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Chemodenervation for the Treatment of Facial Dystonia
Ophthalmic Technology Assessment
Chemodenervation for the Treatment of Facial Dystonia A Report by the American Academy of Ophthalmology Jurij R. Bilyk, MD,1 Michael T. Yen, MD,2 Elizabeth A. Bradley, MD,3 Edward J. Wladis MD,4 Louise A. Mawn, MD5 Purpose: To review the medical literature on the outcomes and complications of various Food and Drug Administration-approved botulinum toxins for benign essential blepharospasm (BEB) and hemifacial spasm (HFS). Methods: Literature searches were last conducted in February 2017 in PubMed for articles published in English and in the Cochrane Library database without language limitations; studies published before 2000 were excluded. The combined searches yielded 127 citations. Of these, 13 articles were deemed appropriate for inclusion in this assessment, and the panel methodologist assigned ratings to them according to the level of evidence. Results: A combined total of 1523 patients (1143 with BEB and 380 with HFS) were included in the 13 studies. Five studies provided level I evidence, 2 studies provided level II evidence, and 6 studies provided level III evidence. Pretarsal injections were more efficacious than preseptal injections (96% vs. 86%, respectively). Pretarsal injections also resulted in a higher response rate on clinical scales (P < 0.05) and a longer duration of maximum response for both HFS and BEB. Patients with HFS require lower overall doses of onabotulinumtoxinA than patients with BEB for a similar duration of effect. Adverse events were dose related, and they occurred more frequently in patients who were given more units. Conclusions: Level I evidence supports the efficacy of Botox (Allergan Corp., Irvine, CA), Meditoxin, and Xeomin (Merz Pharmaceuticals, Frankfurt am Main, Germany) for the treatment of BEB. Meditoxin and Botox have equivalent effectiveness and incidence of adverse events for BEB and HFS. Dysport (Ipsen Biopharmaceuticals, Inc, Paris, France) seems to have efficacy similar to Botox and Meditoxin for BEB and HFS, but any definitive conclusions from the 2 level II studies in this review are limited by differences in the methodologies used. Higher doses of Botox and Dysport result in more adverse events. Repeated treatments using Botox seem to maintain efficacy for treatment of facial dystonias over a follow-up period of at least 10 years, based on level III evidence. Ophthalmology 2018;-:1e9 ª 2018 by the American Academy of Ophthalmology
The American Academy of Ophthalmology prepares Ophthalmic Technology Assessments to evaluate new and existing procedures, drugs, and diagnostic and screening tests. The goal of an Ophthalmic Technology Assessment is to review systematically the available research for clinical efficacy and safety. After review by members of the Ophthalmic Technology Assessment Committee, other Academy committees, relevant subspecialty societies, and legal counsel, assessments are submitted to the Academy’s Board of Trustees for consideration as official Academy statements. The purpose of this assessment by the Ophthalmic Technology Assessment Committee Oculoplastics and Orbit Panel was to analyze the efficacy of various Food and Drug Administration (FDA)-approved botulinum toxin preparations in the treatment of benign ª 2018 by the American Academy of Ophthalmology Published by Elsevier Inc.
essential blepharospasm (BEB) and hemifacial spasm (HFS).
Background The first clinical use for botulinum toxin was described in 1980 by Scott,1 who reported on its potential efficacy in the treatment of strabismus. The toxin blocks release of acetylcholine at the neuromuscular junction, resulting in temporary paresis of the muscle. In 1989, the United States FDA approved the use of onabotulinumtoxinA (Botox; Allergan Corp., Irvine, CA) for the treatment of strabismus and blepharospasm associated with dystonia, including BEB and HFS in patients 12 years of age and https://doi.org/10.1016/j.ophtha.2018.03.013 ISSN 0161-6420/18
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Ophthalmology Volume -, Number -, Month 2018 older.2 OnabotulinumtoxinA also is marketed under the names Botox Cosmetic, Vistabel, and Vistabex. Of the 7 known botulinum neurotoxins (AeG), only 2 (A and B) are approved by the FDA for clinical use in the United States. Since the initial introduction of Botox, 2 additional botulinum toxin A preparations have been approved for use in facial dystonias: abobotulinumtoxinA (Dysport [also called Reloxin and Azzalure]; Ipsen Biopharmaceuticals, Inc., Paris, France) and incobotulinumtoxinA (Xeomin; Merz Pharmaceuticals, Frankfurt am Main, Germany).3 Although units are not interchangeable between neurotoxins, some consensus in dosing regimens exists. Dysport is similar to Botox, but has a dose ratio of approximately 2e4:1 for the treatment of BEB and HFS.3e5 The dose ratio of Xeomin (1e1.2:1) is identical or nearly identical to that of Botox.3 During the manufacturing of Xeomin, complexing proteins are removed to allow for unreconstituted toxin to be stored at room temperature as well as potentially to reduce the development of antibotulinumtoxinA antibodies, which theoretically could result in tachyphylaxis, although this hypothesis remains unproven.3,6 Botulinum toxin B preparations are limited to rimabotulinumtoxinB (MyoBloc; NeuroBloc, Solstice Neurosciences, US WorldMeds, Louisville, KY). Myobloc has higher autonomic side effects than Botox does and therefore is used more often for nonmotor abnormalities (e.g., hyperhidrosis, sialorrhea). The dose ratio between Botox and MyoBloc varies between 1 to 24 and 100.
Question for Assessment The focus of this assessment was to address the following question: What is the efficacy of various FDA-approved botulinum toxin preparations in the treatment of facial dystonias (BEB and HFS)?
Description of Evidence Literature searches were conducted last on February 28, 2017, in PubMed for articles published in English and in the Cochrane Library database without a language limitation. Because the goal of this assessment was to compare various botulinum toxins for facial dystonia and not simply to report on the efficacy of Botox, publications before 2000 were excluded. The combined searches yielded 127 citations. The following search terms were used along with date, publication, and language filters: botulinum toxins, onabotulinumtoxinA, rimabotulinumtoxinB, incobotulinumtoxinA, botulinum, Botox, Myobloc, Xeomin, hemifacial spasm, blepharospasm, and Meige syndrome. Inclusion criteria required that the study population comprised primarily patients with BEB, HFS, or other facial dystonias and that it included at least 25 patients treated with chemodenervation and followed up for at least 6 weeks. Analysis was confined to products approved by the FDA. Of the 127 citations, 13 studies met the inclusion criteria and were abstracted for review. Abstracted data included study design, number of patients, patient demographics, diagnosis (BEB, HFS, or oral facial dystonia [Meige] syndrome),
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chemodenervation agent(s) used, clinical assessments before and after treatment, and adverse events. The methodologist (E.A.B.) then assigned a rating to each study based on the rating scale developed by the Oxford Centre for Evidence-Based Medicine.7 A level I rating was assigned to well-designed and well-conducted randomized clinical trials, a level II rating was assigned to well-designed case-control and cohort studies and lower-quality randomized studies, and a level III rating was assigned to case series, case reports, and lower-quality cohort and case-control studies. Five of the 13 studies were rated level I, 2 were rated level II, and 6 were rated level III.
Clinical Rating Scales Many rating, or assessment, scales initially were used to measure the efficacy of Botox against placebo when treating BEB. Since then, a variety of rating scales have been used to determine the efficacy of botulinum toxin preparations to treat BEB and HFS, as shown in Table 1.8e11 As noted in a review by Wabbels et al,12 BEB rating scales can be divided into 3 categories: clinical, activities of daily living, and global activity. Clinical scales (e.g., Jankovic Rating Scale [JRS]) are used by observer evaluators and activities of daily living scales (e.g., Blepharospasm Disability Index [BSDI]) are used by patients for self-assessment. Global activity scales (e.g., Patient Evaluation of Global Response [PEGR]) measure the overall, rather than disease-specific, effects of treatment, and typically they are limited to secondary-outcome analyses in most studies. The 2 most widely used grading systems are the JRS9 and the BSDI.11e13 Both have limitations in sensitivity when used to assess mild disease. The JRS consists of 2 categories, severity and spasm frequency, and each category is divided into 5 levels (0e4) on a Likert-type scale of ascending symptoms. The BSDI survey measures the impact of BEB and BEB treatment on 5 specific activities of daily living and 1 generalized activity (“doing everyday activities”).13 Each activity is rated according to a 5-point scale, with an option to select “not applicable.” Jankovic et al13 used the data of 300 patients with BEB who were treated with either Botox or Xeomin to study the validity of the BSDI compared with other rating scales. Patients completed the rating scales at baseline and 21 days after treatment. A high internal consistency was found between the BSDI and the JRS and PEGR scales. In addition, significant improvement in both JRS and BSDI scores for both Botox and Xeomin were noted. The authors stressed that the use of BSDI is important in evaluating treatment efficacy in BEB to demonstrate improvement in quality-of-life metrics. The use of both observer-based evaluations (usually for primary outcomes) and patient self-assessment scales (usually for secondary outcomes) is becoming more prevalent.
Published Results The published results on the efficacy of various FDAapproved botulinum toxin preparations for the treatment of
Table 1. Summary of Reviewed Studies
Mean Duration (Median, Range)
Primary Outcome Measures
Prospective, doubleblind, placebo controlled
Xeomin vs. placebo
BEB
109 (109, 0)
6 wks (6 wks, NR)
JRS, BSDI, PEGR
Xeomin vs. placebo for BEB
Roggenkamper et al, 200636
I
Phase 3, double-blind, parallel group
Xeomin, Botox
BEB
304 (304, 0)
16 wks
JRS, BSDI
Comparison of efficacy between Xeomin and Botox
Truong et al, 200822
I
Phase 2, double-blind, parallel group
Dysport, placebo
BEB
85 (85, 0)
16 wks (16 wks, 0)
Modified BDS, FIM, SRS, VAS
Efficacy of Dysport for BEB at 3 doses
Wabbels et al, 201144
I
Prospective, doubleblind, parallel group
Xeomin, Botox
BEB
63 (63,0)
8 wks (8 wks, 0)
BSDI, JRS, PGA
Comparison of efficacy between Xeomin and Botox
Yoon et al, 200933
I
Phase 3, prospective, double-blind
Meditoxin, Botox
BEB
52 (52, 0)
4 wks (4 wks, 0)
SS (5 grades), patient selfassessment
Jankovic, 20096
II
Prospective, doubleblind, parallel group
Xeomin, Botox
BEB
300 (300, 0)
109e112 days (109e112 days, NR)
JRS, BSDI, PGA
% of patients with improvement in >1 grade of SS at 4 wks after injection. Meditoxin:Botox ¼ 1:1. Noninferiority of Xeomin vs. Botox. Botox:Xeomin ¼ 1:1.
