Efficacy of botulinum toxin injection in treating primary inferior oblique overaction: A retrospective cohort study

Abstract

Objective

To evaluate the efficacy and short-term safety of botulinum toxin type A (BTX-A) injection into the inferior oblique muscle for treating inferior oblique overaction (IOOA) in a pediatric cohort.

Methods

We conducted a retrospective cohort study at King Khaled Eye Specialist Hospital & Research Center, Riyadh, Saudi Arabia, including children aged 2–15 years with IOOA treated with BTX-A injections between June 2022 and September 2024. Data on demographics, baseline IOOA grade, associated strabismus, and postoperative complications were collected. All included eyes had a baseline IOOA grade of 2+ to 4+ and underwent a 5.00 units injection of BTX-A (Botox, Allergan Inc., Irvine, California, USA) to the inferior oblique muscle in a trans-conjunctival technique. The primary outcome was IOOA resolution, defined as postoperative IOOA grade of 0 or +1 at three months following the injection.

Results

Twenty-three patients (42 eyes) were analyzed. Median age was 6 years (IQR: 5–8), with 56% were female. Bilateral IOOA was present in 83% of included patients, esotropia in 91%, and exotropia in 9%. Three months after injection, 54% of eyes achieved complete or near complete IOOA resolution, and 76% improved by at least one grade. Exotropia decreased from 36% at two weeks to 5% at three months (p < 0.001), while ptosis declined from 29% to 2% (p < 0.001).

Conclusions

BTX-A injection into the IO muscle is effective and safe for primary IOOA, with significant short-term improvement and minimal transient complications. The long-term sustainability of the IOOA improvement post BTX-A injection is unknown.

Keywords

Botulinum toxin inferior oblique overaction pediatric strabismus ocular alignment minimally invasive treatment binocular vision

Introduction

Ocular motility disorders represent a significant cause of visual morbidity in pediatric populations, often leading to both functional and psychosocial impairments if not addressed. Among these disorders, inferior oblique overaction (IOOA) is notably prevalent, characterized by excessive elevation of the adducted eye and frequently associated with V-pattern strabismus.^1,2 Conventional management strategies typically involve surgical weakening procedures, such as inferior oblique myectomy, recession, or anteriorization, all of which have demonstrated efficacy in reducing over-elevation and enhancing binocular alignment.^3,4 However, these surgical interventions are not without risks, including overcorrection, consecutive binocular misalignment, restriction of ocular motility, fat adherence syndrome, complications related to general anesthesia, and prolonged recovery periods.^5,6

Over the past three decades, botulinum toxin type A (BTX-A) has emerged as a less invasive alternative for the management of strabismus. Initially introduced in the early 1980s and subsequently approved by the FDA in 1989, BTX-A causes temporary chemodenervation of the targeted muscle, thereby enhancing sensory fusion and neuromuscular adaptation, which can contribute to sustained alignment.⁵

BTX-A is well-established in the treatment of horizontal strabismus, including infantile esotropia, with numerous studies demonstrating its short- and medium-term efficacy, favorable alignment outcomes, low complication rates, and the potential to delay or even reduce the necessity for incisional surgery in selected cases.^1–3

Despite the existing research, evidence regarding its role in IOOA remains sparse. Most studies focus on secondary IOOA associated with superior oblique palsy and V-pattern strabismus, frequently documenting temporary improvements. However, these studies often employ varied methodologies, involve small sample sizes, and lack consistent outcome definitions.^2,4,6 Additionally, there is a limited understanding of whether the presence of bilateral versus unilateral disease or the performance of concurrent procedures on other muscles influences the efficacy or complication rates following BTX-A injection.^3,7 These gaps hinder the development of standardized treatment protocols and limit the generalizability of current findings, underscoring the need for larger, methodologically robust studies to clarify the safety and efficacy of BTX-A in IOOA.^8,9

The objective of this study was to assess the efficacy and short-term safety of direct BTX-A injection into the inferior oblique muscle for the treatment of IOOA in a pediatric cohort. We specifically investigated the extent of IOOA resolution and the development of postoperative complications over time, analyzing ocular outcomes on a per eye basis while summarizing baseline demographic characteristics per patient, in accordance with the STROBE guidelines for cohort studies.¹⁰

Methods

Study design and ethical considerations

This retrospective cohort study was conducted at King Khaled Eye Specialist Hospital & Research Center (KKESH&RC) in Riyadh, Saudi Arabia, from June 1, 2022, to September 30, 2024. The study adhered to the principles outlined in the Declaration of Helsinki, and approval was obtained from the Institutional Review Board of KKESH&RC (IRB Approval Number: RD/26001/IRB/0590-24). To maintain participant confidentiality, all data were de-identified.

