analysed received a total of 268 injections(average of 1.6 injections per child); 117 children received one injec-tion only. The maximum number of injections was 17, given to a childat 3-6 monthly intervals for continued cosmetic correction of her stra-bismus. Fig. 1b shows the number of injections per child according toage. Most of the children were four years or over, and there was abimodal distribution as shown in the graph. As can be seen, the olderchildren tended to have a higher number of injections: this is becausethese children were more likely to have repeated injections for cosmet-ic reasons.
Follow-up ranged from 3 to 100 months; 60% of the children had afollow-up of one year or longer. The mean follow-up period was 18.8months and the standard deviation was 19.2 months.
Fig. 1b. Number of botulinum toxininjections given per child over theduration of the study. The olderchildren (over 11) were more likely toreceive more than one injection.
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therapeutic aim The children were grouped according to the aimof toxin injection as best judged by reviewing their notes. Fig. 2 showsthe indication according to age of the child. It can be seen that youngerchildren (under 11) were more likely to be treated to improve or restorebinocularity, although the figures show some evidence of a bimodaldistribution with a few older children receiving toxin for this reason.Older children (over 11) were more likely to receive botulinum toxintreatment as a post-operative diplopia test or to temporarily improvecosmetic alignment of the eyes. Treatment of incomitant strabismuswas not associated with age.
potential binocularity group Those children in whom the in-dication was to restore or improve binocular function were a selectedgroup in whom there was reasonable evidence that the child at somestage had been in possession of a degree of binocularity: e.g. a childwith a late or sudden onset of strabismus who had previously hadstraight eyes. This group comprised 54 patients, largely in the under 11age group, as shown in Fig. 2.
Improved binocularity was judged at the clinic orthoptic assessmentby any improvement in stereotests such as Wirt fly, Frisby or Lang, orby improved control of binocular movements such as better reportedcontrol of an intermittent divergent strabismus.
Of the 54 children, 29 had improved or restored binocularity aftertoxin treatment which was still present at the last visit: this is a 54%success rate. Considering those cases with at least 12 months follow-up, 18 of the 37 in this subgroup (49%) had improved or restoredbinocularity. Many of those children in whom toxin did not restorebinocular function subsequently had surgery for this reason. A further15 of the 54 showed improved binocularity after an operation. In 10 ofthese 15, toxin had transiently produced improved binocularity whichhad quickly regressed. The remaining 10 patients showed no improve-ment with either toxin or surgery where performed.
Fig. 3a shows the outcome in this group with a breakdown according
Fig. 2. Therapeutic aim of botulinumtoxin injection. This bar chart showsthe aim at time of treatment, as judgedby a review of the notes. If the childwas judged to have some binocularpotential, e.g. evidence of previousbinocularity, it was assumed that theintention of toxin injection was torestore this. If toxin was given toestablish any risk of post-operativediplopia or to improve cosmesis, theseindications were often co-existent andhave been assessed together.
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to diagnosis. Those benefitting most from toxin injection alone werechildren with a diagnosis of intermittent exotropia or consecutive es-otropia from recent surgery. Children with recent onset esotropia ben-efitted from toxin treatment but subsequent surgery was often addition-ally required. It should be remembered that this was a very select groupof patients and only those with considered binocular potential wereincluded.
predicted non-binocular group The second and largest groupcomprised 82 children who were not considered to have any binocularpotential but who were either considering surgery and had a risk ofpost-operative diplopia or who were not candidates for further opera-tion (e.g. multiple previous operations) and were treated with toxin totemporarily realign the eyes for cosmetic reasons. This group was in-cluded together because children could be classified under both of theseindications: e.g. children might have their eyes straightened with toxinas a post-operative diplopia test and then decide to continue with long-term injection treatment, or have one injection for cosmetic reasons andthen opt for an operation as they disliked the injection therapy. Further-more, even when the injection was given with the intention to improvecosmesis, information as to the post-operative diplopia risk becameavailable when the eyes were better aligned.
The post-operative diplopia test involves injecting one extraocularmuscle (e.g. the medial rectus in a convergent strabismus or the lateralrectus in a divergent strabismus) to align the eyes. If the patient appre-ciates diplopia when the eyes are straight, this implies a high risk ofirreversible diplopia after surgery (‘positive’ post-operative diplopiatest). If no diplopia is appreciated when the eyes are aligned then therisk of post-operative diplopia is low (‘negative’ post-operative diplo-pia test). The effect of the toxin was allowed to wear off completely(i.e. ocular position allowed to return to that recorded prior to injec-tion) before embarking on surgical correction of the strabismus.
In this group of 82 children, 72 (88%) showed informative post-operative diplopia tests. All these had associated improved cosmesisalbeit often short-term. Eleven showed positive post-operative diplopia
Fig. 3a. Outcome in the group ofchildren considered to have binocularpotential before treatment (n=54). Theeffect of botulinum toxin injection ishere considered according to initialdiagnosis, and whether the strabismuswas esotropia (ET) or exotropia (XT).Improved binocularity was judged byany comments in the clinical notes asto improved binocular function onorthoptic testing. Botulinum toxin wasconsidered to be ‘informative’ ifinitial improved binocularity wasnoted after toxin treatment, and thendecreased, but improved again aftersurgical correction.
