To the best of our knowledge, this is the first study of its kind to evaluate the efficacy and the safety of BTX-A injection for the treatment of lower limb spasticity in pediatric patients with genetic etiology.
In our cohort, 70% of patients were of 1st-degree cousins marriage and 40% had a similar family history, highlighting the consequences of consanguineous marriage on the increased rate of neurogenetic disorders in our region (Tadmouri et al., 2009). It is worth mentioning that 55% of our patients had other comorbidities and 63.5% were dependent on their caregivers either totally (35% with GMFCS IV and V) or partially (28.5% with GMFCS III). This reflects the financial, physical, and mental burden on these families which in turn will affect their quality of life. It is well known that genetic disorders present with multisystem involvement whether neurological or non-neurological with movement disorders being the most significant disabling morbidity (Ortigoza-Escobar, 2020).
Spastic diplegia was the most prevalent topographic pattern identified (90%) while the rest of the patients had spastic quadriplegia with talipus equinovarus and scissoring being the most common deformity (90%) encountered. This explains why our entire patients except one patient required injection of multiple muscle groups to relieve spasticity. Although this is not the common practice in non-ambulatory patients for concerns about developing adverse effects, however, our results showed functional improvement despite the progressive course of the disease with high safety profile. All our patients had acceptable mild transient local pain except one patient who initially presented with an unidentified multisystem neurological disorder but was later diagnosed with mitochondrial cytopathy after receiving the BTX-A and experiencing complications. The patient developed severe respiratory distress and renal shutdown which resolved without long-term consequences. This observation supports the existing literature on the general safety of BTX-A injections in pediatric patients with CP (Delgado et al., 2010)and the risk of severe respiratory distress and mortality in multilevel injections (Howell et al., 2007), especially in patients with mitochondrial cytopathy (Gioltzoglou, 2005).
The results of this study revealed that BTX-A injections were effective in achieving the preset functional goals of “muscle tone reduction, easing the patient care and rehabilitation” in pediatric patients with genetic disorders. We found that the overall responder rate was 90% based on GAS scores, where 20 % achieved the preset goals, 55% of patients achieved a better outcome than anticipated and 15% achieved the best possible outcome. We believe that this would have not been accomplished without receiving intensive rehabilitation and using appropriate orthotics. Similar promising findings were reported with functional and symptomatic improvement according to GAS in adult patients with poststroke lower limb spasticity (Munain et al., 2019).
Furthermore, this functional improvement was supported by the significant improvement in the GMFCS and the MAS scores after BTX-A injection. These findings are consistent with previous research on BTX-A injections for the treatment of spasticity in children with CP due to perinatal complications (Delgado et al., 2010). The MAS scores showed the best response at the first follow-up visit (1st month) as compared to the 3rd and 6th months post-BTX-A injection. However, although the improvement tended to decline by the 6th month, still there was a statistically significant improvement as compared to the initial MAS scores. This corresponds with the known process of recovery of neuromuscular transmission from 6 to 8 weeks, as new nerve terminals sprout (Rogozhin et al., 2008).
There are limited publications ``mainly case reports” on the efficacy and safety of using BTX-A injections in patients with genetic disorders. It was effectively and safely used for the treatment of lower limb spasticity and dystonia in patients with Glutaric aciduria type I (Burlina et al., 2004), HSS/PKAN (Lin et al., 2018; Neves et al., 2008), MLD (Borges et al., 2020; Singh et al., 2009), Pelizaeus-Merzbacher disease (PMD)(Brender et al., 2015), SLS (Anil G, 2019; Cho et al., 2018; Hidalgo et al., 2017), Alexander disease (Machol et al., 2018), Aicardi-Goutières syndrome (AGS) (Videira et al., 2020), Cockayne syndrome (Hsu et al., 2021)and in combination with epidural analgesia in one child with MSUD (Kaki & Arab, 2012). BT-XA was also used for treating seven patients with severe opisthotonus; three of them with genetically identified etiology including “PKAN, hypomyelination leukodystrophy-14 and CASK-related disorder”(Hull et al., 2021).On the other hand, BTX-A was not effective and showed a low safety profile when used for the treatment of salivary drooling and foot inturning in patients with mitochondrial cytopathy(Gioltzoglou, 2005), which was in agreement with our findings that was discussed earlier.
Overall, this study supports the potential benefit and high safety profile of using BTX-A in combination with intensive rehabilitation for treating lower limb spasticity in this unique cohort of children with genetic disorders.
Limitations
Limitations of this study include its retrospective design and the relatively small number of patients, however; this is difficult to avoid since it involves a relatively rare target population with genetic disorder from a single center. This might limit the generalizability of the results. Therefore, we believe that although the study’s sample, albeit small, it can be considered as a nidus for future research in this population.