BOTULINUM ALIGNMENT FOR CONGENITAL ESOTROPIA* BY Malcolm R. Ing, MD INTRODUCTION
ALAN SCOTT'S INGENIOUS DISCOVERY OF CHEMODENERVATION BY DILUTE
injections of botulinum A toxin to alter ocular muscle alignment in humans was first reported in 1980.1 Since then, however, there have been only a few published reports on the use of the toxin in childhood strabismus.2-4 Scott and associates5 reported 66% of infantile esotropes achieved alignment of within 10 prism diopters (PD) of orthophoria with slightly over 2 years of follow-up. They considered their alignment results to be comparable to those of some investigators using incisional surgery. However, other investigators using incisional surgery have reported the more efficient results of larger amounts of surgery to alter large-angle infantile esotropia.6-10 Furthermore, in a study comparing botulinum toxin versus surgical treatment, Biglan and associates1" concluded that chemodenervation was not as successful as traditional strabismus surgery for the treatment of infantile esotropia. These investigators reported that one third of 12 infants could be successfully aligned, but they concluded that ophthalmologists could achieve a better rate of correction in 1 week with surgery rather than after several weeks of fluctuating alignment following botulinum injections.1' In addition to the controversy concerning the efficiency ofbotulinum to secure satisfactory motor alignment, the results of sensory testing in botulinum-aligned congenital esotropes have not been reported.12 The purpose of this paper is to report an independant study of the motor alignment and results of sensory testing of a group of patients with congenital (essential infantile) esotropia aligned to within 10 PD of orthophoria for at least 6 months and followed for at least 3 years.
*From the Division of Ophthalmology, Department of Surgery, University of Hawaii, John A. Burns School of Medicine, Honolulu.
TR. AM. OPHTH. Soc. vol. LXXXX, 1992
362
Ing PATIENT SELECTION AND METHODS
The same techniques used to determine the results of early surgical alignment for congenital esotropial3 were used to conduct an objective multicenter study of patients with congenital esotropia aligned by botulinum injection. Each surgeon was asked to select the patients who fulfilled the following requirements: (1) a history of esotropia confirmed by an ophthalmologist's exam by the age of 1 year, (2) alignment to within 10 PD of orthophoria for a minimum of 6 months by botulinum injection alone by the age of 2 years, and (3) sufficient maturity to reliably respond to sensory testing. Patients with neurologic abnormalities were excluded. The author visited the center to examine the patients whom he did not treat himself The author performed an examination of each patient for the study prior to reviewing the clinical record. The tests were uniformly performed on all patients with the same testing instruments. The corrected Snellen visual acuity was obtained. Cover testing was performed with strict accommodation control techniques that included wearing full refractive correction and fixating 20/30 letter targets at distance and near. Various cover tests included the cover-uncover test, simultaneous prism and cover test, and alternating cover test. Versions were tested, including an examination for A- or V-patterns. Sensory testing was performed with (1) Bagolini striated glasses with fixation light at 1/3 m, (2) Worth 4-dots at 1/3 m with larger (macro) conventional dots and smaller (micro) dots, and (3) Polaroid Titmus vectographic stereotest. At the end of the motor and sensory tests, the patient's clinical record was examined and abstracted with emphasis on obtaining the following data: (1) age at onset of esotropia by history; (2) first confirmation of the esotropia by an ophthalmologist; (3) initial cycloplegic retinoscopy; (4) initial measurements with prisms; (5) age at which initial alignment to within 10 PD of orthophoria had been achieved for a minimum of 6 months; (6) complications such as transient ptosis; (7) adjunctive measures, such as occlusion, glasses, miotics, and prisms; and (8) the impression of the patient's ophthalmologist regarding the status of binocularity. After examining the compiled histories, further refinement was attempted to identify patients with acquired or accommodative esotropia, since these patients would be eliminated from the study. RESULTS
One patient (case 13) was eliminated from the analysis because he received his initial examination at the age of 3 years and was judged to have acquired esotropia.
Botulinum for Congenital Esotropia
363
For the purposes of comparison, the patients are presented in the Appendix in ascending order of age of alignment by botulinum injection. There were six male and six female patients. The age at examination for this study ranged from 4 years to 7 years (average, 6 years). The ages of confirmation of the congenital nature of the strabismus ranged from 3 months to 11 months (average age, 5.9 months). Initial refractive errors included 1 myope and 11 hyperopes ranging from 0.25 to 8 D (average, 2.2 D). The initial deviation as determined by the treating ophthalmologist ranged from 20 to 70 PD (average, 41 PD). The youngest age of initial medial rectus injection was 4 months, and the oldest was 1 year 9 months. The average age of initial treatment was 7.7 months for the group as a whole. The age at which satisfactory alignment was achieved, however, ranged from 7 months to 1 year 11 months (average age, 13 months). Significantly, therefore, there was a lag time between initial treatment and alignment ranging from 1 month to 18 months (case 12), average lag time was 5 months. The number of medial recti injections to reach alignment by the time of the study correlated with the quantity of the initial deviation. TABLE I: CORRELATION OF INITIAL DEVIATION AND NUMBER OF MEDIAL RECTI INJECTIONS DEVIATION
(PD)
30 35 40 - 60 70 20
NO. OF INJECTIONS
2
-
2
or
3 4
3
CASE NO.
2, 6, 11, 12 8, 10 3, 4, 5, 7, 9 1
The motor alignment at the time of the study ranged from 0 deviation to 30 PD of esotropia. Six of the patients had 10 PD or less of residual deviation. However, 6 of the 12 patients were wearing base-out prisms of a total of 4 to 8 PD to help neutralize the residual deviation. Transient unilateral ptosis following medial rectus chemodenervation was a common occurrence and was found in 8 of the 12 patients. Nevertheless, this complication did not seem to preclude satisfactory alignment or the ability to demonstrate subsequent binocularity on sensory testing. A binocular response with Bagolini striated glasses was found in 10 of 12 patients examined for sensory evidence of binocularity.
