Long-Term Efficacy and Safety of Botulinum Toxin Injections in Dystonia
2. Long-Term Experience and Efficacy
|Author/Year; No. Pts.||Mean Follow-up Period||BoNT Indication; BoNT type||Mean Age (years)||Mean Dose (MU)||Response||Side Effects||Outcomes|
|Tan, et al., 1999 ; 162||4.4 ± 3.8 (range: 0.3 to 10 years)||Oromandibular dystonia (OMD); OnabotulinumtoxinA||57.9 ± 15.3||Per muscle: masseter 54.2 ± 15.2; submentalis 28.6 ± 16.7; Cumulative: 778.8 ± 884.4 (masseter) 226.1 ± 342 (submentalis)||68% had global rating ≥3; mean peak effect: 3.1 ± 1.0 ; mean global effect: 3.0 ± 1.0; mean total duration response: 16.4 ± 7.1 weeks||31% (most common: dysarthria and dysphagia), only 11% of all visits||Jaw-closing dystonia responds better than jaw-opening or mixed dystonias.|
|Kessler, et al., 1999 ; 303||3.2 (range: 1.3 to 5.9 years)||Cervical dystonia (CD); AbobotulinumtoxinA||41 (range: 17 to 69)||Per session: 778 ± 253; Median Cumulative Dose: 7430 (range: 2700 to 22,475)||Highly significant average score  reduction from 10 points on initial presentation to 4 points after 15 injections. The mean score decrease after the first injection was 3.7 ± 1.9 points ||75% (most common: dysphagia, neck muscle weakness, hoarseness, dry mouth), 22% of all visits||Most patients underwent dramatic improvement after the first few injections. However, the true quality of treatment cannot reliably be judged before the sixth to eighth injections. BoNT treatment is equally effective in pure rotational torticollis and in more complex forms of CD. The relative improvement was similar for all patients irrespective of their disease severity.|
|Hsiung, et al., 2002 ; 235||2–12 years||CD (45%), hemifacial spasm (HS) (30%), blepharospasm (BP) (15%), other focal or segmental dystonia (10%); Onabotulinumtoxin A||Range: 21–86 years; CD 48 (21–80); HS 57 (28–86); BP 60 (30–82)||CD 222, HS 29.4, BP 51.5||At 2 years, HS patients had the highest response rate of sustained benefit, with 96% reporting 50% or better improvement, followed by BP 92% and CD 68%, these sustained benefits were similar at 5 years||27% (most common: CD: dysphagia and muscle atrophy, HS: ptosis and facial asymmetry, BP: ptosis and dry eyes); 65% of adverse effects occurred during the first 4 years of treatment||Most of the patients showed a prolonged sustained benefit with repeat injections, with only slight decrease seen at 5 years compared with at 2 years. Most patients who responded had sustained benefit over 5 or more years. The highest frequency of side effects occurred in patient with BP, followed by patients with HS, and CD. The main reason for discontinuation of treatment was lack of benefit (primary or secondary resistance 39%).|
|Snir, et al., 2003 ; 27 ||BP: 33.5 ± 13.3 months (low dose) and 26.1 ± 11.0 months (high dose); HS: 23.8 ± 6.6 months (low dose) and 31.6 ± 8.6 months (high dose)||BP (17 patients) and HS (10 patients); Onabotulinumtoxin A||Men (14/27): 75.7 ± 9.2 and women (13/27): 74.0 ± 4.7||BP: 16.0 ± 1.4 (low dose) and 24.2 ± 1.4 (high dose); HS: 16.8 ± 1.2 (low dose) and 25.0 ± 1.8 (high dose)||BS: mean dose/patient changed from 16.0 ± 1.4 U (lower dose) to 24.2 ± 1.4 U (higher dose), the shift occurred after a mean of 8.8 ± 2.9 treatments per patient HS: mean dose/patient changed from 16.8 ± 1.2 U (lower dose) to 25.0± 1.8 U (higher dose), the shift occurred after a mean of 6.5± 2.3 treatments per patient||70% had dry eye, followed by ptosis and strabismus||The mean interval of relief was longer with the lower dose than with the higher dose in BS, and similar for both dose ranges in HS. The dose was increased over time by 50% to achieve 3 to 4 months of symptomatic relief with minimal complications. The HS group switched to the higher dose earlier than the BS group.|
