ABSTRACT
This article reports the tolerance and long-term safety profiles of botulinum neurotoxin type A among Asian patients with benign essential blepharospasm (BEB) and hemifacial spasm (HFS). We performed a retrospective review of clinical documents and procedure records of consecutive BEB and HFS patients receiving onabotulinum toxin A (Botox) treatment in our clinic over the past 20 years. We reviewed the information of 105 patients diagnosed with BEB (n = 31) and HFS (n = 74). All of the patients were Asian. The mean age of disease onset was 59 (range 37–80) years old for BEB and 61 (range 31–83) for HFS. The mean follow up was 84 (range 12–240) months and the mean number of sessions per patient was 19 (range 1–61). The botulinum toxin dose per session increased significantly in both BEB (16.5 versus 21.6 units, p < .05) and HFS (22.6 versus 26.9 units, p < .05) patients after a mean of 18 sessions; however, the onset time, effective duration and subjective treatment outcome were similar over time in both BEB and HFS patients. At least one local complication was reported among 26% and 41% of patients with BEB and HFS respectively, with ptosis (32%) being most frequent.
KEYWORDS: Botulinum neurotoxin, hemifacial spasm, benign essential blepharospasm, tolerance
Introduction
Botulinum neurotoxins are bacterial exotoxins produced by several bacteria of the genus Clostridia and they interfere with the exocytotic release of vesicular neurotransmitters in both motor and sensory neurons.1,2 The limited diffusion of botulinum neurotoxin from the site of injection as well as its reversibility gives this toxin good therapeutic potential.3 The first clinical use of botulinum neurotoxin was reported in 1980 by Scott et al. in the treatment of strabismus.4 Botulinum neurotoxin has been reported as an effective treatment in a diverse group of ophthalmology disorders such as benign essential blepharospasm (BEB), hemifacial spasm (HFS), and paralytic strabismus.5–7
Both BEB and HFS are facial dystonias that can impair daily activities and affect psychosocial life. Any delay in treatment may lead to serious complications, such as functional blindness and poor quality of life.8 Botulinum neurotoxin is a popular and well-established treatment for both movement disorders.9
Common side effects of botulinum neurotoxin include pain at injection sites, diplopia, ptosis, and dry eyes, but all are reversible.10 Serious systemic complications are rare and include dysphagia, dysphonia, dyspnoea and respiratory distress.11
Development of tolerance is an adaptive response of the body to prolonged exposure to a drug. It is commonly reported in antiepileptic drugs.
Tolerance occurs when the body becomes accustomed to the medication so that a higher dosage is needed to give a similar therapeutic effect.12 Poor continued responsiveness to botulinum neurotoxin among different muscle disorders have been reported, and one of the explanations would be an immunological response with the development of antibodies.13 Jankovic and Schwartz reported that the level of antibodies correlated with the complete failure of response to botulinum neurotoxin injections.14 However, Siatkowski et al. reported that the presence of antibodies failed to correlate with the patient’s clinical response among patients with BEB, HFS, and spasmodic torticollis.15
Our clinic has been serving those with BEB and HFS for over 20 years at Tung Wah Eastern Hospital in Hong Kong. In this study, we aim to report the long-term complications and report any tolerance to botulinum toxin in patients with BEB and HFS from our experience.
Materials and method
This retrospective observational study was approved by the Institutional Review Board of the Hong Kong East Cluster and the reference number was HKECREC-2019016. The study was conducted in accordance with the Declaration of Helsinki. The procedure records and medical documents of patients referred to our clinic between 1 January 2000 and 31 December 2019 were independently reviewed by two ophthalmology trainees. Only patients diagnosed with BEB and HFS clinically by our oculoplastic consultant were included. Patients under the age of 18 and those who received botulinum neurotoxin treatment for other types of neuromuscular disorders were excluded. Patients who received less than 15 injection sessions or who had been followed up for less than 5 years were included in the review of side effects only and they were excluded in the analysis of the long-term outcome of the botulinum neurotoxin treatment.
