Original Investigation
A Survey of Current Blepharospasm Treatment Patterns Among Oculoplastic Surgeons Talmage J. Broadbent, M.D., Ph.D., Ralph E. Wesley, M.D., and Louise A. Mawn, M.D. Vanderbilt Eye Institute, Vanderbilt University School of Medicine, Nashville, Tennessee, U.S.A.
Purpose: To determine the current practice pattern of ASOPRS members injecting onabotulinumtoxinA for Blepharospasm. Methods: An invitation to participate in a web-based, anonymous survey was sent to current members of American Society of Ophthalmic Plastic and Reconstructive Surgeons (ASOPRS) via e-mail. The survey consisted of 9 questions and used the Research Electronic Data Capture online application. Institutional Review board approval was obtained for this study. Results: Forty-one percent of ASOPRS members invited responded to the survey. The mean initial dose of onabotulinumtoxinA used was 22.5 units per side and the most common number of injection sites was greater than 7 per side. Only 12 of the 247 responding surgeons who treat benign essential blepharospasm with onabotulinumtoxinA reported that their initial injection pattern is with 3 or fewer sites per side as per the Food and Drug Administration (FDA)–approved recommendations. Conclusions: Survey of current trends in the management of blepharospasm with onabotulinumtoxinA by ASOPRS members showed that the mean initial dose used to treat blepharospasm patients was 22.5 (standard deviation ± 9.5 units, range 2.5 to 50 units per side). There is significant variation in the treatment doses. The majority of ASOPRS members do not follow the FDA-approved recommendation for dosing. (Ophthal Plast Reconstr Surg 2016;32:24–27)
B
enign essential blepharospasm is a craniofacial movement disorder characterized by repeated forcible contraction of the eyelid and forehead muscles. These contractions result in repeated involuntary blinking that can interfere with patient’s vision and in severe cases can result in functional blindness. Blepharospasm has been shown to cause significant distress and decreased quality of life with patients being limited in a wide variety of activities and mobility.1,2 It is usually an adult onset disease and many different treatments have been utilized in an attempt to minimize patient symptoms and improve quality of life.3 Botulinum toxin has become the pharmacologic mainstay of treatment since studies Accepted for publication December 11, 2014. Supported in part by an unrestricted grant to the Vanderbilt Eye Institute and Physician Scientist Award from Research to Prevent Blindness, New York, NY. A has received honoraria from Company Z. B is currently receiving a grant (#12345) from Organization Y, and is on the speaker's bureau for Organization X the CME organizers for Company A. For the remaining authors none were declared. Supported in part by an unrestricted grant to the Vanderbilt Eye Institute and Physician Scientist Award to Dr. Mawn from Research to Prevent Blindness, New York, NY. The authors have no financial or conflict of interest to disclose. Address correspondence and reprint requests to Louise Mawn, M.D., Vanderbilt Eye Institute, 2311 Pierce Avenue, Nashville, TN 37232–8808. E-mail: [email protected] DOI: 10.1097/IOP.0000000000000405
24
showed its effectiveness and OnabotulinumtoxinA (Botox) was approved by the FDA for treatment of blepharospasm in 1989.4–8 OnabotulinumtoxinA is supplied in vials of 100 Units of lyophilized toxin. The vacuum-dried botulinum toxin powder is reconstituted with saline to achieve the desired concentration of the injection. The FDA specified that 100 [+ or −] 30 Units should be the quantity of toxic activity dispensed in vials.9 The medication guide, which accompanies the vial of onabotulinumtoxinA, approved by the U.S. Food and Drug Administration indicates that the initial recommended dose is 1.25 Units to 2.5 Units injected into the medial and lateral pretarsal orbicularis oculi of the upper eyelid and into the lateral pretarsal orbicularis oculi of the lower eyelid.10 Despite its common use, there is significant variety in the dose and pattern with which botulinum toxin is used to treat blepharospasm. To gain a better understanding of the variety of current practice patterns among ophthalmic plastic surgeons, a survey was created and distributed to practicing surgeons, and information regarding their treatment patterns was collected.
METHODS A 9-question web-based survey was created using the Research Electronic Data Capture application.11 The survey contained both multiple choice and short response type of questions and was limited to the treatment of functional blepharospasm. The survey was approved for use by the Institutional Review Board. The survey was distributed by e-mail to a list of members of the American Society of Ophthalmic Plastic and Reconstructive Surgeons (ASOPRS), which was obtained and used with the permission of ASOPRS. Invitations were sent out to the individuals on the list along with up to 2 follow-up invitations. The survey remained open to collect responses for 3 weeks. The survey data were collected in an anonymous fashion. The data were collected and stored in the Research Electronic Data Capture online database. The collected data were analyzed with univariate linear regression or made into contingency tables and evaluated using with chi-squared testing. The statistics were performed using GraphPad Prism software. The overall alpha level was selected to be 0.05 and the p value reported resulted from 2-tailed t test. A total of 6 regression analyses were performed and the Bonferroni correction (corrected p value 0.0083) was used to correct for multiple comparisons. For questions with short response options, only discrete responses were included in the analysis, responses that reported a range were not included.