|Haussermann, et al., 2004 ; 100||61.02 ± 54.53 months (median 49: range 3–143)||CD; AbobotulinumtoxinA||47.23 ± 14.28||Per session: 800.79 ± 241; Cumulative: 10,154.45 ± 10,202.96||Global subjective BoNT effect score  over the whole treatment period was 1.93 ± 1.18; at therapy onset Tsui severity scale: 8.98 ± 3.66; segmental or multisegmental spread of dystonia developed in 33% of patients during follow-up||34% (most common: weakness of cervical muscles, mild dysphagia, generalized weakness); 33% stopped therapy due to travel inconvenience and side effects||Patients showed high adherence to BoNT treatment over time. More than 60% of patients continued with BoNT injections after up to 12 years. The mean BoNTdose of 800 MU may have been a relatively high dose compared to other studies, increasing frequency of side effects.|
|Skogseid, et al., 2005 ; 78||5.5 (range: 1.5 to 10 years)||CD; OnabotulinumtoxinA||Range: 18–75||111 (range: 82 to 190)||The median VAS score of Global Burden of Disease  prior to treatment was 8.0 (4.8–10) and at the time of treatment evaluation it was 4.0 (1.0–8.0). The median difference in VAS scores prior to and at treatment evaluation in individual patients was 4.0 (1.0–7.0) p < 0.001. Median TWSTRS total score at the time of treatment evaluation was 33 in the total population, 31 in the ‘Good effect’ group and 37 in the “Unsatisfactory effect” group, p = 0.021||42% (most common: dysphagia, injection site pain, neck muscle weakness, hypophonia)||Longitudinal studies of individual patients showed that changes in the complexity of CD during treatment occur in 36%; 19% had developed less complex patterns and 17% more complex patterns. High degree of patient satisfaction with long-term BoNT treatment was confirmed by the patients’ effect scores being excellent, good or moderate in 85%, and by a marked reduction of “Global Burden of Disease” during treatment in most patients. The doctors’ independent effect scores were excellent, good or moderate in >90% of the patients, and correlated well with the patients’ scores.|
|Mejia, et al., 2005 ; 45||15.8 ± 1.5 years||CD 37%, craniocervical dystonia 21%, cranial dystonia 13%, BP 9%, OMD 4%, FHD (focal hand dystonia) 4%, others ; BoNT-A and BoNT-B||51.8 ± 11.6||First session: 154.3 ± 98.9; most recent session: 221.2 ± 129.4; difference was statistically significant (p < 0.0001)||Average peak effect of 2.9 ± 1.5 (first injection) vs. 3.7 ± 0.6 (most recent injection); total duration response of 11.6 ± 7.1 weeks (first injection) vs. 15.4 ± 3.4 weeks (most recent injection)||Initial visit: 35% (most common: dysphagia and ptosis). Most recent injection visit: 22% (most common: ptosis and dysphagia)|
|Schuele, et al., 2005 ; 84||23 months (range 2 to 76 months)||FHD; AbobotulinumtoxinA||45.9||Initial total dose per treatment: 126.9 (range: 5 to 420); last total dose per treatment: 112.2 (range; 3 to 1000)||58 (69%) of the musicians experienced benefit, among them 38 indicated that the treatment led to noticeable improvement in their performance ability||98% patients: weakness; 56% reported excessive weakness after at least one injection preceding the period of max improvement|
