Botulinum toxin is a neurotoxin produced by the bacterium Clostridium botulinum. Among the seven known serotypes (A to G), type A is the most potent and most widely used clinically.
The application of botulinum toxin to strabismus treatment began in 1973 when San Francisco ophthalmologist Alan B. Scott injected type A botulinum toxin into the extraocular muscles of rhesus monkeys. He injected the medial and lateral rectus muscles of eight rhesus monkeys via the conjunctiva, observing temporary muscle paralysis and permanent changes in eye position.
The first human report was made in 1981. Injections in 42 patients with horizontal strabismus showed effects lasting up to 411 days after the last injection. On December 29, 1989, type A botulinum exotoxin (BTX-A) was approved by the U.S. FDA for the treatment of strabismus and blepharospasm.
It was approved in Japan as a strabismus treatment in 2015 (brand name Botox®). In the four years following approval, approximately 1,500 procedures were performed. Insurance coverage is for strabismus patients aged 12 and older, regardless of comitant or incomitant strabismus, and includes both horizontal and vertical deviations.
Basic treatments for strabismus include refractive correction, amblyopia training, prism therapy, orthoptic training, pharmacotherapy (e.g., botulinum toxin), and surgery. Botulinum toxin therapy is positioned as an alternative or adjunct to surgery, and the risks and benefits of each treatment should be comprehensively evaluated when choosing a treatment 3).
The three main commercially available preparations are as follows.
OnabotulinumtoxinA (Botox®): The first developed formulation. It serves as the standard unit reference in clinical practice.
AbobotulinumtoxinA (Dysport®): 1 unit of Botox is equivalent to 3–5 units of Dysport.
IncobotulinumtoxinA (Xeomin®): Shows equivalent efficacy (1:1) and side effect rates to Botox.
QWhen did botulinum toxin treatment for strabismus begin?
A
It started with animal experiments in 1973, and the first report of efficacy in humans was in 1981. The FDA officially approved it for strabismus treatment in 1989, and it has since become widespread worldwide. In Japan, it was approved in 2015 and is covered by insurance for strabismus patients aged 12 and older.
QAt what age can botulinum toxin therapy be received?
A
Insurance coverage is for strabismus patients aged 12 and older. Use in children under 12 is off-label, but early treatment for infantile esotropia has been attempted in other countries, with reports of good corrective effects.
Small to moderate esotropia/exotropia: Deviation angle less than 40 PD. Expected to have comparable effect to surgery.
Acute comitant esotropia: Cases with acute onset and unstable deviation angle.
Postoperative residual or consecutive strabismus: Ocular misalignment persisting 2–8 weeks or more after surgery.
Acute paralytic strabismus: Mainly abducens nerve palsy. Aimed at reducing diplopia until recovery from palsy.
Abducens nerve palsy: BTX injection (chemodenervation) into the medial rectus muscle is useful for reducing secondary contracture, improving compensatory head posture, and decreasing the final deviation angle 1).
Active thyroid eye disease: During the active inflammatory phase when surgery is not recommended, BTX may be used for temporary diplopia relief 1).
Low efficacy or contraindicated
Large-angle deviation used alone: Success rate decreases for deviations of 55 PD or more.
Restrictive or mechanical strabismus: Fibrosis due to trauma or chronic thyroid eye disease.
The botulinum toxin molecule consists of a heavy chain (H chain) and a light chain (L chain) linked by a disulfide bond. The H1 subunit binds to the nerve terminal and is taken into the cell via endocytosis.
The light chain cleaves the SNAP-25/syntaxin complex, inhibiting the release of acetylcholine. As a result, transmission of motor impulses through the neuromuscular junction is blocked, causing flaccid paralysis of the extraocular muscles.
The temporal changes in clinical effects are as follows:
Onset of paralysis: 2–4 days after injection
Duration of clinical effect: 5–8 weeks
Muscle function recovery: 5–14 weeks (depends on injection site, dose, and muscle innervation density)
Botulinum toxin treatment causes pharmacological recession of the injected muscle. During paralysis, the injected muscle lengthens and the antagonist muscle contracts. The pharmacological effect itself usually disappears within 3 months, but mechanical, proprioceptive, and binocular visual effects during the paralysis period contribute to long-term ocular alignment stability.
