Supervisor: Dalia Jarušaitienė

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1 Lithuanian University of Health Sciences

Department of Ophthalmology

FINAL MASTER THESIS FOR PROGRAMME OF INTEGRATED STUDIES MEDICINE THE EFFICACY AND COMPLICATIONS OF BOTULINUM A TOXIN IN THE TREATMENT OF

HORIZONTAL STRABISMUS

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1. SUMMARY

Author: Henoch David Habtezion

Title: The Efficacy and Complications of Botulinum A Toxin in The Treatment of Horizontal

Strabismus

Aim of the thesis: To select and analyse scientific articles describing the efficacy and complications of

botulinum A toxin injections for treatment of horizontal strabismus.

Objectives of the thesis: To determine if botulinum A toxin injections can achieve satisfactory

resolution (defined as a reduction of ≥10 prism dioptres [PD]) of horizontal strabismus at least 6 months after the intervention,comparatively to surgical interventions. To determine how long botulinum A toxin injections’ effect on horizontal strabismus lasts. To determine if there are any side effects with botulinum A toxin injections; and if so, identify which ones.

Method: This systematic literature review is structured according to the PRISMA (Preferred Reporting

Items for Systematic Reviews and Meta-Analyses) guidelines. The online database „PubMed” was used to search for scientific publications dating from years 2011 to 2021. The key words used to search were: (Botulinum toxin OR Botulinum A toxin OR Pharmacological management) AND (Strabismus OR infantile esotropia OR exotropia OR intermittent exotropia OR convergence strabismus OR acute onset esotropia OR residual esotropia OR divergence strabismus). The publications were collected according to the PICOS (population, interventions, comparative, results, study design) system. Exclusion and inclusion criteria were written based on PRISMA and those written in the LSMU regulations. Included publications were analysed.

Results: Out of 162 publications, 34 full publications were analysed and 4 publications fulfilled the

criteria and were selected for this systematic literature review. H. Gursoy MD. et al. 2012 [1] and M. J. Wan et al. 2017 [2] compared the safety and efficacy of botulinum A toxin injections with conventional medial rectus recession. Neither of them found any statistically significant difference in efficacy nor complications between the two treatment options (68% vs 67%, on average, respectively). The remaining two publications (J. Chen et al. 2013 [3] and M. E. Razavi et al. 2014 [4]) performed no comparisons and had a much lower success rate (38%), but their definition of successful treatment differed from the ones in this literature review and from the first two publications mentioned.

Conclusion: There is no statistically significant difference in short nor long-term efficacy between

incisional surgery and BTA injections in the treatment of horizontal strabismus. They both provide satisfactory results. The treatment effect of BTA injections on horizontal strabismus lasts for at least 7 years. The most common complications of botulinum A toxin injections reported were transient ptosis, diplopia, vertical deviation, overcorrection, abduction deficiency, and significant inferior oblique muscle overaction.

Recommendations: The sample sizes of the reviewed publications were too small to recommend a

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2. CONFLICT OF INTEREST

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3. ABBREVIATIONS

1. BTA – Botulinum A toxin 2. CP – Cerebral palsy 3. PD – Prism dioptre(s)

4. PICOS – Population, intervention, comparison, outcome, study design.

5. PRISMA – Preferred Reporting Items for Systematic reviews and Meta-Analyses. 6. SIOMO – Significant inferior oblique muscle overaction

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4. TERMS

1. Chemodenervation – Intramuscular BTA injection

2. Euthyroid – Normal levels of thyroid hormones in serum

3. Margin-reflex distance 1 – Distance (in mm) between the light reflex and the lower border of the middle of the upper eyelid while the patient is in primary position.

4. Orthophoria – A theoretical ideal status of binocular fixation where the lines of vision meet exactly at the object they are directed towards.