Kongsengdao and Kritalukkul, 201228
II
Prospective, doubleblind, randomized, crossover
Dysport, Meditoxin
HFS
26 (0, 26)
24 wks (24 wks, 0)
Quality-of-life analysis (4 questions), HFS30, SF-36, AIMS (Thai version), CES-D
Study Type
Rating Scale(s)
Efficacy of Dysport vs. Meditoxin. Dysport: Meditoxin ¼ 4.8:1.
Findings Xeomin is effective for BEB. AEs more common with Xeomin compared with placebo. No neutralizing antibodies found. No difference in efficacy, duration, AEs, laboratory testing, or neurologic examinations between Xeomin and Botox. Efficacy and AEs are dose related. Eighty units of Dysport per session may be best balance between efficacy and AEs. No difference between Xeomin and Botox at 4 wks and 8 wks. Nonsignificant trend of greater improvement with Botox at 4 and 8 wks. No difference in efficacy or AEs between Meditoxin and Botox at 4 wks. No antibodies found at 4 wks. No difference in efficacy, onset of effect, duration, or AEs between Xeomin A and Botox. No difference in primary outcome measures between 2 drugs. However, a significantly lower difference in total intensity score, daily duration of muscle spasm, and mean duration of
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(Continued)
Ophthalmic Technology Assessment
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Jankovic et al, 201145
Bilyk et al
Toxin(s)
Facial Dystonia(s)
Author(s), Year
Level of Evidence
Total No. of Patients Completing Study (Benign Essential Blepharospasm, Hemifacial Spasm)
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Table 1. (Continued.)
Author(s), Year
Level of Evidence
Study Type
Toxin(s)
III
Retrospective, noncomparative
Botox, Dysport
Çakmur et al, 200227
III
Retrospective
Cillino et al, 20102
III
Defazio et al, 200217
BEB
113 (113, 0)
Botox
BEB, HFS
53 (25, 28)
Prospective, noncomparative
Botox
BEB, HFS
131 (73, 58)*
III
Retrospective
Botox
HFS
65 (0, 65)
Grosset et al, 201530
III
Retrospective
Dysport, Xeomin
BEB, HFS
Suputtitada et al, 200423
III
Not recorded
Botox
HFS
Mean Duration (Median, Range)
Rating Scale(s)
Primary Outcome Measures
72 mos (NR, NR)
JRS
Clinical features and therapeutic outcomes in BEB.
BEB: 3.1 yrs (NR, 3e4) HFS: 3.3 yrs (NR, 1e7)
JRS, TWSTRS
Efficacy of pretarsal vs. preseptal orbicularis oculi injection.
>10 yrs (NR, NR)
Self-evaluation scale
Dose escalation of BTX-A.
10 yrs (NR, NR)
Self-evaluation scale
Response to Botox in HFS at yrs 1 10.
110 (19, 91)
91 wks (NR, 52e219 wks)
Comparison of Dysport and Xeomin at 4:1 dosing ratio for BEB and HFS.
112 (0, 112)
3.4 yrs (NR, NR)
2 patient selfassessments (efficacy and duration of effect) 4-point scale
Low-dose Botox for HFS.
Findings functional impairment at 4 wks of treatment was noted with Dysport. Showed overall efficacy of Botox and Dysport for BEB without separate analysis of each agent. Higher response rate and lower AEs to Botox with pretarsal injection. Pain of injection not measured. BEB patients required higher Botox dose than HFS patients. Response rate to BTX for BEB and HFS stable over 10-yr study duration. Higher efficacy of Botox with older age. No loss of Botox efficacy for HFS over 10-yr period. No difference in efficacy, duration of effect, and AEs at 4:1 ratio. 96.7% of patients with >80% improvement. No statistical analysis performed.
AE ¼ adverse event; AIMS ¼ Abnormal Involuntary Movement Scale; BEB ¼ benign essential blepharospasm; BEBþ ¼ Meige syndrome; BDS ¼ Blepharospasm Disability Scale; BSDI ¼ Blepharospasm Disability Index; BSGS ¼ Blepharospasm Graduation Scale; CES-D ¼ Center for Epidemiologic Studies Depression Scale; FIM ¼ Frequency of Involuntary Movement; HFS ¼ hemifacial spasm; HFS-30 ¼ Hemifacial Spasm-30; HFSES ¼ Hemifacial Spasm Evaluation Scale; JRS ¼ Jankovic Response Scale; NR ¼ not reported; PGA ¼ Patient Global Assessment; SF-36 ¼ Medical Outcome Study Short Form 36; SRS ¼ Severity Rating Scale; SS ¼ Severity of Spasm; TWSTRS ¼ Toronto Western Spasmodic Torticollis Rating Scale; VAS ¼ Visual Analog Scale. *Patients with spastic entropion not included in this analysis.
Ophthalmology Volume -, Number -, Month 2018
Aquino et al, 201240
Facial Dystonia(s)
Total No. of Patients Completing Study (Benign Essential Blepharospasm, Hemifacial Spasm)
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Ophthalmic Technology Assessment
Table 2. Summary of Adverse Events Reported* Adverse Event Ptosis Diplopia Facial weaknessz Ecchymosis Dry eye/eye burning Mouth droop Photophobia Blurred vision Epiphora
Botox (%) 2,6,17,23,33,44
4.5e29.4 0e8.62,17,23 3e1117,23 8.6e22.62,44 0e2.72,6,33 1.72 0e3.42,6 0e3.22,6 0e0.62,23
Dysporty (%)
Xeomin (%)
Meditoxin (%)
Placebo (%)
13e5822 10e1622 NR NR 322 NR NR 23e4222 6e1722
6.1e18.96,44,45 NR NR 2.745e27.344 0.7e18.96,44,45 NR 1.46 1.4e5.445 2.745
6.433 NR NR NR 7.633 NR NR NR NR
5.945 NR NR 2.945 11.845 NR NR 5.945 2.945
NR ¼ not recorded. *An additional 24 patients who received onabotulinumtoxinA (oBTX-A) for treatment of entropion were not included in this review. y Data from Truong et al22 are listed as a range of dose-related adverse events. z In patients with hemifacial spasm.
BEB and HFS are presented by specific botulinum toxin for both types of dystonia. OnabotulinumtoxinA (Botox) Hemifacial Spasm. Botox has a proven efficacy in the management of HFS.14e16 However, previous studies on this subject are limited to less than 5 years of follow-up. Defazio et al17 (level III) described their findings from a multicenter study on the long-term efficacy (>10 years) of Botox in the management of HFS in which injections were limited to the orbicularis oculi muscle. The response rate was 96%, with a mean duration of effect of 12.6 weeks ( 5.7 weeks), consistent with previous studies.18e21 Importantly, treatment failures occurred mostly during the first year of therapy, when dosing and the pattern of injection may be unclear. Specifically, the authors noted no statistically significant differences in the number of annual treatments or cumulative annual dose per patient, amount of Botox per treatment session, response rate, or duration of effect when comparing first- and tenth-year data. However, the dropout rate during the course of the study was high (19%), and efficacy was measured using a 3-point patient self-assessment scale rather than an observer-based scale (e.g., JRS). Cillino et al2 (level III) reported on the long-term efficacy of Botox for BEB, HFS, and spastic entropion. Their patient cohort consisted of 58 patients with HFS whom they studied retrospectively using 10 years of follow-up data. The dose per patient with HFS and entropion was significantly lower than that for BEB (P < 0.0005), but durations of effect between BEB and HFS were similar. Duration of effect increased for both BEB and HFS over time (P < 0.05), and drug-dose escalation analysis concluded that there was a greater efficacy of injection in older patients, consistent with other studies and presumably because of a decreased muscle bulk when compared with younger individuals.22 Suputtitada et al23 (level III) presented their findings after using low-dose Botox in 112 patients with HFS over an 8-year span. Unlike in the study by Defazio et al,17 the injection sites also included middle and lower facial and neck musculature. However, only the orbicularis oculi and oris muscles were injected 100% of the time. The mean
overall duration of response was 4.1 months (range, 3e6 months), and a high, “excellent,” response rate (96.7%) was reported. The study by Suputtitada et al has significant drawbacks that limit the strength of any conclusions, including use of a unique observer scale, a variable pattern of injection, and a lack of statistical analysis. The most conservative conclusion from this study is that Botox is effective in treating HFS over a span of 10 injections (with an average overall duration of injection effect of 4.1 months [range, 3e6 months], which calculates to a span of 41 months [range, 30e60 months]). Blepharospasm. The site of periocular Botox injection has been studied previously for BEB and apraxia of eyelid opening.24e26 Çakmur et al27 (level III) retrospectively studied Botox injections into the preseptal and pretarsal orbicularis oculi muscle in patients with both BEB and HFS. The results confirmed those from previous studies.24,26 Pretarsal injections were more effective than preseptal injections (96% vs. 86%, respectively). Pretarsal injections also resulted in a higher response rate on both clinical scales (P < 0.05) and a longer duration of maximum response for both HFS and BEB. In patients with HFS, pretarsal injections also resulted in a significantly lower rate of adverse events (P < 0.05; Table 2) compared with preseptal injections. One of the limitations of the study by Çakmur et al is that patients were not randomized to preseptal or pretarsal injections. As already noted, Cillino et al2 retrospectively studied the long-term efficacy of Botox for facial dystonia. Seventy-three patients with BEB were studied using a 3-point patient self-assessment scale in addition to indices to evaluate drug-dose escalation. Patients with BEB required a significantly higher average dose of Botox compared with patients with HFS. However, the mean duration of effect was similar (18.212.3 weeks for BEB and 20.611.6 weeks for HFS), as were the proportions of BEB and HFS patients who reported adverse events. Both BEB and HFS patients showed an increase in mean dosages over time, especially after the first 3 to 4 injections, suggesting that early underdosing had occurred; this finding was most prominent in older patients.