364
Ing
The conventional-sized (macro) Worth 4-dots were fused by 6 of 12 patients. However, only one patient was able to fuse the smaller (micro) dots as well as the larger ones; thus a relatively large suppression scotoma was demonstrated in the majority of the patients who were capable of fusion. Five patients who fused also demonstrated stereopsis. One patient demonstrated stereopsis but no fusion. All of these patients showed only gross stereoacuity. A comparison can be made of this investigator's opinion versus that of the original ophthalmologists' opinion. Eleven of the 12 patients were thought to have binocularity by the patient's ophthalmologist. However, utilizing the motor and sensory tests, this investigator could agree that only five of these patients had strong enough evidence for binocularity by these tests. DISCUSSION
Von Noorden, 14 in his discussion of the results of botulinum treatment for childhood strabismus, proposed that a scientific comparison of chemodenervation and surgical alignment could only be achieved in a prospective randomized study. As previously noted, however, the age of alignment does not necessarily coincide with the age of first surgery. 13 Furthermore, in this study, the age of satisfactory alignment lagged behind the age of initial injection by an average of 5 months. Therefore, a retrospective study of cases adequately aligned by botulinum would probably still be the best available data base from which to derive conclusions concerning the efficacy of the chemical denervation technique. The results of the present study demonstrate conclusively that binocular vision, despite being described as subnormal by von Noorden,15 is possible in approximately one half of the botulinum-aligned patients if this alignment was secured by age 2 years for a minimum of 6 months. These treated congenital esotropes in the present study demonstrated small residual angles of deviation, but some were able to demonstrate fusion with the Worth 4-dots. Since two previous studies had demonstrated that all patients who fused Worth 4-dots could also demonstrate fusional vergences when tested with a major amblyoscope, this latter instrument was not used for the present study.'16"7 In addition to fusion, gross stereoacuity was found in five patients and, in general, the binocular result fell within the confines of Parks' monofixation syndrome similar to that result of surgically aligned cases. Previous studies have shown that sensory testing is a necessary component of an investigation of binocularity,
Botulinum for Congenital Esotropia
365
because a patient may have relatively straight eyes but no binocularity on sensory testing (eg, case 8). 13 Although approximately one half of the patients demonstrated a binocular result, at least 1 month was necessary after treatment to achieve satisfactory alignment. In contrast to the botulinum-aligned patients, a study of 90 patients surgically aligned by 24 months of age showed that 80 (88%) achieved this alignment within 1 week following initial surgery. 13 It was evident that larger deviations (40 PD or more of esotropia) required at least three medial rectus muscle injections. This necessity of more than one treatment session led, undoubtedly, to further delay in achieving satisfactory alignment. It should be pointed out, also, that this group of botulinum-aligned patients represented the best case results of treatment, and these same patients had a slightly smaller initial deviation (average, 41 PD) when compared with larger series of surgically treated patients. For example, the 90 patients aligned by 24 months previously studied by this author were found to have an average initial deviation more typical of congenital esotropia (average, 59 PD).'3 In contrast to the 5 of 12 patients in the present study, 71 of 90 surgically aligned patients previously examined by this author were able to fuse and demonstrate gross stereopsis using the same testing methods.13 Although the size of the present study group is small, and the results must be considered only preliminary, the findings suggest that alignment by botulinum is less likely to produce sensory evidence of binocularity than is surgical treatment. There is a statistically significant difference in the outcome of the same tests between the two groups (chisquare = 8.05, P < 0. 005). One may speculate on the reason for not achieving as great a rate of success with botulinum treatment. However, since the average size of initial deviation was actually smaller in the botulinum-treated group compared with the surgically treated group (41 PD versus 59 PD), it is unlikely that the initial size of the deviation was the reason for less success in the botulinum-treated group. SUMMARY
This is the first report of a group of patients with congenital esotropia examined for motor and sensory evidence of binocularity a minimum of 3 years after alignment by botulinum. Evidence for binocularity was clearly present in approximately one half of the patients. Lag time to satisfactory
366
Ing
alignment was at least 1 month (average, 5 months) following the initial botulinum injection. The results must be considered preliminary. However, when these results are compared with those of patients with congenital esotropia aligned by incisional surgery by age 2 years and examined with the same testing devices by this same investigator, botulinum alignment appears to be less effective than surgical alignment in establishing evidence for binocularity (P < 0.005). ACKNOWLEDGMENT
The author wishes to acknowledge Drs Alan Scott and Elbert Magoon, without whose great cooperation this study could not have been completed.
1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
11. 12.
13. 14.
15.
REFERENCES Scott AB: Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. Ophthalmology 1980; 87:1044-1049. Magoon E, Scott AB: Botulinum toxin chemodenervation in infants and children: An alternative to incisional strabismus surgery. J Pediatr 1987; 110:719-722. Scott AB: Botulinum injection treatment of congenital esotropia, in M Lenk-Schafer (ed): Orthoptic Horizons: Transactions of the Sixth International Orthoptic Congress. London, British Orthoptic Society, 1988, pp 294-299. Magoon EH: Chemodenervation of strabismic children: A 2- to 5-year follow-up study compared with shorter follow-up. Ophthalmology 1989; 96:931-934. Scott AB, Magoon EH, McNeer KW, et al: Botulinum treatment of childhood strabismus. Ophthalmology 1990; 97:1434-1438. Helveston EM, Ellis FD, Schott J, et al: Surgical treatment of congenital esotropia. Am J Ophthalmol 1983; 96:218-228. Kushner BJ, Morton GV: A randomized comparison of surgical procedures for infantile esotropia. Am J Ophthalmol 1984; 98:50-61. Mims JL III, Treff GL, Kincaid M, et al: Quantitative surgical guidelines for infantile esotropia: Characterization for the dose-response curve (effect/mm curve) for bimedial recessions. Binocular Vis 1985; 1:7-22. Bartley GB, Dyer JA, Ilstrup DM: Characteristics of recession-resection and bimedial recession for childhood esotropia. Arch Ophthalmol 1985; 103:190- 195. Scott WE, Reese PD, Hirsh CR, et al: Surgery for large-angle congenital esotropia: Two vs three and four horizontal muscles. Arch Ophthalmol 1986; 104:374-377. Biglan AW, Bumstine RA, Rogers GL, et al: Management of strabismus with botulinum A toxin. Ophthalmology 1989; 96:935-943. Hague S, Lee JP: Botulinum toxin: An alternative to squint surgery in childhood, in E Campos (ed): Strabismus and Ocular Disorders: Proceedings of the Sixth Meeting of the International Strabismological Association. New York, Macmillan, 1990, pp 413-420. Ing MR: Early surgical alignment for congenital esotropia. Trans Am Ophthalmol Soc 1981; 79:625-663. Von Noorden G: Discussion of Scott AB, Magoon E, McNeer K, et al. Botulinum treatment of strabismus in children. Trans Am Ophthalmol Soc 1990; 87:174-184. Von Noorden GK: A reassessment ofinfantile esotropia. XLIV Edward Jackson Memorial Lecture. Am J Ophthalmol 1988; 105:1-10.
