Why Do Patients Discontinue Botulinum Toxin for Dystonia?

[[{"attributes":{},"fields":{}}]] MIAMI—Botulinum toxin injection is the first-line treatment for most focal dystonias. The therapy improves function in many patients, but registry studies suggest that discontinuation is relatively common, said Cynthia L. Comella, MD, Professor of Neurology at Rush University Medical Center in Chicago. The fact that the treatment effect may wear off between injections, which typically are administered at least 12 weeks apart, and unrealistic patient expectations may contribute to patient dissatisfaction, Dr. Comella said at the First Pan American Parkinson’s Disease and Movement Disorders Congress.

A Potent Neurotoxin

The FDA first approved botulinum toxin in 1989 for the treatment of strabismus, blepharospasm, and hemifacial spasm. Early reports also described its use in cervical dystonia, spasmodic dysphonia, oral mandibular dystonia, focal hand dystonia, and focal leg and truncal dystonias.

Four preparations of botulinum toxin—three serotype A (ie, onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA) and one serotype B (rimabotulinumtoxinB)—are available in the United States. A 2008 evidence-based review assessed the level of evidence for botulinum toxin in movement disorders, including blepharospasm (level B), hemifacial spasm (level C), cervical dystonia (level A), upper focal limb dystonia (level B), lower focal limb dystonia (level C), and adductor laryngeal dystonia (level B). An update in 2016 incorporated additional trials for cervical dystonia and blepharospasm, and the authors separated the level of evidence by toxin type for those indications. A paucity of class I trials limits the strength of the evidence for certain indications, but botulinum toxin still is the treatment of choice for those indications, Dr. Comella said.

Blepharospasm

Studies have found that as many as 90% of patients with blepharospasm improve with botulinum toxin treatment. As in other indications, however, the treatment effect may not be sustained between injections. A retrospective chart review of 41 patients with primary blepharospasm and 23 patients with secondary blepharospasm found that the patient-reported duration of treatment benefit was less than 10 weeks. Yet early studies of immunoresistance with botulinum toxin treatment led to a recommendation that injections be given 12 weeks apart. “Perhaps we are overdoing this 12-week rule,” Dr. Comella said. “In some patients, in order to maintain their functional capacity, we may want to consider injecting sooner.” Additional research is needed to determine optimal dosing intervals.

The development of neutralizing antibodies with current formulations of botulinum toxin appears to be rare, and the effects of neutralizing antibodies are not well understood, Dr. Comella said. Brin et al studied the immunogenicity of onabotulinumtoxinA in 326 patients with cervical dystonia who received a median of nine treatments over an average of 2.5 years. Four patients (1.2%) developed neutralizing antibodies, and one of the four patients who developed neutralizing antibodies continued to respond to treatment.

Cervical Dystonia Registries

CD PROBE, a registry study of patients who received onabotulinumtoxinA for cervical dystonia, enrolled 1,046 patients. Overall, 26.2% of patients experienced adverse events, most commonly mild to moderate muscle weakness and dysphagia. Over three injection series, 52% of the patients discontinued the study. The ANCHOR-CD registry study of abobotulinumtoxinA had a discontinuation rate of 36.6%. “If [botulinum toxin] is such an effective treatment in controlled clinical trials … why did these patients discontinue [therapy]?”

Dr. Comella and Kailash Bhatia, MD, DM, Professor of Clinical Neurology at University College London, conducted an international survey of self-identified patients with cervical dystonia to assess patients’ perceptions of their illness and its management. Of the more than 900 patients who were receiving botulinum toxin, 56% were fairly or very satisfied with the treatment, whereas 25% were fairly or very dissatisfied.

A survey by Sethi et al of 136 patients with cervical dystonia found that 51% were very satisfied and 43% were somewhat satisfied with botulinum toxin treatment, but 45% would prefer a treatment cycle of 10 weeks or fewer. “The benefits of the injection wore out before the next injection was permitted,” Dr. Comella said. “That gave them two to three weeks of not doing very well, which caused some dissatisfaction.”

Evidente et al studied the effect of flexible injection intervals in the two pivotal trials of incobotulinumtoxinA for blepharospasm and cervical dystonia. After an initial double-blind, placebo-controlled period, dosing intervals became flexible during a 68-week open-label extension. During that time, patients could request treatment after a six-week interval, and physicians would administer the treatment at that time if a patient’s dystonia was at a certain level of severity. Among patients with blepharospasm, 26.5% of treatments were administered at less than 10 weeks during the flexible dosing period. Among patients with cervical dystonia, 29.5% of treatments were administered at less than 10 weeks. Flexible dosing was well tolerated, and no additional safety concerns were observed when treatment was given sooner than 12 weeks after the last injection, compared with treatment given after 12 or more weeks.

