POLSKI
Introduction
Botulinum toxin (BTX) is a neurotoxin produced by anaerobic, spore-forming, Gram-positive bacilli of clostridium botulinum. There are eight naturally occurring serotypes of the toxin: A, B, C1, C2, D, E, f and G. [1] The medical use of BTX dates back to the 1970s, when an American ophthalmologist Allan B. Scott first employed it to treat strabismus. Since then, Scott and other researchers began using it for various conditions involving excessive muscle contractions, e.g., blepharospasm. [2] However, the toxin’s actual origin goes back several centuries, with documented outbreaks of foodborne botulism as early as the 10th century. [3]
Today, it is commonly associated with its cosmetic use in aesthetic medicine, but its range of applications is much broader and continues to expand. In this article, we chose to focus on the role of BTX in neurology and selected some of the currently known methods of its application in this field.
Aim of the study
This systematic review aims to review therapeutic use of botulinum neurotoxin (BTX) within the area of neurology. The purpose of the authors was to gather the most important information regarding the topic.
Pharmacokinetics and mechanism of action
BTX’s primary mechanism involves the inhibition of acetylcholine release at the neuromuscular junction, leading to muscle paralysis. The process begins when BTX binds specifically to high-affinity receptors on the presynaptic membrane of cholinergic neurons. Then the toxin-receptor complex undergoes endocytosis, forming an endocytic vesicle within the neuron and acidification within the vesicle triggers a conformational change, allowing the light chain of BTX to translocate into the cytosol. The light chain, a zinc-dependent endopeptidase, cleaves specific SNARE proteins (e.g., SNAP-25), which are essential for vesicle fusion and neurotransmitter release. By disrupting SNARE-mediated vesicle fusion, BTX effectively blocks acetylcholine release, resulting in flaccid paralysis of the targeted muscle. [4,5,6,8]
BTX is administered via intramuscular or subcutaneous injections. Initial weakening does not occur for several days and the peak occurs in the order of several weeks. Effects subside at 2 months and strength generally returns to normal by 3 up to 6 months. The distribution of BTX is primarily localized to the area of injection, as it is distributed mainly by convection and there is likely little diffusion. BTX is active in the presynaptic terminal until metabolized. [5,7,8]
Indications for botulinum toxin in neurology
Cervical dystonia
Dystonia is a neurological syndrome characterized by persistent involuntary muscle contractions that often lead to twisting, repetitive movements or abnormal body postures. Cervical dystonia (CD) specifically affects the neck muscles. [9] CD most commonly begins between the 4th and 5th decade of life, with a higher prevalence in women than in men. Although it is generally regarded as idiopathic or genetically driven, CD can also develop secondary to factors such as head trauma or exposure to certain medication, especially neuroleptics. Idiopathic CD is the largest subgroup of dystonia. [10] BTX injections are commonly recognized as an effective treatment for CD. The approach to administering these injections can vary depending on several factors, including the technique. BTX is injected directly into the overactive muscles. There are 3 primary methods for guiding the injections: identifying anatomical landmarks by palpation, by USG, or by EMG. [11]
An online survey conducted by Boyce et al., involving 128 individuals with cervical dystonia, mostly women (77%) with an average age of 59, revealed that the majority (52%) rated their condition as mild to moderate and reported an average pain level of 5 out of 10. Among the respondents, 64% (82 individuals) were receiving regular BTX injections, and 86% of those reported experiencing positive effects from the treatment. [12] The effectiveness of BTX treatment is affected by several factors, including the dosage, frequency and number of injections, the guidance method used during administration, and whether physiotherapy is used alongside or after. Currently, there is no agreed-upon standard for defining the duration of BTX’s therapeutic effect in CD. The timing of reinjections should be tailored to each patient, depending on their clinical requirements. [13]
1.1. Spasticity
