Therapeutic Management of Post-Stroke Spasticity in Adults With Botulinum Toxin

PSS is a common complication affecting individuals who have experienced a stroke, with prevalence rates ranging from 4% to 43%, depending on the time since stroke onset.^1-3 PSS can significantly impair motor function and quality of life, particularly when affecting the lower limbs.^1,4 BoNT-A injections have emerged as a key therapeutic option for managing focal spasticity in both upper and lower limbs, as recommended by treatment guidelines.^1,3
 
The landscape of BoNT-A therapies for PSS encompasses 3 main formulations: onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA. While these formulations share the same active ingredient, they vary in their associated proteins and albumin content, with negligible impact on clinical efficacy. Equivalence ratios have been proposed to guide dosing across different brands, although no clinical studies have directly compared their effect durations. Several factors, including the type of BoNT preparation, injection site, and dose, can influence treatment outcomes, emphasizing the need for tailored approaches in clinical settings.²
 
Despite the established efficacy of BoNT-A formulations in managing PSS, questions remain regarding the optimal timing of treatment initiation, particularly in the acute phase following stroke onset. While guidelines recommend early intervention, BoNT-A is often administered during the chronic phase due to the variable prevalence of PSS and limited evidence from clinical trials.³ Future research in PSS should focus on conducting well-designed clinical trials to further evaluate the efficacy and safety of BoNT-A treatments, particularly in lower-limb spasticity.¹ Such research will help clarify the optimal timing of BoNT-A administration in relation to stroke onset and its impact on treatment outcomes in routine clinical practice.
 
With more than 11 years of experience, Parneet K. Grewal, MD, is a vascular neurologist and clinical assistant professor of neurology at the Medical University of South Carolina in Charleston. Clinically, Dr Grewal’s specialties include stroke, transient ischemic attack, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome, and myoclonic epilepsy associated with ragged red fibers. In this article, Dr Grewal explores the treatment landscape for managing PSS in adult patients using BoNT and sheds light on future directions for research.

Can you elaborate on the significance of achieving high rates of primary and secondary objectives in post-stroke lower-limb spasticity management using BoNT-A?

Stroke is a major cause of disability, leading to strength loss, skill decline, spasticity, and abnormal posture. The study by López de Munain et al demonstrated the effectiveness of BoNT-A injections in treating lower-limb spasticity in adults post-stroke. Using goal attainment scaling for personalized evaluation based on patient-set goals, these findings offer valuable insights into BoNT-A treatment efficacy from a patient’s perspective.⁵
 
Patient-identified primary treatment goals commonly focus on mobility and positioning improvement, with secondary goals including enhancing mobility and reducing pain. By addressing functional limitations and pain based on patient preferences and expectations, the study’s results indicate that a significant number of patients achieve primary and secondary goals after a single cycle of BoNT-A was administered in accordance with clinical practice guidelines. Notably, 88.3% of primary goals and 79.1% of secondary goals were achieved, signifying clinically meaningful functional and symptomatic improvements.⁵
 
Overall, current literature indicates that BoNT-A treatment has demonstrated effectiveness in improving function and relieving symptoms of lower-limb spasticity post-stroke, as indicated by meeting primary and secondary objectives through personalized goals.⁵ By emphasizing personalized treatment goals, clinicians like myself can tailor interventions to individual patient needs, ultimately enhancing outcomes and quality of life.

Could you discuss the identified predictive factors, such as the impact of increasing time since the onset of stroke and the absence of a stiff knee, on the attainment of treatment objectives?

Two key factors influence how patients respond to BoNT-A treatment and achieve their treatment goals. These factors include time since stroke onset and the absence of stiff knee spasticity pattern. The odds of reaching primary goals decrease as time since stroke onset increases (odds ratio, 0.907; 95% CI, 0.827-0.995; P =.038). Early treatment post-stroke with BoNT-A increases the likelihood of goal achievement and improvement compared to delayed treatment.⁵
 
Stiff knee gait, a common abnormal post-stroke pattern, hinders achievement of treatment goals by affecting knee flexion during walking. Patients without this gait pattern are more likely to reach primary goals, highlighting the challenge posed by stiff knee spasticity. Primary treatment goals include enhancing mobility and positioning, which may be harder to achieve with stiff knee spasticity after BoNT-A injections.⁵
 
Early intervention in managing PSS is of utmost importance, as delaying treatment can lead to a decreased likelihood that patients will attain their primary goals related to mobility and positioning.^3,5 This finding aligns with prior research, emphasizing the significance of early BoNT-A treatment for lower-limb spasticity post-stroke and the impact of specific spasticity patterns on treatment outcomes.⁵ Understanding these predictive factors can assist clinicians in optimizing treatment strategies and enhancing patient outcomes.