5. Primary position – A head & eye position where the patient is looking forward with relaxed facial muscles.

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5. INTRODUCTION

Strabismus has historically been considered to be a surgically treated condition, with documentations of surgeries stretching back as far as the 18th_{century [5]. However, the pioneer A.B.} Scott introduced chemodenervation via bilateral botulinum A toxin (BTA) injections into m. rectus medialis as an option to surgery back in 1981 [6]. In spite of the fact that numerous clinical trials regarding its efficacy and safety have been produced over the decades, surgery remains the first line treatment [7–9]. And in Lithuania, BTA injections are never used to treat strabismus. Even though BTA injections are less invasive and probably cheaper, our guidelines have remained the same.

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6. AIM AND OBJECTIVES OF THE THESIS

Work aim:

• To select and analyse scientific articles describing the efficacy and complications of BTA injections for treatment of horizontal strabismus.

Work objectives:

1. To determine if BTA injections can achieve satisfactory resolution (defined as a reduction of ≥10 prism dioptres [PD]) of horizontal strabismus at least 6 months after the intervention, comparatively to surgical interventions.

2. To determine how long BTA injections’ effect on horizontal strabismus lasts.

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7. LITERATURE REVIEW

7.1 BOTULINUM A TOXIN

BTA is a neurotoxin produced by the bacterium Clostridium botulinum, 150 000-DA in size, consisting of a smaller active subunit (light chain) with zink-endopeptidase activity, and a larger nontoxic subunit (heavy chain) [10]. The heavy chain facilities entrance into motor neurons via binding to sialic acid receptors and glycoproteins on their surfaces, triggering endocytosis of the toxin [10].

Once entered, the toxin spreads to the motor endplate, and the light chain permanently inactivates the proteins (exactly which proteins depends on the serotype of the toxin) that facilitate the release of acetylcholine, which blocks cholinergic neurotransmission and causes flaccid paralysis of the affected muscles [10]. For normal function of the muscle to be regained, the motor end plate would need to be regenerated and new synaptic connections need to be formed, which usually takes approximately 3 months [11].

7.2 BOTULINUM A TOXIN USAGE FOR OPHTHALMOLOGICAL

CONDITIONS OTHER THAN HORIZONTAL STRABISMUS

7.2.1 Thyroid-related orbitopathy (TRO)

With a prevalence of 16 per 100 000 people per year, TRO is one of the most common autoimmune diseases treated by ophthalmologists [12]. Management of TRO is often challenging for medical professionals due to its widely inconsistent clinical course, as it can present with any combination of eyelid retraction and oedema, proptosis, diplopia, horizontal and vertical strabismus, cyclotropia, optic nerve compression etc. [13,14]. Prisms can be used to manage diplopia in cases of small deviations, but surgery is contraindicated until an euthyroid state has been achieved [13]. A few clinical trials have shown that TRO can be successfully treated with BTA injections.

M. Akbari et al. 2016 [15] gathered 20 patients (out of which 10 predominantly had esotropia, 8 hypotropia and 2 mixed) for their clinical trial and found that 55% (8 esotropia, 1 hypotropia and both mixed) were successfully treated.

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10 tangible improvement, meaning that 7 (31.8%) patients after the injections didn’t need surgery whatsoever, and that 6 (27.3%) patients needed a less extensive surgery than originally planned.

Lastly, O. Karabulut et al. 2020 [16] published a trial where they specifically examined the effects of transconjunctival injections of BTA into the superior tarsal border, to treat upper eyelid retraction associated with TRO. They found that 58 out of 71 (81.7%) of the affected eyes achieved and maintained normal margin-reflex distances (MRD1) for 4 months after the initial injection.

7.2.2 Spasmodic senile lower lid entropion

I. Iozzo et al. 2016 [17] have analyzed 11 patients, ages 62-72 years old, for 24 months after they injected BTA into their m. orbicularis oris 3 mm below the eyelash margin. The injections were repeated in case of failed treatment. The check-ups were performed 3, 6, 9, 12 and 24 months after the first injection, and they reported that the success rate at those intervals were 10/11, 9/11, 8/11, 11/11 and 9/11, respectively.