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16. Ing M, Costenbader FD, Parks MM, et al: Early surgery for congenital esotropia. Am J Ophthalmol 1966; 61:1419-1427. 17. Parks MM: The monofixation syndrome. Trans Am Ophthalmol Soc 1969; 67:609-657.
DISCUSSION
DR BRIAN R. YOUNGE. This paper reports the results of 12 patients with congenital esotropia treated by injections of botulinum and compares these results with those of surgical management, using the same criteria of sensory testing. This is of key importance to the study, as is the fact that the author was the independent evaluator of the selected patients. The only problem with the study has to do with numbers. Twelve patients in comparison with the 90 surgically treated patients studied in great detail previously by the author makes for difficulty in drawing hard conclusions, despite statistical significance. Ideally, one would like to see a large group of congenital esotropes randomly selected to receive either the botoxin or surgical treatment, with a similar objective assessment of results. Nonetheless, the usefulness of the botulinum injections for strabismus should be kept in mind for certain instances. Most certainly, paretic strabismus as in sixth nerve palsy is such an instance, regardless of the cause, assuming recovery does not take place within 3 to 4 weeks. One might consider the use of botulinum as an adjunct to surgery, in cases either undercorrected or overcorrected. Lag time and multiple injections do represent a problem, and a one-time surgical intervention may be the best choice for congenital esotropia, given today's safety of general anesthesia and the end results of sensory testing as found in this study. The ease of use of this injection technique is not widely appreciated by general ophthalmologists, largely because of the cost of the medication, the need for electromyographic monitoring, and the unfamiliarity with the procedure. I have found that most ophthalmologists are not very eager to learn even the simple technique of eyelid injections for hemifacial spasm or essential blepharospasm, let alone for strabismus, either paretic or otherwise. Thank you for this opportunity to discuss this paper, and my congratulations to the author for his diligence in assessing this treatment. DR EDWARD L. RAAB. I enjoyed Doctor Ing's presentation, and perhaps in support of his conclusion I would like to offer an observation that has troubled me. That occurs in the treatment of these esotropia patients, when we try to achieve early alignment. We go to a significant amount of difficulty to eliminate such associated conditions as inferior oblique overaction. Even though in the primary position this well may generate no vertical misalignment at all. The reason behind this is that in ordinary use of the eyes only slightly off primary position, vertical alignments can be generated. Doctor Ing didn't mention rotational effects, but presumably abduction is limited and, of course, for a substantial number of months. We are trying to eliminate small degrees of misalignment slightly off primary position and here we may be talking about adopting a technique that just goes ahead and creates this. This, I don't know if that is the reason for your
368
Ing
conclusion but I think it is possibly in line with it. I would like to hear your comment on that. DR ALBERT W BIGLAN. Doctor Ing should be congratulated on his effort to put the role of botulinum toxin in perspective for the treatment of infantile esotropia. He conducted his study by going to the offices of two experienced ophthalmologists and accurately measured patients treated with the botulinum toxin using a standardized examination protocol. The quality of the exams by an unbiased examiner adds strength to his observations. The goal of treatment of infantile esotropia is to achieve a satisfactory motor alignment and also to achieve the highest level of sensory function or binocular cooperation as possible. The motor alignment is a bit problematic in this study. It took as many a four injection treatments to achieve alignment and sometimes it took an average of 5 months to achieve alignment. This is a bit longer than most ophthalmologists are willing to accept for this condition. The sensory results are about equal to other surgical studies. The groups are small in comparison with the studies evaluating traditional surgical and incisional treatment. Botulinum toxin may find a niche for treatment for a very small number of cases of infantile esotropia or congenital esotropia. I can think of one patient I recently had experience with. A premature infant with bronchopulmonary dysplasia was too sick to undergo a general anesthetic. This patient had an esotropia for 6 months as a result of a sixth cranial nerve palsy which was either congenital or due to an intraventricular hemorrhage. The child was 9 months of age at the time of treatment and had a right esotropia of 30 PD. This patient was treated with 21/2 U of botulinum A toxin about 1 month ago and now has straight eyes. So, there appears to be some role in treating young children with this agent. DR JOSEPH C. FLANAGAN. Congratulations on an excellent paper. My comments are certainly antidotal. Approximately 8 months ago I had the opportunity to evaluate a 7-year-old boy who had had an injection of botulinum toxin for esotropia. By history, approximately 2 weeks after injection, the esotropia increased from approximately 30 PD to 90 PD. Also, visual acuity had diminished from the 20/40 range to the level of hand motions. I wondered if, during the course of this study, any complications of this nature, or other complications were encountered with this treatment modality? DR MALCOLM ING. I would like to thank the discussants for their comments on the paper, especially Doctor Younge for his analysis of what I am trying to say here. The small size of the group was a problem. I am afraid that is a result of actually trying to get as many cases as possible together. These cases actually represent the best cases of the doctors who had experience with the technique, and these were all the cases they could get together that were old enough for me to test. So I have to apologize for the small size. Nevertheless, they were intensively studied. The biggest problem here, I think, is that the average size of the deviation in congeni-
Botulinum for Congenital Esotropia
369
tal esotropia is large enough to require multiple injections. We just have to say that. This is not to deny that botulinum might not be useful as an adjunct to surgical treatment but it is questionable as a replacement. Whenever a new modality of treatment comes along, you have to compare it with what is available with a conventional technique. And basically, I didn't feel it actually measured up in results to the surgical treatment. Doctor Raab mentioned the vertical misalignment possibility. Yes, we do, in surgery, always try to eliminate all deviation all at once, if we can. That would be that we would go after vertical and horizontal as well when present. We try to establish as straight of eyes as possible and preferably, in the midline. I did look for the characteristic head turn that would develop in some of the patients following treatment. However, when I documented that their eyes were straight with head turn, that was at the time at which I considered that the eyes were within 10 PD of orthophoria, and I started marking the 6 month intervals from there. So, despite the fact that they did have a head turn initially I did allow that, when I did do the analysis, that the eyes were straight. That is when I documented the time period of straight eyes. Doctor Biglan also mentioned motor alignment problems. I think that he has experience using both techniques. It was really his comment 2 years ago that he felt that in the average case of congenital esotropia, botulinum really didn't offer a good alternative. Doctor Flanagan, the ptosis was the only major complication. You can call it major in a sense that when it is there, it could have threatened results by developing amblyopia in the child. Nevertheless, amblyopia did not develop in any of these cases from ptosis. There were no perforations, there were no other major problems, and in the case that you mentioned, I don't know. Unless I had more details, I don't know how to explain the drop in vision in that particular case you mentioned. I want to thank all of you for your discussion.