Spasticity is a type of motor dysfunction marked by a velocity-dependent increase in muscle tone due to exaggerated stretch reflexes. Over time, it can lead to complications such as muscle atrophy, fibrosis and contractures, which negatively affect a patient’s daily functioning. Various central nervous system disorders can cause spasticity, including multiple sclerosis, cerebral palsy, stroke, spinal cord injuries and traumatic brain injuries. Among these, stroke is a major cause of spasticity in adults, with approximately half of stroke survivors developing this condition, often resulting in serious limitations in performing everyday tasks. [14] To manage spasticity, BTX is injected intramuscularly, temporarily inducting localized muscle paralysis and potentially providing pain relief that can persist for 3 to 4 months. [15]
Current research supports the effectiveness of BTX injections in reducing spasticity. A cohort study conducted by Aygün Bilecik et al. in 2013-2019 involved 85 hemiplegic patients with a mean age of approximately 50 years, who were divided into 2 groups and received BTX injections targeting different muscle groups. Notably, patients in Group 2, who underwent 5 treatment sessions, demonstrated significantly greater reductions in MAS scores for specific muscles and achieved higher fAT scores than those in Group 1, who received only a single session. In general, BTX therapy resulted in notable improvements in MAS, Brunnstrom and fAT scores among all participants. [16] On the other hand, the long-term effects of BTX injections on muscle strength are still not clearly understood. [17]
1.2. Hemifacial spasm
Hemifacial spasm (HfS) is a neuromuscular condition, for which involuntary rhythmic muscle contractions on one side of the face are characteristic. They often lead to reduced quality of life due to social discomfort. [18] HfS is an uncommon disorder, with global prevalence estimates of 14.5 per 100,000 among women and 7.4 per 100,000 among men, indicating that women are almost twice as likely to be affected. The condition typically develops during adulthood, most often between the 4th and 6th decades of life. [19] BTX injections have proven to be an effective treatment option and are considered the preferred therapy for HfS. [20] Clinicians introduce the medication directly to the muscles involved in HfS, which are: orbicularis oculi, corrugator supercilii, zygomaticus major, zygomaticus minor, levator labii superioris alaeque nasi, risorius, orbicularis oris, mentalis, depressor anguli oris, and platysma. [21]
Research shows that BTX not only reduces the physical symptoms of HfS, but also leads to improvements in somatization, tension, anxiety, depression and emotional sensitivity. A study conducted by Wei et al. involved 65 patients with HfS and 65 healthy controls matched for comparison. To assess psychological well-being, all participants completed the Cornell Medical Index (CMI) self-assessment questionnaire. HfS patients received localized injections of BTX and the severity of their muscle spasms was categorized using the Cohen hierarchical criteria. The effectiveness of BTX treatment was evaluated by comparing clinical and psychological measures taken before the injections and again 2 months after. Before treatment, HfS patients showed significantly higher scores in areas such as somatization, depression, anxiety, poor adaptation, sensitivity, anger, tension and overall distress compared to the control group. Two months after BTX administration, 42 patients (64.6%) experienced complete relief, 16 (24.6%) has notable improvement, 7 (10.8%) had partial relief and none showed no response, resulting in a total effectiveness rate of 89.2%. Additionally, post-treatment assessments revealed significant reductions in scores related to somatization, depression, anxiety, poor adaptation, sensitivity, anger, tension and overall distress compared to outstart. [22]
Hyperhidrosis
Hyperhidrosis is a medical condition characterized by excessive sweating. It can affect specific areas, such as the palms, soles, underarms or face, or occur more generally across almost the whole body. It can either be primary (90%) or secondary. Secondary hyperhidrosis is often linked to an underlying disease, most commonly endocrine or neurological, but it can also result from medication side effects, infections, cancers, metabolic or hormonal imbalances and cardiovascular issues. [23]