|Berman, et al., 2005 ; 24 ||26.2 ± 20.4 months (range: 3 to 64 months)||CD; BoNT-B||60.4 ± 12.0 (range: 36 to 82)||14,828 ± 6824 (range: 2500 to 28,000)||Many patients required dose escalation to obtain an optimal response. In the last visit 12 patients demonstrated ongoing benefit and 50% became nonresponders (33% primary and 66% secondary)||Out of 87 injections with evaluable data: 23% had minor adverse events: dry mouth,neck pain, dysphagia, and headache||The use of BoNT-B at doses greater than the current recommended guidelines may be necessary to adequately treat some patients with severe CD both with and without prior BoNT-A resistance. The majority but not all BoNT-A resistant CD patients treated with BoNT-B became resistant to BoNT-B within 2 years or 5 injection cycles.|
|Mohammadi, et al., 2009 ; 207||AbobotulinumtoxinA: 7.3 ± 3.1 years (max 14 years); OnabotulinumtoxinA: 5.0 ± 2.2 (max 12 years)||CD; AbobotulinumtoxinA 163, OnabotulinumtoxinA 44||58 ± 27 (range: 22–95)||AbobotulinumtoxinA: 389 ± 144; OnabotulinumtoxinA: 145 ± 44||The duration of treatment effect was 11 ± 1.6 weeks in the AbobotulinumtoxinA group and 10 ± 2.4 in the OnabotulinumtoxinA group. The GGI  was rated 2.5 ± 0.3 for AbobotulinumtoxinA and 2.2 ± 0.4 for OnabotulinumtoxinA||Neck muscle weakness in 5% and 7% of treatment sessions, dysphagia in 8% and 9% and pain at injection site in 9% and 6% for AbobotulinumtoxinA and OnabotulinumtoxinA, respectively||Satisfying effects with relatively low mean doses of AbobotulinumtoxinA and low to average mean doses of OnabotulinumtoxinA. Lower rates of side effects without difference between AbobotulinumtoxinA and OnabotulimtoxinA. Weakness of the study may be the fact that clinical score scales such as the Tsui score or the TWSTRS were not used. However the GGI proved to be useful as a practical alternative.|
|Bentivoglio, et al., 2009 ; 128||15-year period||BP; OnabotulinumtoxinA and AbobotulinumtoxinA ||At onset: 57.7 ± 10.3 (range: 6 to 81)||34 ± 15 (range: 7.5 to 140) for OnabotulinumtoxinA; 152 ± 54 (range: 40 to 400) for AbobotulinumtoxinA||Mean duration of clinical improvement was higher after the injection of AbobotulinumtoxinA (80.1 ± 36.3 days) than OnabotulinumtoxinA (66.2 ± 39.8 days) with p < 0.05. In a six-point scale , the mean efficacy of both treatments was 3.60 ± 1.3 (3.51 ± 1.4 OnabotulinumtoxinA and 3.85 ± 1.2 AbobotulinumtoxinA, p < 0.01)||21.8% of OnabotulinumtoxinA and 31.6% of AbobotulinumtoxinA patients; most common: palpebral ptosis in both followed by hematoma after OnabotulinumtoxinA and diplopia after AbobotulinumtoxinA||The dose of both BoNTs were significantly increased over time. The differences in outcomes and side effects suggest that, albeit the active drug is the same, OnabotulinumtoxinA and AbobotulinumtoxinA should be considered as two different drugs. No correlation was found between dose and occurrence of side effects. Treatment failure (less that 20% of amelioration) occurred in 7.7% of OnabotulinumtoxinA treatments and 3.6% of AbobotulinumtoxinA, p = 0.0093).|
