Coverage Policy Manual
Policy #: 2018002
Category: Surgery
Initiated: January 2018
Last Review: June 2018
  Chemodenervation, Botulinum Toxins

Description:
Botulinum is a family of toxins produced by the anaerobic organism Clostridia botulinum. Four formulations have been approved by the U.S. Food and Drug Administration (FDA). Botulinum Toxin  injections have been used to treat various focal muscle spastic disorders and excessive muscle contractions such as dystonias, spasms, twitches, etc. Although labeled indications of these agents differ; all are FDA-approved for treating cervical dystonia in adults. Botulinum toxin products are also used for a range of off-label indications.
 
There are 7 distinct botulinum serotypes designated as type A, B, C-1, D, E, F, and G. In the United States, 4 preparations of botulinum are commercially available, three using type A serotype and one using type B. The brand names of the botulinum toxin products were changed in 2009; trade names and product formulations did not. The 3 formulations of botulinum toxin type A are currently called onabotulinumtoxinA (Botox), abobotulinumtoxinA (Dysport), and incobotulinumtoxinA (Xeomin). Botox has been available on the U.S. market the longest and has been the most widely used formulation. Xeomin, the newest product marketed in the United States, consists of the pure neurotoxin without complexing proteins and is the only product stable at room temperature for up to 4 years. RimabotulinumtoxinB contains botulinum toxin type B, currently marketed as Myobloc.
 
Among the botulinum toxin products, onabotulinumtoxinA (Botox) is approved by the Food and Drug Administration (FDA) for the most indications.
 
All botulinum toxin products carry black box warnings of the potential for a distant spread of the toxin effect. The warning notes that the risk of symptoms may be greatest in children treated for spasticity but symptoms can also occur in adults.
 
Three products, Botox (marketed as Botox Cosmetic), Dysport, and Xeomin are approved for temporarily improving the appearance of glabellar (frown) lines in adults.
 
The botulinum toxin products have also been used for a wide variety of off-label indications.
 
In rare cases, patients do not respond to botulinum toxin (primary resistance), and a small percentage of adults develop secondary resistance after long-term treatment. Reasons for resistance include injection of incorrect muscles, unrealistic expectations of a complete cure, and interference from associated disorders that mask perception of response (Hyman, 2004). In 3% to 10% of adults, true secondary resistance arises due to the development of antibodies that specifically neutralize the activity of botulinum toxin (Hsiung, 2002; Mejia, 2005). That neutralizing antibodies directly cause resistance has been shown in a case study in which a patient with severe dystonia, secondary resistance, and detectable neutralizing antibodies was treated with repeated plasma exchange and depletion of serum antibodies; subsequent treatment with the same botulinum toxin type was successful (Naumann, 1998). Non-neutralizing antibodies may also develop in patients but have no effect on outcomes. The predisposing factors are not completely understood but include the use of higher doses, shorter intervals between repeat treatments, and younger age (Mahant, 2000). In 2 studies of pediatric patients treated for spasticity, neutralizing antibodies were detected in 28% to 32% of patients (Herrman, 2004; Koman, 2001). Recommendations for avoiding eventual resistance are using the lowest dose possible to obtain a clinical response and scheduling intervals of 10 to 12 weeks between injections, if possible.
 
Patients who develop secondary resistance to botulinum toxin type A may stop treatment for several months and then undergo retreatment with likely success; however, the duration of response is often short, because neutralizing antibodies may redevelop quickly (Sankhla, 1998). Alternatively, the patient may be administered botulinum toxin type B, with which neutralizing antibodies to toxin type A will not interfere. However, the duration of effect is shorter, and adverse effects have occurred at higher frequencies than for botulinum toxin type A (Mahant, 2000; Dutton,2006).
 
Confirmation of neutralizing antibodies to botulinum toxin type A in research studies (mice) has most often been accomplished using 2 techniques: (1) an injection of patient serum (Pearce, 1994) or (2) an in vitro toxin-neutralizing assay based on a mouse diaphragm nerve-muscle preparation (Goschel, 1997). While sensitive, neither assay is appropriate for a clinical laboratory setting. Other assay formats have been explored, such as immunoprecipitation, Western blot, and enzyme-linked immunosorbent assay. However, unless only the protein sequences that specifically react with neutralizing antibodies are employed, these formats detect both neutralizing and non-neutralizing antibodies (Herrmann, 2004; Cordivari, 2006; Hanna, 1998), and would therefore result in significant numbers of false-positive results. An option for some patients might be to inject toxin into the frontal muscle above 1 eyebrow; a toxin-responsive patient would have asymmetry of the forehead on attempted frowning, whereas a nonresponsive patient would not (Hanna, 1998).
 
REGULATORY STATUS
In 1991, Botox® (Allergan, Irvine, CA) was approved by FDA. In 2000, Myobloc® (Solstice Neurosciences [South San Francisco, CA]) was approved by FDA. In 2009, Dysport® (Medicis Pharmaceutical, now Ipsen Biopharm [Basking Ridge, NJ]) was approved by FDA. In 2010, Xeomin® (Merz Pharmaceuticals [Raleigh, NC]) was approved by FDA (FDA, 2009).
 
