In our study on 186 patients treated with BoNT for movement disorders or sialorrhea, we observed a high variability in time to onset and duration of BoNT efficacy. Our analyses showed that such a variability can be predicted by specific demographic and clinical characteristics. In particular, we observed that the total BoNT dose injected is significantly associated with the time to onset and duration of efficacy, independently from the underlying disease. However, in the multivariate analysis, time to onset of BoNT efficacy was mainly predicted by age, with older patients showing a shorter time to achieve benefit from treatment. The duration of BoNT efficacy was predicted by type of toxin, doses, and underlying clinical condition.

While previous data already analyzed the duration of BoNT efficacy for different diseases [7,8,9,10], the literature is less informative about the time to onset of BoNT efficacy and its modifiers.

Among the few studies which analyzed time to onset of BoNT efficacy for movement disorders, an average time of 5.4 days for facial hemispasm [11], 7.1 days for blepharospasm [12], and 6.1 days for different movement disorders was observed, in the absence of an influence of the type of toxin [11,12,13]. Considering blepharospasm, facial hemispasm, cervical dystonia, focal limb dystonia, oromandibular dystonia, and sialorrhea, we found an average of 6.7 days of time to onset of BoNT efficacy, which is consistent with previous findings. Moreover, our analysis on factors influencing the variability of outcome showed that age is inversely correlated with time to onset (i.e., time to onset is shorter in older patients), even when controlling for sex, years of BoNT treatment, doses, type of toxin, and clinical condition. This finding could be explained by the muscular changes in aging, related to the increasing percentage of type I fibers compared to type II and the progressive loss and enlargement of active motor units [14]. Similarly, the proportional volume of fat and fibrovascular tissue increases in parotid glands with age, with a reduction of the volume of acini, the functional part of the gland [15].

Literature data seem to suggest that the duration of neuromuscular blockade differs according to the BoNT serotypes [16], but clinical comparisons on injected patients reported mixed results. Some studies revealed a similar duration of effect of BoNT-A formulations [7, 10, 12]; others found conflicting results, with longer efficacy duration of onaBoNT-A vs. aboBoNT-A in patients treated for cervical dystonia, hemifacial spasm and blepharospasm and longer efficacy duration of aboBoNT-A vs. onaBoNT-A for hemifacial spasm [11, 17]. A crossover study investigating the use of ona- and aboBoNT-A in cervical dystonia, blepharospasm and hemifacial spasm, with dose ratios of 5:1 and 4:1, found that duration of BoNT efficacy was longer with onaBoNT-A [18]. A similar study conducted with patients treated for cervical dystonia with ona- and aboBoNT-A at a ratio of 3:1 suggested a similar effect duration [7]. Our analysis revealed that the type of toxin did not influence time to onset but influenced duration of BoNT efficacy, with onaBoNT-A achieving a longer duration of efficacy than incoBoNT-A independently from clinical condition and doses (Fig. 1). At a conversion rate of 3:1, aboBoNT-A did not reveal any significant difference when compared with onaBoNT-A.

BoNTa efficacy in different types of toxins. a Days between BoNT injection and perceived improvement of symptoms. b Days between BoNT injection and perceived wearing off of the effect. aBoNT botulinum toxin

The extent of paresis provoked by the botulinum toxin is correlated to the dose, but it isn’t clear if the dose affects duration of action. It has been proposed that when lower doses of BoNT are used, duration correlates with the amount injected, while duration saturates around 3 months when higher doses are used [3]. Poewe et al., in 1998, conducted a study with the objective to analyze the dose–response correlation in a group of 75 treatment-naïve patients affected by cervical dystonia. Results demonstrated a positive dose–response correlation for the magnitude and duration of improvement, but also for the occurrence of adverse events [19]; however, in another study conducted in 2016 they reported that duration of treatment did not change, regardless of the dose used [20]. Li et al. compared high versus low doses of BoNT (25 U vs 50 U) in patients with hemifacial spasm and time to onset didn’t differ significantly, but duration of efficacy was longer with the higher dose [21]. A review conducted by Flynn and coll., examining duration of effect of botulinum toxin for facial aesthetic applications, concluded that dose-duration relationships are not robust and require additional investigations [22]. Differently from previous studies, we found that doses are relevant in determining the duration of BoNT efficacy, with higher doses correlated to a lower duration of efficacy. It can be hypothesized that patients receiving higher doses of BoNT were those patients with a more severe disease, for whom a higher dosage was applied due to early recurrence of symptoms.

It is important to highlight that although we explored the main clinical and demographic predictors, the multivariate model explained a significant yet small part of the outcome variability (i.e., 12% and 20%). This finding could be explained by the fact that other relevant features, such as target muscles, variability of injection between patients, depth of muscle below the skin, heterogeneity in disease severity, recall bias, and toxin dilution, should be considered as possible modifiers in the BoNT outcome.

The strength of our findings is tempered by some limitations. First of all, the main outcomes are based on a patient’s self-assessment of their symptoms, rather than objective scale-based measures. The clinical ground of the study and the inclusion of different movement disorders led us to opt for such a subjective evaluation, which is typically used during clinical practice.

Furthermore, ambiguity may exist regarding the exact definition of treatment time to onset and duration of BoNT efficacy according to subjects and underlying clinical conditions. On the other hand, the literature does not provide specific indications on the best way to assess BoNT efficacy in terms of onset and duration, with many not-validated methods proposed, such as the diminished muscle activity assessed either by the physician or the patient [3]. The main parameter used in the literature to evaluate the duration of efficacy of BoNT is the duration of clinical response, but many surrogates, as duration of peak to benefit, the last moment after treatment in which a difference in muscle lengthening can be detected, the relapse rate (time to return to baseline level) and time between injections, have been used, accounting for the variability of findings [5, 22]. Finally, we decided to include in the analyses the five patients with oromandibular dystonia; however, we acknowledge that the sample size for this category of patients is probably too small to obtain significant results. We also performed the multivariate analyses excluding this subgroup of five patients without differences in p values and R2 of the total model (data not presented).

Taking into account the above-mentioned limitations, our data provide useful information on clinical and demographic data influencing two relevant patient-centered parameters of BoNT efficacy in different movement disorders. In particular, we found that: (i) sex, age, years of BoNT treatment, doses, type of toxin, and clinical condition are relevant in determining the variability of both time to onset and duration of BoNT efficacy; (ii) age in particular is a strong predictor of time to onset, with older patients showing an earlier BoNT effect; and (iii) type of BoNT, dosages, and the underlying clinical condition are the main predictive factors of duration of BoNT efficacy. In conclusion, we found novel potential predictors of BoNT efficacy worthy of being assessed in future studies and during clinical practice.