|Cillino, et al., 2010 , 155 ||Followed up for at least 10 years||BP: 73 patients, HS: 58 patients, and spastic entropion (SE): 24 patients; OnabotulinumtoxinA||BP: 71.4 ± 12.3; HS: 71.7 ± 11.4; SE: 78.6 ± 8.9 (p = 0.024)||BP: 28.2 ± 12.2; HS: 18.7 ± 9.4; SE: 10.6 ± 4.7||Mean effect duration for patient in weeks: BP: 18.2 ± 12.3; HS: 20.6 ± 11.6; SE: 13.7 ± 7.0 (inter-group difference: p = 0.009). Significant intra-group differences were found for mean dosages, which increased significantly (p < 0.05) after the first 3 or 4 doses of treatment for both BP and HS groups||31.5% in BP, 31.0% in HS, and 4.2% in SE. Most common: upper lid ptosis, diplopia, ecchymosis, and injection-site bruising. Total side effects difference among 3 groups: p = 0.023||There was statistically significant difference in the mean BoNT-A dose received by patients among the 3 groups (p < 0.0005). A total of 96% of patients with BP, 98% of patient with HS, and 100% of patients with SE had significant relief of their symptoms. Subgroup analysis according to age (< or ≥ 65 years) indicates a significant increase in duration of relief and mean doses over the follow-up period in older but not younger BP and HS patients.|
|Lungu, et al., 2011 ; 20 ||13.6 ± 2.5 years||FHD; Ona botulinumtoxinA (except for one single injection of RimabotulinumtoxinB in one patient)||46.6 ± 9.45||Per session: 46.4 ± 24.6||Most patients (11 of 20) experienced mild average benefit (grade 2) ; patients received a higher mean dose at the end of the follow-up period compared to the initial treatment (50 vs.25 MU respectively, p < 0.00005). The benefit was higher with the last injection compared to the initial (47% vs. 26%, p = 0.039)||All patients tolerated the discomfort of multiple injections well; there were no serious adverse effects; two patients discontinued treatment due to insufficient response||There was large variability in the frequency of treatments, likely reflecting the fact that while FHD makes particular activities difficult or impossible, it is not otherwise disabling or painful. The musicians were more likely to wait longer between injections (19.9 ± 12.4 months for musicians vs. 7.7 ± 2.3 for nonmusicians, p < 0.002). Patients continued therapy for over 10 years in spite of only mild benefit, suggesting that even partial improvement may be worthwhile.|
|Ramirez-Castaneda and Jankovic, 2012;  104||19.4 ± 2.9 years||Dystonia; BoNT-A and BoNT-B||48.9 ± 12.4||Per session (at time of last injection): 300 ± 205||70% had global rating ≥3; mean peak effect: 3.7 ± 0.45; mean duration of maximal response: 15.5 ± 7.0 weeks.||13.4% at the time of their last visit; most common: blurred vision and dysphagia||Persistent improvement of dystonia severity and function is maintained over time with minimal adverse effects, thus supporting the conclusion that BoNT is a safe and effective long-term treatment for focal and segmental dystonia.|
3. Immunogenicity and Therapeutic Response
4. Adverse Effects and Treatment Failures
5. Conclusions and Future Directions
References and Notes
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- Dystonia type: writing, 9; musician, 5 (piano, 2; guitar, 1; drums, 1; trumpet, 1); typing, 1; and mixed, 5.
- Subjective scale based on percent restoration of normal function: 0 none, 1 minimal (1%–25% restoration of function), 2 mild (26%–50%), 3 moderate (51%–75%), 4 excellent (76%–100%).
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Ramirez-Castaneda, J.; Jankovic, J. Long-Term Efficacy and Safety of Botulinum Toxin Injections in Dystonia. Toxins 2013, 5, 249-266. https://doi.org/10.3390/toxins5020249
Ramirez-Castaneda J, Jankovic J. Long-Term Efficacy and Safety of Botulinum Toxin Injections in Dystonia. Toxins. 2013; 5(2):249-266. https://doi.org/10.3390/toxins5020249Chicago/Turabian Style
Ramirez-Castaneda, Juan, and Joseph Jankovic. 2013. "Long-Term Efficacy and Safety of Botulinum Toxin Injections in Dystonia" Toxins 5, no. 2: 249-266. https://doi.org/10.3390/toxins5020249