If binocular fusion is achieved during transient overcorrection, orthophoria may be maintained even after the pharmacological effect subsides (sensory adaptation). This is one mechanism by which a single injection can produce a permanent effect.
4. Diagnosis and Examination Methods (Injection Technique)
The following points must be observed during administration3).
Provide sufficient written explanation to the patient (or surrogate) and obtain written consent (patient registration is mandatory)
Identify the target site using an electromyograph or similar device, or by surgical exposure of the extraocular muscle during injection
After treatment, add 0.5% sodium hypochlorite solution to any residual solution and instruments that have come into contact with the drug to inactivate and dispose of them
Follow the dosage, administration, and precautions in the package insert
There is no unified standard for dosage. The most commonly used dose is 2.5 to 5 U of Botox. Adjust according to age, angle of deviation, and type of strabismus.
Target
Dose (Botox)
Under 3 years old (<30 PD)
Dominant eye 2.5U, non-dominant eye 2.5U
Under 3 years old (≥30 PD)
Dominant eye 2.5U, non-dominant eye 5U
3–10 years old
Dominant eye 2.5U, non-dominant eye 5U
Medial rectus / Lateral rectus
3–5U
Superior rectus
1.5U
Inferior oblique / Inferior rectus
1.5–2.5U
With fibrosis
10U
When using Disport, apply a correction factor of 3 to 5 times that of Botox.
Dilute 50–100 U of botulinum toxin powder with 2 mL of irrigation fluid (BSS) to obtain a concentration of 5 U per 0.1 mL. Use within 6 hours after reconstitution. The lethal dose in a 70 kg human is 5,000 U (more than 1,000 times the clinical dose), so the clinical dose is well within the safety margin.
Insert a needle (27G or 30G) tangentially through the conjunctiva to directly approach the target muscle. Electromyography (EMG) is useful for identifying small muscles but is usually unnecessary for injections into the medial or lateral rectus muscles.
QIs general anesthesia required for injection?
A
In adults, the procedure can be performed under topical anesthesia alone. General anesthesia is recommended for children and uncooperative adults, but the duration of general anesthesia is shorter than that for surgery.
5. Standard Treatment (Treatment Outcomes and Effects by Indication)
For comitant esotropia with small to moderate preoperative deviation (less than 35 PD), BTX injection shows success rates comparable to surgery. A 2017 meta-analysis (9 studies) reported a pooled success rate of 76% for medial rectus BTX injection in infantile esotropia. Although use in children under 12 years is off-label, early treatment for infantile esotropia has been attempted in other countries with good corrective effects reported. Advantages include the ability to achieve orthophoria with a single injection without tenotomy of the developing medial rectus, and the expected effect of preventing contracture and progression of convergence excess, despite risks of transient overcorrection and ptosis.
For large-angle comitant esotropia, combining surgery with BTX injection may improve outcomes. In a 2024 retrospective case series of deviations of 55 PD or more, adjunctive BTX-A use resulted in success in 75% of esotropia patients and 50% of exotropia patients.
After the initial administration, observe for 4 weeks. If the effect is insufficient, additional doses up to twice the initial dose can be administered 3).
If the previous effect diminishes, re-administration up to twice the previously administered single dose is possible. However, avoid re-administration within 3 months 3). After treatment, ophthalmological observation should be performed, and if any abnormalities are found, immediate detailed examination should be conducted 3).
BTX injection (chemodenervation) into the medial rectus muscle is useful for reducing secondary medial rectus contracture during the recovery phase of palsy, improving compensatory head posture, and reducing the final deviation angle 1). Surgery is performed if deviation persists 6 months after onset. For large deviations, a technique combining vertical rectus transposition with BTX injection has been reported 1).
Chemodenervation may be used to temporarily reduce diplopia during the active inflammatory phase when surgery is not indicated 1). Surgery is considered after the active phase has subsided and the deviation angle has been stable for at least 6 months 1).
