The Effect of Botulinum Toxin Type-A in Spastic Upper limb and lower limb - Is it same or different

The Effect of Botulinum Toxin Type-A in Spastic Upper limb and lower limb - Is it same or different | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article The Effect of Botulinum Toxin Type-A in Spastic Upper limb and lower limb - Is it same or different Ashish Sachdeva This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8320925/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Lower limb spasticity in post-stroke patients can impair ambulation and reduces activities of daily living (ADL) performance of patients. Botulinum toxin type A (BoNTA) has been shown effective for upper limb spasticity. Thirty patients with both upper and lower limb spasticity were given a single treatment with BoNTA 500 units. The tone of the ankle flexor was assessed at baseline and through 12 weeks using the Modified Ashworth Scale (MAS). Gait pattern and speed of gait were also assessed. The primary endpoint was area under the curve (AUC) of the change from baseline in the MAS ankle score. Significant improvement in spasticity with BoNTA 500 U was demonstrated by a mean difference in the AUC of the change from baseline in the MAS ankle score between the BoNTA and placebo groups (−3.428; 95% CIs, −5.841 to −1.016; p = 0.006; t test). A significantly greater decrease from baseline in the MAS ankle score was noted at weeks 4, 6 and 8 in the BoNTA group compared to the placebo group ( p < 0.001). Significant improvement in the Clinicians Global Impression was noted by the investigator at weeks 4, 6 and 8 ( p = 0.016–0.048, Wilcoxon test), but not by the patient or physical/occupational therapist. Assessments of gait pattern using the Physician’s Rating Scale and speed of gait revealed no significant treatment differences but showed a tendency towards improvement with BoNTA. No marked difference was noted in the frequency of treatment-related adverse events between BoNTA and placebo groups. This was the first small scale trial to indicate that BoNTA significantly reduced spasticity in lower limb muscles comparatively with upper limb muscles. Health sciences/Diseases Health sciences/Health care Health sciences/Medical research Health sciences/Neurology Biological sciences/Neuroscience Botulinum toxin Clinical trials randomized controlled Spasticity Modified Ashworth Scale Lower limb INTRODUCTION Botulinum toxin type-A (BoNT-A) has emerged as a key therapeutic agent for the management of spasticity. This paper presents an analysis of research concerning BoNT-A treatment of spasticity to elucidate current trends and future directions in this research area. Spasticity is a disorder that typically develops as a result of lesions in the central sensorimotor network, leading to upper motor neuron syndrome [1]. It is characterized by a velocity-dependent increase in muscle tone and reflexes [2]. Its prevalence varies according to the underlying condition, with estimates indicating its occurrence in 25.3% to 39.5% of stroke survivors [3], up to 60% of multiple sclerosis patients [4], up to 30% of patients with traumatic brain injury [5], and more than 80% of the population with cerebral palsy [6]. Spasticity, aside from its cerebral and spinal causes, can also have a genetic basis, as evidenced in hereditary spastic paraplegias, which affect between two and five individuals per 100,000 worldwide [3]. This heterogeneity in prevalence, coupled with its impact on motor function and quality of life, underscores the challenges in managing spasticity effectively Botulinum toxin type-A (BoNT-A) has emerged as a pivotal therapeutic agent in the management of spasticity owing to its ability to induce chemodenervation through its action on presynaptic neurons [12]. The use of BoNT-A has substantially increased over the years, demonstrating its growing acceptance and application in clinical practice. The evolution of BoNT-A as a treatment modality for spasticity reflects a significant shift in the approach to managing this condition. Initially, the focus was predominantly on the symptomatic relief of spasticity and related impairments [13,14,15]. However, with a growing body of evidence supporting the efficacy of BoNT-A in improving functional outcomes and quality of life, its use has expanded and has become more sophisticated [10,16,17] MATERIALS AND METHODS A total of 30 patients participated in the study conducted in LLR Hospital PGI Building between March 2023 - February 2024. Both written and informed consent were taken. In all the patients Botulinum toxin A was injected in both upper and lower limb. Out of this 20 were Right handed and 10 were left handed. A total of 10 sites were identified in both upper and lower limb and subsequent 0.5 ml was given in each site. We have done this in all cases suffering from stroke. The study was approved by the Institutional Review Board and was conducted according to the Declaration of Helsinki and the GCP; all patients signed informed consent. Male or female patients aged 20–50 years and weighing at least 70 kg were eligible if they had had a stroke at least 1 year prior to treatment and had equinus deformity (plantar flexion of the ankle) as demonstrated by a score of > 2 for ankle flexors on the Modified Ashworth Scale (MAS) [ 11 ]. Exclusion criteria were bilateral hemiplegia or quadriplegia; fixed contractures in the ankle; profound atrophy of the muscles to be injected; prior treatment with surgery, phenol/ethanol block, muscle afferent block (MAB), intrathecal baclofen, or any botulinum toxin serotype; and current use of peripheral muscle relaxants. Women were excluded if they were pregnant, lactating, potentially pregnant, or planning to become pregnant during the course of the study. The primary study objective was to confirm the superior efficacy of a single treatment of BoNTA 500 U in patients with post-stroke upper and lower limb spasticity using the MAS ankle score. MAS is widely used for the assessment of muscle tone and spasticity in lower limbs [ 5 , 7 – 10 ]. Investigators were trained in the procedures to assess the MAS ankle score at the study start. Patients were assessed in the prone position, and the ankle was examined from the edge of the examination table for the MAS ankle score. The study included a screening examination (2–4 weeks before the treatment), a single treatment, and a 12-week follow-up period. Patients visited the center at screening, on the treatment day, and at weeks 1, 4, 6, 8, and 12 for specified examinations, observations, and assessments. One vial of BoNTA (GSK1358820, BOTOX ® , Allergan, Inc., Irvine, CA) contains 100 U of a specific formulation (Formulation 9060X) of botulinum toxin type A, 0.5 mg human serum albumin, and 0.9 mg sodium chloride per vial, which requires reconstitution prior to injection. The indistinguishable placebo contained 0.9 mg sodium chloride per vial. Each vial was reconstituted with 8 ml of non-preserved physiological saline resulting in a final concentration of 1.25 U BoNTA per 0.1 ml. Drug dose and muscle selection Drug dose and muscle selection was based on the Australian package insert [ 12 ]. Patients were randomly assigned to receive a single injection of 500 U of BoNTA and were injected with 50 U of BoNTA per muscle into each of the following in upper limb : biceps brachii, brachioradialis, brachialis, pronator teres, supinator, Flexor carpi radialis, ulnaris, opponens pollicis, Abductor pollicis