All patients received the same brand of product (onabotulinumtoxin A) from Allergan, also known as Botox. Each botulinum toxin product was reconstituted with 2.5 ml of 0.9% non-preserved sterile saline. Five units of botulinum toxin were injected at each of the five periorbital injection sites and perioral site in HFS patients (Figure 1); the selection of the injection sites largely depended on the location of muscle spasm. We intended to follow the same dosing schedules to the previous injection if the outcome was satisfactory to the patient. The pretarsal portion of the orbicularis oculi muscle was the preferred injection site for BEB patients, and the levator palpebral superioris area was avoided as an injection site. All patients were auto-rotated in a fixed period of 4–5 months.
Figure 1.
The six sites of botulinum toxin injections (red arrows) in the hemifacial spasm patients
During each injection session, the onset time of action, duration of treatment effect, complications, and the subjective spasm alleviation scale score (SSAs) of the previous injection session were documented by a single oculoplastic surgeon. The duration of the treatment effect was defined as the interval between the first day of improvement and the first day of spasm recurrence after treatment. Subjective treatment outcome was measured using the SSAs, which involved self-evaluation of the disease impact on activities of daily living (ADL): 0 = severe effect on ADL; 1 = partial effect on ADL; 2 = no effect on ADL.16
All statistical analyses were performed using the SPSS statistical software package (Window version 24.0; IBM Corp., Armonk, New York; USA). The test of significance was performed with p < .05 and a confidence interval (CI) of 95%. The comparative analysis was measured using paired and unpaired T-test, Fisher’s exact test, and chi-square test. Numerical results were presented as mean ± standard deviation (SD) and range, unless otherwise stated. We compared the difference of botulinum toxin dose at the 3rd and the 18th sessions, as they represent the dose at the end of the first and the sixth years.
Results
The information on 106 patients was reviewed. There were 31 BEB (20 = female) and 75 (57 = female) HFS patients, and all were Asian. The mean age of disease onset was 59 ± 10 (range: 37–80) and 61 ± 12 (range: 31–83) years for BEB and HFS, respectively. All BEB patients presented bilaterally and all HFS patients presented unilaterally.
The total number of injection sessions was 1997 and the mean number of injection sessions per patient was 19 ± 10 (range 1–61) over a mean follow-up of 84 ± 50 (range 12–240) months. The mean number of injection sessions per year per patient was 2.9 ± 0.6. Three patients declined further treatment due to clinical remission after their 7th (BEB), 9th (BEB), and 22nd (HFS) injection sessions. Two HFS patients refused further treatment after their first injection session due to blurred vision and the perception of flashing lights, respectively. Both visual complaints resolved within 6 weeks. One BEB patient declined further treatment after the fifth session due to an unsatisfactory therapeutic outcome.
Regarding the BEB patients, 26 (84%) received at least 18 injection sessions over a minimum period of 6 years. The mean botulinum toxin dose increased every year without reaching a plateau as shown in Figure 2. The difference in mean dose per session, onset time, effective duration of treatment and SSA scores for the BEB between the first year and the sixth year of treatment are shown in Table 1. We performed subgroup analysis for the change botulinum toxin dose from the first year to the sixth year of treatment. The mean dose per session increased in males (15.8 ± 4.3 versus 21.5 ± 5.2 units, p = .0388), females (17.3 ± 4.0 versus 21.7 ± 4.2 units, p = .0300), patients aged below 65-years-old (15.1 ± 4.3 versus 21.0 ± 6.2 units, p = .0380) and aged above 64-years-old (16.8 ± 8.4 versus 21.9 ± 3.1 units, p = .0120), between the 3rd session and the 18th session.
Figure 2.
The mean botulinum toxin dose over 6 years (total of 18 injections) among the benign essential blepharospasm patients
Table 1.