A. Deka et al. 2011 [18] published their results of a clinical trial where they gave BTA injections, subcutaneously over m. orbicularis oris below the eyelash margin of the lower lid, to 17 patients aged 40-79 years, and found that all of them were successfully treated and that the effect lasted 12-15 weeks. There were no reinjections performed in this trial.

7.2.3 Cerebral palsy and esotropia

A. Ameri et al. 2015 [19] performed a non-comparative, prospective interventional case series where they injected a single dose of BTA into both medial rectus muscles. They found that among 44 patients with cerebral palsy (CP) and esotropia 61.4% (n=30/44) of their patients were successfully treated (defined as ±10 PD from orthophoria in primary position) 1 year after the injection.

7.2.4 Dry eye syndrome

There is some evidence to support that BTA can be of use in treatment of severe dry eye syndrome [20]. A study published in 2014 included 60 test subjects with dry eye syndrome in a randomized non-controlled trial. 36 were treated with preloaded single-use punctal plugs and 24 received a subcutaneous injection of BTA medial to the lower punctum of both eyelids.

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11 Note, however, that both this, and all other studies on the usage of BTA for treatment of dry eye syndrome that this author could find, had a very small sample size [21]. Clinical trials involving more patients is required before drawing any form of meaningful conclusion.

7.2.5 Blepharospasm

This overactivation of m. orbicularis oris has been shown to be effectively treated with intramuscular injections of BTA by Jankovic et al. in a randomized, placebo-controlled, double-blind trial published in 2011 [22]. With 109 subjects they found that the patients that were administered BTA injections had a clinically significant improvement over the placebo group.

7.3 BOTULINUM A TOXIN USAGE OUTSIDE THE FIELD OF

OPHTHALMOLOGY

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8. RESEARCH METHODOLOGY AND METHODS

8.1 TYPE OF STUDY

This study is a systematic literature review.

8.2 SEARCH METHOD

This systematic literature review is structured according to the PRISMA guidelines [28]. The online database „PubMed” was used to search for scientific publications. The key words used to search were: (Botulinum toxin OR Botulinum A toxin OR Pharmacological management) AND (Strabismus OR infantile esotropia OR exotropia OR intermittent exotropia OR convergence strabismus OR acute onset esotropia OR residual esotropia OR divergence strabismus). Last search date: 11/4-2021.

8.3 INCLUSION AND EXCLUSION CRITERIA

The publications were collected according to the PICOS system (table 1), which was applied to answer the 3 objectives of this systematic literature review:

1. To determine if BTA injections can achieve satisfactory resolution (defined as a reduction of ≥10 PD) of horizontal strabismus at least 6 months after the intervention, comparatively to surgical interventions.

2. To determine how long BTA injections’ effect on horizontal strabismus lasts.

3. To determine if there are any side effects with BTA injections; and if so, identify their nature and frequency.

After accumulating the articles, they were scrutinised based on the rules (table 2) provided by LSMU as well as the PRISMA statement (figure 1).

Table 1. PICOS

Population (P) Patients with any form of horizontal strabismus

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Comparison (C) Not BTA injections, but various surgical

interventions or no intervention whatsoever

Outcome (O) Altered degree of strabismus, measured in PD, as

well as any noted complications and if so, their prevalence

Study design (S) Clinical trials

Table 2. Inclusion and exclusion criteria

Inclusion criteria Exclusion criteria

BTA toxin is used Duplicates

Published in English Published in a non-English language Published less than 10 years ago Published more than 10 years ago

The method of study is explained in detail Vagueness regarding the method of the study Sample group is clearly defined Sample group is vaguely or not defined The publication is of some form a clinical trial,

cohort study, case study or in some other way provides new clinical data.

The publication is a literature review, systematic review, or in any way does not provide new clinical data.

The full publication is accessible via the Lithuanian University of Health Sciences’ computer network.