370
Ing APPENDIX AGE (YB MO)
AGE (YRBMO)
SUBJECT
AT EXAM
FIRST INITIAI, INITIAI RFE DIAGNOSEI) BY Nil) (SPII EQUIV) DEVIATION
INJECTION DOSE
AT
(U)
INJECTION
INITIAL
ADEQUA'E ALIGNMENT
LAG TIME
1 ER (Dr B) 6:4
0:3
-1.00 -1.00
ET70
RMR 1.25 LMR 2.5 RMR 2.5 LMR 5.0
0:4 0:4 0:6 2:2
0:7
0:3
2 RH (Dr B) 5:2
0:4
+1.50 +1.50
ET 30
LMR 2.5 LMR 2.5
0:4 2:1
0:7
0:3
3 AR (Dr B) 6:6
0:6
+1.75 +2.00
ET45
RMR2.6 LMR 5.0 LMR 5.0
0:6 1:9 4:11
0:7
0:1
4 JG (Dr B) 6:11
0:7
+1.50 +1.50
ET50
LMR 1.25 RMR 3.75 RMR 6.25
0:7 0:8 1:8
0:8
0:1
5 KR (Dr B) 6:7
0:3
+3.00 +2.50
ET60
RMR 1.5 LMR 3.75 RMR 5.0
0:7 0:7 2:0
0:8
0: I
6 KK (Dr B) 4:0
0:3
+3.25 +3.87
ET 20
LMR 2.5 RMR 2.5
0:5 0:8
1:0
0:7
7 JR (Dr B) 7:0
0:5
+3.00
ET60
RMR 1.25 LMR 2.5
0:6 0:7
1:1
0:7
+2.50 8 NQ (Dr A) 5:6
0:11
+0.37 +0.50
ET 35
RMR 2.5 LMR 2.5
1:2 1:2
1:3
0:1
9AK(DrA) 6:10
0:10
+7.87 +8.00
ET 40
RMR 3.5 LMR 2.5 RMR 2:0
1:1 1:1
1:4
0:3
2:0
10 HE (Dr B) 4:10
0:6
+2.00 +1.50
ET 35
RMR 2.5 LMR 5.0 LMR 10
0:7 0:11 1:8
1:9
1:2
11 NK (Dr A) 6:2
0:9
+0.25 0.0()
ET 25
RMR 2.5 LMR 3.7
1:3 1:5
1:9
0:6
12 AH (Dr B) 6:11
0:4
+0.50 +0.50
ET 25
RMR 1.25 LMR 2.5 LMR 5.0
0:5 0:10 1:3
1:11
1:6
13 MV (Dr A) 10:0
3:0
-9.00 -9.00
ET 10
RMR 1.25 LMR 1.25
3:11 3:11
4:2
0:3
Alt,
bif, bifocal; CC,
DVD,
ET, esotropia; LMR, left medial rectus;
Botulinum for Congenital Esotropia
PRESENT V'ISUAL ACUITY
PRESENT ALIGNMENT DISTANCE ANI) NEAR
COMMENTS
371 FOR E.VIIFENCE BINECULARITY
STRIATED GIASSES
WORTII 4-DOT MACRO/ MICRO
ACUITY SECONDS OF ARC)
EXAM
OWN MD
Binoc
+/-
3000
+
+
STEREO-
BINOCUtARIT
THIIS
20/25 20/25
DVD DVD'
20/30 20/30
ET cc 12 Ptosis prisms ET'cc 20, ET'bif 10
Binoc
+ /-
None
+
+
20/30 20/30
ET cc 12 ET'cc 14, DVD'
Ptosis prisms
Binoc
-/-
3000
+
+
20/25 20/30
ET cc 25 ET'cc 16
Latent nystagmus prisms
Binoc
+/-
400
+
+
Ptosis prisms
Binoc
-/-
None
None
_
+
3000
+
+
Myopic
20/200 ET cc 15, DVD 20/30 ET'cc 15
Binoc
20/30 20/30
ETcc8-16 ET'cc 20
20/70 20/30
ET cc 16-20
20/30 20/30
XT cc 4, DVD XT'cc 10, DVD'
20/30 20/40
ET cc 10 - 25, DVD A-pattern ET'cc 10 - 14, DVD' (A-pattern)
Ptosis prisms
Binoc
Ptosis prisms
Alt
None
_
+
Binoc
3000
+
+
+/ +
ET'cc 16-20
20/70 EX cc 0 20/100 EX'cc 0
Ptosis
Binoc
+ /-
3000
+
+
20/25 20/25
ET cc 10 - 25, DVD Ptosis ET'cc 30, ET'bif 0
Binoc
-/-
None
_
+
20/30 20/30
ET cc 20 ET'cc 30
Ptosis prisms
Binoc
+ /-
None
20/60 20/40
ET cc 4 ET'cc 4
Ptosis myopic
Binoc
+ /-
None
+
+
RMR, right medial
recttus; XT, exotropia.
