The role of botulinum toxin in the treatment of patients in strabology and neurology outpatient clinics

INTRODUCTION

Botulinum toxin (BTX) is an exogenous neurotoxin produced by the Gram-positive, anaerobic, spore-forming bacterium Clostridium botulinum. This bacterium is found in the gastrointestinal tracts of animals as well as in the external environment, such as soil and water reservoirs. It produces 8 antigenically distinct types of exotoxins (A, B, C, C2, D, E, F, G), of which A, B, and E are associated with botulism. Type A is considered the most potent exotoxin and is widely used in ophthalmology, neurology, and cosmetology. The mechanism of action of BTX involves blocking the release of acetylcholine – the primary neuromuscular transmitter. The neurotoxin can act at neuromuscular junctions, within autonomic ganglia, and at postganglionic sympathetic and parasympathetic nerve terminals. Intramuscular administration of the toxin inhibits the secretion of acetylcholine from presynaptic motor neurons, resulting in isolated paralysis of the target muscle. Chemical denervation persists for approximately 3 months, and the recovery of neuronal activity occurs through nerve sprouting and the formation of new synaptic connections [1]. BTX type A (BTX-A) is available in several formulations, the most well-known of which are: Dysport (abobotulinumtoxin A), Botox (onabotulinumtoxin A), and Xeomin (incobotulinumtoxin A). The toxin dosage is determined in mouse units (U). One U corresponds to the median lethal dose administered intraperitoneally that causes the death of 50% of a group of female Swiss-Webster mice weighing 18–20 g [1–3]. In 1970, research began on the application of BTXA in the treatment of strabismus. Alan Scott was the first to use BTX-A in the laboratory, and the injections showed that after a few days the muscles became paralyzed, which caused a change in the position of the eyeball in experimental animals. Fifty-two years have passed since the publication of the first results. The first clinical application of BTX involved a subject recovering from retinal detachment surgery, who presented with ocular alignment disorders. The botulinum injection improved the alignment for several weeks. This initial success in treating strabismus paved the way for the use of BTX in patients with blepharospasm, cervical dystonia (torticollis), and hip muscle spasticity in multiple sclerosis [4]. Initially, toxin administration into the extraocular muscles was indicated for the treatment of paralytic strabismus. In subsequent years, it has been successfully applied in:

Evidence suggests that BTX may serve as an alternative to surgical treatment [1].

The current use of BTX in patients aims to:

BTX is also used for aesthetic purposes, including improving facial symmetry, reducing wrinkles, and reducing eyelid retraction.

TREATMENT OF RESTRICTIVE STRABISMUS

Restrictive strabismus may have a congenital, traumatic, post-inflammatory, or myopathic etiology. These disorders may manifest as movement deficits in various directions:

Merino et al. [6] conducted a 10-year retrospective study involving 27 patients with acquired restrictive strabismus, aged 18 years or older, treated with BTX. Diplopia was present in 100% of patients prior to injections. Following BTX administration, diplopia persisted in 59.3% of patients. The mean number of injections was 1.6. Surgical treatment was necessary for 51.9% of patients, while prismatic correction was applied in 14.8% of cases. Ultimately, BTX treatment was successful in 37% of patients. In the study by Granet [7], a total of 22 patients treated with BTX injections were retrospectively evaluated. In seven individuals (32%), the deviation decreased to a level where surgery was no longer necessary. In six patients (27%), surgery was required, but the improvement in ocular alignment allowed for a modification of the original surgical plan. In four patients (18%), the deviation continued to progress following BTX administration. Treatment effectiveness was higher when the pre-treatment deviation was < 20 prism diopters. In total, one-third of patients avoided surgical intervention, and an additional 27% showed a reduction in deviation prior to surgery.