CODING
CPT has chemodenervation codes for neck, larynx, extremity, and trunk muscles:
 
64616: Chemodenervation of muscle(s); neck muscle(s), excluding muscles of the larynx, unilateral (eg, for cervical dystonia, spasmodic torticollis)
64617: larynx, unilateral, percutaneous (eg, for spasmodic dysphonia), includes guidance by needle electromyography when performed
64642: Chemodenervation of one extremity; 1-4 muscle(s)
64643: each additional extremity, 1-4 muscle(s) (List separately in addition to code for primary procedure)
64644: Chemodenervation of one extremity; 5 or more muscle(s)
64645: each additional extremity, 5 or more muscle(s) (List separately in addition to code for primary procedure)
64646: Chemodenervation of trunk muscle(s); 1-5 muscle(s)
64647: 6 or more muscle(s)
 
There are specific CPT codes for chemodenervation of the bladder and chemodenervation associated with the treatment of chronic migraine:
 
52287: Cystourethroscopy, with injection(s) for chemodenervation of the bladder
64615: Chemodenervation of muscle(s); muscle(s) innervated by facial, trigeminal, cervical spinal and accessory nerves, bilateral (eg, for chronic migraine)
 
There are specific CPT codes (43201, 43236) for upper gastrointestinal endoscopy procedures with submucosal injection, any substance. These codes could apply to the use of botulinum toxin for the treatment of achalasia.
 
CPT also has a code for chemodenervation of parotid and submandibular salivary glands such as that to treat sialorrhea:
 
64611: Chemodenervation of parotid and submandibular salivary glands, bilateral
 
If fewer than 4 salivary glands are injected, code 64611 is to be reported with a modifier -52 to signify reduced service.
 
The use of botulinum toxin for the treatment of hyperhidrosis is addressed in policy #2000034.

Policy/
Coverage:
Effective June 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Before consideration of coverage may be made, it should be established that the patient has been unresponsive to conventional methods of treatment, such as medication, physical therapy and other appropriate methods used to control and/or treat the specified covered condition(s).
  
There may be patients who require electromyography in order to determine the proper injection site(s).  CPT +95874 is the appropriate code for reporting electromyography in conjunction with chemodenervation.
 
The use of botulinum toxin meets primary coverage criteria for effectiveness and is covered for the following indications:
 
  • Cervical dystonia (spasmodic torticollis)
  • Cervical dystonia (spasmodic torticollis)
  • Spasticity:
      • in the flexor muscles of the elbow, wrists and fingers in adults
      • related to stroke or traumatic brain injury (in flexor muscles other than elbow, wrists and fingers in adults)
      • related to cerebral palsy (in flexor muscles other than elbow, wrists and fingers in adults)  
  • Spasticity of Lower Limbs in pediatric patients 2 years of age and older
  • Spastic hemiplegia
  • Facial nerve (VII) disorders
  • Idiopathic torsion dystonia
  • Symptomatic torsion dystonia
  • Spasmodic dysphonia
  • Organic writer’s cramp
  • Hereditary spastic paraplegia
  • Orofacial dyskinesis, Meige syndrome
  • Strabismus
  • Blepharospasm
  • Neuromyelitis optica
  • Multiple sclerosis or Schilder’s disease
  • Laryngeal spasm
  • Achalasia unresponsive to dilation therapy or who are poor surgical candidates
  • Chronic anal fissure
  • Incontinence related detrusor overactivity
  • Incontinence of neurogenic origin (spinal cord injury, multiple sclerosis) that is inadequately controlled with anticholinergic therapy
  • Prevention (treatment) of chronic migraine headache in the following situations:
      • Initial 6-month trial: Adult patients who:
          • meet International Headache Classification (ICHD-2) diagnostic criteria for chronic migraine headache (e.g. migraine headaches lasting at least 4 hours on at least 15 days per month; migraine headaches for at least 3 months); and
          • have symptoms that persist despite adequate trials of at least 2 agents from different classes of medications used in the treatment of chronic migraine headaches, (e.g. antidepressants, antihypertensives and antiepileptics).
      • Continuing treatment beyond 6-months:
          • Migraine headache frequency reduced by at least 7 days per month, (Represents a 50% reduction in migraine days) or
          • Migraine headache duration reduced at least 100 hours per month.
 
NOTE: The botulinum toxin preparations are not interchangeable. Dosing will vary according to the product used. The recommended dosage of onabotulinum toxin A (Botox) used in the treatment of chronic migraine is a maximum total dose of 155 Units, as 0.1 mL (5 Units) injections per each site divided across 7 head/neck muscles. The safety and efficacy are not established in patients under 18 years of age for the prophylaxis of headaches in chronic migraine.
 
Payment will be allowed for one injection per site regardless of the number of injections made into the site. A site is defined as including muscles of a single contiguous body part, such as, face, neck, etc.
 
Each Botulinum Toxin treatment cycle for chronic migraine headaches, will be separated by a minimum of 12 weeks.
 
Botulinum Toxin treatment cycle for other indications listed, will be separated by a minimum of 90 days.
 
Coverage of treatments provided may be continued unless any two consecutive treatments, utilizing an appropriate or maximum dose of Botulinum Toxin, failed to produce satisfactory clinical response.  Providers must also document the results of and the response to these injections after every third session.
 
Requests may be considered for continued treatment during a treatment period or for resumption at a later date if satisfactory results have not been obtained, if compelling clinical evidence of medical necessity is presented.
  
Payment will be allowed for one injection per site regardless of the number of injections made into the site. A site is defined as including muscles of a single contiguous body part, such as, face, neck, etc.
   
Documentation should include the following elements:
    • Support for the medical necessity of the injection;
    • A covered diagnosis;
    • A statement that traditional methods of treatments have been tried and proven unsuccessful;
    • Dosage and frequency of the injections;
    • Support of the clinical effectiveness of the injections;
    • Specify the site(s) injected.
 
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
   
The use of botulinum toxins for any indication not specifically listed as meeting primary coverage criteria above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. For contracts without primary coverage criteria, the use of botulinum toxins for any indication not specifically listed as meeting primary coverage criteria above is considered investigational.  Investigational services are specific contract exclusions in most member benefits certificates of coverage.
 
The use of botulinum toxin for the prevention of headaches that do not meet the above criteria, including but not limited to, the treatment of acute or episodic migraines does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. For contracts that do not have primary coverage criteria, the use of botulinum toxin for the prevention of headaches that do not meet the above criteria, including but not limited to, the treatment of acute or episodic migraines is considered investigational. Investigational services are contract exclusions in most member benefit certificates of coverage.
 