ALAN SCOTT'S INGENIOUS DISCOVERY OF CHEMODENERVATION BY DILUTE
injections of botulinum A toxin to alter ocular muscle alignment in humans was first reported in 1980.1 Since then, however, there have been only a few published reports on the use of the toxin in childhood strabismus.2-4 Scott and associates5 reported 66% of infantile esotropes achieved alignment of within 10 prism diopters (PD) of orthophoria with slightly over 2 years of follow-up. They considered their alignment results to be comparable to those of some investigators using incisional surgery. However, other investigators using incisional surgery have reported the more efficient results of larger amounts of surgery to alter large-angle infantile esotropia.6-10 Furthermore, in a study comparing botulinum toxin versus surgical treatment, Biglan and associates1" concluded that chemodenervation was not as successful as traditional strabismus surgery for the treatment of infantile esotropia. These investigators reported that one third of 12 infants could be successfully aligned, but they concluded that ophthalmologists could achieve a better rate of correction in 1 week with surgery rather than after several weeks of fluctuating alignment following botulinum injections.1' In addition to the controversy concerning the efficiency ofbotulinum to secure satisfactory motor alignment, the results of sensory testing in botulinum-aligned congenital esotropes have not been reported.12 The purpose of this paper is to report an independant study of the motor alignment and results of sensory testing of a group of patients with congenital (essential infantile) esotropia aligned to within 10 PD of orthophoria for at least 6 months and followed for at least 3 years.
*From the Division of Ophthalmology, Department of Surgery, University of Hawaii, John A. Burns School of Medicine, Honolulu.
TR. AM. OPHTH. Soc. vol. LXXXX, 1992
362
Ing PATIENT SELECTION AND METHODS
The same techniques used to determine the results of early surgical alignment for congenital esotropial3 were used to conduct an objective multicenter study of patients with congenital esotropia aligned by botulinum injection. Each surgeon was asked to select the patients who fulfilled the following requirements: (1) a history of esotropia confirmed by an ophthalmologist's exam by the age of 1 year, (2) alignment to within 10 PD of orthophoria for a minimum of 6 months by botulinum injection alone by the age of 2 years, and (3) sufficient maturity to reliably respond to sensory testing. Patients with neurologic abnormalities were excluded. The author visited the center to examine the patients whom he did not treat himself The author performed an examination of each patient for the study prior to reviewing the clinical record. The tests were uniformly performed on all patients with the same testing instruments. The corrected Snellen visual acuity was obtained. Cover testing was performed with strict accommodation control techniques that included wearing full refractive correction and fixating 20/30 letter targets at distance and near. Various cover tests included the cover-uncover test, simultaneous prism and cover test, and alternating cover test. Versions were tested, including an examination for A- or V-patterns. Sensory testing was performed with (1) Bagolini striated glasses with fixation light at 1/3 m, (2) Worth 4-dots at 1/3 m with larger (macro) conventional dots and smaller (micro) dots, and (3) Polaroid Titmus vectographic stereotest. At the end of the motor and sensory tests, the patient's clinical record was examined and abstracted with emphasis on obtaining the following data: (1) age at onset of esotropia by history; (2) first confirmation of the esotropia by an ophthalmologist; (3) initial cycloplegic retinoscopy; (4) initial measurements with prisms; (5) age at which initial alignment to within 10 PD of orthophoria had been achieved for a minimum of 6 months; (6) complications such as transient ptosis; (7) adjunctive measures, such as occlusion, glasses, miotics, and prisms; and (8) the impression of the patient's ophthalmologist regarding the status of binocularity. After examining the compiled histories, further refinement was attempted to identify patients with acquired or accommodative esotropia, since these patients would be eliminated from the study. RESULTS
One patient (case 13) was eliminated from the analysis because he received his initial examination at the age of 3 years and was judged to have acquired esotropia.
Botulinum for Congenital Esotropia
363
For the purposes of comparison, the patients are presented in the Appendix in ascending order of age of alignment by botulinum injection. There were six male and six female patients. The age at examination for this study ranged from 4 years to 7 years (average, 6 years). The ages of confirmation of the congenital nature of the strabismus ranged from 3 months to 11 months (average age, 5.9 months). Initial refractive errors included 1 myope and 11 hyperopes ranging from 0.25 to 8 D (average, 2.2 D). The initial deviation as determined by the treating ophthalmologist ranged from 20 to 70 PD (average, 41 PD). The youngest age of initial medial rectus injection was 4 months, and the oldest was 1 year 9 months. The average age of initial treatment was 7.7 months for the group as a whole. The age at which satisfactory alignment was achieved, however, ranged from 7 months to 1 year 11 months (average age, 13 months). Significantly, therefore, there was a lag time between initial treatment and alignment ranging from 1 month to 18 months (case 12), average lag time was 5 months. The number of medial recti injections to reach alignment by the time of the study correlated with the quantity of the initial deviation. TABLE I: CORRELATION OF INITIAL DEVIATION AND NUMBER OF MEDIAL RECTI INJECTIONS DEVIATION
(PD)
30 35 40 - 60 70 20
NO. OF INJECTIONS
2
-
2
or
3 4
3
CASE NO.
2, 6, 11, 12 8, 10 3, 4, 5, 7, 9 1
The motor alignment at the time of the study ranged from 0 deviation to 30 PD of esotropia. Six of the patients had 10 PD or less of residual deviation. However, 6 of the 12 patients were wearing base-out prisms of a total of 4 to 8 PD to help neutralize the residual deviation. Transient unilateral ptosis following medial rectus chemodenervation was a common occurrence and was found in 8 of the 12 patients. Nevertheless, this complication did not seem to preclude satisfactory alignment or the ability to demonstrate subsequent binocularity on sensory testing. A binocular response with Bagolini striated glasses was found in 10 of 12 patients examined for sensory evidence of binocularity.