Study population and eligibility criteria

Children aged two to fifteen years with a confirmed diagnosis of IOOA who received BTX-A injections into the inferior oblique muscle during the study period were included. The IOOA could present either as an isolated condition or in association with horizontal strabismus, such as esotropia or exotropia, in which patients may have undergone complementary or adjuvant surgical procedures or additional BTX-A injections targeting these concomitant deviations. Exclusion criteria encompassed a history of vertical strabismus surgery, neurological disorders affecting ocular motility, contraindications to BTX-A or general anesthesia, insufficient follow-up data, or the presence of amblyopia in cases of unilateral amblyopia. Demographic variables such as age, sex, and laterality, along with clinical information including IOOA grade, associated strabismus, and prior surgical history, were collected for all eligible participants.

Study setting

All procedures were conducted within the Pediatric Ophthalmology and Strabismus Division at KKESH&RC, a tertiary referral center with a specialization in pediatric ocular motility disorders.

Intervention protocol

Each patient was administered an injection of 5.00 units of BTX-A (Botox, Allergan Inc., Irvine, California, USA), which was prepared and reconstituted with 2.00 milliliters of normal saline under sterile conditions in the hospital pharmacy. The injections were performed under general anesthesia delivered via facemask without intubation. Exposure was achieved using Moody fixation forceps (Storz Instruments, St. Louis, Missouri, USA) placed at the inferotemporal limbus to position the eye in adduction and elevation and, thus, to optimize access to the inferior oblique muscle and to provide direct visualization for precise injection placement. Following identification of the pinkish hue of the inferior oblique muscle, the injection was administered transconjunctivally using a 30-gauge needle (Figure 1). The procedure was conducted by experienced pediatric ophthalmologists without conjunctival incision or dissection and without direct grasping of the muscle. For patients with bilateral IOOA, injections were administered in one or both eyes as clinically indicated. Simultaneous procedures on other extraocular muscles, if required, were conducted.

Figure 1.

The photograph shows the transconjunctival inferotemporal approach, with the globe positioned in adduction and elevation to expose the muscle belly. A 30-gauge needle is used to inject the BTX-A precisely into the muscle under direct visualization without any conjunctival dissection. This photo was obtained after taking the consent from the child's guardian.

Data collection and outcome measures

Data were extracted from electronic medical records into a standardized spreadsheet (Microsoft Excel 365, Microsoft Corp., Redmond, WA, USA), incorporating demographic information such as age, sex, laterality, and amblyopia status, alongside clinical data including baseline IOOA grade, associated strabismus (esotropia and exotropia), history of previous surgeries, number of BTX-A injections, and follow-up outcomes. The latter included IOOA grading at baseline, two weeks, two months, and three months post-injection, as well as the incidence of postoperative complications such as transient exotropia or ptosis. Resolution of IOOA was defined as a postoperative IOOA grade of 0 or +1 on the standardized grading scale.¹¹ Demographic and systemic variables were summarized per patient, whereas ocular outcomes were reported per eye to capture inter-eye variability.

Sample size consideration

All eligible patients within the study period were included. Due to the retrospective nature of the study, a formal sample size calculation was not conducted. Nevertheless, the study aimed to achieve a minimum power of 80% at a 5% significance level to detect clinically meaningful differences in IOOA resolution rates across various time points.

Statistical analysis

Data cleaning and coding were executed using Excel 365 (Microsoft Corporation, Redmond, Washington, USA), while all statistical analyses were performed with Stata version 17.0 (StataCorp., College Station, TX, USA). Categorical variables were summarized as frequencies and percentages, whereas continuous variables were characterized by the median, interquartile range (IQR), and range (minimum–maximum). For inferential analysis, the Chi-square test or Fisher's exact test was employed to assess associations between categorical variables. Differences in continuous variables across groups were evaluated using the independent Student's t-test, or the Mann–Whitney U test when parametric assumptions were not satisfied. Paired categorical data, such as the presence or absence of postoperative complications across follow-up visits, were analyzed using McNemar's test. Statistical significance was determined at a p-value of less than 0.05 for all comparisons.

Results

A total of 23 patients, encompassing 42 eyes, satisfied the inclusion criteria and were subsequently analyzed. All patients completed the follow-up period of 3 months. The median age at the time of the initial injection was six years (IQR: 5–8), with a range spanning from three to thirteen years. Of the patients, thirteen (56%) were female. Bilateral IOOA was identified in 19 patients (83%), with esotropia being the most prevalent concurrent strabismus (91%), followed by exotropia (9%). Most eyes (83%) required only a single injection, while the remainder underwent two injection sessions. Injection into other extraocular muscles during the same session of IO injection was performed in 40 (95%) eyes. In addition, only 2 (28.6%) of the 7 eyes which underwent 2 sessions, had botulinum toxin injections to other extraocular muscles during the second session of IO injection (Table 1).

Table 1.