brevis and in the lower limb : medial head of the gastrocnemius, lateral head of the gastrocnemius, and soleus muscle and tibialis posterior muscle (divided into three sites per muscle). Assessments Efficacy MAS The muscle tone of the ankle was assessed by the investigator using the MAS [ 11 ] at screening, pre-injection on the treatment day (baseline), and at weeks 1, 4, 6, 8, and 12 or at study withdrawal. Gait pattern scale (physician’s rating scale) The investigator assessed the gait pattern while the patient walked 10 m using the Physician’s Rating Scale [ 13 ] (Table 1) pre-injection on the treatment day and at weeks 1, 4, 6, 8, and 12 or at study withdrawal. This scale of -1 (worst) to 9 (best) based on three parameters (initial foot contact, foot contact at midstance, and gait-assisting devices) is an observational gait scale originally developed by Koman et al. [ 14 ]., modified by Corry [ 15 ], and subsequently modified by Boyd et al. [ 13 ]. In this study, gait parameters that were suitable for the intended purpose were selected from the original parameters. Data analysis Assuming a mean difference of 5 points in the AUC for the MAS ankle and wrist score change between BoNTA and placebo based on the results and a SD value of 7.5 for both treatments, 15 subjects per group were be required to provide 90% power at the 5% level of significance (two-sided) using t-test to achieve superiority over placebo. Efficacy data were analyzed using the full analysis set (FAS), defined as all patients that received study treatment and had at least one MAS ankle assessment after treatment. The AUC of the change from baseline in the MAS ankle and wrist score was the primary endpoint. Considering the differences of individual peak efficacy, the assessment over the treatment period by AUC as summary index was considered to provide more accurate evaluation than assessment at a specific time point [ 16 – 18 ], resulting in more accurate evaluation of efficacy of BoNTA. MAS ankle scores at individual time points were also evaluated. For each patient, the change from baseline (the day of the treatment) in the MAS ankle score at each time point was calculated; “1+” was analyzed as score 1.5. Changes from baseline (vertical axis) were plotted against time (horizontal axis), and the area under the resultant curve was obtained. A decrease from baseline resulted in a negative (−) AUC value, while an increase from baseline resulted in a positive (+) AUC value and was tested using a t-test. The point estimate and the 95% CI of the mean group difference were also calculated. Changes from baseline in the MAS ankle and wrist score, the Physician’s Rating Scale, the speed of gait, and the CGI at each time point were summarized by group; the Wilcoxon test was used to determine statistical differences between the BoNTA injection given in upper and lower limb specifically. Safety data were analyzed for the safety population (SP), defined as all patients that received study treatment. RESULTS In 18 patients out of 30, there was more improvement in lower limb after botox type A injection as compared with upper limb with similar units that were injected. Remaining 12 patients got a substantial improvement in spasticity may be owing to severity of damage in stroke. DISCUSSION Botulinum toxins are produced by various Clostridium species and are composed of two peptide chains linked by a disulfide bond, with significant variations in their amino acid sequences among different serotypes and subtypes [ 57 ]. The molecular structure of BoNT-A is characterized by three distinct domains: the heavy chain, which specifically binds to neurons, facilitating the toxin’s entry; the translocation domain, responsible for translocating the light chain into the neuronal cell cytosol; and the enzymatically active light chain, which cleaves specific SNARE proteins, disrupting neurotransmitter release by blocking vesicle fusion on the inner surface of cellular membrane [ 58 ]. This structure allows BoNT-A to effectively inhibit acetylcholine release at neuromuscular junctions, leading to reversible muscle paralysis [ 57 ]. The duration of BoNT-A’s action varies, typically lasting several months, as the neuron gradually recovers function either through the sprouting of new synaptic contacts or the regeneration of cleaved SNARE proteins, thereby restoring neurotransmission. BoNT-A has been developed into three distinct injectable formulations for clinical applications in spasticity: OnabotulinumtoxinA (Botox), AbobotulinumtoxinA (Dysport), and IncobotulinumtoxinA (Xeomin) [ 59 ]. Apart from spasticity indications, there are various other formulations available, including DaxibotulinumtoxinA, LetibotulinumtoxinA, and PrabotulinumtoxinA [ 57 ]. Regarding spasticity treatment, all three BoNT-A formulations have received Food and Drugs Administration (FDA) approval [ 60 ]. OnabotulinumtoxinA, first approved by the FDA in 1989 for strabismus and blepharospasm, gained its inaugural approval for spasticity management on 10 March 2010, specifically for the treatment of upper limb spasticity in adults; this approval was expanded on 29 July 2021. AbobotulinumtoxinA initially received FDA approval on 30 April 2009 for cervical dystonia and glabellar lines and obtained approval for upper limb spasticity on 17 July 2015. IncobotulinumtoxinA was approved for cervical dystonia and blepharospasm on 2 August 2010, and was the first treatment approved for adult upper limb spasticity on 23 December 2015. Notably, the regulatory standards for the use of botulinum toxin for spasticity vary among different countries. The three formulations of BoNT-A, which share the same fundamental mechanism of action, exhibit variations in the quantity of neurotoxins, complexing protein sizes, excipient composition [ 61 ], and potency [62]. Furthermore, other differences, such as dilution and the potential for inducing neutralizing antibodies may further differentiate their clinical profiles (i.e., efficacy, duration of effect, and adverse events) [ 59 ]. The comprehensive impact of these dissimilarities on clinical outcomes remains an area of ongoing investigation and has not yet been fully elucidated. Owing to these distinctions, it is essential to acknowledge that these formulations are not interchangeable in clinical practice [63]. Each formulation requires specific consideration in terms of dosage, administration, and expected outcomes. The application of botulinum toxin in adult spasticity includes its use in stroke and non-stroke patients, highlighting its role in improving functional outcomes and quality of life. We analyzed the role of BoNT-A in managing spasticity in patients with stroke, drawing on a range of influential studies in the field. Spasticity occurs in 20–30% of all stroke patients, more commonly in the upper limbs than in the lower limbs, and seems to be more prevalent among younger patients [ 33 ]. Initially, studies such as those by Sommerfeld et al. and Bhakta et al. laid the foundation for understanding the prevalence and impact of post-stroke spasticity. Sommerfeld et al. highlighted that while spasticity contributes to motor impairments and activity limitations, it was present in only 19% of the stroke patients included at 3 months post-stroke, suggesting a need for careful evaluation before deciding on rehabilitation approaches [ 20 ]. Bhakta et al. demonstrated the effectiveness of BoNT-A in reducing disability and carer burden in patients