 

Limb Dystonia

In limb dystonia, mostly occupational dystonias have been studied, including writer’s cramp and musician’s dystonia. The most frequent adverse event with botulinum toxin is weakness, which may lead to discontinuation. In a 2007 study of abobotulinumtoxinA for writer’s cramp that used continuation of treatment as the primary outcome, 70% of patients who received active treatment continued treatment, compared with 32% of patients in the placebo group. Hand weakness occurred in about 90% of patients in the active treatment group, however, compared with 25% of patients in the placebo group, and 25% of patients in the active treatment group discontinued because of hand weakness.

Neurologists adjust a patient’s injections based on the patient’s response to the previous treatment, so treatment may become more beneficial as neurologists optimize the injection pattern and dosing.

Why Might Treatment Fail?

Injection of botulinum toxin into the wrong muscle may be a common reason for lack of efficacy. Stress-induced exacerbation or inadequate dose may be other reasons for treatment failure. Uncommon reasons for lack of efficacy include change in dystonia and immunoresistance. In addition, patients may discontinue treatment because of the expense or inconvenience, Dr. Comella said.

Neurologists should help set realistic expectations for treatment. “We must manage patient expectations. It is not a cure. This may not restore you to perfect movement,” Dr. Comella said. “Too often we tell them how well they are going to do without giving them a more realistic view.”

Future Directions

Neurologists need better long-term outcome data to understand the effects of botulinum toxin in dystonia, and telemedicine may be an ideal way to assess the treatment’s long-term efficacy, Dr. Comella said. Remote evaluations could supplement in-person evaluations and avoid reliance on patients’ retrospective reports.

An investigational formulation of botulinum toxin, daxibotulinumtoxinA, is being developed by Revance Pharmaceuticals. It contains a peptide excipient that is designed to produce a longer treatment effect. A phase II open-label study is evaluating the formulation in patients with cervical dystonia, said Dr. Comella, who is one of the study investigators. One cohort of 12 patients received between 100 units and 200 units of the neurotoxin. The patients’ mean Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) score change from baseline was 33% at 24 weeks. Investigators observed a clinically meaningful benefit by Week 2. The preliminary results are promising, but “we have much more work to do before this [formulation] could be available to us,” Dr. Comella said.

—Jake Remaly

Suggested Reading

Brin MF, Comella CL, Jankovic J, et al. Long-term treatment with botulinum toxin type A in cervical dystonia has low immunogenicity by mouse protection assay. Mov Disord. 2008;23(10):1353-1360.

Comella C, Bhatia K. An international survey of patients with cervical dystonia. J Neurol. 2015;262(4):837-848.

Evidente VG, Truong D, Jankovic J, et al. IncobotulinumtoxinA (Xeomin) injected for blepharospasm or cervical dystonia according to patient needs is well tolerated. J Neurol Sci. 2014;346(1-2):116-120.

Jankovic J, Adler CH, Charles D, et al. Primary results from the cervical dystonia patient registry for observation of onabotulinumtoxina efficacy (CD PROBE). J Neurol Sci. 2015;349(1-2):84-93.

Kruisdijk JJ, Koelman JH, Ongerboer de Visser BW, et al. Botulinum toxin for writer’s cramp: a randomised, placebo-controlled trial and 1-year follow-up. J Neurol Neurosurg Psychiatry. 2007;78(3):264-270.

Martinez-Ramirez D, Giugni JC, Hastings E, et al. Comparable botulinum toxin outcomes between primary and secondary blepharospasm: A retrospective analysis. Tremor Other Hyperkinet Mov (NY). 2014;4:286.

Sethi KD, Rodriguez R, Olayinka B. Satisfaction with botulinum toxin treatment: a cross-sectional survey of patients with cervical dystonia. J Med Econ. 2012;15(3):419-423.

Simpson DM, Blitzer A, Brashear A, et al. Assessment: Botulinum neurotoxin for the treatment of movement disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2008;70(19):1699-1706.

Simpson DM, Hallett M, Ashman EJ, et al. Practice guideline update summary: Botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2016;86(19):1818-1826.