TREATMENT OF PARALYTIC STRABISMUS

The use of BTX in the acute phase of paralytic deviations represents an alternative to surgical treatment and may lead to an improvement in the clinical condition of patients. This therapy may result in the elimination or reduction of diplopia, decrease in the angle of strabismus, limitation of contracture of the antagonist muscle in large-angle deviations, reduction of compensatory head posture, and restoration of fusion. In chronic cases, BTX may be used in patients who are not eligible for surgical treatment due to general medical conditions, as well as an adjunct to surgical intervention [8]. In abducens nerve palsy, BTX injection into the antagonistic medial rectus muscle may constitute a treatment method in the early period after the onset of the palsy. In many cases, it also eliminates the need for surgical correction. Denervation of the antagonistic medial rectus muscle leads to a reduction in its tension and prevents the development of contractures, which facilitates the recovery of the paralyzed lateral rectus muscle. As a consequence, restoration of proper ocular alignment and improvement of abduction may be achieved. In the study by Metz et al. [9], a total of 29 patients with uni-lateral sixth nerve palsy were examined. In the study group, 27 patients (93%) received a single BTX injection, 1 patient (3%) received 2 injections, and 1 patient (3%) received 3 injections. Full recovery of ocular motility was achieved in 22 patients (76%). Among them, 19 achieved single binocular vision with orthophoria and sensory fusion. In the remaining 7 patients, limitation of abduction persisted. In 2 of these cases, sensory fusion in the primary position was achieved without the need for prisms; 3 patients required prism correction, while 2 ultimately underwent surgical treatment at a later stage. In cases of oculomotor nerve palsy, BTX injection can be a useful and rapid method for reducing symptoms of double vision. Talebnejad et al. [10] administered BTX injections to 9 patients. The subjects had acute, partial traumatic third nerve palsy lasting less than 2 months. During a 3-month follow-up period, the patients’ condition remained stable. The peak effect of the toxin developed approximately 2 weeks after the procedure. Out of 9 patients, as many as 7 (77.8%) showed significant improvement, achieving single vision in the primary position. In the remaining 2 patients, a satisfactory effect was not achieved despite repeating the BTX injections; 6 months after the procedure, they underwent extra-ocular muscle surgery. Although BTX is successfully used in third and sixth nerve palsies, its effectiveness in the case of fourth nerve palsy is considered limited. Garnham et al. [11] analyzed the study results of 20 patients with unilateral and bilateral fourth nerve palsy who were treated with BTX injections. The study showed that toxin injection may offer certain benefits for patients with residual postoperative deviations, particularly when administered into the inferior rectus muscle. However, the authors of the paper emphasize that the use of BTX as a primary therapy for fourth nerve palsy is limited. Differences in outcomes may be a consequence of the small number of studies conducted on large patient populations.

TREATMENT OF CONCOMITANT STRABISMUS

BTX is used in both adults and children for the treatment of concomitant strabismus. Congenital esotropia and acute acquired esotropia are characterized by a large angle of deviation; in such cases, the administration of BTX provides significant benefits prior to potential surgical intervention. Surgery assisted by BTX yields better results than injection alone. BTX treatment is also recommended for patients with a small angle of deviation, as it is associated with less trauma, procedural simplicity, lower costs, and rapid recovery [7].

The treatment of small- to moderate-angle horizontal strabismus with BTX-A injection can achieve results comparable to traditional surgical methods in terms of restoring proper ocular alignment. Binenbaum et al. [12] evaluated the effectiveness of BTX-A compared to extraocular muscle surgery in patients with horizontal concomitant strabismus. In comparative studies, motor efficacy was maintained at approximately 60%, and in one study, the success rate of toxin injections exceeded that of surgical treatment. In pediatric patients with esotropia and exotropia, a high motor success rate (87–89%) has been demonstrated when injecting more than one muscle. In contrast, adults who received single injections into a horizontal rectus muscle showed less favorable outcomes. BTX-A injections are most effective in strabismus with small to moderate deviations. The authors emphasize that the cumulative success rate increases with repeated injections, highlighting the potential usefulness of this therapy in cases requiring gradual correction. A significant advantage of this therapeutic procedure is the favorable safety profile of BTX. Adverse effects, such as transient ptosis and vertical ocular deviation, occur relatively frequently; however, they almost always resolve spontaneously. Permanent complications, such as persistent vertical deviations or consecutive constant exotropia, are rare. BTX injection is a rapid therapeutic method that can also be performed using a transconjunctival technique, which reduces the risks associated with intubation and exposure to anesthetic agents, particularly in pediatric patients. However, achieving proper ocular alignment may require multiple injections. BTX seems to offer a minimally invasive early-intervention strategy capable of postponing – and in some cases limiting – the need for surgical management. It also represents an alternative to surgical treatment in patients with acute acquired comitant esotropia (AACE), especially in cases where surgery has been deferred. In a multicenter study, Cheung et al. [13] compared the efficacy of BTX injections with surgical strabismus treatment in children with AACE. The study demonstrated that in short-term follow-up, both methods achieved comparable motor success. After 6 months, it was 70.2% for the chemodenervation group and 79.6% for the surgical group; and after 12 months, 62.9% and 77.8%, respectively. In the long-term analysis (24 months), the success rate was significantly higher in the surgically treated group (86.4%) than in the group subjected to BTX injection (52%). This may suggest that surgical treatment provides more sustained long-term results. However, it should be noted that 24-month data were available for only 48% of the patients, which may have led to an underestimation of the long-term results. The study also demonstrated that the presence of amblyopia in a patient worsens the prognosis for both therapeutic options. One of the key predictors of motor success proved to be early intervention: a shorter interval between the onset of strabismus and the start of treatment correlates with higher effectiveness, regardless of the method used. For this reason, the authors recommend prompt initiation of treatment, even in the presence of amblyopia.