RESULTS A total of 621 survey invitations were sent to ASOPRS members. A total of 253 surveys were completed representing a 41% completion rate for this survey. A total of 6 respondents indicated that they did not treat functional blepharospasm patients and they were excluded from any further analysis. A reproduction of the questions asked in this computer based survey is found in Figure 1. Of those who participated in the survey, 9.3% had been in been treating blepharospasm patients for 0 to 5 years, 16.6% for 5 to 10 years, 16.6% for 10 to 15 years, and 57.5% for greater than 15 years (Fig. 2). Of those who participated in the survey, 18.7% reported treating between 0 and 3 patients a month, 28.9% between 4 and 6 patients, 20.7% between 7 and 10 patients, and 31.7%
Ophthal Plast Reconstr Surg, Vol. 32, No. 1, 2016
Ophthal Plast Reconstr Surg, Vol. 32, No. 1, 2016
Treatment Blepharospasm
FIG. 1. Reproduction of the survey
B
A
C
FIG. 2. Demographics of those who responded to the survey. A, Number of years that they have been treating blepharospasm with botulinum toxin injections. B, Number of blepharospasm patients treated per month. C, Percent of respondents who participated in clinical trials which lead to FDA approval of botulinum toxin use for the treatment of blepharospasm.
more than 10 functional blepharospasm patients per month (Fig. 2). Only 16.7% of participants responded that they had participated in the clinical trials that lead to FDA approval of OnabotulinumtoxinA as a treatment for blepharospasm (Fig. 2). Participants were asked if they initiated treatment of blepharospasm patients with the FDA-approved regimen of 3 injection sites (the medial and lateral pretarsal orbicularis oculi of the upper eyelid and into the lateral pretarsal orbicularis oculi of the lower eyelid), with up to a maximum dose of 5.0 Units per site (total of 15 units per side). Twelve of the 247 (4.9%) respondents answered yes they followed this recommendation, while 235 of 247 (95.1%) answered that they did not (Fig. 3). Ophthalmic plastic surgeons reported using a wide variety of doses when initiating treatment for new blepharospasm patients. The mean initial dose used to treat blepharospasm patients was 22.5 (standard deviation ± 9.5 Units) Units per side (Table 1) with the range including reports from 2.5 to 50 Units per side. The most common initial dose in the
FIG. 3. Percent of ophthalmic plastic surgeons who start treatment of blepharospasm patients with the FDA-recommended dosing regimen of onabotulinumtoxinA
© 2015 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
25
Ophthal Plast Reconstr Surg, Vol. 32, No. 1, 2016
T. J. Broadbent et al.
TABLE 1. Summary of the doses used to treat blepharospasm patients Years of experience treating blepharospasm patients
Average Initial dose in units per side. Mean (SD)
Maximum dose in units per side for a stable patient. Mean (SD)
Minimum dose in units per side for a stable patient. Mean (SD)
19.99 (7.54) 19.64 (6.62) 21.75 (8.50) 23.86 (10.65) 22.48 (9.56)
41.54 (12.37) 44.45 (15.18) 49.80 (25.03) 51.13 (24.27) 48.89 (22.39)
16.28 (5.94) 15.00 (7.57) 18.24 (9.94) 18.34 (11.67) 17.58 (10.39)
15 years Total
TABLE 2. Usual number of injection sites used by those who start treatment with the FDA-recommended treatment pattern Do you start treatment with the FDA recommended dosage?
Usual number of injection sites per side 3 or less
4
5
6
7
Greater than 7
Total
No Yes Total
2 (1%) 3 (25%) 5 (2%)
23 (10%) 3 (25%) 26 (11%)
58 (25%) 1 (8%) 59 (25%)
41 (17%) 3 (25%) 44 (18%)
36 (15%) 0 (0%) 36 (15%)
73 (31%) 2 (17%) 75 (30%)
233 (100%) 12 (100%) 245 (100%)
survey was 25 units per side which was favored by 24% of respondents. The mean minimum dose required to maintain a stable patient was 17.6 (standard deviation ± 10.4 Units) units per side, with a range including responses from 2 to 50 Units per side. The most common minimum dose required to maintain a stable patient was 25 Units per side, which was reported by 17% of respondents. The mean maximum dose required to maintain a stable blepharospasm patient was 48.6 (standard deviation ± 22.4 Units) units per side (Table 1) with the responses ranging from 4 to 200 Units per side. The most common maximum dose required to maintain a stable blepharospasm patient was 50 Units per side, which was reported by 38% of respondents. Further analysis showed that there was a small but significant positive correlation between years in practice and higher initial doses used to treat blepharospasm patients (r2 = 0.031, p value 0.0071). When asked about their usual injection pattern, 2% of respondents indicated that they usually treated with 3 or fewer injection sites, 10.6% reported 4 sites, 24.1% 5 sites, 18% 6 sites, 14.7% 7 sites, and 30.6% greater than 7 injection sites (Table 2). Those indicating that they initiated treatment in accordance with the FDA recommendation tended to inject fewer sites but this trend did not reach statistical significance (Table 2).