Baseline demographic and clinical characteristics of patients undergoing botulinum toxin type A injection for IOOA.

Variable		Median	IQR	Smallest	Largest
n = 23 Patients (42 eyes)
Age (Years)		6	(5–8)	3	13
Preop. BCVA (logMAR)	OD	0.2	(0.0–0.3)	0	0.7
Preop. BCVA (logMAR)	OS	0.2	(0.0–0.3)	0	0.7
		Frequency	Percent
Gender	Male	10	(44)
Gender	Female	13	(56)
Laterality	Bilateral	19	(83)
Laterality	Unilateral	4	(17)
Associated strabismus indication for BTX-A	ET	21	(91)
Associated strabismus indication for BTX-A	XT	2	(9)
		Total	23 Patients
Eye	OD	20	(48)
	OS	22	(52)
Previous strabismus procedure	Yes (Strabismus surgery)	1	(2)
	Yes (Bilateral BTX-A to medial rectus)	24	(58)
	None	17	(40)
Simultaneous BTX-A to other muscles (initial session)	Yes	40	(95)
	No	2	(5)
Number of BTX-A sessions	One	35	(83)
	Two	7	(17)
		Total	42 Eyes

Legend: BTX-A = Botulinum toxin type A; BCVA = Best corrected visual acuity; logMAR = logarithm of the minimum angle of resolution; IOOA = Inferior oblique overaction; OD = Right eye; OS = Left eye; ET = Esotropia; XT = Exotropia; NA = missing data.

At baseline, 100% of eyes presented with IOOA (grades +2 to +4). Three months after a single injection, 54% of eyes showed complete resolution or only minimal residual overaction (grade 0 or +1). Improvement by at least one grade was documented in 76% of treated eyes, with only one case (3%) demonstrating worsening compared to baseline (Table 2).

Table 2.

Change in inferior oblique overaction grade from preoperative assessment to three months post-BTX-A.

	IOOA degree	Frequency (%)	p-value
n = 42 eyes	IOOA degree	Frequency (%)	p-value
Preoperative (BTX-A) IOOA	+2	22 (52)	<0.001
	+3	18 (43)
	+4	2 (5)
		42 (100)
IOOA three months after BTX-A	0	14 (33)
	+1	9 (21)
	+2	10 (24)
	+3	7 (17)
	NA	2 (5)
		42 (100)
	Improved	32 (76)
	Equal	9 (21)
	Worsened	1 (3)
		42 (100)

Legend: BTX-A = botulinum toxin type A; IOOA = inferior oblique overaction; NA = missing data.

The incidence of postoperative exotropia demonstrated a significant decline during the follow-up period. Initially, at two weeks post-surgery, exotropia was observed in 36% of eyes. This percentage decreased to 5% at three months. Statistical analysis using McNemar's test confirmed a significant reduction in exotropia between the two-week and three-month intervals (p < 0.001) (Table 3).

Table 3.

Reduction of exotropia prevalence following inferior oblique BTX-A injection over time.

n = 42 eyes		Frequency (%)
XT observed two weeks after BTX-A	Yes	15 (36)
	No	27 (64)
XT observed two months after BTX-A	Yes	3 (7)
	No	39 (93)
XT observed three months after BTX-A	Yes	2 (5)
	No	40 (95)

	Frequency (%)		p-value (McNemar's)
Comparison Interval	Resolved XT	New XT	p-value (McNemar's)
2 weeks → 3 months	13 (31)	0	0.000244
Paired absolute risk difference of −31.0 percentage points

Legend: BTX-A = botulinum toxin type A; XT = exotropia.

At the two-week mark, eyelid ptosis was observed in 29% of eyes; however, by the three-month follow-up, it had resolved in nearly all eyes, with no new occurrences reported after the initial postoperative period. The reduction in ptosis between the two-week and three-month intervals was statistically significant (p < 0.001) (Table 4).

Table 4.

Time-dependent resolution of eyelid ptosis following inferior oblique BTX-A injection.

Eyelid ptosis
n = 42 eyes		Frequency (%)
Two weeks after BTX-A	Yes	12 (29)
Two weeks after BTX-A	No	30 (71)
Two months after BTX-A	Yes	2 (5)
Two months after BTX-A	No	40 (95)
Three months after BTX-A	Yes	1 (2)
Three months after BTX-A	No	41 (98)

	Frequency (%)		p-value (McNemar's)
Comparison Interval	Resolved Ptosis	New Ptosis	p-value (McNemar's)
2 weeks - 2 months	10 (24)	0	<0.001
2 weeks - 3 months	11 (26)	0	<0.001
2 months - 3 months	1 (2)	0	1

Legend: BTX-A = botulinum toxin type A.