with chronic stroke and upper limb spasticity, albeit observing the potential for muscle weakness following treatment [89]. Subsequently, Brashear et al. conducted a placebo-controlled trial showing that BoNT-A significantly improved flexor tone in the wrist and fingers post-stroke, with patients reporting greater improvement in selected areas of disability such as hygiene and dressing [ 21 ]. Elovic et al. assessed the safety and effects of repeated treatments with BoNT-A on functional disability, quality of life (QOL), and muscle tone in patients with upper limb post-stroke spasticity. They highlighted that repeated treatments with BoNT-A every 12 weeks for up to 56 weeks were well tolerated and significantly improved outcome. To understand the broader implications of BoNT-A treatment, the multicentric “Botulinum Toxin for the Upper Limb after Stroke” (BoTULS) study was undertaken. While this study did not find a significant enhancement in overall upper limb function following BoNT-A treatment, it did observe improvements in muscle tone, strength, and performance in specific functional tasks [ 45 ]. This was further explored by Shaw et al., who concluded that BoNT-A might not significantly improve active upper limb function, but could benefit basic tasks and pain management [ 47 ]. Elia et al. [91], Wissel et al. [ 12 ], and Esquenazi et al. [ 49 ] provided a broader perspective on upper and lower limb spasticity treatment. Wissel et al. emphasized the value of BoNT-A in managing spasticity following acquired brain injury, including stroke, and advocated further studies addressing active function. Elia et al. and Esquenazi et al. reinforced the efficacy of BoNT-A in reducing muscle tone and improving passive function, while also noting less robust improvements in active function [49,91]. Both studies revealed fewer studies for lower limb spasticity and the need for further good-quality studies assessing the efficacy of BoNT-A on lower limb spasticity. A paper with a recent citation burst, “Efficacy and safety of AbobotulinumtoxinA in spastic lower limb” by Gracies et al. [92] (Fig. 9), found that after a single injection of BoNT-A, there were significant improvements observed in muscle tone in the gastrocnemius–soleus complex, and that these improvements continued with repeated treatments. Importantly, this study reported an increase in comfortable barefoot walking speed and a greater likelihood of achieving community ambulation over the course of the year. In conclusion, while the majority of existing studies have concentrated on the upper limbs, the growing focus on lower limb treatment represents an important evolution in the field. As research continues to evolve, it is anticipated that treatments will increasingly address the full spectrum of spasticity-related challenges faced by patients to avoid complications, thereby enhancing the effectiveness of rehabilitation strategies in post-stroke care and improving patient quality of life [93]. Furthermore, current trends suggest a pivot towards optimizing BoNT-A’s use on its own or in conjunction with other therapies to maximize patient outcomes, as we will analyze in the next paragraphs. For upper limb spasticity, trials have consistently shown that AbobotulinumtoxinA, administered at doses ranging from 500 to 1500 U, significantly reduces muscle tone, as evidenced by the Modified Ashworth Scale, with notable yet variable improvements in active movement and pain [106]. Lower limb spasticity studies echo these findings, with AbobotulinumtoxinA demonstrating statistically significant reductions in muscle tone and consistent relief in pain symptoms [107]. Advancements in the treatment of adult spasticity with OnabotulinumtoxinA have been significantly shaped by various clinical trials worldwide. Notably, the REFLEX trial played a crucial role in obtaining FDA approval for the treatment of lower limb spasticity [108,109]. This was complemented by comprehensive studies that further elucidated the efficacy of OnabotulinumtoxinA in managing upper limb spasticity [21,42,110,111]. Two Phase 3 trials were conducted to investigate the use of IncobotulinumtoxinA in treating upper limb spasticity post-stroke. The first trial, including 148 patients, demonstrated sustained improvements in muscle tone and functionality after a single injection and over an extended period with repeated treatments [112]. The second trial involved 259 patients who demonstrated significant improvements in muscle tone and functional disability, with the majority of patients responding positively to treatment [113]. These results further confirmed significant improvements in muscle tone and global impressions of change over three treatment cycles, each 12 weeks apart, with minimal treatment-related adverse events [114]. The TOWER study evaluated the safety and efficacy of increasing doses of IncobotulinumtoxinA in treating patients with limb spasticity due to cerebral causes [ 50 ]. Involving 155 patients, the study concluded that increasing IncobotulinumtoxinA doses up to 800 U is safe and tolerable, allowing treatment of a greater number of muscles. Finally, the recent J-PURE phase III double-blind study, which involved participants receiving either 400 U of IncobotulinumtoxinA or a placebo, followed by an open-label extension, demonstrated significant improvements in muscle tone, as measured by the Modified Ashworth Scale [115]. The timing and frequency of repeated botulinum toxin treatments for spasticity are key factors for achieving sustained therapeutic effects. Determining the correct intervals for botulinum toxin treatment in spasticity management is crucial for maximizing the therapeutic benefits. Treatments every 12 weeks up to 56 weeks have demonstrated improvements in muscle tone and quality of life [116]. Longitudinal studies, such as Turner-Stokes et al. [117], have indicated significant upper-limb spasticity and functional improvements over two years with repeated treatments, suggesting maximum efficacy after two to three cycles, especially by week 12 [118]. Research has also explored the efficacy and safety of shorter intervals between injections [119]. In this context, considering molecular pharmacodynamics is essential: it was found that BoNT-A’s maximum effect on muscle spasticity, as measured by changes in the MAS, peaks around 5 weeks post-injection, with variations in effect duration among different formulations. AbobotulinumtoxinA, for instance, maintains its effects for up to approximately 13.1 weeks. This is longer than OnabotulinumtoxinA and others, which last about 8.6 weeks [120]. Moreover, it seems that there is a correlation between the dose and the duration of BoNT-A effect. According to the dose–duration correlation, the amount of BoNT-A administered can impact how long its therapeutic effects last, with higher doses potentially leading to a longer duration of action up to a saturation point near three months, after which additional increases in dose fail to significantly prolong its efficacy [121,122]. Timing of treatment initiation following the onset of spasticity plays a crucial role. While many studies have mainly focused on patients with long-term spasticity (averaging 2.5 years after stroke), it is imperative to discuss the benefits and considerations of early BoNT-A injection (within 3 months of the stroke) [123]. Early treatment refers to initiating medical interventions or therapies as soon as possible after the onset