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Ophthalmology Volume -, Number -, Month 2018 AbobotulinumtoxinA (Dysport) Hemifacial Spasm. A comparative study over 24 weeks of Dysport and Meditoxin (Korean onabotulinumtoxinA) in the treatment of HFS was published by Kongsengdao and Kritalukkul (level II evidence).28 A total of 26 patients completed the study. Patients underwent an identical injection pattern to the orbicularis oculi and oris muscles with either 15 units of Dysport or 3.125 units of Botox. At the 4-week assessment, the mean intensity score, mean duration of facial spasms per day, and mean duration of functional impairment per day were significantly lower with Dysport than with Meditoxin, whereas the daily qualityof-life assessments showed no difference. Any conclusion on the differences in efficacy between the 2 agents must be considered somewhat speculative, because dose ratios between Dysport and Botox or Meditoxin varied widely between 1 and 13.3 to 1 in several studies.29e32 That said, 1 large, prospective trial4 concluded that a dose equivalency of Dysport and Botox of 4:1 for the treatment of BEB and HFS is optimal, whereas others have concluded that a ratio of 3:1 is optimal.3 The dose ratio of Meditoxin and Botox seems to be 1:1.3,33,34 The ratio of approximately 4.8:1 of Dysport to Meditoxin in the cohort of Kongsengdoa and Kritalukkul is high compared with that reported by others.4 Therefore, the perceived superior efficacy of Dysport in the Kongsengdoa and Kritalukkul study simply may have been the result of higher doses when compared with Meditoxin. Blepharospasm. Truong et al22 (level I) studied the efficacy of 3 doses of Dysport against placebo in the treatment of BEB in a randomized, double-blind, parallelgroup study. Dysport demonstrated significant efficacy at all doses compared with the placebo at the 4- and 12-week modified Blepharospasm Disability Scale (BDS), and there was a dose-related effect on the score. Efficacy was noted through 16 weeks at 80-unit and 120-unit doses. Adverse events were dose related, and they occurred more frequently in patients receiving 120 units. The authors concluded that Dysport improved the symptoms of BEB across all scales studied, consistent with previous studies on the subject.9,10,15,18,25,35e39 The authors also noted that 80 units of Dysport per injection session, which is lower than the average dose recommended in other studies,29 may strike the best balance between efficacy and adverse events in patients with BEB. Aquino et al40 (level III) retrospectively studied 125 patients with BEB over a 17-year span to evaluate the clinical features and therapeutic outcomes of Botox and Dysport. However, the authors reported on efficacy of botulinum toxin overall, without a separate analysis of the Botox and Dysport outcomes. Therefore, the individual efficacy of each agent in the treatment of BEB cannot be gleaned from the manuscript. Similarly, adverse events occurred in 14% of all patients (ptosis, blurred vision, diplopia, foreign body sensation), but no specific incidences were listed (Table 2). Grosset et al30 (level III) reported on their experience in switching patients with facial and cervical dystonia from Dysport to Xeomin. Data for analysis were available on 257 patients, of whom 19 had BEB and 91 had HFS. (The
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remaining 147 patients had cervical or localized dystonia, generalized dystonia, or both and are not included in this review.) For the patients with BEB and HFS, the authors found that a mean dose ratio of 4.07:1 ( 0.5) between Dysport and Xeomin, respectively, at the beginning of the study and 3.89:1 ( 0.58) at the close of the study 52 to 219 weeks later resulted in clinical equivalency. They concluded that a dose ratio of approximately 4:1 resulted in similar efficacy, duration of benefit, and adverse events with no significant change in dose ratio over the span of the study. Of note, in a meta-analysis on the subject, Dashtipour et al5 found that a dose ratio of 2.5 to 3.0:1 of Dysport to Botox “provides comparable safety and efficacy for therapeutic movement disorders [cervical dystonia and BEB] chemodenervation procedures.” Finally, the authors noted a mean cost reduction of 76.7% ( 14.8%) in shifting patients from Dysport to Xeomin. This study was performed in the United Kingdom, and the cost metrics reported may not be applicable elsewhere.3,41,42 IncobotulnumtoxinA (Xeomin) Blepharospasm. Xeomin has documented efficacy in the treatment of BEB, and it performs similarly to Botox.36,43 Wabbels et al44 (level I) published their experience using these agents in the management of BEB. The authors performed a randomized, double-blind, parallel-group study of 65 German patients with BEB (63 completed the study) using a 1:1 dose ratio for Botox and Xeomin. The 4- and 8week BSDI and JRS scores showed no significant difference between the 2 BTX-A preparations. Wabbels et al noted that, compared with previous studies, their patient cohort was treated with higher total doses of Botox or Xeomin and had a higher mean age; they possibly had a longer history of BEB and previous botulinumtoxinA injections. Jankovic et al45 (level I) presented their findings of a double-blind, multicenter trial comparing Xeomin with placebo in the treatment of 109 patients with BEB. Patients were randomized at a 2:1 ratio for Xeomin and placebo, respectively, and were assessed at 3 and 6 weeks after injection using the JRS, BSDI, and PEGR. Xeomin had significantly higher efficacy than placebo in the treatment of BEB across all scales. A noninferiority study by Jankovic6 (level II) comparing Xeomin with Botox in the treatment of 300 patients with BEB also was published. Of note, study investigators determined the number and distribution of injection sites for individual patients, and the total dose of BTX-A varied between patients based on their previous prestudy injections. Significant and statistically similar improvements in JRS were noted for both agents at 3 weeks. Onset, duration, and waning of effect were statistically similar for Xeomin and Botox. Likewise, adverse events were similar for both groups. The author concluded that both agents had similar efficacy at a 1:1 dose ratio.
Conclusions The evidence from the 13 studies reviewed for this assessment indicates that Botox, Xeomin, and Dysport
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Ophthalmic Technology Assessment
injections are highly effective treatments for BEB and HFS. Level I evidence supports the effectiveness of both Botox and Xeomin for the treatment of BEB. Two studies36,44 show equal effectiveness of Botox and Xeomin in the treatment of BEB, and 1 additional trial45 proves the effectiveness of Xeomin for BEB compared with placebo. Of note, all 3 studies used widely accepted rating scales (JRS, BSDI). Durations of effect and incidence of adverse events were similar between Botox and Xeomin at a 1:1 dosage ratio.36,44 There is level I evidence33 that demonstrates equivalent effectiveness and incidence of adverse events when Meditoxin is compared with Botox. Dysport seems to have effectiveness similar to Botox and Meditoxin for BEB and HFS, but any definitive conclusions from the 2 studies28,40 (level II and level III, respectively) in this review are limited by the methodologies used as well as the dose ratios of Dysport to other agents. Truong et al22 (level I) demonstrated the effectiveness of Dysport for BEB at 3 escalating doses compared with placebo. A dose per session of 80 units for BEB seems to be a reasonable compromise between effectiveness and the incidence of adverse events. Additional conclusions can be gleaned from this review. Level III evidence in 2 retrospective studies2,17 shows more than 95% response rates of Botox for the treatment of BEB and HFS. Patients with HFS require lower overall doses of Botox than patients with BEB, but the durations of effect are similar.2 Higher doses of Botox and Dysport result in a higher incidence of adverse events.17,22 Pretarsal injections of Botox are more effective than preseptal injections (96% vs. 86%) and have fewer adverse events.27 Botox remains effective for treatment of facial dystonias over a period of at least 10 years based on level III evidence.17,23 Correct dosing and pattern of injection may be unclear over the first 3 to 4 injections in facial dystonias,17 which potentially may affect final analysis of studies on the use of botulinum toxin for these disorders. Finally, older patients (>65 years) require lower doses of botulinum toxin for the treatment of BEB and HFS, most likely because of loss of muscle mass with age.2 This finding is important to keep in mind to prevent overdosing of older patients with facial dystonia over the long-term course of treatment.
Future Research Meaningful comparison of various botulinum toxins for the management of facial dystonias is hampered by the lack of standardized ratings scales across studies. The JRS, BSDI, and PEGR seem to be the most widely used scales in level I studies,12 and use of these scales in future studies would provide for comparability of outcomes with prior studies. Of note, however, is the fact that these scales may not be sensitive enough to detect less substantial differences in efficacy between various botulinum toxin preparations.12 Furthermore, most scales are more effective at measuring the response in patients who have more severe dystonia; many studies include patients with mild dystonia, potentially limiting the usefulness of rating scales. In addition, the number of available scales as well as individual study modifications to scales makes comparison
across studies and botulinum toxin agents difficult. Ratings scales need to be developed to assess subtle differences in effectiveness more accurately between agents in patients with mild facial dystonia. Conversion dosage ratios between Dysport and other agents (Botox, Xeomin, Meditoxin) have not been determined definitively, making it difficult to conduct studies comparing Dysport and other botulinum toxin A preparations. The accepted range for BEB seems to vary between 2.5 and 4.0:1 for Dysport and Botox.3,5 This is a wide dose ratio that requires better delineation for the clinical application of Dysport in the treatment of BEB and HFS.