DISCUSSION Blepharospasm is a recognized cause of visual impairment, which usually can be effectively managed with injection of botulinum toxin. In addition to oculoplastic surgeons, blepharospasm patients may also be treated by general ophthalmologists, neurophthalmologists, or neurologists. The survey was sent only to ASOPRS members and as such it does not reflect the current treatment practices of other health care practitioners or groups. Membership in ASOPRS is restricted to ophthalmologists who are board certified by the American Board of Ophthalmology and who have also passed rigorous tests in ophthalmic plastic surgery. The ASOPRS membership represents an expert group in the treatment of periocular movement disorders; the starting doses used by ASOPRS members may be more appropriate than the label indication, FDA-approved doses. Rigorous prospective clinical trials studying botulinum toxin treatment for blepharospasm are lacking, a 2005 Cochrane review concluded that because 90% of benign essential blepharospasm patients have been shown to benefit from botulinum toxin, in the published open studies, it would likely be unethical to perform placebo controlled trials of efficacy.12 A number of open label or small placebo controlled studies have been conducted, which all have shown a remarkable success rate in treating blepharospasm and
26
improving patient quality of life.13,14 Doses used in these studies range from less than 10 Units per side to more than 80 Units per side. These varied dosing regimens have come about in part because of the difficulty of quantifying small degrees of clinical improvement after treatment and significant disease variability between patients. Our data show that there is significant variation among the clinical practice patterns of ASOPRS members. The mean initial dose 22.5 Units per side and the most common initial dose 25 Units per side reported in this study falls within the range of doses used in previous clinical trials. Our survey found a small positive correlation between years of experience in treating blepharospasm patients and higher initial dose for new patients. It is possible that this is due to an acquired comfort level with higher doses of botulinum toxin through years of experience or that those with the most experience tend to treat patients with more advanced disease. It is also possible that the correlation is explained by a feeling that higher doses lead to better clinical results for these physicians. It is clear from the results of this survey that the vast majority of ASOPRS members do not follow the FDA-approved treatment regimen when initiating treatment of blepharospasm patients. The FDA-approved recommendation includes both a maximum toxin dose (15 Units per side) and injection site number (3 per side). In our survey, 60 of the responding surgeons indicated that they start with an initial dose of 15 Units or less per side which is consistent with the FDA recommendation. This number is much larger than the 12 respondents who indicated that they followed the FDA-approved regimen. This implies that most of these surgeons are spreading their treatments over more than 3 injection sites. In fact, of the 60 surgeons using less than 15 Units per side on initial treatment only 5 report that they usually inject 3 or fewer sites per side. The most common injection pattern reported in the survey was greater than 7 injections per side which was favored by 75 (30%) respondents. Several different injection patterns have been published to date although no 1 pattern is likely to be ideal of all patients. Several clinical studies have shown, however, that pretarsal injections are more likely to be effective than injections in the preseptal or orbital injections alone.15–17 Various methods have been evaluated to try and improve the effectiveness of OnabotulinumtoxinA. Studies testing the effect of concentration on injection efficacy found a decrease in pain with higher concentrations but no difference in efficacy.18 Treatment response to OnabotulinumtoxinA has been shown to vary among patients and between treatment
© 2015 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
Ophthal Plast Reconstr Surg, Vol. 32, No. 1, 2016
sessions of the same patient.19 Seemingly conflicting reports of patients needing increasing, decreasing, or stable dosing of OnabotulinumtoxinA are likely due to the variation in both disease severity and response to treatment in different patients.19–21 One study of OnabotulinumtoxinA use for blepharospasm showed that the total dose varied from 12.5 to 75.0 Units per eye but that once an appropriate dose was reached the patient was maintained at this dose.19 Another study found that a mean 50% increase in total dose (66 Units to 98 Units) was needed over the first 6 injections but that then most patients remained stable.21 Other studies have sought to explain why some patients experience decreased effect over series of injections.20 This study is limited in a few important ways. The survey was designed to evaluate how oculoplastic surgeons treat blepharospasm with OnabotulinumtoxinA. To keep the survey as straightforward as possible, information regarding the other commercially available botulinum toxin preparations were not asked for or collected. For comparison, IncobotulinumtoxinA is the other botulinum toxin approved by the FDA for treatment of blepharospasm; in clinical studies, the mean dose was 33.5 Unit per side and the mean number of injection sites was 6.22 Also this study was restricted to the treatment of blepharospasm. There were not questions regarding the treatment of Meige syndrome or Hemifacial spasm; it is important to make this distinction as both the dose and duration of treatment vary between benign essential blepharospasm, Meige syndrome, and Hemifacial spasm. This survey of ASOPRS members showed that the typical starting dose used to treat blepharospasm patients was 22.5 Units per side. The FDA-approved recommendations for treatment of blepharospasm should reflect this established treatment pattern.