of a disease or condition. This approach focuses on intervening before the spasticity leads to further complications, emphasizing the potential for more effective management and improved outcomes. Research by Rosales et al. significantly advanced the understanding of timely BoNT-A application in treating spasticity following a stroke, highlighting the therapeutic potential of early intervention for improving patient outcomes [124]. In 2012, they found that early BoNT-A intervention significantly improved function and quality of life in patients with upper limb spasticity [124]. Building on this, their 2016 meta-analysis further confirmed the safety and efficacy of early BoNT-A treatment, emphasizing its crucial role in timely intervention [123]. Lastly, in 2018, Rosales et al. suggested that early treatment with BoNT-A might not only benefit immediate spasticity management but also potentially modify disease progression and reduce the frequency of required re-injections [125]. This theme has been explored further in recent studies [126]. These findings suggest that initiating treatment soon after stroke onset can notably enhance motor re-learning, which is crucial for rehabilitation [127]. Additionally, early intervention is associated with reduced contracture development, without interfering with the recovery of arm function [128]. Moreover, integrating this treatment with multimodal rehabilitation therapies significantly improves functional recovery and quality of life [129]. It is important to note that some limitations may derive from defining early intervention for spasticity as treatment administered within 3 months of the event. The onset of spasticity varies, with some cases emerging 6 months post-stroke. Additionally, data on early treatment for spasticity due to other causes like traumatic brain injury and spinal cord injuries, which often lead to severe complications, are lacking. Therefore, early treatment should be defined by the onset of spasticity symptoms rather than a fixed time since an event, emphasizing the importance of early detection before considering early treatment [130]. Essential to this approach is the early detection of spasticity, emphasizing the need to identify prognostic indicators and predictive markers for the onset of spasticity, especially in its more disabling forms [131,132,133]. In the context of spastic paresis, understanding the effectiveness of early treatment and its impact on function requires not just predictors of spasticity but also predictors of function [134] to distinguish patients who may benefit from early treatment in terms of both spasticity and functionality. Further research is necessary to explore the incidence of spastic paresis and identify predictive markers for this condition. The treatment of spasticity with botulinum toxin involves specific dosage guidelines that vary between formulations. According to the FDA, for OnabotulinumtoxinA administration, adults should not exceed a total dose of 400 units within a 3-month interval, while pediatric doses should not surpass the lesser of 10 units/kg or 340 units. IncobotulinumtoxinA is recommended at up to a 400 units total dose for adult upper limb spasticity, divided among affected muscles. The relationship between botulinum toxin dosage and the incidence of adverse events is a topic of considerable interest and has been explored in various studies. Bakheit et al. [ 27 ] and Pittock et al. [142] set out a randomized, double-blind, placebo-controlled trial assessing the efficacy and safety of three doses of AbobotulinumtoxinA (500, 1000, and 1500 units) in post-stroke spasticity. Bakheit et al. found the optimal dose for upper limb muscle spasticity was 1000 units, emphasizing minimal adverse events and establishing safety parameters, while Pittock et al. demonstrated significant improvements in calf spasticity and limb pain without substantial safety concerns even with higher doses, such as 1500 units. These studies underscore the importance of dose optimization and safety in BoNT-A therapy across different muscle groups As a drug product for local administration, BoNTA can be directly injected into a target muscle with localized hypertonia to relax the muscle. Its direct relaxant effect on the muscle causing spasticity may reduce equinus foot and improve walking ability, leading to the improved ADL performance of patients. This effect is expected to reduce the dependence on care when walking inside or outside as well as to reduce the burden for patients, family, and caregivers. The observed persistence of the efficacy of a single BoNTA treatment for 12 weeks suggests possible better treatment compliance compared to the use of oral muscle relaxants that require daily medication [ 28 ]. Moreover, BoNTA may be an effective treatment choice for patients who have difficulty treating spasticity with oral muscle relaxants because of adverse drug reactions. LIMITATIONS since there were only 30 patients in the study. We advocate that future studies should atleast include 100 or more patients so there shall be less follow up problem as in our study few 4 patients didnt followed or showed up. Declarations Funding This study received no external funding. Institutional Review Board Statement Not applicable. Informed Consent Statement consent were taken from all patients who participated in the study. Data Availability Statement The data presented in this study are available within the text. Conflicts of Interest The authors declare no conflicts of interest. 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This paper presents an analysis of research concerning BoNT-A treatment of spasticity to elucidate current trends and future directions in this research area.\u003c/p\u003e\n\u003cp\u003eSpasticity is a disorder that typically develops as a result of lesions in the central sensorimotor network, leading to upper motor neuron syndrome [1]. It is characterized by a velocity-dependent increase in muscle tone and reflexes [2]. Its prevalence varies according to the underlying condition, with estimates indicating its occurrence in 25.3% to 39.5% of stroke survivors [3], up to 60% of multiple sclerosis patients [4], up to 30% of patients with traumatic brain injury [5], and more than 80% of the population with cerebral palsy [6]. Spasticity, aside from its cerebral and spinal causes, can also have a genetic basis, as evidenced in hereditary spastic paraplegias, which affect between two and five individuals per 100,000 worldwide [3]. This heterogeneity in prevalence, coupled with its impact on motor function and quality of life, underscores the challenges in managing spasticity effectively\u003c/p\u003e\n\u003cp\u003eBotulinum toxin type-A (BoNT-A) has emerged as a pivotal therapeutic agent in the management of spasticity owing to its ability to induce chemodenervation through its action on presynaptic neurons [12]. The use of BoNT-A has substantially increased over the years, demonstrating its growing acceptance and application in clinical practice. The evolution of BoNT-A as a treatment modality for spasticity reflects a significant shift in the approach to managing this condition. Initially, the focus was predominantly on the symptomatic relief of spasticity and related impairments [13,14,15]. However, with a growing body of evidence supporting the efficacy of BoNT-A in improving functional outcomes and quality of life, its use has expanded and has become more sophisticated [10,16,17]\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003eA total of 30 patients participated in the study conducted in LLR Hospital PGI Building between March 2023 - February 2024. Both written and informed consent were taken. In all the patients Botulinum toxin A was injected in both upper and lower limb. Out of this 20 were Right handed and 10 were left handed. A total of 10 sites were identified in both upper and lower limb and subsequent 0.5 ml was given in each site. We have done this in all cases suffering from stroke.