Recent studies provide strong evidence that injections of BTX into areas affected by hyperhidrosis can significantly decrease localized sweating across various regions, with minimal risk of serious side effects. [24] The literature includes a study conducted by Antón Andrés et al., which included 31 patients with severe primary axillary hyperhidrosis. Some of them underwent multiple BTX treatments during follow-up, totaling 82 procedures. Participants were randomly assigned to receive either 50 or 100 units of BTX per axilla. The severity of sweating was measured using the Hyperhidrosis Disease Severity Scale (HDSS), while the impact on quality of life was evaluated with the Dermatology Life Quality Index (DLQI). Treatment with BTX effectively reduced sweating severity and enhanced patients’ quality of life, with no notable differences observed between the two dosage groups. [25]
Another study conducted by Patrick et al. presents a case of a 68-year-old woman with postmenopausal craniofacial hyperhidrosis, who had not responded to primary alternative treatment (such as oral antimuscarinic medication) and was successfully treated with BTX. Injections, that were administered across the forehead along the frontal hairline and around the periauricular scalp, resulted in notable improvement. [26]
Pain
BTX is nowadays also recognized for its ability to alleviate several types of pain, including chronic migraine and neuropathic pain. These clinical effects are primarily attributed to BTX’s capability to block SNARE-dependent vesicle transport, a mechanism that takes place in both motor and sensory neurons. [27]
Chronic migraine (ChM) is a neurological condition characterized by recurring migraine episodes that interfere with daily functioning and greatly reduce quality of life. [34] The trigeminal nerve, along with cervical and occipital nerves, provides most sensory input to the head and face. In ChM, repeated pain signals from these nerves can sensitize central neurons and sustain the condition. Multiple pericranial injections of BTX are often required to target these nerves and reduce peripheral pain signals. By doing so, the treatment helps prevent central nervous system hyperexcitability, which plays a key role in migraine development. [28]
In the course of investigation, the authors came across a study carried out by Aurora et al. consisting of two phase III clinical trials, which assessed the efficacy and safety of BTX in ChM patients over 56 weeks. Patients received either BTX or placebo for the first 24 weeks, followed by three open-label cycles of BTX. Among 1005 patients who completed all five treatment cycles, those who received BTX from the start showed significantly greater reductions in headache frequency, migraine days and severe headache days compared to those who initially received placebo. Additionally, a higher percentage of the first group achieved at least a 50% reduction in headache days. These results suggest that earlier and sustained treatment with BTX provides greater and cumulative benefits in ChM prevention. [29]
Another painful condition, neuropathic pain (NP), is a challenging and often disabling disorder resulting from injury or dysfunction within the somatosensory nervous system. It commonly manifests as persistent pain described as burning, tingling or resembling electric shocks, and can greatly diminish a person’s quality of life. [30] Although the possible application of BTX as a supplementary treatment could help minimize the reliance on multiple medications in the management of NP symptoms, further carefully designed randomized controlled trials are still needed to validate the use of BTX injections as a relatively safe and repeatable treatment option. [31] Additional studies are required to establish the most effective dosage, refine treatment strategies and assess the long-term outcomes of using BTX in the management of NP. [32]
Blepharospasm
Benign essential blepharospasm is a type of focal dystonia involving uncontrollable eyelid closure. This uncommon condition typically arises between the ages 40 and 70, with its likelihood increasing as a person gets older. [33] The exact cause and underlying mechanisms of this disorder remain unclear, though it is usually linked to dysfunction in the basal ganglia. Research suggests that reduced activity of inhibitory neurons in the cerebral cortex, potentially influenced by environmental and genetic factors, also plays a role. Moreover, growing evidence points to dysregulation of key neurotransmitters such as dopamine, serotonin and acetylcholine as contributing factors in the development of blepharospasm. [34] BTX is administered to the muscles surrounding the affected eye to decrease muscle activity. [33] No effective pharmacological method of treatment for blepharospasm was introduced prior to BTX. [34]
