Facts and de facto treatment of spasticity

Abstract

Recent studies have generally shown favorable outcomes for the use of botulinum toxin (BoNT) injections for the treatment of lower extremity spasticity in children with cerebral palsy. The randomized controlled trials and placebo trials are well described although even those and other studies show high variability in methodology for use of BoNT. This raises questions about which strategies are the most effective. In order to hone the technique, the aim of this review is to discuss these specific parameters: toxin type, dosing, series of injections, localization method, age, number of muscles, and troubleshooting poor outcomes.

1. Introduction

The investigation of evidence for chemoneurolysis can lead down many paths of inquiry. These are the poorly signed streets, avenues, alleyways and dead ends we walk every day with our patients. Location methods? How many muscles to inject? Proper dosing? What about concurrent use of other injections like alcohol or phenol? Although the green light for botulinum toxin (BoNT) [1]has been given, the specifics on where to turn for these answers are less attested. Likewise several hard-boiled facts were delivered in a recent meta-analysis [2] but questions remain concerning said crossroads. Fortunately, some smaller studies have left some possible directions. First, consider this synopsis on the meta-analysis before delving into the thick of things.

The debate on spasticity management for children with cerebral palsy (CP) continues. A literature search can quickly find articles of varying results and recommendations. With respect to comparing some of these studies, Cochrane, one of the leading providers of high level clinical data, published a meta-analysis [2] of studies pitting various interventions against botulinum toxin-A (BoNT-A) injections to lower extremities of children with CP. In this analysis, Blumetti et al. sifted through 1397 initial search results based on the evaluation of efficacy of BoNT-A, control groups, randomization, and age (birth to 19 years old). The outcome from 31 studies, which met the inclusion criteria, was moderate to very low quality of evidence that BoNT-A injections improve walking, joint motion, spasticity and outcome satisfaction. When compared to usual care and placebo, BoNT-A showed improvement in gait, joint range of motion, satisfaction and lower extremity spasticity. There was no difference in function between orthotic use and injections. However, improvement in hip range of motion and hip adductor spasticity was seen with BoNT-A. Lastly gait scores were the same with BoNT-A and serial casting. Even though these studies varied widely with methodology, Blumetti et al. have compiled a landmark review of the current data on BoNT-A. These differences in technique may play significant roles in patient outcomes. Also heterogeneity in design was a particular cause of the low level of evidence reported. Many of the studies had comparable outcome measures although varying methodologies were described. Listed below are significant differences of key components in the reported procedures:

Age: on average patients were 3–7 years old

Repeat Injections: Six reported multiple cycles of BoNT-A injections

Toxin Type: Nineteen studies used onabotulinumtoxinA, seven (possibly 8) abobotulinumtoxinA, and one used the HengLi002-type toxin. Three did not describe the toxin injected.

Dosing: OnabotulinumtoxinA studies ranged from approximately 0.5–8 units/kg/muscle. AbobotulinumtoxinA studies ranged from approximately 10–30 units/kg/muscle.

Number of muscles: Seventeen had fixed predetermined specific muscles to receive injections (e.g. all patients in the study only received injections to gastrocnemius). Fourteen studies reported variable muscle selection (5 focused on predetermined muscles of interest and included 1–2 more muscles as needed, 6 described ‘multiple’ or ‘selected’ muscles, etc., 1 listed that some patients had an additional muscle injected for an unknown reason, 2 stated unspecified lower extremity muscles.)

Localization Method: Fifteen used manual palpation, five electrical stimulation, four ultrasound, and seven did not describe their method.

The authors of the Cochrane review analyzed the outcomes of BoNT-A and did not state intentions to evaluate its delivery. These differences in methodology were a cause for the verdict of low quality and may be part of the reason why results of studies varied. In our practice we have seen that each of these factors can play a decisive role in determining effect.

2. Timing of initial injections

The first of these questions and maybe most important are identifying when to start therapy and goals of treatment. As recognized by many, the early intervention of BoNT has changed the landscape of treating CP. Many clinicians start BoNT injections in children who are younger than two to delay orthopedic surgical intervention [3] and to help functional development even though evidence based guidelines are limited. In typically growing children, muscles and bones grow together. However, muscles in children with spasticity are shorter, leading to shorter bones as well because spastic muscles prohibit bone from growing normally [4]. Size and length discrepancies become worse during growth spurts. Spasticity also produces prolonged pressure to growing bones preventing physiologic derotation of the femur. In the hip, this results in coxa valga which causes significant problems with hip abduction and gait [5]. Benefits of early interventions are three-fold: preventing complications of bone structure maturation, prevention of muscle shortening from chronic spasticity [6], and improvement and facilitation of function by relaxing spastic muscles [7]. Close follow up and continuum of care for spasticity throughout the child’s growth are critical to prevent complications from chronic spasticity such as contractures and muscle atrophy from multiple repeated BoNT injections. Using multidisciplinary multi-modality rehabilitation techniques for strengthening weak muscles in conjunction with BoNT injections may mitigate the negative effect of BoNT on spastic muscles.