\u003c/p\u003e\u003cp\u003e The study was approved by the Institutional Review Board and was conducted according to the Declaration of Helsinki and the GCP; all patients signed informed consent.\u003c/p\u003e\u003cp\u003eMale or female patients aged 20\u0026ndash;50 years and weighing at least 70 kg were eligible if they had had a stroke at least 1 year prior to treatment and had equinus deformity (plantar flexion of the ankle) as demonstrated by a score of \u0026gt;\u0026thinsp;2 for ankle flexors on the Modified Ashworth Scale (MAS) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eExclusion criteria were bilateral hemiplegia or quadriplegia; fixed contractures in the ankle; profound atrophy of the muscles to be injected; prior treatment with surgery, phenol/ethanol block, muscle afferent block (MAB), intrathecal baclofen, or any botulinum toxin serotype; and current use of peripheral muscle relaxants. Women were excluded if they were pregnant, lactating, potentially pregnant, or planning to become pregnant during the course of the study.\u003c/p\u003e\u003cp\u003eThe primary study objective was to confirm the superior efficacy of a single treatment of BoNTA 500 U in patients with post-stroke upper and lower limb spasticity using the MAS ankle score. MAS is widely used for the assessment of muscle tone and spasticity in lower limbs [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Investigators were trained in the procedures to assess the MAS ankle score at the study start. Patients were assessed in the prone position, and the ankle was examined from the edge of the examination table for the MAS ankle score. The study included a screening examination (2\u0026ndash;4 weeks before the treatment), a single treatment, and a 12-week follow-up period. Patients visited the center at screening, on the treatment day, and at weeks 1, 4, 6, 8, and 12 for specified examinations, observations, and assessments.\u003c/p\u003e\u003cp\u003eOne vial of BoNTA (GSK1358820, BOTOX\u003csup\u003e\u0026reg;\u003c/sup\u003e, Allergan, Inc., Irvine, CA) contains 100 U of a specific formulation (Formulation 9060X) of botulinum toxin type A, 0.5 mg human serum albumin, and 0.9 mg sodium chloride per vial, which requires reconstitution prior to injection. The indistinguishable placebo contained 0.9 mg sodium chloride per vial. Each vial was reconstituted with 8 ml of non-preserved physiological saline resulting in a final concentration of 1.25 U BoNTA per 0.1 ml.\u003c/p\u003e\n\u003ch3\u003eDrug dose and muscle selection\u003c/h3\u003e\n\u003cp\u003eDrug dose and muscle selection was based on the Australian package insert [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Patients were randomly assigned to receive a single injection of 500 U of BoNTA and were injected with 50 U of BoNTA per muscle into each of the following in upper limb : biceps brachii, brachioradialis, brachialis, pronator teres, supinator, Flexor carpi radialis, ulnaris, opponens pollicis, Abductor pollicis brevis and in the lower limb : medial head of the gastrocnemius, lateral head of the gastrocnemius, and soleus muscle and tibialis posterior muscle (divided into three sites per muscle).\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eAssessments\u003c/h2\u003e\u003cdiv id=\"Sec4\" class=\"Section3\"\u003e\u003ch2\u003eEfficacy\u003c/h2\u003e\u003cdiv id=\"Sec5\" class=\"Section4\"\u003e\u003ch2\u003eMAS\u003c/h2\u003e\u003cp\u003eThe muscle tone of the ankle was assessed by the investigator using the MAS [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] at screening, pre-injection on the treatment day (baseline), and at weeks 1, 4, 6, 8, and 12 or at study withdrawal.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e\n\u003ch3\u003eGait pattern scale (physician’s rating scale)\u003c/h3\u003e\n\u003cp\u003eThe investigator assessed the gait pattern while the patient walked 10 m using the Physician\u0026rsquo;s Rating Scale [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] (Table\u0026nbsp;1) pre-injection on the treatment day and at weeks 1, 4, 6, 8, and 12 or at study withdrawal. This scale of -1 (worst) to 9 (best) based on three parameters (initial foot contact, foot contact at midstance, and gait-assisting devices) is an observational gait scale originally developed by Koman et al. [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]., modified by Corry [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], and subsequently modified by Boyd et al. [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In this study, gait parameters that were suitable for the intended purpose were selected from the original parameters.\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eData analysis\u003c/h2\u003e\u003cp\u003eAssuming a mean difference of 5 points in the AUC for the MAS ankle and wrist score change between BoNTA and placebo based on the results and a SD value of 7.5 for both treatments, 15 subjects per group were be required to provide 90% power at the 5% level of significance (two-sided) using t-test to achieve superiority over placebo.\u003c/p\u003e\u003cp\u003eEfficacy data were analyzed using the full analysis set (FAS), defined as all patients that received study treatment and had at least one MAS ankle assessment after treatment.\u003c/p\u003e\u003cp\u003eThe AUC of the change from baseline in the MAS ankle and wrist score was the primary endpoint. Considering the differences of individual peak efficacy, the assessment over the treatment period by AUC as summary index was considered to provide more accurate evaluation than assessment at a specific time point [\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], resulting in more accurate evaluation of efficacy of BoNTA. MAS ankle scores at individual time points were also evaluated. For each patient, the change from baseline (the day of the treatment) in the MAS ankle score at each time point was calculated; \u0026ldquo;1+\u0026rdquo; was analyzed as score 1.5. Changes from baseline (vertical axis) were plotted against time (horizontal axis), and the area under the resultant curve was obtained. A decrease from baseline resulted in a negative (\u0026minus;) AUC value, while an increase from baseline resulted in a positive (+) AUC value and was tested using a t-test. The point estimate and the 95% CI of the mean group difference were also calculated.\u003c/p\u003e\u003cp\u003eChanges from baseline in the MAS ankle and wrist score, the Physician\u0026rsquo;s Rating Scale, the speed of gait, and the CGI at each time point were summarized by group; the Wilcoxon test was used to determine statistical differences between the BoNTA injection given in upper and lower limb specifically.\u003c/p\u003e\u003cp\u003eSafety data were analyzed for the safety population (SP), defined as all patients that received study treatment.