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8.4 STRATEGY FOR ACQUIRING PUBLICATIONS FROM THE INTERNET

The method applied here is according to the PRISMA statement (figure 1). As such, it was divided into 4 steps:

1. Identification: Firstly, I searched for publications via „Pub Med”. When searching for the key words in the „Pub Med” database without applying any filters, 591 results were found.

2. Screening: I applied the filter „English” and restricted the date of publication to 2011-2021, reducing the number of available publications to 162. Out of those 429 rejected publications, 410 were rejected due to being older than 10 years, and 19 were rejected because they were not published in English.

3. Eligibility: I read the title and abstracts of all of the remaining 162 publications to determine whether or not they are relevant to the aim of this systematic literature review (to select and analyse scientific articles describing the efficacy and complications of BTA injections for treatment of strabismus). Having concluded that 128 publications needed to be excluded, 34 remained.

34 full publications were analysed to assess their relevancy for the aim of this systematic literature review based on the inclusion and exclusion criteria previously determined (table 2). 4 publications fulfilled the criteria.

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9. RESULTS

9.1 MAIN CHARACTERISTICS OF THE PUBLICATIONS

Table 3. Main characteristics of the publications

Publication Sample Intervention PIFU Result Complications

J. Chen et

al. 2013 [3] Children (1-6y old) with infantile esotropia (n=24)

Bilateral CD

(n=24) 2 w, 3 m & 6 m ST 37.5% of CD patients (n=9/24) Mild ptosis: 20.8% (n=5/24)

H. Gursoy MD et al. 2012 [1] Children (<2y old) with infantile esotropia (n=51) Bilateral CD (n=25); bilateral medial rectus recession (n=26) Mean time 84 m for patient with BTA injections; mean time 75 m for patients with surgical recession ST 68% of CD patients (n=17/25); ST 76.9% of surgically treated patients (n=20/26) Accommodative esotropia: - 28% of CD patients (n=7/25) - 15% of surgically treated patients (n=4/26) SIOMO: - 40% of CD patients (n=10/25) - 23% of surgically treated patients (n=6/26) M. J. Wan et al. 2017 [2] Children with acute-onset comitant esotropia (n=49) Bilateral CD (n=16); bilateral medial rectus recession (n=33) 6 m, 18 m ST 67% of CD patients (n=8/12); ST 58% of surgically treated patients (n=18/31)

Mild ptosis: 50% of CD patients (n=8/16) Exotropia: 56% of CD patients (n=9/16) M. E. Razavi et al. 2014 [4] Children (5-18y old) with intermittent exotropia (n=21)

Bilateral CD

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PIFU, post-intervention follow-up; CD, chemodenervation; y, years; m, months; w, weeks; d, days; ST, successfully treated; SIOMO, significant inferior oblique muscle overaction. The result column depicts the last follow-up performed in the study, defining „successful” as an improvement of ≥10 PD over pre-interventional measurements.

From 162 publications, 34 full publications were analysed and 4 publications fulfilled the criteria and were selected for this systematic literature review. J. Chen et al. 2013 [3] and H. Gursoy MD et al. 2012 [1] studied the effects of bilateral BTA injections on patients with infantile esotropia (the latter had a control group), while M. J. Wan et al. 2017 [2] explored the therapeutic effect of such chemodenervation on patients with acute-onset comitant esotropia; and M. E. Razavi et al. 2014 [4] investigated the same management method for intermittent esotropia.

J. Chen et al. 2013 [3] published a randomised pilot study with 2 groups with the aim „To evaluate the feasibility and safety of a revised technique of botulinum toxin A (BTA) injections for the treatment of infantile esotropia.”. This study investigates the effects of bilateral BTA injections of the medial rectus muscles in 24 children (aged 25.8 ± 20.7 months). On top of that, it contrasts those effects with BTA injections mixed with sodium hyaluronate with a different sample group. Since this systematic literature review has no interest in sodium hyaluronate, that second group will not me mentioned further in this review.