OTHER INDICATIONS

BTX is currently a recommended first-line treatment for blepharospasm, alongside pharmacological therapy and surgical intervention. Essential blepharospasm is a focal cranial dystonia characterized by excessive, involuntary, tonic contractions of the orbicularis oculi muscle (pretarsal, preseptal, and orbital parts) and adjacent muscles, including the procerus and corrugator supercilii muscles [14–16]. When the lower facial muscles are also involved, with or without involvement of the neck muscles, the condition is referred to as Meige’s syndrome (MS). Blepharospasm is almost always bilateral and synchronous, and its severity may vary. Primary symptoms include ocular dryness and irritation, as well as photophobia. Excessive activity of these muscles leads to frequent blinking and potentially to sustained eye closure caused by prolonged contractions of the eyelid muscles. Another consequence of impaired muscle contractility within the eye may be the development of dry eye syndrome [15–17]. Essential blepharospasm typically begins in the fifth or sixth decade of life and affects women more frequently than men, with a ratio of 3:1. The prevalence of this disorder is estimated at approximately 10 cases per 100,000 inhabitants [17]. In the vast majority of cases, blepharospasm is idiopathic and primary, with no identifiable underlying cause, and it typically persists throughout the patient’s lifetime. However, the disorder may also occur secondarily as a result of various traumas, stroke, medication use (with neuroleptics being a well-known risk factor), or neurodegenerative diseases. It is also hypothesized that essential blepharospasm may have a genetic basis, as evidenced by a noticeable familial recurrence of the condition; however, the specific genes responsible for its development have not yet been identified [15, 18]. In the study by Amatya et al. [14], BTX-A injections were administered to patients with benign essential blepharospasm, MS, and hemifacial spasm. The effective duration of the toxin’s action was 130 ±20.82 (93–189) days. BTX administration is a minimally invasive procedure, and in over 90% of patients with blepharospasm, improvement occurs within two to five days after the injection [15]. However, this effect is transient, persists for a limited duration, and requires repeated injections.

In cases of lagophthalmos caused by facial nerve palsy, long-term consequences lead to functional, aesthetic, and psychological issues. Lagophthalmos results in ocular irritation, corneal desiccation, and exposure keratopathy. BTX administration represents an effective, non-invasive, and reversible treatment method for patients with lagophthalmos, including cases occurring in the course of thyroid orbitopathy with exophthalmos. BTX injection into the levator palpebrae superioris muscle induces reversible protective ptosis: the upper eyelid droops, reducing corneal exposure and limiting the risk of complications. The procedure is also employed in the treatment of corneal ulcers when other protective measures, such as dressings or artificial tears, prove insufficient. BTX administration is minimally invasive, and the most commonly observed side effects include transient diplopia and eyelid asymmetry [19].

In patients with thyroid orbitopathy, upper eyelid retraction is one of the most common early symptoms. While surgical treatment can be performed in stable patients during the inactive phase, BTX injection offers a less invasive and reversible option for those in the active phase. Improvement in eyelid position is usually visible within 7 days, with the peak effect observed after approximately 1 month. Chemodenervation of striated muscles persists for a period of up to 3 months [20].

Ophthalmology or neurology clinics also treat patients with congenital or acquired forms of nystagmus. One of the treatment options for acquired nystagmus may be the use of BTX. Injections are administered into the extraocular muscles, e.g., into the horizontal rectus muscle in patients with horizontal nystagmus, or into the retrobulbar space. However, this therapy is rarely employed due to potential adverse effects and the need for frequent repeated injections, on average every 2–4 months [21].