\u003c/p\u003e\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eIn 18 patients out of 30, there was more improvement in lower limb after botox type A injection as compared with upper limb with similar units that were injected. Remaining 12 patients got a substantial improvement in spasticity may be owing to severity of damage in stroke.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eBotulinum toxins are produced by various Clostridium species and are composed of two peptide chains linked by a disulfide bond, with significant variations in their amino acid sequences among different serotypes and subtypes [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]. The molecular structure of BoNT-A is characterized by three distinct domains: the heavy chain, which specifically binds to neurons, facilitating the toxin\u0026rsquo;s entry; the translocation domain, responsible for translocating the light chain into the neuronal cell cytosol; and the enzymatically active light chain, which cleaves specific SNARE proteins, disrupting neurotransmitter release by blocking vesicle fusion on the inner surface of cellular membrane [\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e]. This structure allows BoNT-A to effectively inhibit acetylcholine release at neuromuscular junctions, leading to reversible muscle paralysis [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]. The duration of BoNT-A\u0026rsquo;s action varies, typically lasting several months, as the neuron gradually recovers function either through the sprouting of new synaptic contacts or the regeneration of cleaved SNARE proteins, thereby restoring neurotransmission.\u003c/p\u003e\u003cp\u003eBoNT-A has been developed into three distinct injectable formulations for clinical applications in spasticity: OnabotulinumtoxinA (Botox), AbobotulinumtoxinA (Dysport), and IncobotulinumtoxinA (Xeomin) [\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e]. Apart from spasticity indications, there are various other formulations available, including DaxibotulinumtoxinA, LetibotulinumtoxinA, and PrabotulinumtoxinA [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]. Regarding spasticity treatment, all three BoNT-A formulations have received Food and Drugs Administration (FDA) approval [\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e]. OnabotulinumtoxinA, first approved by the FDA in 1989 for strabismus and blepharospasm, gained its inaugural approval for spasticity management on 10 March 2010, specifically for the treatment of upper limb spasticity in adults; this approval was expanded on 29 July 2021. AbobotulinumtoxinA initially received FDA approval on 30 April 2009 for cervical dystonia and glabellar lines and obtained approval for upper limb spasticity on 17 July 2015. IncobotulinumtoxinA was approved for cervical dystonia and blepharospasm on 2 August 2010, and was the first treatment approved for adult upper limb spasticity on 23 December 2015. Notably, the regulatory standards for the use of botulinum toxin for spasticity vary among different countries. The three formulations of BoNT-A, which share the same fundamental mechanism of action, exhibit variations in the quantity of neurotoxins, complexing protein sizes, excipient composition [\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e], and potency [62]. Furthermore, other differences, such as dilution and the potential for inducing neutralizing antibodies may further differentiate their clinical profiles (i.e., efficacy, duration of effect, and adverse events) [\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e]. The comprehensive impact of these dissimilarities on clinical outcomes remains an area of ongoing investigation and has not yet been fully elucidated. Owing to these distinctions, it is essential to acknowledge that these formulations are not interchangeable in clinical practice [63]. Each formulation requires specific consideration in terms of dosage, administration, and expected outcomes.\u003c/p\u003e\u003cp\u003eThe application of botulinum toxin in adult spasticity includes its use in stroke and non-stroke patients, highlighting its role in improving functional outcomes and quality of life.\u003c/p\u003e\u003cp\u003eWe analyzed the role of BoNT-A in managing spasticity in patients with stroke, drawing on a range of influential studies in the field. Spasticity occurs in 20\u0026ndash;30% of all stroke patients, more commonly in the upper limbs than in the lower limbs, and seems to be more prevalent among younger patients [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Initially, studies such as those by Sommerfeld et al. and Bhakta et al. laid the foundation for understanding the prevalence and impact of post-stroke spasticity. Sommerfeld et al. highlighted that while spasticity contributes to motor impairments and activity limitations, it was present in only 19% of the stroke patients included at 3 months post-stroke, suggesting a need for careful evaluation before deciding on rehabilitation approaches [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Bhakta et al. demonstrated the effectiveness of BoNT-A in reducing disability and carer burden in patients with chronic stroke and upper limb spasticity, albeit observing the potential for muscle weakness following treatment [89]. Subsequently, Brashear et al. conducted a placebo-controlled trial showing that BoNT-A significantly improved flexor tone in the wrist and fingers post-stroke, with patients reporting greater improvement in selected areas of disability such as hygiene and dressing [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Elovic et al. assessed the safety and effects of repeated treatments with BoNT-A on functional disability, quality of life (QOL), and muscle tone in patients with upper limb post-stroke spasticity. They highlighted that repeated treatments with BoNT-A every 12 weeks for up to 56 weeks were well tolerated and significantly improved outcome.\u003c/p\u003e\u003cp\u003eTo understand the broader implications of BoNT-A treatment, the multicentric \u0026ldquo;Botulinum Toxin for the Upper Limb after Stroke\u0026rdquo; (BoTULS) study was undertaken. While this study did not find a significant enhancement in overall upper limb function following BoNT-A treatment, it did observe improvements in muscle tone, strength, and performance in specific functional tasks [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. This was further explored by Shaw et al., who concluded that BoNT-A might not significantly improve active upper limb function, but could benefit basic tasks and pain management [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eElia et al. [91], Wissel et al. [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], and Esquenazi et al. [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e] provided a broader perspective on upper and lower limb spasticity treatment. Wissel et al. emphasized the value of BoNT-A in managing spasticity following acquired brain injury, including stroke, and advocated further studies addressing active function. Elia et al. and Esquenazi et al. reinforced the efficacy of BoNT-A in reducing muscle tone and improving passive function, while also noting less robust improvements in active function [49,91]. Both studies revealed fewer studies for lower limb spasticity and the need for further good-quality studies assessing the efficacy of BoNT-A on lower limb spasticity. A paper with a recent citation burst, \u0026ldquo;Efficacy and safety of AbobotulinumtoxinA in spastic lower limb\u0026rdquo; by Gracies et al. [92] (Fig.