Francisco et al discuss varying conversion ratios between onabotulinumtoxinA and abobotulinumtoxinA, ranging from 1:1 to 1:11 in clinical studies.⁶ Given the lack of a universally agreed-upon conversion ratio, how would you approach determining an appropriate conversion ratio in real-world scenarios when transitioning patients between these 2 formulations to manage PSS? Additionally, in your experience, how does the lack of standardized conversion ratios impact the continuity and effectiveness of BoNT-A treatment in patients with PSS, and what strategies do you employ to mitigate potential risks during transitions between formulations?

BoNTs are well-established treatment options for conditions like spasticity, and there are multiple serotypes currently available worldwide. The 3 most common products for spasticity are onabotulinumtoxinA (Botox^®), abobotulinumtoxinA (Dysport^®), and incobotulinumtoxinA (Xeomin^®).² Despite differences among these products, their therapeutic effects are all mediated by the 150 kilodalton (kDa) BoNT.⁷ However, due to dosing variations, each product has unique dosing guidelines based on potency units. Each manufacturer determines the potency of the neurotoxin by measuring its median lethal dose, which varies between manufacturers.² This indicates that although the neurotoxin is the same, precise doses are not directly interchangeable between different products.^6,7 While each product has a similar safety profile, determining an appropriate conversion ratio between onabotulinumtoxinA and abobotulinumtoxinA for managing spasticity poses challenges due to the lack of a universally agreed-upon conversion ratio.⁶
 
As a clinician, I rely on various considerations and approaches in my practice to navigate this process. First, reviewing clinical studies and US Food and Drug Administration (FDA)-approved dosing data packets provides initial guidance, though individual patient responses must be considered. Second, a thorough patient assessment is crucial, considering factors like spasticity severity, distribution, duration, and previous toxin injection responses. Muscle mass, severity of spasticity, and individual characteristics can influence the conversion ratio between toxins.⁶ I recommend starting conservatively to minimize risks when transitioning between formulations and adjusting doses based on the patient response through dose titration.
 
Collaboration with a multidisciplinary team offers valuable insights for determining conversion ratios and managing transitions between formulations. Close monitoring, patient education, collaboration among healthcare teams, and accurate documentation are essential to ensure continuity of care and optimize treatment plans while minimizing risks during transitions between formulations.

Bensmail et al suggest potential benefits of combined upper- and lower-limb treatment.¹ Can you elaborate on the observed improvements in muscle tone in individuals with multi-focal upper- and lower-limb spasticity, emphasizing the potential efficacy of incobotulinumtoxinA in treating lower-limb clinical patterns?

PSS impacts almost half of stroke survivors, significantly affecting their life as well as their caregivers. While a high degree of spasticity is more frequently found in both upper and lower limbs of these individuals, addressing it holistically is crucial for optimal treatment outcomes.¹
 
When treating spasticity, a comprehensive approach involves simultaneously addressing both upper and lower limbs.¹ Utilizing BoNT-A injections, like incobotulinumtoxinA, can effectively reduce muscle tone and stiffness in targeted muscles, improving mobility, range of motion, and functional abilities — for example, in lower-limb spasticity patterns, which can manifest as stiff knee gait and spasticity in hip abductors and flexors. IncobotulinumtoxinA has demonstrated efficacy in enhancing gait and mobility by targeting these specific muscles. This targeted treatment approach can significantly improve daily activities and independence, reduce caregiver burden, and enhance quality of life.¹
 
A patient-centered approach — tailoring treatment plans to an individual’s needs and goals, and combining upper and lower limb treatments as necessary based on clinical presentation and functional limitations — can provide personalized care that addresses the unique challenges faced by each patient.

A study by Ojardias et al highlights the impact of muscle volume on the dose-expressed effect size.² How does this finding influence the therapeutic approach, and what considerations should practitioners keep in mind when injecting BoNT-A into high-volume vs low-volume muscles in PSS?

The finding that muscle volume influences the dose expressed as a function of effect size of BoNT-A injections in patients with PSS has significant implications for treatment strategies. Practitioners must consider several key factors. First, adjusting the dosage based on muscle volume and its impact on the dose-effect size of the toxin is crucial.² When injecting into muscles with high volume vs low volume, practitioners should adjust the dosage of BoNT-A accordingly. Larger muscles may require higher doses to achieve the desired therapeutic effect, while smaller muscles may respond well to lower doses.^2,8 Additionally, practitioners should be cautious about the risk for adverse events associated with higher doses of BoNT-A. Higher doses may increase the likelihood of adverse events without necessarily improving efficacy.²
 
Some common adverse events associated with BoNT-A injections include botulinum syndrome, fatigue, swallowing disorder, and muscle weakness. Following recommended dosage guidelines can help practitioners reduce the risk for these events. Anatomical factors, such as muscle bundles and fascia, can affect the diffusion of BoNT-A within muscles.² Therefore, it is crucial to consider these factors when choosing injection sites and determining the appropriate amount of BoNT-A for each muscle.
 