REFERENCES 1. Jankovic J, Havins WE, Wilkins RB. Blinking and blepharospasm. Mechanism, diagnosis, and management. JAMA 1982;248:3160–4. 2. Reimer J, Gilg K, Karow A, et al. Health-related quality of life in blepharospasm or hemifacial spasm. Acta Neurol Scand 2005;111:64–70. 3. Faulstich ME, Carnrike CL, Jr, Williamson DA. Blepharospasm and Meige syndrome: a review of diagnostic, aetiological and treatment approaches. J Psychosom Res 1985;29:89–94. 4. Scott AB, Kennedy RA, Stubbs HA. Botulinum A toxin injection as a treatment for blepharospasm. Arch Ophthalmol 1985;103:347–50. 5. Ababneh OH, Cetinkaya A, Kulwin DR. Long-term efficacy and safety of botulinum toxin A injections to treat blepharospasm and hemifacial spasm. Clin Experiment Ophthalmol 2014;42:254–61.
Treatment Blepharospasm
6. Fahn S, List T, Moslowitz C, et al. Double-blind controlled study of botuliunum toxin for blepharospasm. Neurology 1985;35:271–2. 7. Tsoy EA, Buckley EG, Dutton JJ. Treatment of blepharospasm with botulinum toxin. Am J Ophthalmol 1985;99:176–9. 8. Jankovic J, Orman J. Botulinum A toxin for cranial-cervical dystonia: a double-blind, placebo-controlled study. Neurology 1987;37:616–23. 9. Schantz EJ, Johnson EA. Botulinum toxin: the story of its development for the treatment of human disease. Perspect Biol Med 1997;40:317–27. 10. Botox Product Information. Available at http://www.allergan.com/ assets/pdf/botox_pi.pdf. Accessed November 23, 2014. 11. Harris PA, Taylor R, Thielke R, et al. Research electronic data capture (REDCap)–a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42:377–81. 12. Costa J, Borges A, Ferreira JJ, et al. Botulinum toxin type A therapy for blepharospasm. Cochrane Database Syst Rev 2005;1:CD004900. 13. Levy RL, Berman D, Parikh M, et al. Supramaximal doses of botulinum toxin for refractory blepharospasm. Ophthalmology 2006;113:1665–8. 14. Park YC, Lim JK, Lee DK, et al. Botulinum a toxin treatment of hemifacial spasm and blepharospasm. J Korean Med Sci 1993;8:334–40. 15. Esposito M, Fasano A, Crisci C, et al. The combined treatment with orbital and pretarsal botulinum toxin injections in the management of poorly responsive blepharospasm. Neurol Sci 2014;35:397–400. 16. Albanese A, Bentivoglio AR, Colosimo C, et al. Pretarsal injections of botulinum toxin improve blepharospasm in previously unresponsive patients. J Neurol Neurosurg Psychiatry 1996;60:693–4. 17. Cakmur 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;249:64–8. 18. Boyle MH, McGwin G, Jr, Flanagan CE, et al. High versus low concentration botulinum toxin A for benign essential blepharospasm: does dilution make a difference? Ophthal Plast Reconstr Surg 2009;25:81–4. 19. Dutton JJ, Buckley EG. Long-term results and complications of botulinum A toxin in the treatment of blepharospasm. Ophthalmology 1988;95:1529–34. 20. Holds JB, Fogg SG, Anderson RL. Botulinum A toxin injection: failures in clinical practice and a biomechanical system for the study of toxin-induced paralysis. Ophthal Plast Reconstr Surg 1990;6:252–9. 21. Ainsworth JR, Kraft SP. Long-term changes in duration of relief with botulinum toxin treatment of essential blepharospasm and hemifacial spasm. Ophthalmology 1995;102:2036–40. 22. Xeomin prescribing information. Available at: www.xeomin.com/ files/xeomin_PI.pdf. Accessed September 4, 2014.