Comparison of the botulinum toxin dose, onset time of action, effective duration of treatment, and subjective spasm alleviation scale score between the first year (3rd injection) and the sixth year (18th injection)
| First year (3rd injection) | Sixth year (18th injection) | p Value | |
|---|---|---|---|
| Benign Essential Blepharospasm (n =26) | |||
| Botulinum toxin dose ± SD (range) (Units) | 16.5 ± 8.2 (10 - 30) | 21.6 ± 5.0 (12.5 - 30) | < .05 |
| Onset time ± SD (range) (days) | 3.8 ± 1.9 (1 - 7) | 3.6 ± 1.7 (2 - 7) | .549 |
| Effective duration of treatment (months) | 2.9 ± 1.1 (1 - 5) | 2.5 ± 0.9 (1 - 5) | .187 |
| SSAs ± SD |
1.7 ± 0.4 |
1.8 ± 0.5 |
.187 |
| Hemifacial spasm (n = 63) | |||
| Botulinum toxin dose ± SD (range) (Units) | 22.6 ± 6.8 (10 - 50) | 26.9 ± 8.0 (10 - 50) | .05 |
| Onset time ± SD (range) (days) | 4.8 ± 2.3 (0 - 10) | 3.6 ± 2.3 (0 - 14) | .164 |
| Effective duration of treatment (months) | 2.9 ± 1.1 (1 - 6) | 2.7 ± 1.0 (1 - 4.5) | .196 |
| SSAs ± SD | 1.9 ± 0.5 | 1.9 ± 0.5 | .356 |
SSAs = Subjective spasm alleviation score; SD = standard deviation
Regarding the HFS patients, 63 (86%) HFS patients received at least 18 injection sessions over a minimum period of 6 years. The mean botulinum toxin dose increased every year without reaching a plateau as shown in Figure 3. The difference in mean dose per session, onset time, effective duration of treatment and SSA scores for the HFS between the first year and the sixth year of treatment are shown in Table 1. We performed subgroup analysis for the change botulinum toxin dose from the first year to the sixth year of treatment. The mean dose per session ipsilaterally increased in males (22.1 ± 6.4 versus 26.7 ± 7.7 units, p = .481), females (22.8 ± 5.1 versus 27.4 ± 6.8 units, p = .000262), patients aged below 65 years (22.0 ± 5.3 versus 26.3 ± 5.4 units, p = .00555) and patients aged above 64 years (22.8 ± 5.4 vs 27.9 ± 7.2 units, p = .00555), between the 3rd session and the 18th session. The mean onset time of action was 4.8 ± 2.3 (range 0–10) days in a patient’s first year (3rd session) and 3.6 ± 2.3 (range 0–14) days in their 6th year (p = .164).
Figure 3.
The mean average botulinum toxin dose over 6 years (total of 18 injections) among the hemifacial spasm patients
Complications
Among the 31 patients diagnosed with BEB, eight (26%) of them experienced at least one episode of complications. Six (75%) of the eight patients experienced adverse events from the initial five injections.
Among the 75 patients diagnosed with HFS, 31 (41%) patients experienced at least one episode of complications. Seven (55%) of the 31 patients experienced two episodes of complications. Thirteen (42%) of the 31 patients experienced adverse events from the initial five injections.
There were no systemic complication reported. All complications resolved within 6 weeks. The details of the complications are summarised in Table 2.
Table 2.
The details of the post-botulinum toxin injection complications
| Patient | Injection session | Complication | Management | Outcome |
|---|---|---|---|---|
| Benign essential blepharospasm | ||||
| 1 | 1st | Ptosis | Observed and reduced further upper lid injection | Self-resolved in 2 weeks |
| 2 | 2nd | Ptosis Diplopia |
Observed and reduced further upper lid injection | Self-resolved in 2 weeks |
| 3 | 2nd | Ptosis | Observed and reduced further upper lid injection | Self-resolved in 4 weeks |
| 4 | 3rd | Ptosis | Observed and reduced further upper lid injection | Self-resolved in 3 weeks |
| 5 | 3rd | Ptosis | Observed and reduced further upper lid injection | Self-resolved in 3 weeks |
| 6 | 5th | Epiphora | Observed | Self-resolved in 2 weeks |
| 7 |
8th |
Ptosis |
Observed |
Self-resolved in 2 weeks |
| Hemifacial spasm | ||||
| 1 | 1st | Ptosis | Observed and reduced further upper lid injection dose | Self-resolved in 1 week |
| 2 | 1st | Ptosis | Observed and reduced upper lid injection | Self-resolved in 2 weeks |
| 3 | 1st | Blurred vision | Observed and declined further injection | Self-resolved in 4 weeks |