[[{"attributes":{},"fields":{}}]] MIAMI—Botulinum toxin injection is the first-line treatment for most focal dystonias. The therapy improves function in many patients, but registry studies suggest that discontinuation is relatively common, said Cynthia L. Comella, MD, Professor of Neurology at Rush University Medical Center in Chicago. The fact that the treatment effect may wear off between injections, which typically are administered at least 12 weeks apart, and unrealistic patient expectations may contribute to patient dissatisfaction, Dr. Comella said at the First Pan American Parkinson’s Disease and Movement Disorders Congress.

A Potent Neurotoxin

The FDA first approved botulinum toxin in 1989 for the treatment of strabismus, blepharospasm, and hemifacial spasm. Early reports also described its use in cervical dystonia, spasmodic dysphonia, oral mandibular dystonia, focal hand dystonia, and focal leg and truncal dystonias.

Four preparations of botulinum toxin—three serotype A (ie, onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA) and one serotype B (rimabotulinumtoxinB)—are available in the United States. A 2008 evidence-based review assessed the level of evidence for botulinum toxin in movement disorders, including blepharospasm (level B), hemifacial spasm (level C), cervical dystonia (level A), upper focal limb dystonia (level B), lower focal limb dystonia (level C), and adductor laryngeal dystonia (level B). An update in 2016 incorporated additional trials for cervical dystonia and blepharospasm, and the authors separated the level of evidence by toxin type for those indications. A paucity of class I trials limits the strength of the evidence for certain indications, but botulinum toxin still is the treatment of choice for those indications, Dr. Comella said.

Blepharospasm

Studies have found that as many as 90% of patients with blepharospasm improve with botulinum toxin treatment. As in other indications, however, the treatment effect may not be sustained between injections. A retrospective chart review of 41 patients with primary blepharospasm and 23 patients with secondary blepharospasm found that the patient-reported duration of treatment benefit was less than 10 weeks. Yet early studies of immunoresistance with botulinum toxin treatment led to a recommendation that injections be given 12 weeks apart. “Perhaps we are overdoing this 12-week rule,” Dr. Comella said. “In some patients, in order to maintain their functional capacity, we may want to consider injecting sooner.” Additional research is needed to determine optimal dosing intervals.

The development of neutralizing antibodies with current formulations of botulinum toxin appears to be rare, and the effects of neutralizing antibodies are not well understood, Dr. Comella said. Brin et al studied the immunogenicity of onabotulinumtoxinA in 326 patients with cervical dystonia who received a median of nine treatments over an average of 2.5 years. Four patients (1.2%) developed neutralizing antibodies, and one of the four patients who developed neutralizing antibodies continued to respond to treatment.

Cervical Dystonia Registries

CD PROBE, a registry study of patients who received onabotulinumtoxinA for cervical dystonia, enrolled 1,046 patients. Overall, 26.2% of patients experienced adverse events, most commonly mild to moderate muscle weakness and dysphagia. Over three injection series, 52% of the patients discontinued the study. The ANCHOR-CD registry study of abobotulinumtoxinA had a discontinuation rate of 36.6%. “If [botulinum toxin] is such an effective treatment in controlled clinical trials … why did these patients discontinue [therapy]?”

Dr. Comella and Kailash Bhatia, MD, DM, Professor of Clinical Neurology at University College London, conducted an international survey of self-identified patients with cervical dystonia to assess patients’ perceptions of their illness and its management. Of the more than 900 patients who were receiving botulinum toxin, 56% were fairly or very satisfied with the treatment, whereas 25% were fairly or very dissatisfied.

A survey by Sethi et al of 136 patients with cervical dystonia found that 51% were very satisfied and 43% were somewhat satisfied with botulinum toxin treatment, but 45% would prefer a treatment cycle of 10 weeks or fewer. “The benefits of the injection wore out before the next injection was permitted,” Dr. Comella said. “That gave them two to three weeks of not doing very well, which caused some dissatisfaction.”

Evidente et al studied the effect of flexible injection intervals in the two pivotal trials of incobotulinumtoxinA for blepharospasm and cervical dystonia. After an initial double-blind, placebo-controlled period, dosing intervals became flexible during a 68-week open-label extension. During that time, patients could request treatment after a six-week interval, and physicians would administer the treatment at that time if a patient’s dystonia was at a certain level of severity. Among patients with blepharospasm, 26.5% of treatments were administered at less than 10 weeks during the flexible dosing period. Among patients with cervical dystonia, 29.5% of treatments were administered at less than 10 weeks. Flexible dosing was well tolerated, and no additional safety concerns were observed when treatment was given sooner than 12 weeks after the last injection, compared with treatment given after 12 or more weeks.