© 2015 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
27
A Survey of Current Blepharospasm Treatment Patterns Among Oculoplastic Surgeons Talmage J. Broadbent, M.D., Ph.D., Ralph E. Wesley, M.D., and Louise A. Mawn, M.D. Vanderbilt Eye Institute, Vanderbilt University School of Medicine, Nashville, Tennessee, U.S.A.
Purpose: To determine the current practice pattern of ASOPRS members injecting onabotulinumtoxinA for Blepharospasm. Methods: An invitation to participate in a web-based, anonymous survey was sent to current members of American Society of Ophthalmic Plastic and Reconstructive Surgeons (ASOPRS) via e-mail. The survey consisted of 9 questions and used the Research Electronic Data Capture online application. Institutional Review board approval was obtained for this study. Results: Forty-one percent of ASOPRS members invited responded to the survey. The mean initial dose of onabotulinumtoxinA used was 22.5 units per side and the most common number of injection sites was greater than 7 per side. Only 12 of the 247 responding surgeons who treat benign essential blepharospasm with onabotulinumtoxinA reported that their initial injection pattern is with 3 or fewer sites per side as per the Food and Drug Administration (FDA)–approved recommendations. Conclusions: Survey of current trends in the management of blepharospasm with onabotulinumtoxinA by ASOPRS members showed that the mean initial dose used to treat blepharospasm patients was 22.5 (standard deviation ± 9.5 units, range 2.5 to 50 units per side). There is significant variation in the treatment doses. The majority of ASOPRS members do not follow the FDA-approved recommendation for dosing. (Ophthal Plast Reconstr Surg 2016;32:24–27)
B
enign essential blepharospasm is a craniofacial movement disorder characterized by repeated forcible contraction of the eyelid and forehead muscles. These contractions result in repeated involuntary blinking that can interfere with patient’s vision and in severe cases can result in functional blindness. Blepharospasm has been shown to cause significant distress and decreased quality of life with patients being limited in a wide variety of activities and mobility.1,2 It is usually an adult onset disease and many different treatments have been utilized in an attempt to minimize patient symptoms and improve quality of life.3 Botulinum toxin has become the pharmacologic mainstay of treatment since studies Accepted for publication December 11, 2014. Supported in part by an unrestricted grant to the Vanderbilt Eye Institute and Physician Scientist Award from Research to Prevent Blindness, New York, NY. A has received honoraria from Company Z. B is currently receiving a grant (#12345) from Organization Y, and is on the speaker's bureau for Organization X the CME organizers for Company A. For the remaining authors none were declared. Supported in part by an unrestricted grant to the Vanderbilt Eye Institute and Physician Scientist Award to Dr. Mawn from Research to Prevent Blindness, New York, NY. The authors have no financial or conflict of interest to disclose. Address correspondence and reprint requests to Louise Mawn, M.D., Vanderbilt Eye Institute, 2311 Pierce Avenue, Nashville, TN 37232–8808. E-mail: [email protected] DOI: 10.1097/IOP.0000000000000405
24
showed its effectiveness and OnabotulinumtoxinA (Botox) was approved by the FDA for treatment of blepharospasm in 1989.4–8 OnabotulinumtoxinA is supplied in vials of 100 Units of lyophilized toxin. The vacuum-dried botulinum toxin powder is reconstituted with saline to achieve the desired concentration of the injection. The FDA specified that 100 [+ or −] 30 Units should be the quantity of toxic activity dispensed in vials.9 The medication guide, which accompanies the vial of onabotulinumtoxinA, approved by the U.S. Food and Drug Administration indicates that the initial recommended dose is 1.25 Units to 2.5 Units injected into the medial and lateral pretarsal orbicularis oculi of the upper eyelid and into the lateral pretarsal orbicularis oculi of the lower eyelid.10 Despite its common use, there is significant variety in the dose and pattern with which botulinum toxin is used to treat blepharospasm. To gain a better understanding of the variety of current practice patterns among ophthalmic plastic surgeons, a survey was created and distributed to practicing surgeons, and information regarding their treatment patterns was collected.
METHODS A 9-question web-based survey was created using the Research Electronic Data Capture application.11 The survey contained both multiple choice and short response type of questions and was limited to the treatment of functional blepharospasm. The survey was approved for use by the Institutional Review Board. The survey was distributed by e-mail to a list of members of the American Society of Ophthalmic Plastic and Reconstructive Surgeons (ASOPRS), which was obtained and used with the permission of ASOPRS. Invitations were sent out to the individuals on the list along with up to 2 follow-up invitations. The survey remained open to collect responses for 3 weeks. The survey data were collected in an anonymous fashion. The data were collected and stored in the Research Electronic Data Capture online database. The collected data were analyzed with univariate linear regression or made into contingency tables and evaluated using with chi-squared testing. The statistics were performed using GraphPad Prism software. The overall alpha level was selected to be 0.05 and the p value reported resulted from 2-tailed t test. A total of 6 regression analyses were performed and the Bonferroni correction (corrected p value 0.0083) was used to correct for multiple comparisons. For questions with short response options, only discrete responses were included in the analysis, responses that reported a range were not included.