364
Ing
The conventional-sized (macro) Worth 4-dots were fused by 6 of 12 patients. However, only one patient was able to fuse the smaller (micro) dots as well as the larger ones; thus a relatively large suppression scotoma was demonstrated in the majority of the patients who were capable of fusion. Five patients who fused also demonstrated stereopsis. One patient demonstrated stereopsis but no fusion. All of these patients showed only gross stereoacuity. A comparison can be made of this investigator's opinion versus that of the original ophthalmologists' opinion. Eleven of the 12 patients were thought to have binocularity by the patient's ophthalmologist. However, utilizing the motor and sensory tests, this investigator could agree that only five of these patients had strong enough evidence for binocularity by these tests. DISCUSSION
Von Noorden, 14 in his discussion of the results of botulinum treatment for childhood strabismus, proposed that a scientific comparison of chemodenervation and surgical alignment could only be achieved in a prospective randomized study. As previously noted, however, the age of alignment does not necessarily coincide with the age of first surgery. 13 Furthermore, in this study, the age of satisfactory alignment lagged behind the age of initial injection by an average of 5 months. Therefore, a retrospective study of cases adequately aligned by botulinum would probably still be the best available data base from which to derive conclusions concerning the efficacy of the chemical denervation technique. The results of the present study demonstrate conclusively that binocular vision, despite being described as subnormal by von Noorden,15 is possible in approximately one half of the botulinum-aligned patients if this alignment was secured by age 2 years for a minimum of 6 months. These treated congenital esotropes in the present study demonstrated small residual angles of deviation, but some were able to demonstrate fusion with the Worth 4-dots. Since two previous studies had demonstrated that all patients who fused Worth 4-dots could also demonstrate fusional vergences when tested with a major amblyoscope, this latter instrument was not used for the present study.'16"7 In addition to fusion, gross stereoacuity was found in five patients and, in general, the binocular result fell within the confines of Parks' monofixation syndrome similar to that result of surgically aligned cases. Previous studies have shown that sensory testing is a necessary component of an investigation of binocularity,
Botulinum for Congenital Esotropia
365
because a patient may have relatively straight eyes but no binocularity on sensory testing (eg, case 8). 13 Although approximately one half of the patients demonstrated a binocular result, at least 1 month was necessary after treatment to achieve satisfactory alignment. In contrast to the botulinum-aligned patients, a study of 90 patients surgically aligned by 24 months of age showed that 80 (88%) achieved this alignment within 1 week following initial surgery. 13 It was evident that larger deviations (40 PD or more of esotropia) required at least three medial rectus muscle injections. This necessity of more than one treatment session led, undoubtedly, to further delay in achieving satisfactory alignment. It should be pointed out, also, that this group of botulinum-aligned patients represented the best case results of treatment, and these same patients had a slightly smaller initial deviation (average, 41 PD) when compared with larger series of surgically treated patients. For example, the 90 patients aligned by 24 months previously studied by this author were found to have an average initial deviation more typical of congenital esotropia (average, 59 PD).'3 In contrast to the 5 of 12 patients in the present study, 71 of 90 surgically aligned patients previously examined by this author were able to fuse and demonstrate gross stereopsis using the same testing methods.13 Although the size of the present study group is small, and the results must be considered only preliminary, the findings suggest that alignment by botulinum is less likely to produce sensory evidence of binocularity than is surgical treatment. There is a statistically significant difference in the outcome of the same tests between the two groups (chisquare = 8.05, P < 0. 005). One may speculate on the reason for not achieving as great a rate of success with botulinum treatment. However, since the average size of initial deviation was actually smaller in the botulinum-treated group compared with the surgically treated group (41 PD versus 59 PD), it is unlikely that the initial size of the deviation was the reason for less success in the botulinum-treated group. SUMMARY
This is the first report of a group of patients with congenital esotropia examined for motor and sensory evidence of binocularity a minimum of 3 years after alignment by botulinum. Evidence for binocularity was clearly present in approximately one half of the patients. Lag time to satisfactory
366
Ing
alignment was at least 1 month (average, 5 months) following the initial botulinum injection. The results must be considered preliminary. However, when these results are compared with those of patients with congenital esotropia aligned by incisional surgery by age 2 years and examined with the same testing devices by this same investigator, botulinum alignment appears to be less effective than surgical alignment in establishing evidence for binocularity (P < 0.005). ACKNOWLEDGMENT
The author wishes to acknowledge Drs Alan Scott and Elbert Magoon, without whose great cooperation this study could not have been completed.
1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
11. 12.
13. 14.
15.
REFERENCES Scott AB: Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. Ophthalmology 1980; 87:1044-1049. Magoon E, Scott AB: Botulinum toxin chemodenervation in infants and children: An alternative to incisional strabismus surgery. J Pediatr 1987; 110:719-722. Scott AB: Botulinum injection treatment of congenital esotropia, in M Lenk-Schafer (ed): Orthoptic Horizons: Transactions of the Sixth International Orthoptic Congress. London, British Orthoptic Society, 1988, pp 294-299. Magoon EH: Chemodenervation of strabismic children: A 2- to 5-year follow-up study compared with shorter follow-up. Ophthalmology 1989; 96:931-934. Scott AB, Magoon EH, McNeer KW, et al: Botulinum treatment of childhood strabismus. Ophthalmology 1990; 97:1434-1438. Helveston EM, Ellis FD, Schott J, et al: Surgical treatment of congenital esotropia. Am J Ophthalmol 1983; 96:218-228. Kushner BJ, Morton GV: A randomized comparison of surgical procedures for infantile esotropia. Am J Ophthalmol 1984; 98:50-61. Mims JL III, Treff GL, Kincaid M, et al: Quantitative surgical guidelines for infantile esotropia: Characterization for the dose-response curve (effect/mm curve) for bimedial recessions. Binocular Vis 1985; 1:7-22. Bartley GB, Dyer JA, Ilstrup DM: Characteristics of recession-resection and bimedial recession for childhood esotropia. Arch Ophthalmol 1985; 103:190- 195. Scott WE, Reese PD, Hirsh CR, et al: Surgery for large-angle congenital esotropia: Two vs three and four horizontal muscles. Arch Ophthalmol 1986; 104:374-377. Biglan AW, Bumstine RA, Rogers GL, et al: Management of strabismus with botulinum A toxin. Ophthalmology 1989; 96:935-943. Hague S, Lee JP: Botulinum toxin: An alternative to squint surgery in childhood, in E Campos (ed): Strabismus and Ocular Disorders: Proceedings of the Sixth Meeting of the International Strabismological Association. New York, Macmillan, 1990, pp 413-420. Ing MR: Early surgical alignment for congenital esotropia. Trans Am Ophthalmol Soc 1981; 79:625-663. Von Noorden G: Discussion of Scott AB, Magoon E, McNeer K, et al. Botulinum treatment of strabismus in children. Trans Am Ophthalmol Soc 1990; 87:174-184. Von Noorden GK: A reassessment ofinfantile esotropia. XLIV Edward Jackson Memorial Lecture. Am J Ophthalmol 1988; 105:1-10.