References 1. Scott AB. Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. Ophthalmology. 1980;87(10):1044e1049. 2. Cillino S, Raimondi G, Guepratte N, et al. Long-term efficacy of botulinum toxin A for treatment of blepharospasm, hemifacial spasm, and spastic entropion: a multicentre study using two drug-dose escalation indexes. Eye (Lond). 2010;24(4): 600e607. 3. Scaglione F. Conversion ratio between Botox(), Dysport(), and Xeomin() in clinical practice. Toxins (Basel). 2016;865; https://doi.org/10.3390/toxins8030065. 4. Sampaio C, Ferreira JJ, Simoes F, et al. DYSBOT: a singleblind, randomized parallel study to determine whether any differences can be detected in the efficacy and tolerability of two formulations of botulinum toxin type AdDysport and Botoxdassuming a ratio of 4:1. Mov Disord. 1997;12(6): 1013e1018. 5. Dashtipour K, Chen JJ, Espay AJ, et al. OnabotulinumtoxinA and AbobotulinumtoxinA dose conversion: a systematic literature review. Mov Disord Clin Pract. 2016;3(2):109e115. 6. Jankovic J. Clinical efficacy and tolerability of Xeomin in the treatment of blepharospasm. Eur J Neurol. 2009;16(suppl 2): 14e18. 7. Oxford Centre for Evidence-Based Medicine. Levels of evidence (March 2009). http://www.cebm.net/index.aspx? o¼1025; Accessed 24.08.17. 8. Rahman R, Berry-Brincat A, Thaller VT. A new grading system for assessing orbicularis muscle function. Eye (Lond). 2003;17(5):610e612. 9. Jankovic J, Orman J. Botulinum A toxin for cranial-cervical dystonia: a double-blind, placebo-controlled study. Neurology. 1987;37(4):616e623. 10. Iwashige H, Nemeto Y, Takahashi H, Maruo T. Botulinum toxin type A purified neurotoxin complex for the treatment of blepharospasm: a dose-response study measuring eyelid force. Jpn J Ophthalmol. 1995;39(4):424e431. 11. Albanese A, Sorbo FD, Comella C, et al. Dystonia rating scales: critique and recommendations. Mov Disord. 2013;28(7):874e883. 12. Wabbels B, Jost WH, Roggenkämper P. Difficulties with differentiating botulinum toxin treatment effects in essential blepharospasm. J Neural Transm (Vienna). 2011;118(6): 925e943. 13. Jankovic J, Kenney C, Grafe S, et al. Relationship between various clinical outcome assessments in patients with blepharospasm. Mov Disord. 2009;24(3):407e413. 14. Elston JS. The management of blepharospasm and hemifacial spasm. J Neurol. 1992;239(1):5e8.
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Ophthalmology Volume -, Number -, Month 2018 15. Van den Bergh P, Francart J, Mourin S, et al. Five-year experience in the treatment of focal movement disorders with low-dose Dysport botulinum toxin. Muscle Nerve. 1995;18(7): 720e729. 16. Jost WH, Kohl A. Botulinum toxin: evidence-based medicine criteria in blepharospasm and hemifacial spasm. J Neurol. 2001;248(suppl 1):21e24. 17. Defazio G, Abbruzzese G, Girlanda P, et al. Botulinum toxin A treatment for primary hemifacial spasm: a 10-year multicenter study. Arch Neurol. 2002;59(3):418e420. 18. Berardelli A, Formica A, Mercuri B, et al. Botulinum toxin treatment in patients with focal dystonia and hemifacial spasm. A multicenter study of the Italian Movement Disorder Group. Ital J Neurol Sci. 1993;14(5):361e367. 19. Novis SA, De Mattos JP, De Rosso AL. Botulinum toxin in blepharospasm, in hemifacial spasm, and in cervical dystonia: results in 33 patients [in Portuguese]. Arq Neuropsiquiatr. 1995;53(3-A):403e410. 20. Astarloa R, Morales B, Sanchez V, et al. Focal dystonias and facial hemispasm: treatment with botulinum A toxin [in Spanish] Arch Neurobiol (Madr). 1991;54(5):210e217. 21. Park YC, Lim JK, Lee DK, Yi SD. Botulinum A toxin treatment of hemifacial spasm and blepharospasm. J Korean Med Sci. 1993;8(5):334e340. 22. Truong D, Comella C, Fernandez HH, et al. Efficacy and safety of purified botulinum toxin type A (Dysport) for the treatment of benign essential blepharospasm: a randomized, placebo-controlled, phase II trial. Parkinsonism Relat Disord. 2008;14(5):407e414. 23. Suputtitada A, Phanthumchinda K, Locharernkul C, Suwanwela NC. Hemifacial spasm: results of treatment with low dose botulinum toxin injection. J Med Assoc Thai. 2004;87(10):1205e1211. 24. Albanese A, Bentivoglio AR, Colosimo C, et al. Pretarsal injections of botulinum toxin improve blepharospasm in previously unresponsive patients. J Neurol Neurosurg Psychiatry. 1996;60(6):693e694. 25. Kowal L. Pretarsal injections of botulinum toxin improve blephospasm in previously unresponsive patients. J Neurol Neurosurg Psychiatry. 1997;63(4):556. 26. Jankovic J. Pretarsal injection of botulinum toxin for blepharospasm and apraxia of eyelid opening. J Neurol Neurosurg Psychiatry. 1996;60(6):704. 27. Çakmur R, Ozturk V, Uzunel F, et al. Comparison of preseptal and pretarsal injections of botulinum toxin in the treatment of blepharospasm and hemifacial spasm. J Neurol. 2002;249(1): 64e68. 28. Kongsengdao S, Kritalukkul S. Quality of life in hemifacial spasm patient after treatment with botulinum toxin A; a 24week, double-blind, randomized, cross-over comparison of Dysport and Neuronox study. J Med Assoc Thai. 2012;95(suppl 3):S48eS54. 29. Marchetti A, Magar R, Findley L, et al. Retrospective evaluation of the dose of Dysport and BOTOX in the management of cervical dystonia and blepharospasm: the REAL DOSE study. Mov Disord. 2005;20(8):937e944.
30. Grosset DG, Tyrrell EG, Grosset KA. Switch from abobotulinumtoxinA (Dysport(R)) to incobotulinumtoxinA (Xeomin(R)) botulinum toxin formulation: a review of 257 cases. J Rehabil Med. 2015;47(2):183e186. 31. Aoki KR, Ranoux D, Wissel J. Using translational medicine to understand clinical differences between botulinum toxin formulations. Eur J Neurol. 2006;13(suppl 4):10e19. 32. Wohlfarth K, Göschel H, Frevert J, et al. Botulinum A toxins: units versus units. Naunyn Schmiedebergs Arch Pharmacol. 1997;355(3):335e340. 33. Yoon JS, Kim JC, Lee SY. Double-blind, randomized, comparative study of Meditoxin versus Botox in the treatment of essential blepharospasm. Korean J Ophthalmol. 2009;23(3):137e141. 34. Kenney C, Jankovic J. Botulinum toxin in the treatment of blepharospasm and hemifacial spasm. J Neural Transm (Vienna). 2008;115(4):585e591. 35. Nüssgens Z, Roggenkämper P. Comparison of two botulinumtoxin preparations in the treatment of essential blepharospasm. Graefes Arch Clin Exp Ophthalmol. 1997;235(4):197e199. 36. Roggenkämper P, Jost WH, Bihari K, et al. Efficacy and safety of a new botulinum toxin type A free of complexing proteins in the treatment of blepharospasm. J Neural Transm (Vienna). 2006;113(3):303e312. 37. Perman KI, Baylis HI, Rosenbaum AL, Kirschen DG. The use of botulinum toxin in the medical management of benign essential blepharospasm. Ophthalmology. 1986;93(1):1e3. 38. Poungvarin N, Devahastin V, Viriyavejakul A. Treatment of various movement disorders with botulinum A toxin injection: an experience of 900 patients. J Med Assoc Thai. 1995;78(6): 281e288. 39. Price J, Farish S, Taylor H, O’Day J. Blepharospasm and hemifacial spasm. Randomized trial to determine the most appropriate location for botulinum toxin injections. Ophthalmology. 1997;104(5):865e868. 40. Aquino CC, Felicio AC, Castro PC, et al. Clinical features and treatment with botulinum toxin in blepharospasm: a 17-year experience. Arq Neuropsiquiatr. 2012;70(9):662e666. 41. Abogunrin S, Brand S, Desai K, et al. AbobotulinumtoxinA in the management of cervical dystonia in the United Kingdom: a budget impact analysis. Clinicoecon Outcomes Res. 2015;7:441e449. 42. Tilden D, Guarnieri C, Jackson D. Cost-effectiveness of Incobotulinumtoxin-A with flexible treatment intervals compared to Onabotulinumtoxin-A in the management of blepharospasm and cervical dystonia. Value Health. 2015;18(7):A759. 43. Benecke R, Jost WH, Kanovsky P, et al. A new botulinum toxin type A free of complexing proteins for treatment of cervical dystonia. Neurology. 2005;64(11):1949e1951. 44. Wabbels B, Reichel G, Fulford-Smith A, et al. Double-blind, randomised, parallel group pilot study comparing two botulinum toxin type A products for the treatment of blepharospasm. J Neural Transm (Vienna). 2011;118(2):233e239. 45. Jankovic J, Comella C, Hanschmann A, Grafe S. Efficacy and safety of incobotulinumtoxinA (NT 201, Xeomin) in the treatment of blepharospasm-a randomized trial. Mov Disord. 2011;26(8):1521e1528.
Footnotes and Financial Disclosures Originally received: March 9, 2018. Final revision: March 9, 2018. Accepted: March 9, 2018. Available online: ---. 1
Manuscript no. 2018-587.
Wills Eye Hospital, Philadelphia, Pennsylvania.
8
2
Cullen Eye Institute, Baylor College of Medicine, Houston, Texas.
3
Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota.
4
Ophthalmic Plastic Surgery, Lions Eye Institute, Department of Ophthalmology, Albany Medical Center, Albany (Slingerlands), New York, Minnesota.
Bilyk et al 5
Ophthalmic Technology Assessment
Vanderbilt Eye Institute, Vanderbilt University, Nashville, Tennessee.
Financial Disclosure(s): Funded without commercial support by the American Academy of Ophthalmology. The author(s) have no proprietary or commercial interest in any materials discussed in this article. Prepared by the Ophthalmic Technology Assessment Committee Oculoplastics and Orbit Panel and approved by the American Academy of Ophthalmology’s Board of Trustees February 20, 2018.
Abbreviations and Acronyms: BEB ¼ benign essential blepharospasm; BDS ¼ Blepharospasm Disability Scale; BSDI ¼ Blepharospasm Disability Index; FDA ¼ Food and Drug Administration; HFS ¼ hemifacial spasm; JRS ¼ Jankovic Rating Scale; PEGR ¼ Patient Evaluation of Global Response. Correspondence: Ali Al-Rajhi, PhD, MPH, American Academy of Ophthalmology, Quality and Data Science, P. O. Box 7424, San Francisco, CA 94120-7424. E-mail: [email protected].