The use of botulinum toxin at a dose of greater than 155 units per injection or more frequent than every 12 weeks does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. For contracts that do not have primary coverage criteria, the use of botulinum toxin at a dose of greater than 155 units per injection or more frequent than every 12 weeks is considered investigational. Investigational services are contract exclusions in most member benefit certificates of coverage.
  
The use of botulinum toxin for cosmetic purposes is not covered.  Cosmetic services are a contract exclusion.
 
Effective Prior to June 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Before consideration of coverage may be made, it should be established that the patient has been unresponsive to conventional methods of treatment, such as medication, physical therapy and other appropriate methods used to control and/or treat the specified covered condition(s).
  
There may be patients who require electromyography in order to determine the proper injection site(s).  CPT +95874 is the appropriate code for reporting electromyography in conjunction with chemodenervation.
 
The use of botulinum toxin meets primary coverage criteria for effectiveness and is covered for the following indications:
 
        • Cervical dystonia (spasmodic torticollis)
        • Cervical dystonia (spasmodic torticollis)
        • Spasticity:
            • in the flexor muscles of the elbow, wrists and fingers in adults
            • related to stroke or traumatic brain injury (in flexor muscles other than elbow, wrists and fingers in adults)
            • related to cerebral palsy (in flexor muscles other than elbow, wrists and fingers in adults)  
        • Spastic hemiplegia
        • Facial nerve (VII) disorders
        • Idiopathic torsion dystonia
        • Symptomatic torsion dystonia
        • Spasmodic dysphonia
        • Organic writer’s cramp
        • Hereditary spastic paraplegia
        • Orofacial dyskinesis, Meige syndrome
        • Strabismus
        • Blepharospasm
        • Neuromyelitis optica
        • Multiple sclerosis or Schilder’s disease
        • Laryngeal spasm
        • Achalasia unresponsive to dilation therapy or who are poor surgical candidates
        • Chronic anal fissure
        • Incontinence related detrusor overactivity
        • Incontinence of neurogenic origin (spinal cord injury, multiple sclerosis) that is inadequately controlled with anticholinergic therapy
        • Prevention (treatment) of chronic migraine headache in the following situations:
            • Initial 6-month trial: Adult patients who:
                • meet International Headache Classification (ICHD-2) diagnostic criteria for chronic migraine headache (e.g. migraine headaches lasting at least 4 hours on at least 15 days per month; migraine headaches for at least 3 months); and
                • have symptoms that persist despite adequate trials of at least 2 agents from different classes of medications used in the treatment of chronic migraine headaches, (e.g. antidepressants, antihypertensives and antiepileptics).
            • Continuing treatment beyond 6-months:
                • Migraine headache frequency reduced by at least 7 days per month, (Represents a 50% reduction in migraine days) or
                • Migraine headache duration reduced at least 100 hours per month.
 
NOTE: The botulinum toxin preparations are not interchangeable. Dosing will vary according to the product used. The recommended dosage of onabotulinum toxin A (Botox) used in the treatment of chronic migraine is a maximum total dose of 155 Units, as 0.1 mL (5 Units) injections per each site divided across 7 head/neck muscles. The safety and efficacy are not established in patients under 18 years of age for the prophylaxis of headaches in chronic migraine.
 
Payment will be allowed for one injection per site regardless of the number of injections made into the site. A site is defined as including muscles of a single contiguous body part, such as, face, neck, etc.
 
Each Botulinum Toxin treatment cycle for chronic migraine headaches, will be separated by a minimum of 12 weeks.
 
Botulinum Toxin treatment cycle for other indications listed, will be separated by a minimum of 90 days.
 
Coverage of treatments provided may be continued unless any two consecutive treatments, utilizing an appropriate or maximum dose of Botulinum Toxin, failed to produce satisfactory clinical response.  Providers must also document the results of and the response to these injections after every third session.
 
Requests may be considered for continued treatment during a treatment period or for resumption at a later date if satisfactory results have not been obtained, if compelling clinical evidence of medical necessity is presented.
  
Payment will be allowed for one injection per site regardless of the number of injections made into the site. A site is defined as including muscles of a single contiguous body part, such as, face, neck, etc.
   
Documentation should include the following elements:
    • Support for the medical necessity of the injection;
    • A covered diagnosis;
    • A statement that traditional methods of treatments have been tried and proven unsuccessful;
    • Dosage and frequency of the injections;
    • Support of the clinical effectiveness of the injections;
    • Specify the site(s) injected.
 
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
   
The use of botulinum toxins for any indication not specifically listed as meeting primary coverage criteria above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. For contracts without primary coverage criteria, the use of botulinum toxins for any indication not specifically listed as meeting primary coverage criteria above is considered investigational.  Investigational services are specific contract exclusions in most member benefits certificates of coverage.
 
The use of botulinum toxin for the prevention of headaches that do not meet the above criteria, including but not limited to, the treatment of acute or episodic migraines does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. For contracts that do not have primary coverage criteria, the use of botulinum toxin for the prevention of headaches that do not meet the above criteria, including but not limited to, the treatment of acute or episodic migraines is considered investigational. Investigational services are contract exclusions in most member benefit certificates of coverage.
 
The use of botulinum toxin at a dose of greater than 155 units per injection or more frequent than every 12 weeks does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. For contracts that do not have primary coverage criteria, the use of botulinum toxin at a dose of greater than 155 units per injection or more frequent than every 12 weeks is considered investigational. Investigational services are contract exclusions in most member benefit certificates of coverage.
  
The use of botulinum toxin for cosmetic purposes is not covered.  Cosmetic services are a contract exclusion.

Rationale:
Due to the detail of the rationale, the complete document is not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com
 
This evidence review was created in July 1997 and has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through August 23, 2017. For studies published before 2000, it is assumed that botulinum toxin (Botox), the only Food and Drug Administration (FDA)‒approved agent at that time, was used.
 