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16. Ing M, Costenbader FD, Parks MM, et al: Early surgery for congenital esotropia. Am J Ophthalmol 1966; 61:1419-1427. 17. Parks MM: The monofixation syndrome. Trans Am Ophthalmol Soc 1969; 67:609-657.
DISCUSSION
DR BRIAN R. YOUNGE. This paper reports the results of 12 patients with congenital esotropia treated by injections of botulinum and compares these results with those of surgical management, using the same criteria of sensory testing. This is of key importance to the study, as is the fact that the author was the independent evaluator of the selected patients. The only problem with the study has to do with numbers. Twelve patients in comparison with the 90 surgically treated patients studied in great detail previously by the author makes for difficulty in drawing hard conclusions, despite statistical significance. Ideally, one would like to see a large group of congenital esotropes randomly selected to receive either the botoxin or surgical treatment, with a similar objective assessment of results. Nonetheless, the usefulness of the botulinum injections for strabismus should be kept in mind for certain instances. Most certainly, paretic strabismus as in sixth nerve palsy is such an instance, regardless of the cause, assuming recovery does not take place within 3 to 4 weeks. One might consider the use of botulinum as an adjunct to surgery, in cases either undercorrected or overcorrected. Lag time and multiple injections do represent a problem, and a one-time surgical intervention may be the best choice for congenital esotropia, given today's safety of general anesthesia and the end results of sensory testing as found in this study. The ease of use of this injection technique is not widely appreciated by general ophthalmologists, largely because of the cost of the medication, the need for electromyographic monitoring, and the unfamiliarity with the procedure. I have found that most ophthalmologists are not very eager to learn even the simple technique of eyelid injections for hemifacial spasm or essential blepharospasm, let alone for strabismus, either paretic or otherwise. Thank you for this opportunity to discuss this paper, and my congratulations to the author for his diligence in assessing this treatment. DR EDWARD L. RAAB. I enjoyed Doctor Ing's presentation, and perhaps in support of his conclusion I would like to offer an observation that has troubled me. That occurs in the treatment of these esotropia patients, when we try to achieve early alignment. We go to a significant amount of difficulty to eliminate such associated conditions as inferior oblique overaction. Even though in the primary position this well may generate no vertical misalignment at all. The reason behind this is that in ordinary use of the eyes only slightly off primary position, vertical alignments can be generated. Doctor Ing didn't mention rotational effects, but presumably abduction is limited and, of course, for a substantial number of months. We are trying to eliminate small degrees of misalignment slightly off primary position and here we may be talking about adopting a technique that just goes ahead and creates this. This, I don't know if that is the reason for your
368
Ing
conclusion but I think it is possibly in line with it. I would like to hear your comment on that. DR ALBERT W BIGLAN. Doctor Ing should be congratulated on his effort to put the role of botulinum toxin in perspective for the treatment of infantile esotropia. He conducted his study by going to the offices of two experienced ophthalmologists and accurately measured patients treated with the botulinum toxin using a standardized examination protocol. The quality of the exams by an unbiased examiner adds strength to his observations. The goal of treatment of infantile esotropia is to achieve a satisfactory motor alignment and also to achieve the highest level of sensory function or binocular cooperation as possible. The motor alignment is a bit problematic in this study. It took as many a four injection treatments to achieve alignment and sometimes it took an average of 5 months to achieve alignment. This is a bit longer than most ophthalmologists are willing to accept for this condition. The sensory results are about equal to other surgical studies. The groups are small in comparison with the studies evaluating traditional surgical and incisional treatment. Botulinum toxin may find a niche for treatment for a very small number of cases of infantile esotropia or congenital esotropia. I can think of one patient I recently had experience with. A premature infant with bronchopulmonary dysplasia was too sick to undergo a general anesthetic. This patient had an esotropia for 6 months as a result of a sixth cranial nerve palsy which was either congenital or due to an intraventricular hemorrhage. The child was 9 months of age at the time of treatment and had a right esotropia of 30 PD. This patient was treated with 21/2 U of botulinum A toxin about 1 month ago and now has straight eyes. So, there appears to be some role in treating young children with this agent. DR JOSEPH C. FLANAGAN. Congratulations on an excellent paper. My comments are certainly antidotal. Approximately 8 months ago I had the opportunity to evaluate a 7-year-old boy who had had an injection of botulinum toxin for esotropia. By history, approximately 2 weeks after injection, the esotropia increased from approximately 30 PD to 90 PD. Also, visual acuity had diminished from the 20/40 range to the level of hand motions. I wondered if, during the course of this study, any complications of this nature, or other complications were encountered with this treatment modality? DR MALCOLM ING. I would like to thank the discussants for their comments on the paper, especially Doctor Younge for his analysis of what I am trying to say here. The small size of the group was a problem. I am afraid that is a result of actually trying to get as many cases as possible together. These cases actually represent the best cases of the doctors who had experience with the technique, and these were all the cases they could get together that were old enough for me to test. So I have to apologize for the small size. Nevertheless, they were intensively studied. The biggest problem here, I think, is that the average size of the deviation in congeni-
Botulinum for Congenital Esotropia
369
tal esotropia is large enough to require multiple injections. We just have to say that. This is not to deny that botulinum might not be useful as an adjunct to surgical treatment but it is questionable as a replacement. Whenever a new modality of treatment comes along, you have to compare it with what is available with a conventional technique. And basically, I didn't feel it actually measured up in results to the surgical treatment. Doctor Raab mentioned the vertical misalignment possibility. Yes, we do, in surgery, always try to eliminate all deviation all at once, if we can. That would be that we would go after vertical and horizontal as well when present. We try to establish as straight of eyes as possible and preferably, in the midline. I did look for the characteristic head turn that would develop in some of the patients following treatment. However, when I documented that their eyes were straight with head turn, that was at the time at which I considered that the eyes were within 10 PD of orthophoria, and I started marking the 6 month intervals from there. So, despite the fact that they did have a head turn initially I did allow that, when I did do the analysis, that the eyes were straight. That is when I documented the time period of straight eyes. Doctor Biglan also mentioned motor alignment problems. I think that he has experience using both techniques. It was really his comment 2 years ago that he felt that in the average case of congenital esotropia, botulinum really didn't offer a good alternative. Doctor Flanagan, the ptosis was the only major complication. You can call it major in a sense that when it is there, it could have threatened results by developing amblyopia in the child. Nevertheless, amblyopia did not develop in any of these cases from ptosis. There were no perforations, there were no other major problems, and in the case that you mentioned, I don't know. Unless I had more details, I don't know how to explain the drop in vision in that particular case you mentioned. I want to thank all of you for your discussion.