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Chemodenervation for the Treatment of Facial Dystonia A Report by the American Academy of Ophthalmology Jurij R. Bilyk, MD,1 Michael T. Yen, MD,2 Elizabeth A. Bradley, MD,3 Edward J. Wladis MD,4 Louise A. Mawn, MD5 Purpose: To review the medical literature on the outcomes and complications of various Food and Drug Administration-approved botulinum toxins for benign essential blepharospasm (BEB) and hemifacial spasm (HFS). Methods: Literature searches were last conducted in February 2017 in PubMed for articles published in English and in the Cochrane Library database without language limitations; studies published before 2000 were excluded. The combined searches yielded 127 citations. Of these, 13 articles were deemed appropriate for inclusion in this assessment, and the panel methodologist assigned ratings to them according to the level of evidence. Results: A combined total of 1523 patients (1143 with BEB and 380 with HFS) were included in the 13 studies. Five studies provided level I evidence, 2 studies provided level II evidence, and 6 studies provided level III evidence. Pretarsal injections were more efficacious than preseptal injections (96% vs. 86%, respectively). Pretarsal injections also resulted in a higher response rate on clinical scales (P < 0.05) and a longer duration of maximum response for both HFS and BEB. Patients with HFS require lower overall doses of onabotulinumtoxinA than patients with BEB for a similar duration of effect. Adverse events were dose related, and they occurred more frequently in patients who were given more units. Conclusions: Level I evidence supports the efficacy of Botox (Allergan Corp., Irvine, CA), Meditoxin, and Xeomin (Merz Pharmaceuticals, Frankfurt am Main, Germany) for the treatment of BEB. Meditoxin and Botox have equivalent effectiveness and incidence of adverse events for BEB and HFS. Dysport (Ipsen Biopharmaceuticals, Inc, Paris, France) seems to have efficacy similar to Botox and Meditoxin for BEB and HFS, but any definitive conclusions from the 2 level II studies in this review are limited by differences in the methodologies used. Higher doses of Botox and Dysport result in more adverse events. Repeated treatments using Botox seem to maintain efficacy for treatment of facial dystonias over a follow-up period of at least 10 years, based on level III evidence. Ophthalmology 2018;-:1e9 ª 2018 by the American Academy of Ophthalmology
The American Academy of Ophthalmology prepares Ophthalmic Technology Assessments to evaluate new and existing procedures, drugs, and diagnostic and screening tests. The goal of an Ophthalmic Technology Assessment is to review systematically the available research for clinical efficacy and safety. After review by members of the Ophthalmic Technology Assessment Committee, other Academy committees, relevant subspecialty societies, and legal counsel, assessments are submitted to the Academy’s Board of Trustees for consideration as official Academy statements. The purpose of this assessment by the Ophthalmic Technology Assessment Committee Oculoplastics and Orbit Panel was to analyze the efficacy of various Food and Drug Administration (FDA)-approved botulinum toxin preparations in the treatment of benign ª 2018 by the American Academy of Ophthalmology Published by Elsevier Inc.
essential blepharospasm (BEB) and hemifacial spasm (HFS).
Background The first clinical use for botulinum toxin was described in 1980 by Scott,1 who reported on its potential efficacy in the treatment of strabismus. The toxin blocks release of acetylcholine at the neuromuscular junction, resulting in temporary paresis of the muscle. In 1989, the United States FDA approved the use of onabotulinumtoxinA (Botox; Allergan Corp., Irvine, CA) for the treatment of strabismus and blepharospasm associated with dystonia, including BEB and HFS in patients 12 years of age and https://doi.org/10.1016/j.ophtha.2018.03.013 ISSN 0161-6420/18
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Ophthalmology Volume -, Number -, Month 2018 older.2 OnabotulinumtoxinA also is marketed under the names Botox Cosmetic, Vistabel, and Vistabex. Of the 7 known botulinum neurotoxins (AeG), only 2 (A and B) are approved by the FDA for clinical use in the United States. Since the initial introduction of Botox, 2 additional botulinum toxin A preparations have been approved for use in facial dystonias: abobotulinumtoxinA (Dysport [also called Reloxin and Azzalure]; Ipsen Biopharmaceuticals, Inc., Paris, France) and incobotulinumtoxinA (Xeomin; Merz Pharmaceuticals, Frankfurt am Main, Germany).3 Although units are not interchangeable between neurotoxins, some consensus in dosing regimens exists. Dysport is similar to Botox, but has a dose ratio of approximately 2e4:1 for the treatment of BEB and HFS.3e5 The dose ratio of Xeomin (1e1.2:1) is identical or nearly identical to that of Botox.3 During the manufacturing of Xeomin, complexing proteins are removed to allow for unreconstituted toxin to be stored at room temperature as well as potentially to reduce the development of antibotulinumtoxinA antibodies, which theoretically could result in tachyphylaxis, although this hypothesis remains unproven.3,6 Botulinum toxin B preparations are limited to rimabotulinumtoxinB (MyoBloc; NeuroBloc, Solstice Neurosciences, US WorldMeds, Louisville, KY). Myobloc has higher autonomic side effects than Botox does and therefore is used more often for nonmotor abnormalities (e.g., hyperhidrosis, sialorrhea). The dose ratio between Botox and MyoBloc varies between 1 to 24 and 100.
Question for Assessment The focus of this assessment was to address the following question: What is the efficacy of various FDA-approved botulinum toxin preparations in the treatment of facial dystonias (BEB and HFS)?
Description of Evidence Literature searches were conducted last on February 28, 2017, in PubMed for articles published in English and in the Cochrane Library database without a language limitation. Because the goal of this assessment was to compare various botulinum toxins for facial dystonia and not simply to report on the efficacy of Botox, publications before 2000 were excluded. The combined searches yielded 127 citations. The following search terms were used along with date, publication, and language filters: botulinum toxins, onabotulinumtoxinA, rimabotulinumtoxinB, incobotulinumtoxinA, botulinum, Botox, Myobloc, Xeomin, hemifacial spasm, blepharospasm, and Meige syndrome. Inclusion criteria required that the study population comprised primarily patients with BEB, HFS, or other facial dystonias and that it included at least 25 patients treated with chemodenervation and followed up for at least 6 weeks. Analysis was confined to products approved by the FDA. Of the 127 citations, 13 studies met the inclusion criteria and were abstracted for review. Abstracted data included study design, number of patients, patient demographics, diagnosis (BEB, HFS, or oral facial dystonia [Meige] syndrome),
2
chemodenervation agent(s) used, clinical assessments before and after treatment, and adverse events. The methodologist (E.A.B.) then assigned a rating to each study based on the rating scale developed by the Oxford Centre for Evidence-Based Medicine.7 A level I rating was assigned to well-designed and well-conducted randomized clinical trials, a level II rating was assigned to well-designed case-control and cohort studies and lower-quality randomized studies, and a level III rating was assigned to case series, case reports, and lower-quality cohort and case-control studies. Five of the 13 studies were rated level I, 2 were rated level II, and 6 were rated level III.
Clinical Rating Scales Many rating, or assessment, scales initially were used to measure the efficacy of Botox against placebo when treating BEB. Since then, a variety of rating scales have been used to determine the efficacy of botulinum toxin preparations to treat BEB and HFS, as shown in Table 1.8e11 As noted in a review by Wabbels et al,12 BEB rating scales can be divided into 3 categories: clinical, activities of daily living, and global activity. Clinical scales (e.g., Jankovic Rating Scale [JRS]) are used by observer evaluators and activities of daily living scales (e.g., Blepharospasm Disability Index [BSDI]) are used by patients for self-assessment. Global activity scales (e.g., Patient Evaluation of Global Response [PEGR]) measure the overall, rather than disease-specific, effects of treatment, and typically they are limited to secondary-outcome analyses in most studies. The 2 most widely used grading systems are the JRS9 and the BSDI.11e13 Both have limitations in sensitivity when used to assess mild disease. The JRS consists of 2 categories, severity and spasm frequency, and each category is divided into 5 levels (0e4) on a Likert-type scale of ascending symptoms. The BSDI survey measures the impact of BEB and BEB treatment on 5 specific activities of daily living and 1 generalized activity (“doing everyday activities”).13 Each activity is rated according to a 5-point scale, with an option to select “not applicable.” Jankovic et al13 used the data of 300 patients with BEB who were treated with either Botox or Xeomin to study the validity of the BSDI compared with other rating scales. Patients completed the rating scales at baseline and 21 days after treatment. A high internal consistency was found between the BSDI and the JRS and PEGR scales. In addition, significant improvement in both JRS and BSDI scores for both Botox and Xeomin were noted. The authors stressed that the use of BSDI is important in evaluating treatment efficacy in BEB to demonstrate improvement in quality-of-life metrics. The use of both observer-based evaluations (usually for primary outcomes) and patient self-assessment scales (usually for secondary outcomes) is becoming more prevalent.
Published Results The published results on the efficacy of various FDAapproved botulinum toxin preparations for the treatment of
Table 1. Summary of Reviewed Studies
Mean Duration (Median, Range)
Primary Outcome Measures
Prospective, doubleblind, placebo controlled
Xeomin vs. placebo
BEB
109 (109, 0)
6 wks (6 wks, NR)
JRS, BSDI, PEGR
Xeomin vs. placebo for BEB
Roggenkamper et al, 200636
I
Phase 3, double-blind, parallel group
Xeomin, Botox
BEB
304 (304, 0)
16 wks
JRS, BSDI
Comparison of efficacy between Xeomin and Botox
Truong et al, 200822
I
Phase 2, double-blind, parallel group
Dysport, placebo
BEB
85 (85, 0)
16 wks (16 wks, 0)
Modified BDS, FIM, SRS, VAS
Efficacy of Dysport for BEB at 3 doses
Wabbels et al, 201144
I
Prospective, doubleblind, parallel group
Xeomin, Botox
BEB
63 (63,0)
8 wks (8 wks, 0)
BSDI, JRS, PGA
Comparison of efficacy between Xeomin and Botox
Yoon et al, 200933
I
Phase 3, prospective, double-blind
Meditoxin, Botox
BEB
52 (52, 0)
4 wks (4 wks, 0)
SS (5 grades), patient selfassessment
Jankovic, 20096
II
Prospective, doubleblind, parallel group
Xeomin, Botox
BEB
300 (300, 0)
109e112 days (109e112 days, NR)
JRS, BSDI, PGA
% of patients with improvement in >1 grade of SS at 4 wks after injection. Meditoxin:Botox ¼ 1:1. Noninferiority of Xeomin vs. Botox. Botox:Xeomin ¼ 1:1.