Assessment of efficacy for therapeutic intervention involves a determination of whether an intervention improves health outcomes. The optimal study design for this purpose is a randomized controlled trial (RCT) that includes clinically relevant measures of health outcomes. Intermediate outcome measures, also known as surrogate outcome measures, may also be adequate if there is an established link between the intermediate outcome and true health outcomes. Nonrandomized comparative studies and uncontrolled studies can sometimes provide useful information on health outcomes, but are prone to biases such as noncomparability of treatment groups, placebo effect, and variable natural history of the condition.
 
DYSTONIA AND SPASTICITY
This evidence review section is based on a 1996 TEC Assessment (updated in 2004) that focused on the use of botulinum toxin for the treatment of focal dystonia or spasticity, the American Academy of Neurology (AAN) 2008 assessment of movement disorders and spasticity (Naumann, 2008; Simpson, 2008), and additional controlled trials and systematic reviews identified by MEDLINE literature searches.
 
The AAN assessment concluded that the evidence was AAN level A (established as effective, should be done) for equinus varus deformity in children with cerebral palsy and AAN level B (probably effective, should be considered) for upper extremity, for adductor spasticity, and for pain control in conjunction with adductor-lengthening surgery in children with cerebral palsy. The evidence was rated level B for treatment of adult spasticity in the upper- and lower-limb for reducing muscle tone and improving passive function, but insufficient evidence to recommend an optimum technique for muscle localization at the time of injection. The evidence was rated level B for upper-limb focal dystonia but insufficient for lower-limb focal dystonia, and was rated level B for adductor laryngeal dystonia but insufficient for abductor laryngeal dystonia (Simpson, 2008).
 
In a 2013 meta-analysis, Foley et al identified 16 RCTs comparing injection of botulinum toxin with placebo injections or a nonpharmacologic treatment of moderate-to-severe upper-extremity spasticity following stroke (Foley, 2013). Studies evaluated the impact of treatment on activity limitations. Ten trials (total N=1000 patients) had data suitable for pooling. In a pooled analysis of effect size, botulinum toxin was associated with a moderate treatment effect compared with other interventions (standardized mean difference [SMD], 0.54; 95% confidence interval [CI], 0.35 to 0.71; p<0.001). In another systematic review published in 2013, Baker et al pooled RCT data and found a statistically significant benefit of botulinum toxin type A for treating limb spasticity (Baker, 2013). Evidence was limited on botulinum toxin for spasticity-related pain.
 
A 2014 systematic review and meta-analysis by Marsh et al identified 18 studies evaluating botulinum toxin type A for treatment of cervical dystonia; five were RCTs, and the remainder were observational studies (Marsh, 2014). A pooled analysis found the mean duration of effect of botulinum toxin to be 93.2 days (95% CI, 91.8 to 94.6 days) using the fixed-effects model, and 95.2 days (95% CI, 88.9 to 101.4 days) using the random-effects model. Most studies included did not have control groups. A 2016 Cochrane systematic review and meta-analysis of 3 RCTs by Duarte compared botulinum toxin type A with botulinum toxin type B in cervical dystonia (Duarte, 2016). The primary efficacy outcome was improvement on any validated symptomatic rating scale, and the primary safety outcome was the proportion of participants with adverse events. All trials evaluated the effect of a single treatment session using multiple dosing regimens. Reviewers reported no difference between the 2 types of botulinum toxin in terms of overall efficacy or safety. A 2016 Cochrane systematic review and meta-analysis of 4 RCTs (total N=441 participants) by Marques et al compared botulinum toxin type B with placebo in cervical dystonia(Marques, 2016). The primary efficacy outcome was overall improvement on any validated symptomatic rating scale. All trials evaluated the effect of a single treatment session using doses between 2500 U and 10,000 U. Compared with placebo, botulinum toxin type B was associated with an improvement of 14.7% (95% CI, 9.8% to 19.5%) in the patients' baseline clinical status with a placebo-corrected reduction of 2.2 points (95% CI, 1.25 to 3.15 points) in the Toronto Western Spasmodic Torticollis Rating Scale at week 4 after injection.
 
A 2015 systematic review by Dashtipour et al identified 16 RCTs and noncomparative controlled studies evaluating abobotulinumtoxinA in adults with upper-limb spasticity due to stroke (Dashtipour, 2015). Total botulinum toxin dose ranged from 500 to 1500 U. Reviewers did not pool study findings, but they did report that most studies found a statistically significant benefit of botulinum toxin for functioning (as measured by the Modified Ashworth Scale).
 
A 2016 systematic review and meta-analysis by Baker and Pereira identified 25 RCTs that evaluated the efficacy of botulinum toxin type A for limb spasticity on improving activity restriction and quality of life (QOL) outcomes (Baker, 2016). Reviewers reported pooled analysis for 6 RCTs that included upper- and lower-limb trials but were unable to pool studies for QOL measures. Evidence quality for the upper-limb was low/very low. Pooled results showed a significant increase in active function with botulinum toxin type A at 4 to 12 weeks for the upper-limb (SMD=0.32; 95% CI, 0.01 to 0.62; p=0.04) and these effects were maintained for up to 6 months (mean difference [MD], 1.87; 95% CI, 0.53 to 3.21; p=0.006). Reviewers reported no conclusion for efficacy in lower-limb or for QOL measures in either limb. A 2017 systematic review and meta-analysis by Dong et al identified 22 RCTs (total N=1804 participants) that evaluated the efficacy of botulinum toxin type A for upper-limb spasticity after stroke or traumatic brain injury (Dong, 2017). Compared with placebo, botulinum toxin type A treatment resulted in decrease of muscle tone after week 4 (SMD = -0.98, 95% CI, -1.28 to -0.68; I2=66%, p=0.004), week 6 (SMD = -0.85, 95% CI, -1.11 to -0.59; I2=1.2%; p=0.409), week 8 (SMD = -0.87, 95% CI, -1.15 to -0.6; I2=0%, p=0.713), week 12 (SMD = -0.67, 95% CI, -0.88 to -0.46; I2=0%; p=0.896), and week 12 (SMD = -0.73; 95% CI, -1.21 to -0.24; I2=63.5%; p=0.065).
 