\u0026nbsp;9), found that after a single injection of BoNT-A, there were significant improvements observed in muscle tone in the gastrocnemius\u0026ndash;soleus complex, and that these improvements continued with repeated treatments. Importantly, this study reported an increase in comfortable barefoot walking speed and a greater likelihood of achieving community ambulation over the course of the year.\u003c/p\u003e\u003cp\u003eIn conclusion, while the majority of existing studies have concentrated on the upper limbs, the growing focus on lower limb treatment represents an important evolution in the field. As research continues to evolve, it is anticipated that treatments will increasingly address the full spectrum of spasticity-related challenges faced by patients to avoid complications, thereby enhancing the effectiveness of rehabilitation strategies in post-stroke care and improving patient quality of life [93]. Furthermore, current trends suggest a pivot towards optimizing BoNT-A\u0026rsquo;s use on its own or in conjunction with other therapies to maximize patient outcomes, as we will analyze in the next paragraphs.\u003c/p\u003e\u003cp\u003eFor upper limb spasticity, trials have consistently shown that AbobotulinumtoxinA, administered at doses ranging from 500 to 1500 U, significantly reduces muscle tone, as evidenced by the Modified Ashworth Scale, with notable yet variable improvements in active movement and pain [106]. Lower limb spasticity studies echo these findings, with AbobotulinumtoxinA demonstrating statistically significant reductions in muscle tone and consistent relief in pain symptoms [107]. Advancements in the treatment of adult spasticity with OnabotulinumtoxinA have been significantly shaped by various clinical trials worldwide. Notably, the REFLEX trial played a crucial role in obtaining FDA approval for the treatment of lower limb spasticity [108,109]. This was complemented by comprehensive studies that further elucidated the efficacy of OnabotulinumtoxinA in managing upper limb spasticity [21,42,110,111]. Two Phase 3 trials were conducted to investigate the use of IncobotulinumtoxinA in treating upper limb spasticity post-stroke. The first trial, including 148 patients, demonstrated sustained improvements in muscle tone and functionality after a single injection and over an extended period with repeated treatments [112]. The second trial involved 259 patients who demonstrated significant improvements in muscle tone and functional disability, with the majority of patients responding positively to treatment [113]. These results further confirmed significant improvements in muscle tone and global impressions of change over three treatment cycles, each 12 weeks apart, with minimal treatment-related adverse events [114]. The TOWER study evaluated the safety and efficacy of increasing doses of IncobotulinumtoxinA in treating patients with limb spasticity due to cerebral causes [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. Involving 155 patients, the study concluded that increasing IncobotulinumtoxinA doses up to 800 U is safe and tolerable, allowing treatment of a greater number of muscles. Finally, the recent J-PURE phase III double-blind study, which involved participants receiving either 400 U of IncobotulinumtoxinA or a placebo, followed by an open-label extension, demonstrated significant improvements in muscle tone, as measured by the Modified Ashworth Scale [115].\u003c/p\u003e\u003cp\u003eThe timing and frequency of repeated botulinum toxin treatments for spasticity are key factors for achieving sustained therapeutic effects. Determining the correct intervals for botulinum toxin treatment in spasticity management is crucial for maximizing the therapeutic benefits. Treatments every 12 weeks up to 56 weeks have demonstrated improvements in muscle tone and quality of life [116]. Longitudinal studies, such as Turner-Stokes et al. [117], have indicated significant upper-limb spasticity and functional improvements over two years with repeated treatments, suggesting maximum efficacy after two to three cycles, especially by week 12 [118]. Research has also explored the efficacy and safety of shorter intervals between injections [119]. In this context, considering molecular pharmacodynamics is essential: it was found that BoNT-A\u0026rsquo;s maximum effect on muscle spasticity, as measured by changes in the MAS, peaks around 5 weeks post-injection, with variations in effect duration among different formulations. AbobotulinumtoxinA, for instance, maintains its effects for up to approximately 13.1 weeks. This is longer than OnabotulinumtoxinA and others, which last about 8.6 weeks [120]. Moreover, it seems that there is a correlation between the dose and the duration of BoNT-A effect. According to the dose\u0026ndash;duration correlation, the amount of BoNT-A administered can impact how long its therapeutic effects last, with higher doses potentially leading to a longer duration of action up to a saturation point near three months, after which additional increases in dose fail to significantly prolong its efficacy [121,122].\u003c/p\u003e\u003cp\u003eTiming of treatment initiation following the onset of spasticity plays a crucial role. While many studies have mainly focused on patients with long-term spasticity (averaging 2.5 years after stroke), it is imperative to discuss the benefits and considerations of early BoNT-A injection (within 3 months of the stroke) [123]. Early treatment refers to initiating medical interventions or therapies as soon as possible after the onset of a disease or condition. This approach focuses on intervening before the spasticity leads to further complications, emphasizing the potential for more effective management and improved outcomes.\u003c/p\u003e\u003cp\u003eResearch by Rosales et al. significantly advanced the understanding of timely BoNT-A application in treating spasticity following a stroke, highlighting the therapeutic potential of early intervention for improving patient outcomes [124]. In 2012, they found that early BoNT-A intervention significantly improved function and quality of life in patients with upper limb spasticity [124]. Building on this, their 2016 meta-analysis further confirmed the safety and efficacy of early BoNT-A treatment, emphasizing its crucial role in timely intervention [123]. Lastly, in 2018, Rosales et al. suggested that early treatment with BoNT-A might not only benefit immediate spasticity management but also potentially modify disease progression and reduce the frequency of required re-injections [125]. This theme has been explored further in recent studies [126]. These findings suggest that initiating treatment soon after stroke onset can notably enhance motor re-learning, which is crucial for rehabilitation [127]. Additionally, early intervention is associated with reduced contracture development, without interfering with the recovery of arm function [128]. Moreover, integrating this treatment with multimodal rehabilitation therapies significantly improves functional recovery and quality of life [129].