Kongsengdao and Kritalukkul, 201228
II
Prospective, doubleblind, randomized, crossover
Dysport, Meditoxin
HFS
26 (0, 26)
24 wks (24 wks, 0)
Quality-of-life analysis (4 questions), HFS30, SF-36, AIMS (Thai version), CES-D
Study Type
Rating Scale(s)
Efficacy of Dysport vs. Meditoxin. Dysport: Meditoxin ¼ 4.8:1.
Findings Xeomin is effective for BEB. AEs more common with Xeomin compared with placebo. No neutralizing antibodies found. No difference in efficacy, duration, AEs, laboratory testing, or neurologic examinations between Xeomin and Botox. Efficacy and AEs are dose related. Eighty units of Dysport per session may be best balance between efficacy and AEs. No difference between Xeomin and Botox at 4 wks and 8 wks. Nonsignificant trend of greater improvement with Botox at 4 and 8 wks. No difference in efficacy or AEs between Meditoxin and Botox at 4 wks. No antibodies found at 4 wks. No difference in efficacy, onset of effect, duration, or AEs between Xeomin A and Botox. No difference in primary outcome measures between 2 drugs. However, a significantly lower difference in total intensity score, daily duration of muscle spasm, and mean duration of
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(Continued)
Ophthalmic Technology Assessment
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Jankovic et al, 201145
Bilyk et al
Toxin(s)
Facial Dystonia(s)
Author(s), Year
Level of Evidence
Total No. of Patients Completing Study (Benign Essential Blepharospasm, Hemifacial Spasm)
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Table 1. (Continued.)
Author(s), Year
Level of Evidence
Study Type
Toxin(s)
III
Retrospective, noncomparative
Botox, Dysport
Çakmur et al, 200227
III
Retrospective
Cillino et al, 20102
III
Defazio et al, 200217
BEB
113 (113, 0)
Botox
BEB, HFS
53 (25, 28)
Prospective, noncomparative
Botox
BEB, HFS
131 (73, 58)*
III
Retrospective
Botox
HFS
65 (0, 65)
Grosset et al, 201530
III
Retrospective
Dysport, Xeomin
BEB, HFS
Suputtitada et al, 200423
III
Not recorded
Botox
HFS
Mean Duration (Median, Range)
Rating Scale(s)
Primary Outcome Measures
72 mos (NR, NR)
JRS
Clinical features and therapeutic outcomes in BEB.
BEB: 3.1 yrs (NR, 3e4) HFS: 3.3 yrs (NR, 1e7)
JRS, TWSTRS
Efficacy of pretarsal vs. preseptal orbicularis oculi injection.
>10 yrs (NR, NR)
Self-evaluation scale
Dose escalation of BTX-A.
10 yrs (NR, NR)
Self-evaluation scale
Response to Botox in HFS at yrs 1 10.
110 (19, 91)
91 wks (NR, 52e219 wks)
Comparison of Dysport and Xeomin at 4:1 dosing ratio for BEB and HFS.
112 (0, 112)
3.4 yrs (NR, NR)
2 patient selfassessments (efficacy and duration of effect) 4-point scale
Low-dose Botox for HFS.
Findings functional impairment at 4 wks of treatment was noted with Dysport. Showed overall efficacy of Botox and Dysport for BEB without separate analysis of each agent. Higher response rate and lower AEs to Botox with pretarsal injection. Pain of injection not measured. BEB patients required higher Botox dose than HFS patients. Response rate to BTX for BEB and HFS stable over 10-yr study duration. Higher efficacy of Botox with older age. No loss of Botox efficacy for HFS over 10-yr period. No difference in efficacy, duration of effect, and AEs at 4:1 ratio. 96.7% of patients with >80% improvement. No statistical analysis performed.
AE ¼ adverse event; AIMS ¼ Abnormal Involuntary Movement Scale; BEB ¼ benign essential blepharospasm; BEBþ ¼ Meige syndrome; BDS ¼ Blepharospasm Disability Scale; BSDI ¼ Blepharospasm Disability Index; BSGS ¼ Blepharospasm Graduation Scale; CES-D ¼ Center for Epidemiologic Studies Depression Scale; FIM ¼ Frequency of Involuntary Movement; HFS ¼ hemifacial spasm; HFS-30 ¼ Hemifacial Spasm-30; HFSES ¼ Hemifacial Spasm Evaluation Scale; JRS ¼ Jankovic Response Scale; NR ¼ not reported; PGA ¼ Patient Global Assessment; SF-36 ¼ Medical Outcome Study Short Form 36; SRS ¼ Severity Rating Scale; SS ¼ Severity of Spasm; TWSTRS ¼ Toronto Western Spasmodic Torticollis Rating Scale; VAS ¼ Visual Analog Scale. *Patients with spastic entropion not included in this analysis.
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Aquino et al, 201240
Facial Dystonia(s)
Total No. of Patients Completing Study (Benign Essential Blepharospasm, Hemifacial Spasm)
Bilyk et al
Ophthalmic Technology Assessment
Table 2. Summary of Adverse Events Reported* Adverse Event Ptosis Diplopia Facial weaknessz Ecchymosis Dry eye/eye burning Mouth droop Photophobia Blurred vision Epiphora
Botox (%) 2,6,17,23,33,44
4.5e29.4 0e8.62,17,23 3e1117,23 8.6e22.62,44 0e2.72,6,33 1.72 0e3.42,6 0e3.22,6 0e0.62,23
Dysporty (%)
Xeomin (%)
Meditoxin (%)
Placebo (%)
13e5822 10e1622 NR NR 322 NR NR 23e4222 6e1722
6.1e18.96,44,45 NR NR 2.745e27.344 0.7e18.96,44,45 NR 1.46 1.4e5.445 2.745
6.433 NR NR NR 7.633 NR NR NR NR
5.945 NR NR 2.945 11.845 NR NR 5.945 2.945
NR ¼ not recorded. *An additional 24 patients who received onabotulinumtoxinA (oBTX-A) for treatment of entropion were not included in this review. y Data from Truong et al22 are listed as a range of dose-related adverse events. z In patients with hemifacial spasm.
BEB and HFS are presented by specific botulinum toxin for both types of dystonia. OnabotulinumtoxinA (Botox) Hemifacial Spasm. Botox has a proven efficacy in the management of HFS.14e16 However, previous studies on this subject are limited to less than 5 years of follow-up. Defazio et al17 (level III) described their findings from a multicenter study on the long-term efficacy (>10 years) of Botox in the management of HFS in which injections were limited to the orbicularis oculi muscle. The response rate was 96%, with a mean duration of effect of 12.6 weeks ( 5.7 weeks), consistent with previous studies.18e21 Importantly, treatment failures occurred mostly during the first year of therapy, when dosing and the pattern of injection may be unclear. Specifically, the authors noted no statistically significant differences in the number of annual treatments or cumulative annual dose per patient, amount of Botox per treatment session, response rate, or duration of effect when comparing first- and tenth-year data. However, the dropout rate during the course of the study was high (19%), and efficacy was measured using a 3-point patient self-assessment scale rather than an observer-based scale (e.g., JRS). Cillino et al2 (level III) reported on the long-term efficacy of Botox for BEB, HFS, and spastic entropion. Their patient cohort consisted of 58 patients with HFS whom they studied retrospectively using 10 years of follow-up data. The dose per patient with HFS and entropion was significantly lower than that for BEB (P < 0.0005), but durations of effect between BEB and HFS were similar. Duration of effect increased for both BEB and HFS over time (P < 0.05), and drug-dose escalation analysis concluded that there was a greater efficacy of injection in older patients, consistent with other studies and presumably because of a decreased muscle bulk when compared with younger individuals.22 Suputtitada et al23 (level III) presented their findings after using low-dose Botox in 112 patients with HFS over an 8-year span. Unlike in the study by Defazio et al,17 the injection sites also included middle and lower facial and neck musculature. However, only the orbicularis oculi and oris muscles were injected 100% of the time. The mean
overall duration of response was 4.1 months (range, 3e6 months), and a high, “excellent,” response rate (96.7%) was reported. The study by Suputtitada et al has significant drawbacks that limit the strength of any conclusions, including use of a unique observer scale, a variable pattern of injection, and a lack of statistical analysis. The most conservative conclusion from this study is that Botox is effective in treating HFS over a span of 10 injections (with an average overall duration of injection effect of 4.1 months [range, 3e6 months], which calculates to a span of 41 months [range, 30e60 months]). Blepharospasm. The site of periocular Botox injection has been studied previously for BEB and apraxia of eyelid opening.24e26 Çakmur et al27 (level III) retrospectively studied Botox injections into the preseptal and pretarsal orbicularis oculi muscle in patients with both BEB and HFS. The results confirmed those from previous studies.24,26 Pretarsal injections were more effective than preseptal injections (96% vs. 86%, respectively). Pretarsal injections also resulted in a higher response rate on both clinical scales (P < 0.05) and a longer duration of maximum response for both HFS and BEB. In patients with HFS, pretarsal injections also resulted in a significantly lower rate of adverse events (P < 0.05; Table 2) compared with preseptal injections. One of the limitations of the study by Çakmur et al is that patients were not randomized to preseptal or pretarsal injections. As already noted, Cillino et al2 retrospectively studied the long-term efficacy of Botox for facial dystonia. Seventy-three patients with BEB were studied using a 3-point patient self-assessment scale in addition to indices to evaluate drug-dose escalation. Patients with BEB required a significantly higher average dose of Botox compared with patients with HFS. However, the mean duration of effect was similar (18.212.3 weeks for BEB and 20.611.6 weeks for HFS), as were the proportions of BEB and HFS patients who reported adverse events. Both BEB and HFS patients showed an increase in mean dosages over time, especially after the first 3 to 4 injections, suggesting that early underdosing had occurred; this finding was most prominent in older patients.