Three relatively large RCTs are discussed as follows. The first published in 2011 by Shaw et al, randomized 333 patients with poststroke upper-limb spasticity to physical therapy plus Dysport (n=170) or to physical therapy alone (n=163) (Shaw, 2011). The primary outcome, improved function at 1 month according to the Action Research Arm Test, did not differ significantly among groups. Improved function using Action Research Arm Test scores also did not differ significantly between groups at 3 or 12 months. Change in muscle tone, based on mean change in the Motor Assessment Scale score significantly favored the Dysport group (-0.6) over the placebo group (-0.1) at 1 month (p<0.001), but not at 3 and 12 months. The second double-blind RCT published in 2015 by Gracies at al assigned 243 adults with a stroke or brain trauma in the last 5 months to a single injection of abobotulinumtoxinA 500 U (n=81) or 1000 U (n=81) or placebo (n=81) (Gracies, 2015). The primary end point was the change in muscle tone in the primary target muscle group from baseline to 4 weeks as measured by Modified Ashworth Scale. At both doses, abobotulinumtoxinA resulted in greater tone reduction as evidenced by statistically significant reduction in placebo-corrected Ashworth Scale scores from baseline to week 4; abobotulinumtoxinA 500 U group (-0.9; 95% CI -1.2 to -0.6; p<0.001), and abobotulinumtoxinA 1000 U group (-1.1; 95% CI, -1.4 to -0.8; p<0.001 vs placebo). Authors recommended that future trials use active movement and function as primary outcome measures. The third RCT, published in 2016 by Wissel et al, assigned 273 poststroke adults to a 22- to 34-week treatment with onabotulinumtoxinA or placebo and subsequently open-label onabotulinumtoxinA up to 52 weeks (Wissel, 2016). End points included change in pain and responder analysis (defined as proportion of patients with baseline pain ≥4 achieving a ≥30% improvement in pain and a ≥50% improvement in pain interference with work at week 12). Mean pain reduction from baseline at week 12 was -0.77 (95% CI, -1.14 to -0.40) with onabotulinumtoxinA compared with -0.13 (95% CI, -0.51 to 0.24; p<0.05) with placebo. Respective proportion of responders was 53.7% and 37.0%. A European trial evaluated Xeomin for poststroke upper-limb spasticity. Kanovsky et al (2009) randomized 148 patients with poststroke upper-limb spasticity to botulinum toxin or placebo (Kanovsky, 2009). After 4 weeks, a significantly higher response rate was found in all treated flexor muscle groups among patients given Xeomin. The treatment benefit lasted through the week-12 visit. An open-label extension of this trial with 145 participants was published in 2011 (Kanovsky, 2011). Patients received up to 5 additional sets of Xeomin injections, with 12-week intervals between injections. A total of 111 (77%) patients had at least 3 injections, and 72 (50%) had 4 injections. Outcomes were assessed 4 weeks after each injection. Compared with baseline, patients consistently showed improved outcomes at each posttreatment visit. None of the patients developed neutralizing antibodies in the double-blind or extension phases of the study.
 
Most trials that established the efficacy of abobotulinumtoxinA in treating focal spasticity in patients with cerebral palsy were small. Delgado et al (2016) reported on a relatively larger RCT in which 249 cerebral palsy children with dynamic equinus foot deformity were randomized to abobotulinumtoxinA 10 or 15 U/kg per leg, or placebo (Delgado, 2016). The primary outcome measure was change in Modified Ashworth Scale score from baseline to week 4. Of the 246 patients randomized, 226 completed the trial and analysis included 235 (98%) patients. Results showed that both doses of abobotulinumtoxinA resulted in greater improvement in placebo-corrected Ashworth Scale scores (-0.49; 95% CI, -0.75 to -0.23; p<0.001; -0.38; (95% CI, -0.64 to -0.13; p=0.003 respectively).
 
Section Summary: Dystonia and Spasticity
Multiple RCTs and meta-analyses have supported the efficacy of botulinum toxin for treating dystonia and spasticity, which are FDA-labeled indications.
 
STRABISMUS
Strabismus is a condition in which the eyes are not in proper alignment. In 2012, a Cochrane review by Rowe and Noonan evaluated the literature on botulinum toxin for strabismus (Rowe, 2012). Reviewers identified 4 RCTs, all of which were published in the 1990s. Three trials compared botulinum toxin injection with surgery, and one compared botulinum toxin injection with a noninvasive treatment control group. Among the trials that used surgery as a comparator intervention, 2 studies found no statistically significant differences in outcomes between the 2 groups, and one found a higher rate of a satisfactory outcome in the surgery group (defined as <8 prism diopters). The study comparing botulinum toxin with no intervention did not find a significant difference in outcomes in the 2 groups. Complications after botulinum toxin included transient ptosis and vertical deviation; combined complication rates ranged from 24% to 56% in the studies.
 
For patients who failed prior surgery, Tejedor and Rodriguez conducted a trial in 1999 that included 55 children with strabismus who remained symptomatic after surgical alignment (Tejedor, 1999). Patients were randomized to a second surgery (28 patients) or botulinum toxin injection (n=27). Motor and sensory outcomes did not differ significantly in the 2 groups. For instance, at 3 years, 67.8% of children in the reoperation group and 59.2% of children in the botulinum toxin group were within 8 prism diopters of orthotropias (p=0.72). In 1994, Lee et al randomized 47 patients with acute unilateral sixth nerve palsy to botulinum toxin treatment or a no treatment control group Lee, 1994). The final recovery rate was 20 (80%) of 25 in the botulinum toxin group and 19 (86%) of 22 in the control group.
 