 

Limb Dystonia

In limb dystonia, mostly occupational dystonias have been studied, including writer’s cramp and musician’s dystonia. The most frequent adverse event with botulinum toxin is weakness, which may lead to discontinuation. In a 2007 study of abobotulinumtoxinA for writer’s cramp that used continuation of treatment as the primary outcome, 70% of patients who received active treatment continued treatment, compared with 32% of patients in the placebo group. Hand weakness occurred in about 90% of patients in the active treatment group, however, compared with 25% of patients in the placebo group, and 25% of patients in the active treatment group discontinued because of hand weakness.

Neurologists adjust a patient’s injections based on the patient’s response to the previous treatment, so treatment may become more beneficial as neurologists optimize the injection pattern and dosing.

Why Might Treatment Fail?

Injection of botulinum toxin into the wrong muscle may be a common reason for lack of efficacy. Stress-induced exacerbation or inadequate dose may be other reasons for treatment failure. Uncommon reasons for lack of efficacy include change in dystonia and immunoresistance. In addition, patients may discontinue treatment because of the expense or inconvenience, Dr. Comella said.

Neurologists should help set realistic expectations for treatment. “We must manage patient expectations. It is not a cure. This may not restore you to perfect movement,” Dr. Comella said. “Too often we tell them how well they are going to do without giving them a more realistic view.”

Future Directions

Neurologists need better long-term outcome data to understand the effects of botulinum toxin in dystonia, and telemedicine may be an ideal way to assess the treatment’s long-term efficacy, Dr. Comella said. Remote evaluations could supplement in-person evaluations and avoid reliance on patients’ retrospective reports.

An investigational formulation of botulinum toxin, daxibotulinumtoxinA, is being developed by Revance Pharmaceuticals. It contains a peptide excipient that is designed to produce a longer treatment effect. A phase II open-label study is evaluating the formulation in patients with cervical dystonia, said Dr. Comella, who is one of the study investigators. One cohort of 12 patients received between 100 units and 200 units of the neurotoxin. The patients’ mean Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) score change from baseline was 33% at 24 weeks. Investigators observed a clinically meaningful benefit by Week 2. The preliminary results are promising, but “we have much more work to do before this [formulation] could be available to us,” Dr. Comella said.

—Jake Remaly

Suggested Reading

Brin MF, Comella CL, Jankovic J, et al. Long-term treatment with botulinum toxin type A in cervical dystonia has low immunogenicity by mouse protection assay. Mov Disord. 2008;23(10):1353-1360.

Comella C, Bhatia K. An international survey of patients with cervical dystonia. J Neurol. 2015;262(4):837-848.

Evidente VG, Truong D, Jankovic J, et al. IncobotulinumtoxinA (Xeomin) injected for blepharospasm or cervical dystonia according to patient needs is well tolerated. J Neurol Sci. 2014;346(1-2):116-120.

Jankovic J, Adler CH, Charles D, et al. Primary results from the cervical dystonia patient registry for observation of onabotulinumtoxina efficacy (CD PROBE). J Neurol Sci. 2015;349(1-2):84-93.

Kruisdijk JJ, Koelman JH, Ongerboer de Visser BW, et al. Botulinum toxin for writer’s cramp: a randomised, placebo-controlled trial and 1-year follow-up. J Neurol Neurosurg Psychiatry. 2007;78(3):264-270.

Martinez-Ramirez D, Giugni JC, Hastings E, et al. Comparable botulinum toxin outcomes between primary and secondary blepharospasm: A retrospective analysis. Tremor Other Hyperkinet Mov (NY). 2014;4:286.

Sethi KD, Rodriguez R, Olayinka B. Satisfaction with botulinum toxin treatment: a cross-sectional survey of patients with cervical dystonia. J Med Econ. 2012;15(3):419-423.

Simpson DM, Blitzer A, Brashear A, et al. Assessment: Botulinum neurotoxin for the treatment of movement disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2008;70(19):1699-1706.

Simpson DM, Hallett M, Ashman EJ, et al. Practice guideline update summary: Botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2016;86(19):1818-1826.