3. Follow up and repeat injections

After the decision is made when to commence treatment, the next question to consider is: should the patient be treated again? The vital timeframe for post-injection follow up could be when BoNT shows peak effect, which is often three to six weeks after therapy. This is the best time to evaluate tolerance or side effects, such as weakness, along with goal achievement for injections. After outcomes of injections are assessed, additional physical modalities including stretching and strengthening exercise, splinting and braces are prescribed for continual improvement, maintenance of function, and maximal spasticity management. During this follow up visit, we can modify the next repeat injection plan, including dosing and selection of target muscles to maximize the outcome of following procedures and educate parents and/or caretakers about the benefits of goal-oriented continuum of care. We have seen that multiple rounds of injections given at appropriate intervals provide opportunities to optimize dosage and effect of BoNT and avoid adverse events. Additionally functional deterioration and multiple orthopedic intervention may be prevented. This important effect can be missed if the study design has single injection or limited dose range. At this time the decision on whether to discontinue injections must also be considered. If reasonable troubleshooting (described below) of ineffective outcomes has been considered and the patient has not responded to treatment or if the risk of continuing treatment outweighs benefits, further injection therapy should cease.

4. Toxin type

Following scheduling deliberation, selecting the type of toxin is next as it will influence subsequent decisions. How different are the various types of BoNT? Which will have the most robust and longest lasting effect with the least side effects? OnabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA, and prabotulinumtoxinA are all BoNT-A. However, they have different molecular formulations that may react differently. Also these medications do not have the same potency per unit which makes comparing even more difficult. Our practice has not seen an obvious leader of the pack and we lie in wait for signs of subtype superiority.

5. Dosing

Physiologic response to any medication heavily relies on dosing. Not only did the studies vary in doses of the same types of medication but also used different types of BoNT-A. Choosing which medication and how much of the approved range is not very clear. FDA approved prescribing information for abobotulinumtoxinA and onabotulinumtoxinA are listed by the respective manufactures:

AbobotulinumtoxinA

Spasticity for lower limb in pediatric patients: 10–15 units/kg per limb.

Total dose per treatment session must not exceed 15 units/kg for unilateral lower limb and 30 units/kg for bilateral or 1000 units, whichever is lower.

Upper limb excluding spasticity caused by cerebral palsy: 8–16 units/kg per limb max 16 units/ kg or 640 units, whichever is lower.

Treatment follow up injection not less than 3 months [8].

OnabotulinumtoxinA

Pediatric lower limb spasticity excluding spasticity caused by cerebral palsy: 4–8 units/kg (maximum 300 units) divided among affected muscles.

Both lower limbs or upper and lower limbs in combination, the total dose should not exceed 10 units/kg or 340 units, whichever is lower, a 3-month interval [9].

As seen in the reviewed studies, onabotulinumtoxinA can be used at higher doses up to 400 max units. Initial dosing can be ambiguous since there is no formula that can ensure that the procedures are safe and effective. Planning ahead with proper follow-up for titration of future injections can help determine the ideal dose for each patient. Oftentimes dosage is based on degree of spasticity from the Modified Ashworth Scale (MAS) or Modified Tardieu Scale (MTS). Both scales are generally easy to assess with the patient on the clinic table. We also recommend and, maybe more importantly, consider overall function of the muscles when calculating dosage. A simple demonstration of this concept can be explained by considering injections to the quadriceps. Imagine assessing a patient on the exam table with a high degree of spasticity in the quadriceps. The first thought may be to aggressively treat this markedly increased tone. Thinking solely about a high MAS in isolation may direct dosing calculation to be too high. The quadriceps eccentrically contract during initial contact and the loading response allows the lower limb to accept the weight of the body and prevent it from falling. Although a stiff knee gait impairs ambulation, spasticity in quadriceps may assist an otherwise weak muscle during these phases. Erring on the side of under-treatment will prevent overdosing resulting in knee buckling, leaving the patient worse off than baseline. Gait evaluation and other functional observations should guide proper dosing to improve function rather than spasticity alone.