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Ophthalmology Volume -, Number -, Month 2018 AbobotulinumtoxinA (Dysport) Hemifacial Spasm. A comparative study over 24 weeks of Dysport and Meditoxin (Korean onabotulinumtoxinA) in the treatment of HFS was published by Kongsengdao and Kritalukkul (level II evidence).28 A total of 26 patients completed the study. Patients underwent an identical injection pattern to the orbicularis oculi and oris muscles with either 15 units of Dysport or 3.125 units of Botox. At the 4-week assessment, the mean intensity score, mean duration of facial spasms per day, and mean duration of functional impairment per day were significantly lower with Dysport than with Meditoxin, whereas the daily qualityof-life assessments showed no difference. Any conclusion on the differences in efficacy between the 2 agents must be considered somewhat speculative, because dose ratios between Dysport and Botox or Meditoxin varied widely between 1 and 13.3 to 1 in several studies.29e32 That said, 1 large, prospective trial4 concluded that a dose equivalency of Dysport and Botox of 4:1 for the treatment of BEB and HFS is optimal, whereas others have concluded that a ratio of 3:1 is optimal.3 The dose ratio of Meditoxin and Botox seems to be 1:1.3,33,34 The ratio of approximately 4.8:1 of Dysport to Meditoxin in the cohort of Kongsengdoa and Kritalukkul is high compared with that reported by others.4 Therefore, the perceived superior efficacy of Dysport in the Kongsengdoa and Kritalukkul study simply may have been the result of higher doses when compared with Meditoxin. Blepharospasm. Truong et al22 (level I) studied the efficacy of 3 doses of Dysport against placebo in the treatment of BEB in a randomized, double-blind, parallelgroup study. Dysport demonstrated significant efficacy at all doses compared with the placebo at the 4- and 12-week modified Blepharospasm Disability Scale (BDS), and there was a dose-related effect on the score. Efficacy was noted through 16 weeks at 80-unit and 120-unit doses. Adverse events were dose related, and they occurred more frequently in patients receiving 120 units. The authors concluded that Dysport improved the symptoms of BEB across all scales studied, consistent with previous studies on the subject.9,10,15,18,25,35e39 The authors also noted that 80 units of Dysport per injection session, which is lower than the average dose recommended in other studies,29 may strike the best balance between efficacy and adverse events in patients with BEB. Aquino et al40 (level III) retrospectively studied 125 patients with BEB over a 17-year span to evaluate the clinical features and therapeutic outcomes of Botox and Dysport. However, the authors reported on efficacy of botulinum toxin overall, without a separate analysis of the Botox and Dysport outcomes. Therefore, the individual efficacy of each agent in the treatment of BEB cannot be gleaned from the manuscript. Similarly, adverse events occurred in 14% of all patients (ptosis, blurred vision, diplopia, foreign body sensation), but no specific incidences were listed (Table 2). Grosset et al30 (level III) reported on their experience in switching patients with facial and cervical dystonia from Dysport to Xeomin. Data for analysis were available on 257 patients, of whom 19 had BEB and 91 had HFS. (The
6
remaining 147 patients had cervical or localized dystonia, generalized dystonia, or both and are not included in this review.) For the patients with BEB and HFS, the authors found that a mean dose ratio of 4.07:1 ( 0.5) between Dysport and Xeomin, respectively, at the beginning of the study and 3.89:1 ( 0.58) at the close of the study 52 to 219 weeks later resulted in clinical equivalency. They concluded that a dose ratio of approximately 4:1 resulted in similar efficacy, duration of benefit, and adverse events with no significant change in dose ratio over the span of the study. Of note, in a meta-analysis on the subject, Dashtipour et al5 found that a dose ratio of 2.5 to 3.0:1 of Dysport to Botox “provides comparable safety and efficacy for therapeutic movement disorders [cervical dystonia and BEB] chemodenervation procedures.” Finally, the authors noted a mean cost reduction of 76.7% ( 14.8%) in shifting patients from Dysport to Xeomin. This study was performed in the United Kingdom, and the cost metrics reported may not be applicable elsewhere.3,41,42 IncobotulnumtoxinA (Xeomin) Blepharospasm. Xeomin has documented efficacy in the treatment of BEB, and it performs similarly to Botox.36,43 Wabbels et al44 (level I) published their experience using these agents in the management of BEB. The authors performed a randomized, double-blind, parallel-group study of 65 German patients with BEB (63 completed the study) using a 1:1 dose ratio for Botox and Xeomin. The 4- and 8week BSDI and JRS scores showed no significant difference between the 2 BTX-A preparations. Wabbels et al noted that, compared with previous studies, their patient cohort was treated with higher total doses of Botox or Xeomin and had a higher mean age; they possibly had a longer history of BEB and previous botulinumtoxinA injections. Jankovic et al45 (level I) presented their findings of a double-blind, multicenter trial comparing Xeomin with placebo in the treatment of 109 patients with BEB. Patients were randomized at a 2:1 ratio for Xeomin and placebo, respectively, and were assessed at 3 and 6 weeks after injection using the JRS, BSDI, and PEGR. Xeomin had significantly higher efficacy than placebo in the treatment of BEB across all scales. A noninferiority study by Jankovic6 (level II) comparing Xeomin with Botox in the treatment of 300 patients with BEB also was published. Of note, study investigators determined the number and distribution of injection sites for individual patients, and the total dose of BTX-A varied between patients based on their previous prestudy injections. Significant and statistically similar improvements in JRS were noted for both agents at 3 weeks. Onset, duration, and waning of effect were statistically similar for Xeomin and Botox. Likewise, adverse events were similar for both groups. The author concluded that both agents had similar efficacy at a 1:1 dose ratio.
Conclusions The evidence from the 13 studies reviewed for this assessment indicates that Botox, Xeomin, and Dysport
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injections are highly effective treatments for BEB and HFS. Level I evidence supports the effectiveness of both Botox and Xeomin for the treatment of BEB. Two studies36,44 show equal effectiveness of Botox and Xeomin in the treatment of BEB, and 1 additional trial45 proves the effectiveness of Xeomin for BEB compared with placebo. Of note, all 3 studies used widely accepted rating scales (JRS, BSDI). Durations of effect and incidence of adverse events were similar between Botox and Xeomin at a 1:1 dosage ratio.36,44 There is level I evidence33 that demonstrates equivalent effectiveness and incidence of adverse events when Meditoxin is compared with Botox. Dysport seems to have effectiveness similar to Botox and Meditoxin for BEB and HFS, but any definitive conclusions from the 2 studies28,40 (level II and level III, respectively) in this review are limited by the methodologies used as well as the dose ratios of Dysport to other agents. Truong et al22 (level I) demonstrated the effectiveness of Dysport for BEB at 3 escalating doses compared with placebo. A dose per session of 80 units for BEB seems to be a reasonable compromise between effectiveness and the incidence of adverse events. Additional conclusions can be gleaned from this review. Level III evidence in 2 retrospective studies2,17 shows more than 95% response rates of Botox for the treatment of BEB and HFS. Patients with HFS require lower overall doses of Botox than patients with BEB, but the durations of effect are similar.2 Higher doses of Botox and Dysport result in a higher incidence of adverse events.17,22 Pretarsal injections of Botox are more effective than preseptal injections (96% vs. 86%) and have fewer adverse events.27 Botox remains effective for treatment of facial dystonias over a period of at least 10 years based on level III evidence.17,23 Correct dosing and pattern of injection may be unclear over the first 3 to 4 injections in facial dystonias,17 which potentially may affect final analysis of studies on the use of botulinum toxin for these disorders. Finally, older patients (>65 years) require lower doses of botulinum toxin for the treatment of BEB and HFS, most likely because of loss of muscle mass with age.2 This finding is important to keep in mind to prevent overdosing of older patients with facial dystonia over the long-term course of treatment.
Future Research Meaningful comparison of various botulinum toxins for the management of facial dystonias is hampered by the lack of standardized ratings scales across studies. The JRS, BSDI, and PEGR seem to be the most widely used scales in level I studies,12 and use of these scales in future studies would provide for comparability of outcomes with prior studies. Of note, however, is the fact that these scales may not be sensitive enough to detect less substantial differences in efficacy between various botulinum toxin preparations.12 Furthermore, most scales are more effective at measuring the response in patients who have more severe dystonia; many studies include patients with mild dystonia, potentially limiting the usefulness of rating scales. In addition, the number of available scales as well as individual study modifications to scales makes comparison
across studies and botulinum toxin agents difficult. Ratings scales need to be developed to assess subtle differences in effectiveness more accurately between agents in patients with mild facial dystonia. Conversion dosage ratios between Dysport and other agents (Botox, Xeomin, Meditoxin) have not been determined definitively, making it difficult to conduct studies comparing Dysport and other botulinum toxin A preparations. The accepted range for BEB seems to vary between 2.5 and 4.0:1 for Dysport and Botox.3,5 This is a wide dose ratio that requires better delineation for the clinical application of Dysport in the treatment of BEB and HFS.