Subgroup analysis showed that the resolution of IOOA and the decline in complication rates were comparable in patients with unilateral and bilateral disease. No differences were noted based on age or sex, and no adverse events other than transient ptosis and exotropia were reported during follow-up (Tables 1 –4).

Discussion

This retrospective cohort study demonstrates that direct injection of BTX-A into the inferior oblique muscle results in a clinically significant improvement in IOOA in more than half of the treated eyes, with a low incidence of transient complications. Importantly, both unilateral and bilateral cases, including those with asymmetric disease, showed comparable improvements, highlighting the broad applicability of this approach in pediatric primary IOOA.

Our study provides short-term outcomes on the degree of IOOA improvement, particularly primary IOOA, following BTX-A injection; a context currently underrepresented in the literature. However, our findings align with previous research reporting favorable short-term outcomes of BTX-A in the treatment of IOOA associated with superior oblique palsy.^2,4,6,7 For example, Bagheri et al. documented temporary improvement in secondary IOOA after inferior oblique injections, although many patients eventually required repeated treatments or definitive myectomy.² Similarly, Norbury and colleagues observed symptomatic improvement in 71% of cases using a smaller dose (1.25 U compared with 5.00 U in our study), in secondary IOOA related to superior oblique palsy, where recurrent overaction often persisted despite temporary chemodenervation.¹² Differences in dosing, case selection, and the inclusion of primary rather than secondary IOOA likely explain the higher success rate observed in our cohort.

The present findings support the concept that BTX-A weakens the IO muscle pharmacologically, allowing the superior oblique and other depressors to regain balance, thereby correcting abnormal elevation in adduction. Additionally, the simultaneous correction of horizontal deviations in most patients may have contributed to more stable motor alignment and reduced the recurrence risk. Sensory fusion may also play a key role in both the initial achievement and long-term maintenance of ocular alignment following BTX-A injection, as primary IOOA usually occurs in limited gaze positions and rarely compromises binocular vision, preserving the capacity for stable fusion after treatment.¹³

Although ptosis and exotropia in our study cannot be directly attributed to the BTX-A injection to inferior oblique muscle because most of our included eyes had BTX-A injection to the medial rectus muscle during the same procedure, the rapid decline of ptosis and exotropia within two months highlights the safety profile of this minimally invasive approach, particularly for pediatric patients where brief anesthesia and reduced surgical trauma are advantageous. In a retrospective cohort study, there was no complications following BTX-A injection to inferior oblique muscle.¹² Similarly, a retrospective case series found no complications following inferior oblique BTX-A injection.⁸ BTX-A injection offers a useful alternative for children when diagnostic chemodenervation is needed prior to permanent myectomy.

Limitations

The present study acknowledges several limitations that should be considered when interpreting the findings. The relatively brief follow-up period of three months precludes the assessment of the long-term stability of ocular alignment and recurrence rates. Furthermore, being conducted at a single tertiary center with a relatively small sample size, the study's findings may have limited generalizability to broader populations. Additionally, although the injection procedures were standardized, they were performed by multiple surgeons, introducing potential variability in execution. Since inferior oblique BTX-A injections were performed in combination with injections to other extraocular muscles in most of the included eyes, optimal dosage and adverse outcomes cannot be isolated. Current study did not evaluate the torsional and pattern strabismus associated with the IOOA and did not include a detailed assessment of sensory outcomes, such as binocular function or stereopsis, which could offer valuable insights into functional visual benefits. Lastly, the comparison with surgical alternatives was limited, and neither cost-effectiveness nor patient-reported outcomes were evaluated, leaving gaps in understanding the full clinical and economic impact of this treatment modality.

Future research should investigate the long-term outcomes beyond six months to determine whether the improvement in motor alignment is sustained over time. Studies are also needed to explore the relationship between the administered dose and treatment response, and to compare the outcome of a single injection with repeated treatments. Additional work should examine sensory outcomes, including the restoration of binocularity, and incorporate multicenter cohorts with standardized protocols to enhance the generalizability of findings. Furthermore, the use of advanced statistical approaches, such as mixed-effects models or generalized estimating equations, is recommended in larger datasets to account for correlations between eyes within the same patient.

Conclusions

In summary, BTX-A injection into the inferior oblique muscle is a safe, effective, and minimally invasive option for managing IOOA in children, especially when combined with BTX-A treatment for concurrent horizontal strabismus. These findings support incorporating BTX-A into clinical decision-making algorithms for pediatric strabismus, while highlighting the need for larger, prospective studies to refine indications, optimize dosing, and evaluate long-term stability.

Footnotes

Acknowledgments

None.

ORCID iDs

Ghadah AlQahtani

Gorka Sesma

Fawzia AlHaimi

Ethical approval

This research (Project number: RP 24135-R) was approved by the Institutional Review Board Committee (IRB) of the Research department at King Khaled Eye Specialist Hospital on 16 October 2024.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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