370
Ing APPENDIX AGE (YB MO)
AGE (YRBMO)
SUBJECT
AT EXAM
FIRST INITIAI, INITIAI RFE DIAGNOSEI) BY Nil) (SPII EQUIV) DEVIATION
INJECTION DOSE
AT
(U)
INJECTION
INITIAL
ADEQUA'E ALIGNMENT
LAG TIME
1 ER (Dr B) 6:4
0:3
-1.00 -1.00
ET70
RMR 1.25 LMR 2.5 RMR 2.5 LMR 5.0
0:4 0:4 0:6 2:2
0:7
0:3
2 RH (Dr B) 5:2
0:4
+1.50 +1.50
ET 30
LMR 2.5 LMR 2.5
0:4 2:1
0:7
0:3
3 AR (Dr B) 6:6
0:6
+1.75 +2.00
ET45
RMR2.6 LMR 5.0 LMR 5.0
0:6 1:9 4:11
0:7
0:1
4 JG (Dr B) 6:11
0:7
+1.50 +1.50
ET50
LMR 1.25 RMR 3.75 RMR 6.25
0:7 0:8 1:8
0:8
0:1
5 KR (Dr B) 6:7
0:3
+3.00 +2.50
ET60
RMR 1.5 LMR 3.75 RMR 5.0
0:7 0:7 2:0
0:8
0: I
6 KK (Dr B) 4:0
0:3
+3.25 +3.87
ET 20
LMR 2.5 RMR 2.5
0:5 0:8
1:0
0:7
7 JR (Dr B) 7:0
0:5
+3.00
ET60
RMR 1.25 LMR 2.5
0:6 0:7
1:1
0:7
+2.50 8 NQ (Dr A) 5:6
0:11
+0.37 +0.50
ET 35
RMR 2.5 LMR 2.5
1:2 1:2
1:3
0:1
9AK(DrA) 6:10
0:10
+7.87 +8.00
ET 40
RMR 3.5 LMR 2.5 RMR 2:0
1:1 1:1
1:4
0:3
2:0
10 HE (Dr B) 4:10
0:6
+2.00 +1.50
ET 35
RMR 2.5 LMR 5.0 LMR 10
0:7 0:11 1:8
1:9
1:2
11 NK (Dr A) 6:2
0:9
+0.25 0.0()
ET 25
RMR 2.5 LMR 3.7
1:3 1:5
1:9
0:6
12 AH (Dr B) 6:11
0:4
+0.50 +0.50
ET 25
RMR 1.25 LMR 2.5 LMR 5.0
0:5 0:10 1:3
1:11
1:6
13 MV (Dr A) 10:0
3:0
-9.00 -9.00
ET 10
RMR 1.25 LMR 1.25
3:11 3:11
4:2
0:3
Alt,
bif, bifocal; CC,
DVD,
ET, esotropia; LMR, left medial rectus;
Botulinum for Congenital Esotropia
PRESENT V'ISUAL ACUITY
PRESENT ALIGNMENT DISTANCE ANI) NEAR
COMMENTS
371 FOR E.VIIFENCE BINECULARITY
STRIATED GIASSES
WORTII 4-DOT MACRO/ MICRO
ACUITY SECONDS OF ARC)
EXAM
OWN MD
Binoc
+/-
3000
+
+
STEREO-
BINOCUtARIT
THIIS
20/25 20/25
DVD DVD'
20/30 20/30
ET cc 12 Ptosis prisms ET'cc 20, ET'bif 10
Binoc
+ /-
None
+
+
20/30 20/30
ET cc 12 ET'cc 14, DVD'
Ptosis prisms
Binoc
-/-
3000
+
+
20/25 20/30
ET cc 25 ET'cc 16
Latent nystagmus prisms
Binoc
+/-
400
+
+
Ptosis prisms
Binoc
-/-
None
None
_
+
3000
+
+
Myopic
20/200 ET cc 15, DVD 20/30 ET'cc 15
Binoc
20/30 20/30
ETcc8-16 ET'cc 20
20/70 20/30
ET cc 16-20
20/30 20/30
XT cc 4, DVD XT'cc 10, DVD'
20/30 20/40
ET cc 10 - 25, DVD A-pattern ET'cc 10 - 14, DVD' (A-pattern)
Ptosis prisms
Binoc
Ptosis prisms
Alt
None
_
+
Binoc
3000
+
+
+/ +
ET'cc 16-20
20/70 EX cc 0 20/100 EX'cc 0
Ptosis
Binoc
+ /-
3000
+
+
20/25 20/25
ET cc 10 - 25, DVD Ptosis ET'cc 30, ET'bif 0
Binoc
-/-
None
_
+
20/30 20/30
ET cc 20 ET'cc 30
Ptosis prisms
Binoc
+ /-
None
20/60 20/40
ET cc 4 ET'cc 4
Ptosis myopic
Binoc
+ /-
None
+
+
RMR, right medial
recttus; XT, exotropia.