[[{"attributes":{},"fields":{}}]] MIAMI—Botulinum toxin injection is the first-line treatment for most focal dystonias. The therapy improves function in many patients, but registry studies suggest that discontinuation is relatively common, said Cynthia L. Comella, MD, Professor of Neurology at Rush University Medical Center in Chicago. The fact that the treatment effect may wear off between injections, which typically are administered at least 12 weeks apart, and unrealistic patient expectations may contribute to patient dissatisfaction, Dr. Comella said at the First Pan American Parkinson’s Disease and Movement Disorders Congress.

A Potent Neurotoxin

The FDA first approved botulinum toxin in 1989 for the treatment of strabismus, blepharospasm, and hemifacial spasm. Early reports also described its use in cervical dystonia, spasmodic dysphonia, oral mandibular dystonia, focal hand dystonia, and focal leg and truncal dystonias.

Four preparations of botulinum toxin—three serotype A (ie, onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA) and one serotype B (rimabotulinumtoxinB)—are available in the United States. A 2008 evidence-based review assessed the level of evidence for botulinum toxin in movement disorders, including blepharospasm (level B), hemifacial spasm (level C), cervical dystonia (level A), upper focal limb dystonia (level B), lower focal limb dystonia (level C), and adductor laryngeal dystonia (level B). An update in 2016 incorporated additional trials for cervical dystonia and blepharospasm, and the authors separated the level of evidence by toxin type for those indications. A paucity of class I trials limits the strength of the evidence for certain indications, but botulinum toxin still is the treatment of choice for those indications, Dr. Comella said.

Blepharospasm

Studies have found that as many as 90% of patients with blepharospasm improve with botulinum toxin treatment. As in other indications, however, the treatment effect may not be sustained between injections. A retrospective chart review of 41 patients with primary blepharospasm and 23 patients with secondary blepharospasm found that the patient-reported duration of treatment benefit was less than 10 weeks. Yet early studies of immunoresistance with botulinum toxin treatment led to a recommendation that injections be given 12 weeks apart. “Perhaps we are overdoing this 12-week rule,” Dr. Comella said. “In some patients, in order to maintain their functional capacity, we may want to consider injecting sooner.” Additional research is needed to determine optimal dosing intervals.

The development of neutralizing antibodies with current formulations of botulinum toxin appears to be rare, and the effects of neutralizing antibodies are not well understood, Dr. Comella said. Brin et al studied the immunogenicity of onabotulinumtoxinA in 326 patients with cervical dystonia who received a median of nine treatments over an average of 2.5 years. Four patients (1.2%) developed neutralizing antibodies, and one of the four patients who developed neutralizing antibodies continued to respond to treatment.

Cervical Dystonia Registries

CD PROBE, a registry study of patients who received onabotulinumtoxinA for cervical dystonia, enrolled 1,046 patients. Overall, 26.2% of patients experienced adverse events, most commonly mild to moderate muscle weakness and dysphagia. Over three injection series, 52% of the patients discontinued the study. The ANCHOR-CD registry study of abobotulinumtoxinA had a discontinuation rate of 36.6%. “If [botulinum toxin] is such an effective treatment in controlled clinical trials … why did these patients discontinue [therapy]?”

Dr. Comella and Kailash Bhatia, MD, DM, Professor of Clinical Neurology at University College London, conducted an international survey of self-identified patients with cervical dystonia to assess patients’ perceptions of their illness and its management. Of the more than 900 patients who were receiving botulinum toxin, 56% were fairly or very satisfied with the treatment, whereas 25% were fairly or very dissatisfied.

A survey by Sethi et al of 136 patients with cervical dystonia found that 51% were very satisfied and 43% were somewhat satisfied with botulinum toxin treatment, but 45% would prefer a treatment cycle of 10 weeks or fewer. “The benefits of the injection wore out before the next injection was permitted,” Dr. Comella said. “That gave them two to three weeks of not doing very well, which caused some dissatisfaction.”

Evidente et al studied the effect of flexible injection intervals in the two pivotal trials of incobotulinumtoxinA for blepharospasm and cervical dystonia. After an initial double-blind, placebo-controlled period, dosing intervals became flexible during a 68-week open-label extension. During that time, patients could request treatment after a six-week interval, and physicians would administer the treatment at that time if a patient’s dystonia was at a certain level of severity. Among patients with blepharospasm, 26.5% of treatments were administered at less than 10 weeks during the flexible dosing period. Among patients with cervical dystonia, 29.5% of treatments were administered at less than 10 weeks. Flexible dosing was well tolerated, and no additional safety concerns were observed when treatment was given sooner than 12 weeks after the last injection, compared with treatment given after 12 or more weeks.