BTX also plays a significant role in the treatment of chronic migraine, particularly in patients for whom standard pharmacological therapy does not yield the expected benefits. The mechanism of action of BTX involves blocking the release of neurotransmitters and neuropeptides involved in pain processes, which leads to the inhibition of excessive activity in the trigeminal nerve fibers – a key element in the pathophysiology of migraine. The neurogenic inflammatory response in the meninges is also reduced. Clinical studies demonstrate the efficacy of BTX through a significant reduction in both the frequency and severity of migraine attacks reported by patients. Long-term follow-up indicates that the benefits increase with successive treatment cycles. The treatment regimen according to the standard Phase III Research Evaluating Migraine Prophylaxis Therapy protocol involves injections at 31 sites across the head and neck, with a total dose of 155–195 U, repeated every 12 weeks. Modifications in dosing and in the distribution of injection sites are also being investigated, depending on the individual needs of the patient. The BTX injection procedure is generally well- tolerated and minimally invasive; adverse effects are typically mild, transient, and limited to local discomfort at the injection site. The use of BTX in the treatment of chronic migraine leads to a reduction in attack frequency, a decrease in pain intensity, and an improvement in the patient’s quality of life. Although the cost of therapy is high, its safety and efficacy make BTX a promising and effective option for the management of chronic migraine [22].

BTX also finds application in the treatment of dry eye syndrome. Local injection of the toxin causes transient muscle paralysis by disrupting the release of acetylcholine into the neuromuscular junction. A prospective, double-blind, randomized controlled trial was conducted to evaluate the efficacy of BTX-A injections in improving symptoms of dry eye syndrome resistant to conventional treatment. Choi et al. [23] assessed the effect of BTX on cytokine levels in tears and demonstrated a reduction in serotonin levels, which was associated with a decrease in neuropathic pain. In patients receiving the toxin, injections were performed into the medial part of the upper and lower eyelids, as close as possible to the gray line, within the pretarsal portion of the orbicularis oculi muscle. No adverse effects related to BTX administration were reported. Symptom relief persisted for approximately four months. The authors hypothesize that increased tear retention and reduced blink frequency, caused by the toxin, lead to a reduction in friction between the eyelid and the eyeball during blinking. Additionally, the reduction in frictional forces lowers the level of matrix metalloproteinase-9, the presence of which is a good predictive marker for dry eye syndrome – an observation based on qualitative analysis. BTX treatment may also help avoid complications associated with punctal and canalicular plugs, such as displacement, extrusion, epiphora, infection, inflammation, or granulomatous proliferation. Administration of the toxin also weakens the eyelid-closing force, which further reduces friction and microtrauma to the conjunctival and corneal epithelium. Patients opting for BTX therapy must receive injections regularly, due to the gradual waning of the toxin’s effect over time.

SAFETY OF TREATMENT

The BTX injection procedure is widely recognized as safe, with a low risk of both local and systemic adverse effects. Side effects are typically mild, self-limiting, and appear shortly after the injection, usually without requiring treatment. The most common adverse effects occur at the injection site and include bruising, ecchymosis, and hematomas. These are reported in 11–25% of patients and are usually related to the procedure itself rather than the action of the toxin. They are observed more frequently in patients taking anticoagulants. A relatively common complication of BTX therapy is ptosis, which may persist for 2–4 weeks. Injections into the orbicularis oculi, corrugator supercilii, and procerus muscles are associated with the highest probability of eyelid drooping. Ptosis is also the most frequent side effect of BTX treatment for strabismus in children, occurring in 34% of patients and lasting up to 8 weeks. Diplopia occurs relatively rarely, in less than 1% of all injections. BTX may also cause allergic reactions with a wide spectrum of symptoms, ranging from edema and erythema to anaphylactic shock. Some patients experience localized pain associated with the injection or generalized headaches. In rare cases, BTX administration may lead to intraorbital or ocular adverse effects, such as blurred vision, accommodative difficulties, or corneal changes (e.g., epithelial defects, edema, decreased corneal transparency, or retinal detachment). In aesthetic BTX applications, the most common adverse effects include injection-site reactions and allergic responses [3].

CONCLUSIONS

BTX treatment is used in ophthalmology, neurology, and aesthetic medicine. It may serve as a supplement to conservative or surgical therapies, or as an alternative to them. BTX injections provide a rapid therapeutic effect, and the method is less invasive than surgical procedures. It allows for individualized dosing tailored to the patient’s needs, while the temporary duration of action enables therapy adjustments or the selection of alternative treatment options. The main limitation is the transient nature of the effect, which necessitates repeated procedures.