Patient-specific factors, such as muscle tone, severity of spasticity, and treatment goals, should also inform the decision-making process. Tailoring the approach to meet each patient’s unique needs is essential for effective treatment and improved outcomes.

Looking ahead, Picelli et al propose that future research should focus on functional goals, implications of early BoNT-A treatment such as preventing contracture, compliance with rehabilitation programs, and cost analysis.³ What specific research directions and methodologies would you recommend to further explore these topics and provide comprehensive insights into the therapeutic management of PSS?

We established that spasticity is common after a first stroke, with prevalence rates ranging from 4% to 27% within the first 6 weeks, around 19% at 3 months, between 21.7% to 42.6% from 4 to 6 months, and then 17% to 38% at 12 months post-onset.³ While BoNT-A formulations are commonly recommended for PSS treatment, early intervention is often delayed, with chronic stroke patients typically receiving treatment 6 months or more after the stroke.³
 
The present study aimed to assess the impact of the time between stroke onset and initial BoNT-A injection on spasticity treatment outcomes in routine practice. The absence of a consensus on the timing of early treatment (within 3 or 6 months) for BoNT-A complicates matters. Current literature mainly addresses spasticity in patients more than 6 months post-stroke.³
 
Currently, I recommend adhering to research guidelines and methodologies to establish functional goals for early intervention. Future research should concentrate on defining functional objectives and conducting cost analyses to delve deeper into this issue. Research should also focus on prospective studies regarding the impact of early BoNT treatment, evaluating enhancements in daily activities, mobility, quality of life, and patient involvement in rehabilitation programs.
 
The primary goal is to avoid contractures; hence, it is crucial to explore the effectiveness of early BoNT-A treatments, such as onabotulinumtoxinA, within this framework. Additionally, it is important to contrast outcomes between patients receiving early and delayed BoNT injections via longitudinal studies and analyze factors influencing patient adherence to rehab protocols. Employing qualitative research techniques, such as interviews or surveys, and performing cost analyses to assess the economic implications of early vs late BoNT treatment will improve data.
 
Collaboration among neurologists, rehabilitation specialists, and health economists is crucial to address the clinical, functional, and economic aspects of PSS management. By focusing on these research strategies, future studies can offer valuable insights into optimizing PSS management, improving patient outcomes, and guiding evidence-based clinical practices.

This Q&A was edited for clarity and length.

References

1. Bensmail D, Wissel J, Laffont I, et al. Efficacy of incobotulinumtoxinA for the treatment of adult lower-limb post-stroke spasticity, including pes equinovarus. Ann Phys Rehabil Med. 2021;64(2):101376. doi:10.1016/j.rehab.2020.03.005
 
2. Ojardias E, Ollier E, Lafaie L, Celarier T, Giraux P, Bertoletti L. Time course response after single injection of botulinum toxin to treat spasticity after stroke: systematic review with pharmacodynamic model-based meta-analysis. Ann Phys Rehabil Med. 2022;65(3):101579. doi:10.1016/j.rehab.2021.101579
 
3. Picelli A, Santamato A, Cosma M, et al. Early botulinum toxin type a injection for post-stroke spasticity: a longitudinal cohort study. Toxins (Basel). 2021;13(6):374. doi:10.3390/toxins13060374
 
4. Zorowitz RD, Gillard PJ, Brainin M. Poststroke spasticity: sequelae and burden on stroke survivors and caregivers. Neurol. 2013;80(3)(Suppl 2):S45-S52. doi:10.1212/WNL.0b013e3182764c86
 
5. López de Munain LL, Valls-Solé J, Garcia-Pascual I, Maisonobe P; VALGAS investigators group. Botulinum toxin type A improves function according to goal attainment in adults with poststroke lower limb spasticity in real life practice. Eur Neurol. 2019;82(1-3):1-8. doi:10.1159/000503172
 
6. Francisco GE, Balbert A, Bavikatte G, et al. A practical guide to optimizing the benefits of post-stroke spasticity interventions with botulinum toxin A: An international group consensus. J Rehabil Med. 2021;53(1):1-14. doi:10.2340/16501977-2753
 
7. Nestor MS, Arnold D, Fischer DL. The mechanisms of action and use of botulinum neurotoxin type A in aesthetics: key clinical postulates II. J Cosmet Dermatol. 2020;19(11):2785-2804. doi:10.1111/jocd.13702
 
8. Schnitzler A, Dince C, Freitag A, et al. AbobotulinumtoxinA doses in upper and lower limb spasticity: a systematic literature review. Toxins (Basel). 2022;14(11):734. doi:10.3390/toxins14110734