The patients were assessed for a change in angle deviation before the injections, then 2 weeks, 3 months and 6 months post‐injection. Successful treatment was defined as an angle deviation from orthophoria <10 PD in primary position 6 months post-injection. This is an important distinction from the definition held in this systematic literature review, where the definition is a reduction of the angle deviation by ≥10 PD 6 months post-injection. Nevertheless, successful treatment was achieved in 37.5% (n=9/24) of the patients. 28.1% (n=5/24) developed mild ptosis, all of which resolved spontaneously within 6 weeks. No other complications were reported.

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18 chemodenervated patients, and 75 months after the surgery for the surgical patients. Successful treatment was defined as a reduction of angle deviation by ≥10 PD at the final examination.

68% (n=17/25) of the chemodenervated and 77% (n=20/26) of the surgically treated patients were successfully treated, a difference (p=0.87) that was considered to be statistically insignificant. 28% (n=7/25) of the chemodenervated and 15% (n=4/26) of the surgically treated patients acquired accommodative esotropia during the follow-up period. 20% (n=5/25) of the chemodenervated and 7.7% (n=2/26) of the surgically treated patients acquired a high accommodative convergence/accommodation ratio. Significant inferior oblique muscle overaction was established in 40% (n=10/25) of the chemodenervated and 23.1% (n=6/26) of the surgically treated patients. No other complications were reported.

M. J. Wan et al. 2017 [2] published a retrospective, non-randomized, comparative clinical study with the aim „To determine whether botulinum toxin is as effective as strabismus surgery in the treatment of acute-onset comitant esotropia in children.”. They took 49 children (of unspecified age) with acute comitant esotropia, 16 that have been chemodenervated bilaterally (but only 12 returned for the final evaluation) and 33 that have been treated with incisional surgery. All but 3 received 1 injection per eye, one of them received a second injection 10 months after the first one and was considered successfully treated. The remaining 2 patients received a second injection followed by incisional surgery, after the injections were considered to have failed. Successful treatment was defined as a reduction of angle deviation by ≥10 PD at the final examination. The final examination was performed 18 months after the first intervention.

81.2% (n=13/16) of the chemodenervated and 60.6% (n=20/33) of the surgically treated patients were considered successfully treated 6 months after the initial intervention, which was considered to be a statistically insignificant difference (p=0.20). Those results changed to 66.6% (n=8/12) of the chemodenervated and 58.1% (n=18/31) of the surgically treated patients remaining successfully treated 18 months after the initial intervention, which remained to be a statistically insignificant difference (p=0.73). 50% (n=8/16) of chemodenervated patients suffered from mild ptosis and another 56.3% (n=9/16) of them suffered from exotropia following their injections. However, the side effects were short lived and resolved spontaneously within 2 months.

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19 and teenagers (aged 5-18 years) affected by intermittent exotropia. Successful treatment was defined as an angle deviation <10 PD 6 months post-injection.

38.1% (n=8/21) of the chemodenervated patients were considered to be successfully treated 6 months after the initial intervention. 42.8% (9/21) suffered from abduction deficiency one week after the injection, while that number was reduced to 4.1% (n=1/21) 6 months after the injection. 42.8% (n=9/21) suffered from mild ptosis (<2 mm) one week and one month after the injection, which resolved spontaneously for all of the participants by the time they had their 6-month check-up.

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10. DISCUSSION

10.1 THE LONG-TERM EFFICACY OF CHEMODENERVATION

I included 4 clinical trials into this systematic literature review, two of which contrasted the efficacy of bilateral BTA injections as a treatment of strabismus compared to incisional surgery, while the remaining two merely reported the success rate of chemodenervation and compared it to what they found to be feasible. Coincidentally, the two trials that compared chemodenervation with incisional surgery have the same definition of successful treatment as this systematic literature review (a reduction of deviation by ≥10 PD), while the remaining two trials defined successful treatment as ±10 PD from orthophoria in primary position.