Section Summary: Strabismus
Several RCTs from the 1990s had mixed results on the efficacy of botulinum toxin for strabismus. This evidence has not established that botulinum toxin improves outcomes for patients with strabismus. However, treatment is a noninvasive alternative to surgery.
 
BLEPHAROSPASM
Blepharospasm is a progressive neurologic disorder characterized by involuntary contractions of the eyelid muscles; it is classified as a focal dystonia. RCTs have evaluated Botox, Dysport, and Xeomin for the treatment of blepharospasm and found these agents to be effective at improving symptoms(Jankovic, 2009; Nussgens, 1997; Roggenkamper, 2006). No RCTs evaluating Myobloc for treating blepharospasm were identified in literature searches. Dashtipour et al (2015) reported on the results of a systematic review that included 5 RCTs (374 with blepharospasm, 172 with hemifacial spasm) of abobotulinumtoxinA (Dashtipour, 2015). All trials showed statistically significant benefits for the treatment of blepharospasm and hemifacial spasm.
 
Section Summary: Blepharospasm
Multiple RCTs and a systematic review have found that botulinum toxin injection is an effective treatment of blepharospasm.
 
HEADACHE
Botulinum toxin for treatment of pain from migraine and from chronic tension-type headaches was addressed in a 2004 TEC Assessment. Both Assessments concluded that the evidence was insufficient for either indication. Because the placebo response rate is typically high in patients with headache, assessment of evidence focuses on randomized, placebo-controlled trials. More recent literature is discussed below, organized by type of headache. Recent studies have focused on frequency of headache as an outcome measure in addition to pain and headache severity.
 
Migraine Headache
Migraines can be categorized by headache frequency. According to the Third Edition of the International Headache Classification (ICHD-3), migraine without aura (previously known as common migraine) is defined as at least 5 attacks per month meeting other diagnostic criteria (Headache Classification Committee of the IHS, 2013). Chronic migraine is defined as attacks on at least 15 days per month for more than 3 months, with features of migraine on at least 8 days per month.
 
Several RCTs and systematic reviews of RCTs have been published. In 2013, the Agency for Healthcare Research and Quality published a comparative effectiveness review on preventive pharmacologic treatments for migraine in adults (Shamliyan, 2013). The investigators identified 15 double-blind RCTs evaluating botulinum toxin for migraine prevention: 13 used onabotulinumtoxinA and two used abobotulinumtoxinA. In a meta-analysis of 3 RCTs, onabotulinumtoxinA was more effective than placebo in reducing the number of chronic migraine episodes per month by at least 50% (relative risk [RR], 1.5; 95% CI, 1.2 to 1.8). In another pooled analysis, onabotulinumtoxinA was associated with a significantly higher rate of treatment discontinuation due to adverse effects than placebo (RR=3.2; 95% CI, 1.4 to 7.10). Five RCTs compared the efficacy of onabotulinumtoxinA with another medication (topiramate or divalproex sodium). Findings were not pooled, but, for the most part, there were no statistically significant differences in outcomes between the 2 drugs.
 
In 2012, Jackson et al conducted a meta-analysis of RCTs on botulinum toxin type A for the prophylactic treatment of headache in adults; the analysis addressed migraines and other types of headache (Jackson, 2012). Reviewers included RCTs that were at least 4 weeks in duration, had reduction in headache frequency or severity as an outcome, and used patient-reported outcomes. The investigators categorized eligibility criteria as addressing episodic (<15 headaches per month) or chronic headache (≥15 days per month). A total of 10 trials on episodic migraine and 7 trials on chronic migraine were identified. All trials on episodic migraine and 5 of 7 trials on chronic migraine were placebo-controlled; the other 2 trials compared botulinum toxin injections with oral medication. A pooled analysis for chronic migraine (5 trials) found a statistically significantly greater reduction in the frequency of headaches per month with botulinum toxin than with a control intervention (absolute difference, -2.30; 95% CI, -3.66 to -0.94). In contrast, in a pooled analysis on episodic migraine (9 trials), there was no statistically significant difference between groups in the change in monthly headache frequency (absolute difference, -0.05; 95% CI, -0.25 to 0.36).
 
Previously, in 2009, Shuhendler et al conducted a meta-analysis of trials on botulinum toxin for treating episodic migraines (Shuhendler, 2009). Reviewers identified 8 randomized, double-blind, placebo-controlled trials evaluating the efficacy of botulinum toxin type A injections. A pooled analysis of the main study findings found no significant differences between the botulinum toxin type A and placebo groups in change in the number of migraines per month. After 30 days of follow-up, the SMD was -0.06 (95% CI, -0.14 to 0.03; p=0.18). After 90 days, the SMD was -0.05 (95% CI, -0.13 to 0.04; p=0.28). A subgroup analysis examining trials using low-dose botulinum toxin type A (<100 U) compared with trials using high-dose botulinum toxin type A (≥100 U) did not find a statistically significant effect of botulinum toxin type A compared with placebo in either stratum.
 
A pair of multicenter RCTs that evaluated onabotulinumtoxinA (Botox) for chronic migraine was published in 2010. The trials reported findings from the double-blind portions of the industry-sponsored PREEMPT (Phase 2 Research Evaluating Migraine Prophylaxis Therapy) trials 1 and 2 (Aurora, 2010, Diener, 2010).  Trial designs were similar. Both included a 24-week double-blind, placebo-controlled phase prior to an open-label phase. The trials recruited patients meeting criteria for migraine and excluded those with complicated migraine. To be eligible, patients had to report at least 15 headache days during the 28-day baseline period, each headache lasting at least 4 hours. At least 50% of the headaches had to be definite or probable migraine. The investigators did not require that the frequent attacks occur for more than 3 months or exclude patients who overused pain medication, two of the ICHD-2 criteria for chronic migraine. Eligible patients were randomized to 2 cycles of Botox injections 155 U or placebo, with 12 weeks between cycles. Randomization was stratified by frequency of acute headache pain medication used during baseline and whether patients overused acute headache pain medication. (Medication overuse was defined as baseline intake of simple analgesics on at least 15 days, or other medications for at least 10 days, and medication use at least 2 days per week.)
 