 

Limb Dystonia

In limb dystonia, mostly occupational dystonias have been studied, including writer’s cramp and musician’s dystonia. The most frequent adverse event with botulinum toxin is weakness, which may lead to discontinuation. In a 2007 study of abobotulinumtoxinA for writer’s cramp that used continuation of treatment as the primary outcome, 70% of patients who received active treatment continued treatment, compared with 32% of patients in the placebo group. Hand weakness occurred in about 90% of patients in the active treatment group, however, compared with 25% of patients in the placebo group, and 25% of patients in the active treatment group discontinued because of hand weakness.

Neurologists adjust a patient’s injections based on the patient’s response to the previous treatment, so treatment may become more beneficial as neurologists optimize the injection pattern and dosing.

Why Might Treatment Fail?

Injection of botulinum toxin into the wrong muscle may be a common reason for lack of efficacy. Stress-induced exacerbation or inadequate dose may be other reasons for treatment failure. Uncommon reasons for lack of efficacy include change in dystonia and immunoresistance. In addition, patients may discontinue treatment because of the expense or inconvenience, Dr. Comella said.

Neurologists should help set realistic expectations for treatment. “We must manage patient expectations. It is not a cure. This may not restore you to perfect movement,” Dr. Comella said. “Too often we tell them how well they are going to do without giving them a more realistic view.”

Future Directions

Neurologists need better long-term outcome data to understand the effects of botulinum toxin in dystonia, and telemedicine may be an ideal way to assess the treatment’s long-term efficacy, Dr. Comella said. Remote evaluations could supplement in-person evaluations and avoid reliance on patients’ retrospective reports.

An investigational formulation of botulinum toxin, daxibotulinumtoxinA, is being developed by Revance Pharmaceuticals. It contains a peptide excipient that is designed to produce a longer treatment effect. A phase II open-label study is evaluating the formulation in patients with cervical dystonia, said Dr. Comella, who is one of the study investigators. One cohort of 12 patients received between 100 units and 200 units of the neurotoxin. The patients’ mean Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) score change from baseline was 33% at 24 weeks. Investigators observed a clinically meaningful benefit by Week 2. The preliminary results are promising, but “we have much more work to do before this [formulation] could be available to us,” Dr. Comella said.

—Jake Remaly

Suggested Reading

Brin MF, Comella CL, Jankovic J, et al. Long-term treatment with botulinum toxin type A in cervical dystonia has low immunogenicity by mouse protection assay. Mov Disord. 2008;23(10):1353-1360.

Comella C, Bhatia K. An international survey of patients with cervical dystonia. J Neurol. 2015;262(4):837-848.

Evidente VG, Truong D, Jankovic J, et al. IncobotulinumtoxinA (Xeomin) injected for blepharospasm or cervical dystonia according to patient needs is well tolerated. J Neurol Sci. 2014;346(1-2):116-120.

Jankovic J, Adler CH, Charles D, et al. Primary results from the cervical dystonia patient registry for observation of onabotulinumtoxina efficacy (CD PROBE). J Neurol Sci. 2015;349(1-2):84-93.

Kruisdijk JJ, Koelman JH, Ongerboer de Visser BW, et al. Botulinum toxin for writer’s cramp: a randomised, placebo-controlled trial and 1-year follow-up. J Neurol Neurosurg Psychiatry. 2007;78(3):264-270.

Martinez-Ramirez D, Giugni JC, Hastings E, et al. Comparable botulinum toxin outcomes between primary and secondary blepharospasm: A retrospective analysis. Tremor Other Hyperkinet Mov (NY). 2014;4:286.

Sethi KD, Rodriguez R, Olayinka B. Satisfaction with botulinum toxin treatment: a cross-sectional survey of patients with cervical dystonia. J Med Econ. 2012;15(3):419-423.

Simpson DM, Blitzer A, Brashear A, et al. Assessment: Botulinum neurotoxin for the treatment of movement disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2008;70(19):1699-1706.

Simpson DM, Hallett M, Ashman EJ, et al. Practice guideline update summary: Botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2016;86(19):1818-1826.