RESULTS A total of 621 survey invitations were sent to ASOPRS members. A total of 253 surveys were completed representing a 41% completion rate for this survey. A total of 6 respondents indicated that they did not treat functional blepharospasm patients and they were excluded from any further analysis. A reproduction of the questions asked in this computer based survey is found in Figure 1. Of those who participated in the survey, 9.3% had been in been treating blepharospasm patients for 0 to 5 years, 16.6% for 5 to 10 years, 16.6% for 10 to 15 years, and 57.5% for greater than 15 years (Fig. 2). Of those who participated in the survey, 18.7% reported treating between 0 and 3 patients a month, 28.9% between 4 and 6 patients, 20.7% between 7 and 10 patients, and 31.7%
Ophthal Plast Reconstr Surg, Vol. 32, No. 1, 2016
Ophthal Plast Reconstr Surg, Vol. 32, No. 1, 2016
Treatment Blepharospasm
FIG. 1. Reproduction of the survey
B
A
C
FIG. 2. Demographics of those who responded to the survey. A, Number of years that they have been treating blepharospasm with botulinum toxin injections. B, Number of blepharospasm patients treated per month. C, Percent of respondents who participated in clinical trials which lead to FDA approval of botulinum toxin use for the treatment of blepharospasm.
more than 10 functional blepharospasm patients per month (Fig. 2). Only 16.7% of participants responded that they had participated in the clinical trials that lead to FDA approval of OnabotulinumtoxinA as a treatment for blepharospasm (Fig. 2). Participants were asked if they initiated treatment of blepharospasm patients with the FDA-approved regimen of 3 injection sites (the medial and lateral pretarsal orbicularis oculi of the upper eyelid and into the lateral pretarsal orbicularis oculi of the lower eyelid), with up to a maximum dose of 5.0 Units per site (total of 15 units per side). Twelve of the 247 (4.9%) respondents answered yes they followed this recommendation, while 235 of 247 (95.1%) answered that they did not (Fig. 3). Ophthalmic plastic surgeons reported using a wide variety of doses when initiating treatment for new blepharospasm patients. The mean initial dose used to treat blepharospasm patients was 22.5 (standard deviation ± 9.5 Units) Units per side (Table 1) with the range including reports from 2.5 to 50 Units per side. The most common initial dose in the
FIG. 3. Percent of ophthalmic plastic surgeons who start treatment of blepharospasm patients with the FDA-recommended dosing regimen of onabotulinumtoxinA
© 2015 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
25
Ophthal Plast Reconstr Surg, Vol. 32, No. 1, 2016
T. J. Broadbent et al.
TABLE 1. Summary of the doses used to treat blepharospasm patients Years of experience treating blepharospasm patients
Average Initial dose in units per side. Mean (SD)
Maximum dose in units per side for a stable patient. Mean (SD)
Minimum dose in units per side for a stable patient. Mean (SD)
19.99 (7.54) 19.64 (6.62) 21.75 (8.50) 23.86 (10.65) 22.48 (9.56)
41.54 (12.37) 44.45 (15.18) 49.80 (25.03) 51.13 (24.27) 48.89 (22.39)
16.28 (5.94) 15.00 (7.57) 18.24 (9.94) 18.34 (11.67) 17.58 (10.39)
15 years Total
TABLE 2. Usual number of injection sites used by those who start treatment with the FDA-recommended treatment pattern Do you start treatment with the FDA recommended dosage?
Usual number of injection sites per side 3 or less
4
5
6
7
Greater than 7
Total
No Yes Total
2 (1%) 3 (25%) 5 (2%)
23 (10%) 3 (25%) 26 (11%)
58 (25%) 1 (8%) 59 (25%)
41 (17%) 3 (25%) 44 (18%)
36 (15%) 0 (0%) 36 (15%)
73 (31%) 2 (17%) 75 (30%)
233 (100%) 12 (100%) 245 (100%)
survey was 25 units per side which was favored by 24% of respondents. The mean minimum dose required to maintain a stable patient was 17.6 (standard deviation ± 10.4 Units) units per side, with a range including responses from 2 to 50 Units per side. The most common minimum dose required to maintain a stable patient was 25 Units per side, which was reported by 17% of respondents. The mean maximum dose required to maintain a stable blepharospasm patient was 48.6 (standard deviation ± 22.4 Units) units per side (Table 1) with the responses ranging from 4 to 200 Units per side. The most common maximum dose required to maintain a stable blepharospasm patient was 50 Units per side, which was reported by 38% of respondents. Further analysis showed that there was a small but significant positive correlation between years in practice and higher initial doses used to treat blepharospasm patients (r2 = 0.031, p value 0.0071). When asked about their usual injection pattern, 2% of respondents indicated that they usually treated with 3 or fewer injection sites, 10.6% reported 4 sites, 24.1% 5 sites, 18% 6 sites, 14.7% 7 sites, and 30.6% greater than 7 injection sites (Table 2). Those indicating that they initiated treatment in accordance with the FDA recommendation tended to inject fewer sites but this trend did not reach statistical significance (Table 2).