| 4 | 1st 2nd | Ptosis Epiphora | Observed | Both complications self-resolved in 4 weeks |
| 5 | 1st 2nd | Seeing flashes and minimal effect | Observed and declined further injection | Self-resolved in 6 weeks |
| 6 | 1st 5th | Ptosis | Observed and avoided further upper lid injection | Self-resolved in 2 weeks |
| 7 | 1st 7th | Dry eye | Lubricant eyedrop | Self-resolved in 3 weeks |
| 8 | 1st 14th | Epiphora Ptosis | Observed and avoided further upper lid injection | Self-resolved in 4 weeks |
| 9 | 2nd | Ptosis | Observed and avoided further upper lid injection | Self-resolved in 4 weeks |
| 10 | 3rd | Lid swelling and pain at injection site | Observed and avoided further upper lid injection | Self-resolved in 2 weeks |
| 11 | 3rd | Ptosis | Observed and reduced further upper lid injection | Self-resolved in 2 weeks |
| 12 | 5th | Ptosis | Observed and reduced further upper lid injection | Self-resolved in 5 weeks |
| 13 | 5th 7th | Epiphora Ptosis | Observed | Self-resolved in 2 weeks |
| 14 | 6th | Mouth angle drooping Ptosis | Observed and avoided further perioral injection | Self-resolved in 6 weeks |
| 15 | 6th | Dry eye | Lubricant eyedrop | Self-resolved in 4 weeks |
| 16 | 7th 27th | Ptosis Ptosis | Observed | Self-resolved in 2 weeks |
| 17 | 7th | Ptosis | Observed and avoided further upper lid injection | Self-resolved in 4 weeks |
| 18 | 8th | Ptosis | Observed | Self-resolved in 2 weeks |
| 19 | 12th | Ptosis | Observe and avoided further upper lid injection | Self-resolved in 2 weeks |
| 20 | 14th | Ptosis | Observed | Self-resolved in 2 weeks |
| 21 | 14th | Diplopia | Observed | Self-resolved in 1 week |
| 22 | 15th | Diplopia | Observed and reduced further injection dose | Self-resolved in 3 weeks |
| 23 | 15th | Injection site swelling | Observed | Self-resolved in 4 weeks |
| 24 | 16th | Mechanical ptosis with haematoma |
Observed | Self-resolved in 6 weeks |
| 25 | 16th | Ptosis | Observed | Self-resolved in 1 week |
| 26 | 17th | Angle drooping | Observed and reduced further perioral injection | Self-resolved in 2 weeks |
| 27 | 17th | Diplopia | Observed | Self-resolved in 2 weeks |
| 28 | 18th | Ptosis | Observed and avoided further upper lid injection | Self-resolved in 2 weeks |
| 29 | 19th | Ptosis | Observed | Self-resolved in 2 weeks |
| 30 | 23rd | Ptosis | Observed and reduced further upper lid injection | Self-resolved in 6 weeks |
| 31 | 60th | Ptosis Mouth angle drooping |
Observed and reduced further upper lid injection | Self-resolved in 2 weeks |
Discussion
From our 20 years experience of botulinum toxin injections, among 106 patients diagnosed with HFS and BEB, we found that the botulinum toxin dose required increased significantly over time. Meanwhile, there was no difference in terms of the onset time, effective duration, and SSAs. Regarding the long-term complications of Botox injection, 26% and 41% of BEB and HFS patients respectively experienced at least one adverse event following botulinum toxin injection sessions and 75% and 42% of patients respectively experienced post injection complications within the first five injection sessions. No life-threatening events or systemic complications were reported.
Botulinum neurotoxin is a well-established treatment in different movement disorders such as strabismus, neurogenic detrusor overactivity, and chronic migraine.4,17,18 Many consider it as a safe treatment19;however, tolerance to botulinum toxin has not been discussed widely. Ababneh et al.20 reported an increase of botulinum toxin dose required over time among BEB and HFS patients, which was comparable to our study, as we also showed that both the objective and subjective treatment outcome were maintained despite the need for an increase in the botulinum toxin dose. We are uncertain on the endpoint of the increasing trend of botulinum toxin dose over time and a longer follow-up period will be useful to study this tolerance phenomenon. We suggest that the need for an increased dose of botulinum toxin is discussed during the pre-injection consultation.