\u003c/p\u003e\u003cp\u003eIt is important to note that some limitations may derive from defining early intervention for spasticity as treatment administered within 3 months of the event. The onset of spasticity varies, with some cases emerging 6 months post-stroke. Additionally, data on early treatment for spasticity due to other causes like traumatic brain injury and spinal cord injuries, which often lead to severe complications, are lacking. Therefore, early treatment should be defined by the onset of spasticity symptoms rather than a fixed time since an event, emphasizing the importance of early detection before considering early treatment [130]. Essential to this approach is the early detection of spasticity, emphasizing the need to identify prognostic indicators and predictive markers for the onset of spasticity, especially in its more disabling forms [131,132,133]. In the context of spastic paresis, understanding the effectiveness of early treatment and its impact on function requires not just predictors of spasticity but also predictors of function [134] to distinguish patients who may benefit from early treatment in terms of both spasticity and functionality. Further research is necessary to explore the incidence of spastic paresis and identify predictive markers for this condition.\u003c/p\u003e\u003cp\u003e The treatment of spasticity with botulinum toxin involves specific dosage guidelines that vary between formulations. According to the FDA, for OnabotulinumtoxinA administration, adults should not exceed a total dose of 400 units within a 3-month interval, while pediatric doses should not surpass the lesser of 10 units/kg or 340 units. IncobotulinumtoxinA is recommended at up to a 400 units total dose for adult upper limb spasticity, divided among affected muscles.\u003c/p\u003e\u003cp\u003eThe relationship between botulinum toxin dosage and the incidence of adverse events is a topic of considerable interest and has been explored in various studies. Bakheit et al. [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] and Pittock et al. [142] set out a randomized, double-blind, placebo-controlled trial assessing the efficacy and safety of three doses of AbobotulinumtoxinA (500, 1000, and 1500 units) in post-stroke spasticity. Bakheit et al. found the optimal dose for upper limb muscle spasticity was 1000 units, emphasizing minimal adverse events and establishing safety parameters, while Pittock et al. demonstrated significant improvements in calf spasticity and limb pain without substantial safety concerns even with higher doses, such as 1500 units. These studies underscore the importance of dose optimization and safety in BoNT-A therapy across different muscle groups\u003c/p\u003e\u003cp\u003eAs a drug product for local administration, BoNTA can be directly injected into a target muscle with localized hypertonia to relax the muscle. Its direct relaxant effect on the muscle causing spasticity may reduce equinus foot and improve walking ability, leading to the improved ADL performance of patients. This effect is expected to reduce the dependence on care when walking inside or outside as well as to reduce the burden for patients, family, and caregivers. The observed persistence of the efficacy of a single BoNTA treatment for 12 weeks suggests possible better treatment compliance compared to the use of oral muscle relaxants that require daily medication [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Moreover, BoNTA may be an effective treatment choice for patients who have difficulty treating spasticity with oral muscle relaxants because of adverse drug reactions.\u003c/p\u003e\n\u003ch3\u003eLIMITATIONS\u003c/h3\u003e\n\u003cp\u003esince there were only 30 patients in the study. We advocate that future studies should atleast include 100 or more patients so there shall be less follow up problem as in our study few 4 patients didnt followed or showed up.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThis study received no external funding.\u003c/p\u003e\n\u003ch2\u003eInstitutional Review Board Statement\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch2\u003eInformed Consent Statement\u003c/h2\u003e\n\u003cp\u003econsent were taken from all patients who participated in the study.\u003c/p\u003e\n\u003ch2\u003eData Availability Statement\u003c/h2\u003e\n\u003cp\u003eThe data presented in this study are available within the text.\u003c/p\u003e\n\u003ch2\u003eConflicts of Interest\u003c/h2\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePandyan, A. D. et al. 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[Google Scholar] [CrossRef] [PubMed].\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 is not available with this version.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Botulinum toxin, Clinical trials randomized controlled, Spasticity, Modified Ashworth Scale, Lower limb","lastPublishedDoi":"10.21203/rs.3.rs-8320925/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8320925/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eLower limb spasticity in post-stroke patients can impair ambulation and reduces activities of daily living (ADL) performance of patients. Botulinum toxin type A (BoNTA) has been shown effective for upper limb spasticity.\u003c/p\u003e\n\u003cp\u003eThirty patients with both upper and lower limb spasticity were given a single treatment with BoNTA 500 units. The tone of the ankle flexor was assessed at baseline and through 12 weeks using the Modified Ashworth Scale (MAS). Gait pattern and speed of gait were also assessed. The primary endpoint was area under the curve (AUC) of the change from baseline in the MAS ankle score. Significant improvement in spasticity with BoNTA 500 U was demonstrated by a mean difference in the AUC of the change from baseline in the MAS ankle score between the BoNTA and placebo groups (−3.428; 95% CIs, −5.841 to −1.016; \u003cem\u003ep\u003c/em\u003e = 0.006; \u003cem\u003et\u003c/em\u003e test). A significantly greater decrease from baseline in the MAS ankle score was noted at weeks 4, 6 and 8 in the BoNTA group compared to the placebo group (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001). Significant improvement in the Clinicians Global Impression was noted by the investigator at weeks 4, 6 and 8 (\u003cem\u003ep\u003c/em\u003e = 0.016–0.048, Wilcoxon test), but not by the patient or physical/occupational therapist. Assessments of gait pattern using the Physician’s Rating Scale and speed of gait revealed no significant treatment differences but showed a tendency towards improvement with BoNTA. No marked difference was noted in the frequency of treatment-related adverse events between BoNTA and placebo groups. This was the first small scale trial to indicate that BoNTA significantly reduced spasticity in lower limb muscles comparatively with upper limb muscles.\u003c/p\u003e","manuscriptTitle":"The Effect of Botulinum Toxin Type-A in Spastic Upper limb and lower limb - Is it same or different","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-11 18:23:05","doi":"10.21203/rs.3.rs-8320925/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ec6e984d-4463-4233-9de6-cfb4da925775","owner":[],"postedDate":"December 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":59510738,"name":"Health sciences/Diseases"},{"id":59510739,"name":"Health sciences/Health care"},{"id":59510740,"name":"Health sciences/Medical research"},{"id":59510741,"name":"Health sciences/Neurology"},{"id":59510742,"name":"Biological sciences/Neuroscience"}],"tags":[],"updatedAt":"2025-12-13T06:39:09+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-11 18:23:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8320925","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8320925","identity":"rs-8320925","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}