DISCUSSION Blepharospasm is a recognized cause of visual impairment, which usually can be effectively managed with injection of botulinum toxin. In addition to oculoplastic surgeons, blepharospasm patients may also be treated by general ophthalmologists, neurophthalmologists, or neurologists. The survey was sent only to ASOPRS members and as such it does not reflect the current treatment practices of other health care practitioners or groups. Membership in ASOPRS is restricted to ophthalmologists who are board certified by the American Board of Ophthalmology and who have also passed rigorous tests in ophthalmic plastic surgery. The ASOPRS membership represents an expert group in the treatment of periocular movement disorders; the starting doses used by ASOPRS members may be more appropriate than the label indication, FDA-approved doses. Rigorous prospective clinical trials studying botulinum toxin treatment for blepharospasm are lacking, a 2005 Cochrane review concluded that because 90% of benign essential blepharospasm patients have been shown to benefit from botulinum toxin, in the published open studies, it would likely be unethical to perform placebo controlled trials of efficacy.12 A number of open label or small placebo controlled studies have been conducted, which all have shown a remarkable success rate in treating blepharospasm and
26
improving patient quality of life.13,14 Doses used in these studies range from less than 10 Units per side to more than 80 Units per side. These varied dosing regimens have come about in part because of the difficulty of quantifying small degrees of clinical improvement after treatment and significant disease variability between patients. Our data show that there is significant variation among the clinical practice patterns of ASOPRS members. The mean initial dose 22.5 Units per side and the most common initial dose 25 Units per side reported in this study falls within the range of doses used in previous clinical trials. Our survey found a small positive correlation between years of experience in treating blepharospasm patients and higher initial dose for new patients. It is possible that this is due to an acquired comfort level with higher doses of botulinum toxin through years of experience or that those with the most experience tend to treat patients with more advanced disease. It is also possible that the correlation is explained by a feeling that higher doses lead to better clinical results for these physicians. It is clear from the results of this survey that the vast majority of ASOPRS members do not follow the FDA-approved treatment regimen when initiating treatment of blepharospasm patients. The FDA-approved recommendation includes both a maximum toxin dose (15 Units per side) and injection site number (3 per side). In our survey, 60 of the responding surgeons indicated that they start with an initial dose of 15 Units or less per side which is consistent with the FDA recommendation. This number is much larger than the 12 respondents who indicated that they followed the FDA-approved regimen. This implies that most of these surgeons are spreading their treatments over more than 3 injection sites. In fact, of the 60 surgeons using less than 15 Units per side on initial treatment only 5 report that they usually inject 3 or fewer sites per side. The most common injection pattern reported in the survey was greater than 7 injections per side which was favored by 75 (30%) respondents. Several different injection patterns have been published to date although no 1 pattern is likely to be ideal of all patients. Several clinical studies have shown, however, that pretarsal injections are more likely to be effective than injections in the preseptal or orbital injections alone.15–17 Various methods have been evaluated to try and improve the effectiveness of OnabotulinumtoxinA. Studies testing the effect of concentration on injection efficacy found a decrease in pain with higher concentrations but no difference in efficacy.18 Treatment response to OnabotulinumtoxinA has been shown to vary among patients and between treatment
© 2015 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
Ophthal Plast Reconstr Surg, Vol. 32, No. 1, 2016
sessions of the same patient.19 Seemingly conflicting reports of patients needing increasing, decreasing, or stable dosing of OnabotulinumtoxinA are likely due to the variation in both disease severity and response to treatment in different patients.19–21 One study of OnabotulinumtoxinA use for blepharospasm showed that the total dose varied from 12.5 to 75.0 Units per eye but that once an appropriate dose was reached the patient was maintained at this dose.19 Another study found that a mean 50% increase in total dose (66 Units to 98 Units) was needed over the first 6 injections but that then most patients remained stable.21 Other studies have sought to explain why some patients experience decreased effect over series of injections.20 This study is limited in a few important ways. The survey was designed to evaluate how oculoplastic surgeons treat blepharospasm with OnabotulinumtoxinA. To keep the survey as straightforward as possible, information regarding the other commercially available botulinum toxin preparations were not asked for or collected. For comparison, IncobotulinumtoxinA is the other botulinum toxin approved by the FDA for treatment of blepharospasm; in clinical studies, the mean dose was 33.5 Unit per side and the mean number of injection sites was 6.22 Also this study was restricted to the treatment of blepharospasm. There were not questions regarding the treatment of Meige syndrome or Hemifacial spasm; it is important to make this distinction as both the dose and duration of treatment vary between benign essential blepharospasm, Meige syndrome, and Hemifacial spasm. This survey of ASOPRS members showed that the typical starting dose used to treat blepharospasm patients was 22.5 Units per side. The FDA-approved recommendations for treatment of blepharospasm should reflect this established treatment pattern.