In a review by Al-Dabet et al. (2025), outcomes of EMG-guided bilateral BTX-A injection (medial rectus) for Duane syndrome type 1 were reported. In 8 patients under 3 years of age, the mean preoperative esotropia was 32±10 PD. Half achieved orthotropia, while 3 required additional surgery due to persistent esotropia (mean 25 PD) 2).
The deviation angle tends to become unstable over time, making outcomes of resection and recession surgery difficult to predict. BTX injection may be advantageous in such cases.
A Cochrane systematic review (4 trials, 242 participants) concluded that there is only low-certainty evidence to determine the effectiveness of BTX injection as an independent treatment for specific types of strabismus.
QWhich is more effective: botulinum toxin or surgery?
A
For esotropia less than 35 PD, both show equivalent success rates. For large-angle strabismus, surgery combined with BTX is considered advantageous. BTX has the advantage of a simple injection technique and shorter general anesthesia time.
QWhat is the most common side effect?
A
Transient ptosis is the most frequent, occurring in 12% of adults and 25% of children. It is more common with injection into the medial rectus muscle. It usually resolves spontaneously within a few weeks and does not leave serious sequelae.
6. Pathophysiology and detailed mechanism of onset
Botulinum toxin type A is a ~150 kDa dichain protein consisting of a heavy chain (H chain, ~100 kDa) and a light chain (L chain, ~50 kDa) linked by a disulfide bond. The H1 subunit (C-terminal half) specifically binds to the nerve terminal membrane and is taken up into the cell via endocytosis.
The light chain functions as a zinc-dependent endopeptidase, cleaving the SNARE complex including SNAP-25 and syntaxin. Loss of SNARE complex function inhibits fusion of acetylcholine-containing vesicles with the presynaptic membrane, completely blocking acetylcholine exocytosis. Consequently, transmission of motor impulses across the neuromuscular junction is impaired, leading to flaccid paralysis of the extraocular muscles.
Pharmacological Denervation and Mechanisms of Long-Term Effect
During paralysis of the injected extraocular muscle, the antagonist muscle becomes relatively dominant, shifting the eye position toward the corrective direction (pharmacological denervation). During the paralysis period, the injected muscle lengthens and the antagonist muscle contracts. These mechanical and proprioceptive changes contribute to ocular alignment stability after the pharmacological effect subsides (usually 3 months).
Sensory adaptation also significantly contributes to the long-term effect. If binocular fusion is achieved during the transient overcorrection period, orthophoria is maintained even after the effect subsides. This sensory adaptation is the main mechanism by which a single injection can achieve permanent ocular alignment improvement.
Antibodies against botulinum toxin may form. Non-neutralizing antibodies do not attenuate the toxin’s effect at the neuromuscular junction and have no clinical significance. Neutralizing antibodies neutralize BTX at the functional site of the heavy chain and prevent binding to the nerve membrane, but they form in only a very small number of patients. Cross-reactive antibodies between different serotypes have not been identified.
Within 5 to 14 weeks after injection, new nerve sprouts emerge from nerve terminals and form new neuromuscular junctions, restoring muscle function. This reversibility makes botulinum therapy a repeatable treatment.
In recent years, acute acquired comitant esotropia associated with prolonged use of smartphones and digital devices has been increasing. BTX therapy is attracting attention as a promising application for this type of strabismus, and its use in early cases where the deviation angle is not yet stable is being considered.
Surgery Combined with BTX-A for Large-Angle Strabismus
For large-angle esotropia or exotropia of 55 PD or more, a technique combining strabismus surgery with intraoperative BTX-A injection is being studied. In a 2024 retrospective case series, 75% of esotropia patients and 50% of exotropia patients achieved success, suggesting its usefulness as a surgical adjunct.
International trends in expanding indications for children (under 12 years)
In other countries, early BTX treatment for infantile esotropia has been attempted, and a 2017 meta-analysis (9 studies) reported a pooled success rate of 76%. Comparative studies between EMG-guided injection and direct visualization injection (under general anesthesia) are also ongoing.