We postulate that both BEB and HFS patients in our study developed partial immune resistance to botulinum toxin, which over time led to the significantly increased doses required of botulinum toxin without compromising the treatment outcome. We are aware that the rate of increase of botulinum toxin dose went up from the fourth year onwards among the BEB patients, but this was not observed in the HFS patients. This observed phenomenon shows that BEB patients may have developed partial immune resistance, which is comparable with the results of the study published by Levy et al.,21 who found that in BEB patients who showed refractory responses to standard botulinum toxin treatment, a significantly increased dosage could be effective without any significant side effects. Greene et al. reported that 4.3% of the patients with torticollis and serological evidence of antibodies to botulinum toxin had a more frequent rate of injections compared with those who had not developed antibodies.13 Torres et al. reported that immune resistance may develop in patients with cosmetic use of botulinum toxin when a small dose was administered repeatedly.22 Naumann et al. reported several risk factors that can promote antibody formation including overall toxin dose and booster injections; however the presence of antibodies did not predict the clinical success or failure of treatment.23 Further studies are needed to investigate the development of antibodies in BEB and HFS patients who receive long-term botulinum neurotoxin type A treatment.
Onabotulinumtoxin A (Botox) as we use in our clinic is one of the seven botulinum neurotoxin serotypes A-G. Only serotypes A and B are currently available commercially.24 Houser et al. reported that patients showing resistance to one type of botulinum toxin product may benefit from injections with other toxin serotypes.25 The role of different serotypes of botulinum toxin in developing immune resistance has been reported, and those which do not effectively block the biological activity of the toxin may be clinically irrelevant in developing tolerance.26 Botulinum neurotoxin type B was recommended as an alternative for patients with poor response to botulinum neurotoxin type A in cervical dystonia patients,27 and different characteristics of biological activity have been reported among different products of serotype A botulinum neurotoxin in the treatment of patients with BEB and HFS.28
Botulinum toxin has good therapeutic potential due to its high reversibility, as reported by Borodic et al.,29 since repeated injections of botulinum A neurotoxin are not associated with irreversible denervation or changes in the morphology of the orbicularis oculi muscle fibre size. Bladen et al. reported that ptosis was reported in 30% of their facial dystonia patients, and it was the most frequent complication followed by dry eye, which was comparable to our study.6 It has also been reported that life-threatening episodes by systemic spread of the toxin are unlikely with botulinum toxin treatment.10 Vivancos-Matellano et al. reported that adverse events developed at least once in 39% of BEB patients, and no systemic side effects were reported,30 which was comparable to our study where all post injection complications were self-resolving localised conditions, explicable by the limited diffusion of the neurotoxin.31
One of our patients refused further injections after their first injection session due to transient blurring of vision, which self-resolved over 4 weeks. The physical examination was unremarkable in this patient with normal near and distant vision 12 weeks after the injection. The reason for the transient blurred vision was unclear, but one possible explanation would be the transient anticholinergic effects of botulinum toxin, which may result in the loss of accommodation causing blurred vision for near objects.32 All other complications were localised and attributed to “enhanced response”, which results in excessive muscle weakness such as ptosis and diplopia. Otherwise, there was no systemic or life-threatening complication reported.
We recognise that the retrospective nature of this study may involve recall bias; however, we have attempted to minimise this by using the information provided by our patients at the time of consultation despite the fact that there was also recall bias from our patients. We also recognise that five oculoplastic surgeons were involved in the administration of the injections, although each attempted to follow the same protocol, dosing schedule and injection sites as the previous injection if the outcome was satisfactory to the patients. Another limitation is that the use of SSAs in assessing the subjective treatment outcome of botulinum toxin injections may not reflect the whole picture as patients could still recognise a suboptimal response despite it not affecting their activities of daily life. We believe further study with a more comprehensive measurement scale for the subjective treatment outcomes would be beneficial.
Conclusion
In this study of 105 Asian patients with BEB and HFS, the botulinum toxin dose required increased significantly over time; meanwhile, both objective and subjective therapeutic outcome measures were similar. We found that 26% and 41% of patients with BEB and HFS respectively experienced at least one local complication episode, respectively, which all self-resolved within 6 weeks after injection without systemic or life-threatening events. Therefore, in order to fully inform patients at the pre-injection consultation, we suggest including a clear explanation of this potential tolerance phenomenon if long-term botulinum toxin treatment is to be anticipated.
Declaration of interest statement
The authors declare that there are no conflict of interest. The authors alone are responsible for the writing and content of the article.