6. Number of muscles for goal achievement

Now which muscles and how many should be targeted? We also suspect that there are times when injecting a small number of spastic muscles is not enough to reach desired therapeutic outcomes. Injecting more than just the gastrocnemius to improve walking may be needed to achieve goals of treatment. As it is rare that only one muscle is involved, a full evaluation of the child’s ankle, knee and hip is required. Including multiple muscles at times can quickly exceed the limited maximal dose especially in smaller or severely spastic children. Therefore if the manufactures’ recommended weight based maximal dose of BoNT is exceeded but the child would benefit from treatment to additional muscles, phenol or alcohol can be added to make up the difference. The single-event multi-level chemoneurolysis (SEMLC) approach has been developed as CP is a nonfocal condition. A number of overactive muscle groups throughout the leg may need to be targeted in a single session to achieve a specific goal during treatment [7]. Intrathecal baclofen pump (ITB) or selective dorsal rhizotomy (SDR) are also considered to control diffuse and/or severe spasticity. Goal based results of using BoNT along with phenol showed 91.4% attainment compared to BoNT alone with 77.5% [7]. Injecting spastic muscles, as opposed to oral medications, and using ITB to control spasticity, is preferable when goals are improving function of specific muscles [7]. Although ITB is usually an effective option for diffuse and severe spasticity, generalized reduction of spasticity, including extensor spasticity, transfer and ambulatory abilities in walking persons may be compromised [10].

7. Localization method

After the game plan is devised, how can we assure it to be carried out successfully? Although large muscle groups such as hip adductors are distinct, smaller or deeper muscles such as the tibialis posterior are much more difficult to target by palpation alone. With an added level of difficulty presented by muscles in the smaller limbs of children, additional guidance is instrumental. Small deep muscles may be challenging enough to find in children without neurologic pathology but, as seen on ultrasound, chronic spasticity distorts normal anatomy resulting in variable morphology. Cross-sectional drawings in textbooks are based on healthy arrangement and do not demonstrate atrophic or fibrotic muscle shapes. Currently, we do nearly all BoNT injections under ultrasound guidance with sterile technique and/or electrical stimulation. With ultrasound, the needle can be visualized in the target muscle at the appropriate location and depth. Reviews on injection technique showed that ultrasound, electromyography and electrostimulation are superior to manual needle placement [11]. Ultrasound guidance has been recommended to be the most accurate modality of localization [12]. With phenol or alcohol, we prefer electrostimulation guidance to localized specific motor points for injections. At times ultrasound can be used for alcohol or phenol since it is not easy to identify small motor nerves on small atrophic muscles.

8. Troubleshooting poor outcomes

Regardless of increased accuracy and effect of these injections, at times the patient may return for follow up without meeting any treatment goals. Adopting new practices can only go so far if causes of failure are unrecognized. Reasons for missing the mark can be classified as anatomic, dosing, and goal setting. Anatomically, any more than a mild degree of contracture will counter injection effects. Also motor end plates of each particular muscle can be elusive and difficult to find. It is not uncommon that the needle may be in the exact target demonstrated by diagrams but no motor stimulation is seen which makes precise placement of medication uncertain. With regards to dosing, several situations may have unintentional outcomes. Caution must be used with the amount and frequency of alcohol or phenol as both denature protein causing tissue necrosis [13]. We use small doses at multiple sites with electrostimulation guidance to minimize this potentially permanent effect. Dosing may also be too high which can cause weakness. Further, it is well known that an excessive dose of medication injected in the gastrocnemius/soleus for patients with jump gait may instead cause crouched gait. Dosing needs to be balanced between severity of spasticity and muscle function. As stated above, assessment of function is equally as important as degree of spasticity when determining dosage. Another issue with dosing may be related to growth. The optimal amount could be unclear during times of rapid growth. An otherwise adequate dose may not be enough to treat spasticity with increased tension placed by bone elongation. As a final point for dosing, it is not uncommon for a patient to present with an amount of tone too severe to be treated with injections alone and alternative methods of treatment should be pursued. Lastly, and perhaps most importantly, the results of injections may not be satisfactory because of unreal expectations. Education along with experience is required to get everyone on the same page. This can be achieved by using more objective outcome measures such as the goal attainment scale, Edinburgh visual gait score, or measures of function such as pediatric evaluation of disability inventory (PEDI). We have seen improved results with SEMLC but realize it is no ‘panacea’. Therefore quality improvement through examining causes of unmet outcome measures is essential to refining any practice.

9. Conclusion

Studying treatment of spasticity is difficult since there are heterogeneous presentations. Inclusion criteria in research attempts to focus on specific subsets of patients to decrease confounding factors or bias but since patients vary so greatly, results are difficult to apply to the everyday patient. A Cochrane meta-analysis showed there was promising evidence for the use of BoNT-A for the treatment of spasticity in children with CP and also showed that there is a need for more data. Covering more muscles in one procedure may result in better functional outcomes. Early intervention and continuum of care for spasticity in growing children will help functional improvement and also prevent complications from chronic spasticity. Stopping or slowing down BoNT injections in children ages four to six years old [14] may cause significant functional deterioration since this period of growth is when they may benefit from more frequent injections and intense physiotherapy. Children continuously grow, not only during growth spurts, and therefore there is a need for their muscles to be relaxed at all times by various means. The answer is still out there but we recommend considering the above listed items for future research, advancement of injection technique, and bringing the best care to patients.