REFERENCES 1. Jankovic J, Havins WE, Wilkins RB. Blinking and blepharospasm. Mechanism, diagnosis, and management. JAMA 1982;248:3160–4. 2. Reimer J, Gilg K, Karow A, et al. Health-related quality of life in blepharospasm or hemifacial spasm. Acta Neurol Scand 2005;111:64–70. 3. Faulstich ME, Carnrike CL, Jr, Williamson DA. Blepharospasm and Meige syndrome: a review of diagnostic, aetiological and treatment approaches. J Psychosom Res 1985;29:89–94. 4. Scott AB, Kennedy RA, Stubbs HA. Botulinum A toxin injection as a treatment for blepharospasm. Arch Ophthalmol 1985;103:347–50. 5. Ababneh OH, Cetinkaya A, Kulwin DR. Long-term efficacy and safety of botulinum toxin A injections to treat blepharospasm and hemifacial spasm. Clin Experiment Ophthalmol 2014;42:254–61.
Treatment Blepharospasm
6. Fahn S, List T, Moslowitz C, et al. Double-blind controlled study of botuliunum toxin for blepharospasm. Neurology 1985;35:271–2. 7. Tsoy EA, Buckley EG, Dutton JJ. Treatment of blepharospasm with botulinum toxin. Am J Ophthalmol 1985;99:176–9. 8. Jankovic J, Orman J. Botulinum A toxin for cranial-cervical dystonia: a double-blind, placebo-controlled study. Neurology 1987;37:616–23. 9. Schantz EJ, Johnson EA. Botulinum toxin: the story of its development for the treatment of human disease. Perspect Biol Med 1997;40:317–27. 10. Botox Product Information. Available at http://www.allergan.com/ assets/pdf/botox_pi.pdf. Accessed November 23, 2014. 11. Harris PA, Taylor R, Thielke R, et al. Research electronic data capture (REDCap)–a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42:377–81. 12. Costa J, Borges A, Ferreira JJ, et al. Botulinum toxin type A therapy for blepharospasm. Cochrane Database Syst Rev 2005;1:CD004900. 13. Levy RL, Berman D, Parikh M, et al. Supramaximal doses of botulinum toxin for refractory blepharospasm. Ophthalmology 2006;113:1665–8. 14. Park YC, Lim JK, Lee DK, et al. Botulinum a toxin treatment of hemifacial spasm and blepharospasm. J Korean Med Sci 1993;8:334–40. 15. Esposito M, Fasano A, Crisci C, et al. The combined treatment with orbital and pretarsal botulinum toxin injections in the management of poorly responsive blepharospasm. Neurol Sci 2014;35:397–400. 16. Albanese A, Bentivoglio AR, Colosimo C, et al. Pretarsal injections of botulinum toxin improve blepharospasm in previously unresponsive patients. J Neurol Neurosurg Psychiatry 1996;60:693–4. 17. Cakmur 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;249:64–8. 18. Boyle MH, McGwin G, Jr, Flanagan CE, et al. High versus low concentration botulinum toxin A for benign essential blepharospasm: does dilution make a difference? Ophthal Plast Reconstr Surg 2009;25:81–4. 19. Dutton JJ, Buckley EG. Long-term results and complications of botulinum A toxin in the treatment of blepharospasm. Ophthalmology 1988;95:1529–34. 20. Holds JB, Fogg SG, Anderson RL. Botulinum A toxin injection: failures in clinical practice and a biomechanical system for the study of toxin-induced paralysis. Ophthal Plast Reconstr Surg 1990;6:252–9. 21. Ainsworth JR, Kraft SP. Long-term changes in duration of relief with botulinum toxin treatment of essential blepharospasm and hemifacial spasm. Ophthalmology 1995;102:2036–40. 22. Xeomin prescribing information. Available at: www.xeomin.com/ files/xeomin_PI.pdf. Accessed September 4, 2014.
© 2015 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
27