References
- 1.Kumar R, Dhaliwal HP, Kukreja RV, Singh BR.. The botulinum toxin as a therapeutic agent: molecular structure and mechanism of action in motor and sensory systems. Semin Neurol. February, 2016;36(1):10–19. doi: 10.1055/s-0035-1571215. [DOI] [PubMed] [Google Scholar]
- 2.Huang W, Foster JA, Rogachefsky AS. Pharmacology of botulinum toxin. J Am Acad Dermatol. August, 2000;43(2 Pt 1):249–259. doi: 10.1067/mjd.2000.105567. [DOI] [PubMed] [Google Scholar]
- 3.Dressler D. Clinical applications of botulinum toxin. Curr Opin Microbiol. June, 2012;15(3):325–336. doi: 10.1016/j.mib.2012.05.012. [DOI] [PubMed] [Google Scholar]
- 4.Scott AB. Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. J Pediatr Ophthalmol Strabismus. January–February, 1980;17(1):21–25. doi: 10.3928/0191-3913-19800101-06. [DOI] [PubMed] [Google Scholar]
- 5.Broadbent TJ, Wesley RE, Mawn LA. A survey of current blepharospasm treatment patterns among oculoplastic surgeons. Ophthalmic Plast Reconstr Surg. January–February, 2016;32(1):24–27. doi: 10.1097/IOP.0000000000000405. [DOI] [PubMed] [Google Scholar]
- 6.Bladen JC, Feldman I, Favor M, Dizon M, Litwin A, Malhotra R. Long-term outcome of flexible onabotulinum toxin A treatment in facial dystonia. Eye (Lond). March, 2019;33(3):349–352. doi: 10.1038/s41433-018-0203-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Killer HE, Blumer BK, Bähler A. Approach to traumatic sixth nerve palsy with botulinum toxin A. Neuro-Ophthalmology. 1994;14(6):355–358. doi: 10.3109/01658109409024062. [DOI] [Google Scholar]
- 8.Chaudhry N, Srivastava A, Joshi L. Hemifacial spasm: the past, present and future. J Neurol Sci. September15, 2015;356(1–2):27–31. doi: 10.1016/j.jns.2015.06.032. [DOI] [PubMed] [Google Scholar]
- 9.Foster KA. Overview and history of botulinum neurotoxin clinical exploitation. In: Clinical Applications of Botulinum Neurotoxin. Berlin, Germany: Springer; 2014:1–5. [Google Scholar]
- 10.Monheit GD, Pickett A. AbobotulinumtoxinA: a 25-year history. Aesthet Surg J. May1, 2017;37(suppl_1):S4–S11. doi: 10.1093/asj/sjw284. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Omprakash H, Rajendran S. Botulinum toxin deaths: what is the fact? J Cutan Aesthet Surg. 2008;1(2):95–97. doi: 10.4103/0974-2077.44169. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Löscher W, Schmidt D. Experimental and clinical evidence for loss of effect (tolerance) during prolonged treatment with antiepileptic drugs. Epilepsia. August, 2006;47(8):1253–1284. doi: 10.1111/j.1528-1167.2006.00607.x. [DOI] [PubMed] [Google Scholar]
- 13.Greene P, Fahn S, Diamond B. Development of resistance to botulinum toxin type A in patients with torticollis. Mov Disord. March, 1994;9(2):213–217. doi: 10.1002/mds.870090216. [DOI] [PubMed] [Google Scholar]
- 14.Jankovic J, Schwartz K. Response and immunoresistance to botulinum toxin injections. Neurology. September, 1995;45(9):1743–1746. doi: 10.1212/WNL.45.9.1743. [DOI] [PubMed] [Google Scholar]
- 15.Siatkowski RM, Tyutyunikov A, Biglan AW, et al. Serum antibody production to botulinum A toxin. Ophthalmology. December, 1993;100(12):1861–1866. doi: 10.1016/S0161-6420(93)31384-9. [DOI] [PubMed] [Google Scholar]
- 16.Lai KK, Kuk AK, Chan E, Ko ST. The good toxin: 10 years of experience with botulinum toxin A in the treatment of benign essential blepharospasm. Eur J Ophthalmol. May, 2020;26:1120672120925630. [DOI] [PubMed] [Google Scholar]