In light of literature, research conducted by Gaćina et al., investigating the impact of BTX, has shown that patients with essential blepharospasm generally report high levels of satisfaction with the treatment. BTX injections are regarded as the primary treatment for essential blepharospasm and are widely considered the most effective option for providing short-term symptom relief. [35]
Overactive bladder
Overactive bladder (OAB) is defined by storage-related symptoms including urgency, frequent urination and nocturia, with or without the presence of urge incontinence. Occasionally this condition develops following spinal cord injury, bladder obstruction or inflammation, but usually the origin stays unknown. [36] OAB is estimated to impact more than 500 million individuals globally, with prevalence among adults ranging from 17% to 32% across different countries. The likelihood of developing OAB increases with advancing age. [37] BTX is injected directly into the bladder muscles via transurethral injections to block nerve signals that cause OAB. [38] According to the literature, BTX has improved quality of life for patients with OAB, as evidenced by both patient-reported outcomes in clinical trials and observations in clinical practice. [37] Nitti et al. conducted a pooled analysis of four randomized controlled trials, that evaluated the safety and effectiveness of BTX 100 U in men and women with OAB not adequately managed with anticholinergics. A total of 1564 patients were included (194 males, 1370 females). At 12 weeks, BTX significantly reduced daily urinary incontinence episodes compared to placebo in both sexes, with greater improvements seen in patients without benign prostatic hyperplasia. Over 60% of patients receiving the treatment achieved a ≥50% reduction in urinary incontinence episodes. [39]
Table I
Botulinum toxin formulations along with their indications and dosage of OnabotulinumtoxinA. [1,2,3,4,5,6,7]
Choudhury S, Baker MR, Chatterjee S, Kumar H. Botulinum Toxin: An Update on Pharmacology and Newer Products in Development. Toxins (Basel). 2021 Jan 14;13(1):58.
Kim J, Park S, Kwon SY. Botulinum toxin as an effective treatment for persistent twitching in first toe: a detailed case study. J Int Med Res. 2024 Sep;52(9):3000605241285155.
Brin Mf, Blitzer A. The pluripotential evolution and journey of Botox (onabotulinumtoxinA). Medicine (Baltimore). 2023 Jul 1;102(S1):e32373.
Salazar G, Caballero I. Ultrasound-Guided Botulinum Toxin Infiltrations in Essential Tremor Patients: A 36-week follow Up. Tremor Other Hyperkinet Mov (N Y). 2025 Mar 3;15:8.
Motavasseli D, Delorme C, Bayle N, Gracies JM, Roze E, Baude M. Use of Botulinum Toxin in Upper-Limb Tremor: Systematic Review and Perspectives. Toxins (Basel). 2024 Sep 13;16(9):392.
Velickovic M, Benabou R, Brin Mf. Cervical dystonia pathophysiology and treatment options. Drugs. 2001;61(13):1921-43. doi: 10.2165/00003495-200161130-00004. PMID: 11708764.
BOTOX® Consumer Medicine Information leaflet, November 2024, Allergan, Inc., an AbbVie company. © 2024 AbbVie. Published by MIMS January 2025. Available online: https://www.nps.org.au/assets/medicines/923b1908-f8ab-4083-af88-a53300fedb65-reduced.pdf
Conclusions
Botulinum toxin (BTX) has proven to be highly versatile in neurology. BTX demonstrated significant clinical benefits across a wide range of neurological conditions, such as cervical dystonia, spasticity, hemifacial spasm, blepharospasm, pain, hyperhidrosis and overactive bladder. The reviewed literature confirms the efficiency, safety and growing scope of BTX’s medical applications. Adding patient satisfaction and quality of life improvements, BTX continues to evolve as a key tool in the neurological therapeutic field. Expanding our understanding in certain areas, like dosing strategies, treatment intervals, patient selection criteria and efficacy of repeated administrations, will help optimize the therapeutic use of botulinum toxin in neurology and potentially extend its application to additional indications.