References 1. Scott AB. Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. Ophthalmology. 1980;87(10):1044e1049. 2. Cillino S, Raimondi G, Guepratte N, et al. Long-term efficacy of botulinum toxin A for treatment of blepharospasm, hemifacial spasm, and spastic entropion: a multicentre study using two drug-dose escalation indexes. Eye (Lond). 2010;24(4): 600e607. 3. Scaglione F. Conversion ratio between Botox(), Dysport(), and Xeomin() in clinical practice. Toxins (Basel). 2016;865; https://doi.org/10.3390/toxins8030065. 4. Sampaio C, Ferreira JJ, Simoes F, et al. DYSBOT: a singleblind, randomized parallel study to determine whether any differences can be detected in the efficacy and tolerability of two formulations of botulinum toxin type AdDysport and Botoxdassuming a ratio of 4:1. Mov Disord. 1997;12(6): 1013e1018. 5. Dashtipour K, Chen JJ, Espay AJ, et al. OnabotulinumtoxinA and AbobotulinumtoxinA dose conversion: a systematic literature review. Mov Disord Clin Pract. 2016;3(2):109e115. 6. Jankovic J. Clinical efficacy and tolerability of Xeomin in the treatment of blepharospasm. Eur J Neurol. 2009;16(suppl 2): 14e18. 7. Oxford Centre for Evidence-Based Medicine. Levels of evidence (March 2009). http://www.cebm.net/index.aspx? o¼1025; Accessed 24.08.17. 8. Rahman R, Berry-Brincat A, Thaller VT. A new grading system for assessing orbicularis muscle function. Eye (Lond). 2003;17(5):610e612. 9. Jankovic J, Orman J. Botulinum A toxin for cranial-cervical dystonia: a double-blind, placebo-controlled study. Neurology. 1987;37(4):616e623. 10. Iwashige H, Nemeto Y, Takahashi H, Maruo T. Botulinum toxin type A purified neurotoxin complex for the treatment of blepharospasm: a dose-response study measuring eyelid force. Jpn J Ophthalmol. 1995;39(4):424e431. 11. Albanese A, Sorbo FD, Comella C, et al. Dystonia rating scales: critique and recommendations. Mov Disord. 2013;28(7):874e883. 12. Wabbels B, Jost WH, Roggenkämper P. Difficulties with differentiating botulinum toxin treatment effects in essential blepharospasm. J Neural Transm (Vienna). 2011;118(6): 925e943. 13. Jankovic J, Kenney C, Grafe S, et al. Relationship between various clinical outcome assessments in patients with blepharospasm. Mov Disord. 2009;24(3):407e413. 14. Elston JS. The management of blepharospasm and hemifacial spasm. J Neurol. 1992;239(1):5e8.
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Ophthalmology Volume -, Number -, Month 2018 15. Van den Bergh P, Francart J, Mourin S, et al. Five-year experience in the treatment of focal movement disorders with low-dose Dysport botulinum toxin. Muscle Nerve. 1995;18(7): 720e729. 16. Jost WH, Kohl A. Botulinum toxin: evidence-based medicine criteria in blepharospasm and hemifacial spasm. J Neurol. 2001;248(suppl 1):21e24. 17. Defazio G, Abbruzzese G, Girlanda P, et al. Botulinum toxin A treatment for primary hemifacial spasm: a 10-year multicenter study. Arch Neurol. 2002;59(3):418e420. 18. Berardelli A, Formica A, Mercuri B, et al. Botulinum toxin treatment in patients with focal dystonia and hemifacial spasm. A multicenter study of the Italian Movement Disorder Group. Ital J Neurol Sci. 1993;14(5):361e367. 19. Novis SA, De Mattos JP, De Rosso AL. Botulinum toxin in blepharospasm, in hemifacial spasm, and in cervical dystonia: results in 33 patients [in Portuguese]. Arq Neuropsiquiatr. 1995;53(3-A):403e410. 20. Astarloa R, Morales B, Sanchez V, et al. Focal dystonias and facial hemispasm: treatment with botulinum A toxin [in Spanish] Arch Neurobiol (Madr). 1991;54(5):210e217. 21. Park YC, Lim JK, Lee DK, Yi SD. Botulinum A toxin treatment of hemifacial spasm and blepharospasm. J Korean Med Sci. 1993;8(5):334e340. 22. Truong D, Comella C, Fernandez HH, et al. Efficacy and safety of purified botulinum toxin type A (Dysport) for the treatment of benign essential blepharospasm: a randomized, placebo-controlled, phase II trial. Parkinsonism Relat Disord. 2008;14(5):407e414. 23. Suputtitada A, Phanthumchinda K, Locharernkul C, Suwanwela NC. Hemifacial spasm: results of treatment with low dose botulinum toxin injection. J Med Assoc Thai. 2004;87(10):1205e1211. 24. Albanese A, Bentivoglio AR, Colosimo C, et al. Pretarsal injections of botulinum toxin improve blepharospasm in previously unresponsive patients. J Neurol Neurosurg Psychiatry. 1996;60(6):693e694. 25. Kowal L. Pretarsal injections of botulinum toxin improve blephospasm in previously unresponsive patients. J Neurol Neurosurg Psychiatry. 1997;63(4):556. 26. Jankovic J. Pretarsal injection of botulinum toxin for blepharospasm and apraxia of eyelid opening. J Neurol Neurosurg Psychiatry. 1996;60(6):704. 27. Çakmur R, Ozturk V, Uzunel F, et al. Comparison of preseptal and pretarsal injections of botulinum toxin in the treatment of blepharospasm and hemifacial spasm. J Neurol. 2002;249(1): 64e68. 28. Kongsengdao S, Kritalukkul S. Quality of life in hemifacial spasm patient after treatment with botulinum toxin A; a 24week, double-blind, randomized, cross-over comparison of Dysport and Neuronox study. J Med Assoc Thai. 2012;95(suppl 3):S48eS54. 29. Marchetti A, Magar R, Findley L, et al. Retrospective evaluation of the dose of Dysport and BOTOX in the management of cervical dystonia and blepharospasm: the REAL DOSE study. Mov Disord. 2005;20(8):937e944.
30. Grosset DG, Tyrrell EG, Grosset KA. Switch from abobotulinumtoxinA (Dysport(R)) to incobotulinumtoxinA (Xeomin(R)) botulinum toxin formulation: a review of 257 cases. J Rehabil Med. 2015;47(2):183e186. 31. Aoki KR, Ranoux D, Wissel J. Using translational medicine to understand clinical differences between botulinum toxin formulations. Eur J Neurol. 2006;13(suppl 4):10e19. 32. Wohlfarth K, Göschel H, Frevert J, et al. Botulinum A toxins: units versus units. Naunyn Schmiedebergs Arch Pharmacol. 1997;355(3):335e340. 33. Yoon JS, Kim JC, Lee SY. Double-blind, randomized, comparative study of Meditoxin versus Botox in the treatment of essential blepharospasm. Korean J Ophthalmol. 2009;23(3):137e141. 34. Kenney C, Jankovic J. Botulinum toxin in the treatment of blepharospasm and hemifacial spasm. J Neural Transm (Vienna). 2008;115(4):585e591. 35. Nüssgens Z, Roggenkämper P. Comparison of two botulinumtoxin preparations in the treatment of essential blepharospasm. Graefes Arch Clin Exp Ophthalmol. 1997;235(4):197e199. 36. Roggenkämper P, Jost WH, Bihari K, et al. Efficacy and safety of a new botulinum toxin type A free of complexing proteins in the treatment of blepharospasm. J Neural Transm (Vienna). 2006;113(3):303e312. 37. Perman KI, Baylis HI, Rosenbaum AL, Kirschen DG. The use of botulinum toxin in the medical management of benign essential blepharospasm. Ophthalmology. 1986;93(1):1e3. 38. Poungvarin N, Devahastin V, Viriyavejakul A. Treatment of various movement disorders with botulinum A toxin injection: an experience of 900 patients. J Med Assoc Thai. 1995;78(6): 281e288. 39. Price J, Farish S, Taylor H, O’Day J. Blepharospasm and hemifacial spasm. Randomized trial to determine the most appropriate location for botulinum toxin injections. Ophthalmology. 1997;104(5):865e868. 40. Aquino CC, Felicio AC, Castro PC, et al. Clinical features and treatment with botulinum toxin in blepharospasm: a 17-year experience. Arq Neuropsiquiatr. 2012;70(9):662e666. 41. Abogunrin S, Brand S, Desai K, et al. AbobotulinumtoxinA in the management of cervical dystonia in the United Kingdom: a budget impact analysis. Clinicoecon Outcomes Res. 2015;7:441e449. 42. Tilden D, Guarnieri C, Jackson D. Cost-effectiveness of Incobotulinumtoxin-A with flexible treatment intervals compared to Onabotulinumtoxin-A in the management of blepharospasm and cervical dystonia. Value Health. 2015;18(7):A759. 43. Benecke R, Jost WH, Kanovsky P, et al. A new botulinum toxin type A free of complexing proteins for treatment of cervical dystonia. Neurology. 2005;64(11):1949e1951. 44. Wabbels B, Reichel G, Fulford-Smith A, et al. Double-blind, randomised, parallel group pilot study comparing two botulinum toxin type A products for the treatment of blepharospasm. J Neural Transm (Vienna). 2011;118(2):233e239. 45. Jankovic J, Comella C, Hanschmann A, Grafe S. Efficacy and safety of incobotulinumtoxinA (NT 201, Xeomin) in the treatment of blepharospasm-a randomized trial. Mov Disord. 2011;26(8):1521e1528.
Footnotes and Financial Disclosures Originally received: March 9, 2018. Final revision: March 9, 2018. Accepted: March 9, 2018. Available online: ---. 1
Manuscript no. 2018-587.
Wills Eye Hospital, Philadelphia, Pennsylvania.
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2
Cullen Eye Institute, Baylor College of Medicine, Houston, Texas.
3
Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota.
4
Ophthalmic Plastic Surgery, Lions Eye Institute, Department of Ophthalmology, Albany Medical Center, Albany (Slingerlands), New York, Minnesota.
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Ophthalmic Technology Assessment
Vanderbilt Eye Institute, Vanderbilt University, Nashville, Tennessee.
Financial Disclosure(s): Funded without commercial support by the American Academy of Ophthalmology. The author(s) have no proprietary or commercial interest in any materials discussed in this article. Prepared by the Ophthalmic Technology Assessment Committee Oculoplastics and Orbit Panel and approved by the American Academy of Ophthalmology’s Board of Trustees February 20, 2018.
Abbreviations and Acronyms: BEB ¼ benign essential blepharospasm; BDS ¼ Blepharospasm Disability Scale; BSDI ¼ Blepharospasm Disability Index; FDA ¼ Food and Drug Administration; HFS ¼ hemifacial spasm; JRS ¼ Jankovic Rating Scale; PEGR ¼ Patient Evaluation of Global Response. Correspondence: Ali Al-Rajhi, PhD, MPH, American Academy of Ophthalmology, Quality and Data Science, P. O. Box 7424, San Francisco, CA 94120-7424. E-mail: [email protected].
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