- 17.Frampton JE, Silberstein S. Onabotulinumtoxin A: a review in the prevention of chronic migraine. Drugs. April, 2018;78(5):589–600. doi: 10.1007/s40265-018-0894-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Sahai A, Khan MS, Gregson N, Smith K, Dasgupta P, GKT Botulinum Study Group . Botulinum toxin for detrusor overactivity and symptoms of overactive bladder: where we are now and where we are going. Nat Clin Pract Urol. July, 2007;4(7):379–386. doi: 10.1038/ncpuro0839. [DOI] [PubMed] [Google Scholar]
- 19.Jankovic J. Botulinum toxin: state of the art. Mov Disord. August, 2017;32(8):1131–1138. doi: 10.1002/mds.27072. [DOI] [PubMed] [Google Scholar]
- 20.Ababneh OH, Cetinkaya A, Kulwin DR. Long-term efficacy and safety of botulinum toxin A injections to treat blepharospasm and hemifacial spasm. Clin Exp Ophthalmol. April, 2014;42(3):254–261. doi: 10.1111/ceo.12165. [DOI] [PubMed] [Google Scholar]
- 21.Levy RL, Berman D, Parikh M, Miller NR. Supramaximal doses of botulinum toxin for refractory blepharospasm. Ophthalmology. September, 2006;113(9):1665–1668. doi: 10.1016/j.ophtha.2006.03.055. [DOI] [PubMed] [Google Scholar]
- 22.Torres S, Hamilton M, Sanches E, Starovatova P, Gubanova E, Reshetnikova T. Neutralizing antibodies to botulinum neurotoxin type A in aesthetic medicine: five case reports. Clin Cosmet Investig Dermatol. 2013;7:11–17. Published December 18, 2013. doi: 10.2147/CCID.S51938. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Naumann M, Boo LM, Ackerman AH, Gallagher CJ. Immunogenicity of botulinum toxins. J Neural Transm (Vienna). 2013;120(2):275–290. doi: 10.1007/s00702-012-0893-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Dressler D, Hallett M. Immunological aspects of Botox, dysport and myobloc/neurobloc. Eur J Neurol. February, 2006;13(Suppl 1):11–15. doi: 10.1111/j.1468-1331.2006.01439.x. [DOI] [PubMed] [Google Scholar]
- 25.Houser MK, Sheean GL, Lees AJ. Further studies using higher doses of botulinum toxin type F for torticollis resistant to botulinum toxin type A. J Neurol Neurosurg Psychiatry. 1998;64(5):577–580. doi: 10.1136/jnnp.64.5.577. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Benecke R. Clinical relevance of botulinum toxin immunogenicity. BioDrugs. 2012;26:e1–e9. doi: 10.2165/11599840-000000000-00000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Bellows S, Jankovic J. Immunogenicity associated with botulinum toxin treatment. Toxins (Basel). 2019;11(9):491. Published August 26, 2019. doi: 10.3390/toxins11090491. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Badarny S, Susel Z, Honigman S. Effectivity of Dysport in patients with blepharospasm and hemifacial spasm who experienced failure with Botox. Isr Med Assoc J. July, 2008;10(7):520–522. [PubMed] [Google Scholar]
- 29.Borodic GE, Ferrante R. Effects of repeated botulinum toxin injections on orbicularis oculi muscle. J Clin Neuroophthalmol. June, 1992;12(2):121–127. doi: 10.3109/01658109209058127. [DOI] [PubMed] [Google Scholar]
- 30.Vivancos-Matellano F, Rodríguez-Sanz A, Herrero-Infante Y, Mascías-Cadavid J. Efficacy and safety of long-term therapy with type A botulinum toxin in patients with blepharospasm. Neuroophthalmology. November26, 2018;43(5):277–283. doi: 10.1080/01658107.2018.1542009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Brodsky MA, Swope DM, Grimes D. Diffusion of botulinum toxins. Tremor Other Hyperkinet Mov (N Y). 2012;2:tre-02-85-417-1. doi: 10.7916/D88W3C1M. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Hornik A, Gruener G, Jay W. Adverse reactions from botulinum toxin administration. Neuro-Ophthalmology. 2010;34:6–13. doi: 10.3109/01658100903576334. [DOI] [Google Scholar]