LAUSR

We cordially thank Nonnekes and colleagues for emphasizing the scientific importance of the SPASTOX trial. Likewise, we appreciate the perspectives raised in this letter and the opportunity to highlight and discuss some of the lessons learned from it. The purpose of the SPASTOX trial was to assess the efficacy and safety of botulinum toxin type A (BoNT-A) in patients with hereditary spastic paraplegia (HSP) as a whole, not a specific type. Similarly, previous studies have also evaluated patients with different types of HSP, which is completely understandable given the rarity of the disease. For that, a group with common complaints, clinical characteristics, and physical assessment profile was enrolled, according to all the inclusion (and exclusion) criteria carefully described in the “Patients’ Selection” and “Intervention” sections, which were supported by Supporting Information Data S1. Given the wide heterogeneity of HSP and the fact that BoNT-A is a symptomatic (not a disease-modifying) treatment, we believe this strategy is methodologically appropriate, to achieve a more reliable clinical interpretation focused on spasticity and its effects. In this scenario, the injection protocol was planned after a detailed and personalized evaluation that was performed on each patient regarding the gait and balance limitations related to HSP. Then, the doses were determined based on the range cited in previous references in adults, according to modified Ashworth scale (MAS) and Medical Research Council (MRC) and assuming the principle of not providing weakness to achieve the outcomes. Nevertheless, we recognize that we used smaller doses when compared with previous studies, especially for triceps surae, as already discussed. Besides, the SPASTOX trial was a pragmatic clinical trial focused on correlation between treatment and outcomes in a real-world health system practice. In this context, although guided techniques are undoubtedly the gold standard, they are not routinely used worldwide and not in all centers, even in developed countries. Furthermore, the treatment approach used is fully in line with international standards, given that the guideline produced by the 2009 European consensus recommends these techniques for the injection of only deep muscles and muscles that are difficult to locate using only anatomic landmarks, which was not the case for the muscles we evaluated. Guided techniques could actually provide accessibility and distribution of BoNT-A in gracilis and adductor longus, noted by their functional role in adduction, as very well pointed out by Nonnekes and colleagues. Yet, we do not consider this to be a major concern, because we observed clinically a reduction in adductors tone, which was verified objectively through MAS and corroborated with a statistically significant difference in relation to placebo. Further, structured protocols derived from biomechanical gait analysis and other or more injected muscles, as recently performed by other authors, may lead to a more effective management. Hence the SPASTOX trial provides as its main lesson the safety of the treatment with BoNT-A in patients with HSP and the necessity of additional randomized controlled trials to comprehensively, with the minimum of limitations, evaluate the effects of BoNT-A in patients with HSP.