With this difference in mind, the vast gap between the results of these two groups of studies seems more reasonable, with H. Gursoy MD. et al. 2012 [1] and M. J. Wan et al. 2017 [2] in one group stating that their success rates were 68% and 67%, respectively, for their chemodenervated patients; while J. Chen et al. 2013 [3] and M. E. Razavi et al. 2014 [4] in the other group reported that 37.5% and 38%, respectively, were successfully treated via chemodenervation. Unfortunately, none of the publications examined in this systematic literature review provided enough data to allow a recalculation of the success rate of the treatment so that a fair comparison can be made between these 2 groups.

Although only 1 out of the 4 clinical trials examined chemodenervation as a treatment of exotropia, it is worth highlighting that it showed almost an identical success rate to its esotropic counterpart (38% and 37.5%, respectively) [1,4].

In theory, the pharmacokinetic effects of BTA should be reversed approximately 2-3 months after injection [11]. In practice, all of the publications reviewed here have not only shown that the treatment effect remains several months after the injections, but that a satisfactory result comparable with surgical incisions is still maintained 6 months after the time of treatment. The 2 trials that compared the efficacy of chemodenervation with incisional surgery (H. Gursoy MD. et al. 2012 [1] and M. J. Wan et al. 2017 [2]) could not find a statistically significant difference (p=0.87 and p=0.20, respectively) in their success rates (68% vs 76,9% and 81.3% vs 60.6%, respectively).

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21 two measurements, 81.3% and 66.7%, respectively, is a significantly larger change than the surgical counterpart that they reported (60.6% and 58.1%, respectively). This indicates that the effects of BTA injections might wear off much slower than its in vitro pharmacokinetics implies, but that it still will wear off eventually.

However, the findings made by H. Gursoy MD. et al. 2012 [1] point towards the exact opposite, by showing that a group of chemodenervated patients with a mean follow-up time of 84 months still had a rather high rate of successfully treated patients compared to patients treated with incisional surgery (68% vs 76,9%, respectively).

10.2 COMPLICATIONS OF CHEMODENERVATION

Mild ptosis was the most commonly reported complication of chemodenervation with 20.8% to 50% of the patients reporting it, but exotropia (56%), diplopia (52.4%), vertical deviation (47.6%) & accommodative esotropia (28%), all of which resolved spontaneously [2–4]. The only complication that was reported to require further treatment to manage was significant inferior oblique muscle overaction (SIOMO) [1].

Although the frequency of these complications was reported to be higher than in patients treated with incisional surgery, none of the publications found that the difference was statistically significant.

10.3 OTHER DIFFERENCES BETWEEN INCISIONAL SURGERY AND

CHEMODENERVATION

Reduced costs. M. J. Wan et al. 2017 [2] reports that their incisional surgery treatments, on average, cost their healthcare system 2783 USD, while their chemodenervation procedure on average cost them 874 USD – that is less than a third of the price.

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11. CONCLUSION

1. There is no statistically significant difference in short nor long-term efficacy between incisional surgery and BTA injections in the treatment of horizontal strabismus. They both provide satisfactory resolution of horizontal strabismus.

2. The treatment effect of BTA injections on horizontal strabismus lasts for at least 7 years. 3. There is no statistically significant difference in complication rates between incisional

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12. PRACTICAL RECOMMENDATIONS

In spite of the promising results found in all of the examined publications, the largest sample size that received bilateral BTA injections out of all of the publications examined in this systematic literature review was merely 25 patients. With sample sizes this small, it is hard to consider these clinical trials as anything more than pilot studies, intended to encourage larger control trials to be made to confirm or disprove these results. The sample sizes in these publications are simply too small to warrant a change in the recommended first-line treatment of any type of horizontal strabismus.

Nevertheless, despite the small sample sizes, BTA injections could be suitable as a first line treatment for patients that would be unsuitable for extended sedation and in patients expected to need multiple interventions to treat their strabismus.

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