The primary end point in PREEMPT 1 was mean change from baseline in frequency of headache episodes for 28 days ending with week 24. A headache episode was defined as a headache with a start and stop time indicating that pain lasted at least 4 hours. Prespecified secondary outcomes included, among others, change in frequency of headache days (calendar days in which pain lasted at least 4 hours), migraine days (calendar days in which a migraine lasted at least 4 hours), and migraine episodes (migraine with a start and stop time indicating that pain lasted at least 4 hours). Based on availability of data from PREEMPT 1 and other factors, the protocol of the PREEMPT 2 trial was amended (after study initiation but before unmasking) to make frequency of headache days the primary end point of this study. The authors noted that, to control for potential type I error related to changes to the outcome measures, a more conservative p-value (0.01) was used. Several QOL measures were also included in the trials, including the 6-item Headache Impact Test-6 (HIT-6) and the Migraine Specific Quality of Life Questionnaire (MSQ v.2). Key findings of the 2 studies are described below.
 
PREEMPT 1 randomized 679 patients (Aurora, 2010). Mean number of migraine days during baseline was 19.1 in each group. The mean number of headache episodes during the 28-day baseline period was 12.3 in the Botox group and 13.4 in the placebo group. Approximately 60% of patients had previously used at least 1 prophylactic medication and approximately 68% overused headache pain medication during baseline. A total of 296 (87%) of 341 patients in the Botox group and 295 (87%) of 338 patients in the placebo group completed the 24-week double-blind phase. The primary outcome (change from baseline in frequency of headache episodes over a 28-day period) did not differ significantly between groups. The number of headache episodes decreased by a mean of 5.2 in the Botox group and 5.3 in the placebo group (p=0.344). Similarly, the number of migraine episodes did not differ significantly. There was a decrease of 4.8 migraine episodes in the Botox group and of 4.9 in the placebo group (p=0.206). In contrast, there was a significantly greater decrease in the number of headache days and the number of migraine days in the Botox group than in the placebo group. The decrease in frequency of headache days was 7.8 in the Botox group and 6.4 in the placebo group, a difference of 1.4 headache days per 28 days (p=0.006). Corresponding numbers for migraine days were 7.6 and 6.1, respectively (p=0.002). There was significantly greater improvement in QOL in the Botox group vs the placebo group. The proportion of patients with severe impact of headaches (ie, HIT-6 score, ³60) in the Botox group decreased from 94% at baseline to 69% at 24 weeks; in the placebo group, it decreased from 95% at baseline to 80%, a between-group difference of 11% (p=0.001). The authors did not report MSQ scores, but stated that there was statistically significant greater improvement in the 3 MSQ role function domains at week 24 (restrictive, p<0.01; preventive, p=0.05; emotional, p<0.002). Adverse events were experienced by 203 (60%) patients in the Botox group and 156 (47%) patients in the placebo group. Eighteen (5%) patients in the Botox group and 8 (2%) in the placebo group experienced serious adverse events. Treatment-related adverse events were consistent with the known safety profile of Botox.
 
PREEMPT 2 randomized 705 patients (Diener, 2010). Mean number of migraine days during baseline period was 19.2 in the Botox group and 18.7 in the placebo group. Mean number of headache episodes during the 28-day baseline period was 12.0 in the Botox group and 12.7 in the placebo group. Approximately 65% of patients had previously used at least 1 prophylactic medication and approximately 63% overused headache pain medication during baseline. A total of 311 (90%) of 347 patients in the Botox group and 334 (93%) of 358 patients in the placebo group completed the 24-week, double-blind phase. The primary outcome, change from baseline frequency of headache days over a 28-day period (a different primary outcome from PREEMPT 1), differed significantly between groups and favored Botox treatment. The number of headache days decreased by a mean of 9.0 in the Botox group and 6.7 in the placebo group, an absolute difference of 2.3 days per 28 days (p<0.001). Mean number of migraine days also decreased significantly, more in the Botox group (8.7) than in the placebo group (6.3; p<0.001). Unlike PREEMPT 1, there was a significantly greater decrease in headache episodes in PREEMPT 2 in the Botox group (5.3) than in the placebo group (4.6; p=0.003). Change in frequency of migraine episodes was not reported.
 
Similar to PREEMPT 1, QOL measures significantly improved in the Botox group. The proportion of patients reporting that their headaches had a severe impact (score of at least 60 on the HIT-6) severe impact of headaches in the Botox group decreased from 93% at baseline to 66% at 24 weeks; in the placebo group, it decreased from 91% at baseline to 77%. There was a between-group difference of 10% (p=0.003). The authors reported statistically significantly greater improvement in the 3 MSQ role function domains at week 24 (restrictive, preventive, emotional, p<0.001 for each domain). Adverse events were experienced by 226 (65%) patients in the Botox group and 202 (56%) patients in the placebo group. Fifteen (4%) patients in the Botox group and 8 (2%) in the placebo group experienced serious adverse events. As in PREEMPT 1, treatment-related adverse events in PREEMPT 2 were consistent with the known safety profile of Botox.
 