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tests: of these, 9 deferred surgery as they did not want to take the riskof developing post-operative diplopia; 2 had surgery despite the riskand one of these developed transient diplopia post-operatively whichfortunately resolved. The other did not develop diplopia.
Sixty patients showed negative post-operative diplopia tests. Of thesepatients, 32 went on to have surgery and only one developed intermit-tent diplopia post-operatively. This patient had had preoperative diplo-pia which originally improved after surgery and then recurred to alesser exent despite the negative BTXA post-operative diplopia test.
A substantial proportion of the group, 36 of 82 patients, had between2 and 17 injections to maintain alignment.
incomitant strabismus group The final group, numbering 27children, comprised the following:
unilateral IIIrd nerve paresis 1unilateral VIth nerve paresis 7bilateral VIth nerve paresis 5unilateral Duane’s 5bilateral Duane’s 2fibrosed or lost muscle 5oculomotor apraxia 1accommodation spasm 1
These children were treated for a variety of reasons, including to re-store binocular function, as a post-operative diplopia test or to relax amuscle prior to transposition surgery.
Of the 12 children with VIth nerve paresis, 6 (3 unilateral and 3bilateral) achieved improved or restored binocular function as a resultof toxin injection which was still present at the last follow-up appoint-ment. Three of the children with VIth nerve paresis (2 unilateral and 1bilateral) had toxin to relax the medial rectus prior to transpositionsurgery.
Eight children (including the one child with oculomotor apraxia) hadtoxin as a post-operative diplopia test. 7 of these were negative and onepositive.
Five children with unilateral Duane’s syndrome were treated (allaffecting the left eye only). Three had BTXA as a post-operative diplo-
Fig. 3b. Outcome in the group ofchildren treated for cosmetic reasonsor as a post-operative diplopia test(n=82). This group of older childrenwere considered to have a ‘negative’test if the eyes were aligned by toxin,when no evidence of diplopia wasseen; a ‘positive’ test if the eyes werealigned by toxin and clear evidence ofpost-operative diplopia was seen; anda ‘non-informative’ test if thebotulinum toxin injection did notinduce sufficient alteration in ocularalignment to assess risk; 88% (n=72)of the tests were informative.
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pia test: two of these showed diplopia in the primary position aftertoxin injection and declined surgery and the third did not show diplopiabut also declined surgery. Of the other two children treated, one achievedimproved binocular single vision and the other showed a cosmeticimprovement in ocular position and declined surgery.
Two children had bilateral Duane’s syndrome: both of these weretreated with BTXA as a post-operative diplopia test and both showedno diplopia in the primary position. These two children had successfulsurgical correction of their strabismus with improved ocular alignmentwithout loss of binocularity.
Five children were treated with BTXA as a diagnostic tool to inves-tigate a suspected lost or fibrosed muscle. All had had previous surgerybefore treatment. In three cases a medial rectus contracture was sus-pected to be causing limited abduction: on toxin injection to the medialrectus these showed improved abduction, demonstrating the medialrectus contracture. In one case a ‘lost’ medial rectus was suspected, andinjection of the lateral rectus did not reveal any underlying medialrectus function, confirming the suspicion. The last child had had sevenoperations to correct a right convergent squint, six on the right eye.This 13-year-old girl had a residual right esotropia and BTXA paralysisof her right medial rectus showed no residual right lateral rectus func-tion, either because the muscle had been ‘lost’ or severely damaged byprevious surgery. She continued to have three BTXA injections to theright medial rectus as a cosmetic treatment for her strabismus.
The one child with accommodation spasm had BTXA to one medialrectus which demonstrated a potential for restored binocular vision,although this was not maintained. This 12-year-old girl subsequentlyunderwent bilateral Faden sutures which improved her ocular control.
anaesthesia and complications As described above, 73 chil-dren up to age 11 were treated under ketamine anaesthesia and theremaining 90 children, 11 years of age and over, were treated awakeunder local anaesthesia. Complications were all minor and transient,none lasting more than two months and none having significant se-quelae. The three complications recorded were ptosis, hypertropia andsubconjunctival haemorrhage. Fig. 4 shows the incidence of each com-plication in either group. As can be seen, complications were morefrequent in the ketamine group, with 33% ptosis as compared to 17%ptosis in the local anaesthetic group. This is thought to be because,without patient co-operation to move the eyes to record a strong EMGsignal, the localisation of injection is less accurate under general ana-esthesia. Ptosis very rarely covered the visual axis (personal observa-tion, J.P. Lee) although the extent was not consistently recorded. Inmost cases it resolved by two weeks and in all cases by two months.In no case did any degree of ptosis-related amblyopia ensue.
Discussion The first major study of the use of botulinum toxin inchildhood strabismus was published by Scott et al. in 1990.3 This studyexamined the results of BTXA treatment of 362 children between theages of 2 months and 12 years, and showed that with an average of 1.7injections, 61% of children maintained an alignment correction within
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10 prism dioptres (PD) of ortho position after an average of 26 monthsof follow-up. Subdivision of cases showed that the frequency of correc-tion to 10 PD or less was: all esotropia 66%, infantile esotropia 65%,and exotropia 45%. This study did not specifically investigate outcomein terms of binocular function, but speculated that the better results fortoxin treatment in younger patients may be due to binocular fusion.
A smaller study by Magoon et al.4 examined the long-term efficacyof botulinum toxin treatment in children under 14 years, with a follow-up time of 2 to 5.5 years. They showed that in 50 esotropes the averagepretreatment deviation of 35 PD was reduced to an average of 5 PD,and in 12 exotropes the average deviation of 30 PD was reduced to 5PD. No long-term complications were seen.
McNeer5 recently demonstrated the therapeutic potential of botuli-num toxin in the treatment of essential infantile esotropia in children of4 years and younger. He examined 76 children between the ages of 4months and 4 years with essential infantile esotropia. They all receivedsimultaneous bilateral injections of BTXA to the medial rectus musclesunder general anaesthesia; 36 patients required repeat bilateral injec-tions. The mean preinjection esotropic deviation of 33 PD was reducedto 2 PD. Binocular alignment was achieved in 89%.
Spencer6 examined the use of botulinum toxin in childhood intermit-tent exotropia. He studied a group of 32 children between the ages of3 months and 12 years. They received simultaneous bilateral injectionsof BTXA to the lateral rectus muscles, under general anaesthesia. Sta-ble binocular alignment of the eyes was achieved in 22 patients (69%).
Tejedor7 has shown that in retreatment of children after surgery foracquired esotropia, botulinum toxin injection is equally as effective assurgery. In this prospective study of 47 patients under the age of 11years, there was no significant difference between the motor and sen-sory outcomes of patients receiving surgical correction or BTXA forretreatment after a first surgical procedure for acquired esotropia.
Fig. 4. Complications were limited.The most frequent complication wastransient ptosis in 17% of the childrentreated under local anaesthesia and33% of children treated under generalanaesthesia.
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111BTXA in childhood strabismus
In this paper, we have presented the results of a retrospective studyof 163 children treated with botulinum toxin for strabismus at our in-stitution. We have found botulinum toxin to be useful in three selectedgroups of children up to and including 16 years of age. Our age distri-bution includes four children under four years, but the majority were inthe 4-16 year age group and it is therefore to this age group that ourconclusions largely apply. It includes an older group of children thanin the studies discussed above, but demonstrates the progression be-tween younger children and teenagers. Follow-up in our study groupwas relatively short at 18 months, but within these limitations the fol-lowing conclusions can be drawn as to those groups of children likelyto benefit from such therapy. These are:
1. Children in whom there is evidence of recent or threatened loss ofbinocular vision. Those who benefit most are children with decompen-sating intermittent exotropia and post-operative consecutive esotropia.In this group, presumably once the BTXA has straightened the eyesenough for fusion to occur, the stimulus from the brain to maintainbinocular function helps to maintain ocular alignment.
2. If a child is not considered to have any binocular potential, but thereis a risk of post-operative diplopia, BTXA is useful in aligning the eyesto assess the extent of this risk. In children who have had multipleoperations or for some other reason are not suitable candidates forsurgery, repeated BTXA injections are a satisfactory method of main-taining ocular alignment in the older children who are able to toleratethis treatment.
3. Children with incomitant strabismus often react unpredictably tosurgery and so BTXA, being reversible, is a useful investigative andoccasionally therapeutic tool. In sixth nerve paresis it can restore bin-ocularity.
References1 Scott AB. Botulinum toxin injection
into extraocular muscles as analternative to strabismus surgery.Ophthalmology 1980;87:1044-9.
2 Rosenbaum AL. The current use ofbotulinum toxin therapy in strabismus(editorial). Arch Ophthalmol 1996;114:213-4.
3 Scott AB, Magoon EH, McNeer KW,Stager DR. Botulinum treatment ofchildhood strabismus. Ophthalmology1990;97:1434-8.
4 Magoon EH. Chemodenervation ofstrabismic children. A 2 to 5 yearfollow-up study compared withshorter follow-up. Ophthalmology
1989;96:931-4.5 McNeer KW, Tucker MG, Spencer
RF. Botulinum toxin management ofessential infantile esotropia inchildren. Arch Ophthalmol 1997;115:1411-8.
6 Spencer RF, Tucker MG, Choi RY,McNeer KW. Botulinum toxinmanagement of childhood intermittentexotropia. Ophthalmology 1997;104:1762-7.
7 Tejedor J, Rodrigez JM. Retreatmentof children after surgery for acquiredesotropia: reoperation versusbotulinum injection Br J Ophthalmol1998;82:110-4.
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