Also published in 2010 was a pooled analysis of findings from the PREEMPT 1 and 2 trials; this analysis was also industry-sponsored (Dodick, 2010). There were 688 patients in the Botox group and 696 in the placebo group in the pooled analysis of outcomes at week 24. In the combined analyses, there was a significantly greater reduction in change from baseline in frequency of headache days, migraine days, headache episodes, and migraine episodes in the Botox group than in the placebo group. For example, the pooled change in mean frequency of headache days was 8.4 in the Botox group and 6.6 in the placebo group (p<0.001). Mean difference in number of headache days over a 28-day data collection period was 1.8 (95% CI, 1.13 to 2.52). The pooled change in frequency of headache episodes was 5.2 in the Botox group and 4.9 in the placebo group, a relative difference of 0.3 episodes (95% CI, 0.17 to 1.17; p=0.009). Between-group differences, though statistically significant, were relatively small and may not be clinically meaningful. In the pooled analysis, the authors also reported the proportion of patients with at least a 50% decrease from baseline in the frequency of headache days at each time point (every 4 weeks from week 4 to week 24). For example, at week 24, the proportion of participants with at least a 50% reduction in headache days was 47.1% in the Botox group and 35.1% in the placebo group. In contrast, the difference in the proportion of patients experiencing at least a 50% reduction in headache episodes did not differ significantly between groups at 24 weeks or at most other time points, with the exception of week 8. The article did not report the proportion of participants who experienced at least a 50% reduction in migraine days or migraine episodes. The pooled analysis showed statistically significant differences for the change in proportion of patients with severe headache impact as assessed using the HIT-6 and change in MSQ domains.
 
Several issues are worth noting about the methods and findings of the PREEMPT studies. There was a statistically significant difference in headache episodes in PREEMPT 2 but not PREEMPT 1 (for which it was the primary outcome); the primary outcome was changed after initiation of PREEMPT 1. Moreover, one of the main secondary outcomes in PREEMPT 1 (change in the number of migraine episodes) was not reported in the second trial; the authors did not discuss this omission. In addition, the individual studies did not include threshold response to treatment (eg, at least a 50% reduction in headache or migraine frequency) as a key outcome. The pooled analysis did report response rates, but as secondary efficacy outcomes.
 
Most patients in both trials fulfilled criteria for medication overuse headache, and therefore many may have been experiencing secondary headaches rather than chronic migraines. If patients had secondary headaches, detoxification alone might have been sufficient to change their headache pattern to an episodic one. The clinical relevance of less than a 2-day difference in reduction in number of headache days is uncertain, though consistent with reductions previously reported in several medication trials.
 
Another RCT assessed use of botulinum toxin for treating chronic migraine was published by Cady et al (2011) (Cady, 2011). The trial included patients who met ICHD-2 criteria for chronic migraine. Patients were randomized to receive treatment with Botox (n=29) or topiramate (n=30). At the 12-week follow-up, the end of the double-blind phase of the study, treatment effectiveness did not differ significantly between groups. For the primary end point (Physician Global Assessment at week 12), physicians noted improvement in 19 (79%) of 24 patients in the Botox group and 17 (71%) of 24 patients in the topiramate group; 9 patients (15%) were not available for this analysis.
 
Medication Overuse Headache
According to the ICHD-2, medication overuse headache is a different diagnostic classification than chronic migraine (Silberstein, 2005). In 2013, Silberstein et al published a subanalysis of pooled PREEMPT data limited to patients with headache medication overuse at baseline (Dilberstein, 2013). A total of 904 patients who indicated they had medication overuse headache were included; 445 were randomized to the botulinum toxin group and 459 to the placebo group. At the end of week 24, there was a significantly greater reduction in outcomes, including headache days, headache episodes, and moderate-to-severe headache days, in the botulinum toxin group than in the placebo group. For example, the number of headache days per month decreased by a mean of 8.2 in the botulinum toxin group and 6.2 in the placebo group (p<0.001). This is a single analysis of RCT data and provides insufficient evidence that botulinum toxin is effective for patients with the diagnosis of medication overuse headache.
 
Tension Headache
The 2012 meta-analysis by Jackson et al (discussed above) identified 7 RCTs evaluating botulinum toxin for treating chronic tension-type headaches; all were placebo-controlled (Jackson, 2012). A pooled analysis of these 7 studies did not find a statistically significant difference in change in the monthly number of headache days in the botulinum toxin group vs the placebo group (difference, -1.43; 95% CI, -3.13 to 0.27). The trial with the largest sample size (Silberstein et al, 2006) included 300 patients randomized to 1 of 4 doses of botulinum toxin or placebo. Overall, there was no statistically significant difference between the botulinum toxin groups and the placebo group in mean change from baseline to 90 days in number of headache days per month.
 
Chronic Daily Headache
Although chronic daily headache is not recognized in the ICHD, it is commonly defined to include different kinds of chronic headache (eg, chronic or transformed migraine, daily persistent headache). It may also include chronic tension-type headache, addressed above. The 2102 meta-analysis by Jackson identified 3 RCTs comparing botulinum toxin type A with placebo in patients having at least 15 headaches per month (Jackson, 2012). A pooled analysis of data from these 3 trials found a significantly greater reduction in the number of headaches per month with botulinum toxin than with placebo (absolute difference, -2.06; 95% CI, -3.56 to -0.56). Individually, only 1 (Ondo et al, 2004) of the 3 trials found a statistically significant benefit with botulinum toxin treatment. Ondo included 60 patients, some with chronic migraines and chronic tension-type headache. The Ondo study found significantly greater reduction in the number of headache-free days over weeks 8 to 12 with botulinum toxin than with placebo (p<0.05), but there was no statistically significant between-group difference in reduction in headache-free days over the entire 12-week study period (p=0.07). The other 2 studies evaluated more patients: 355 in Mathew et al (2005) and 702 in Silberstein et al (2005). Neither found a statistically significant difference in the reduction in the number of headache days per month with botulinum toxin. The available evidence from RCTs is conflicting and insufficient for conclusions.
 
Cluster Headache
No controlled trials were identified for cluster headache.
 
Cervicogenic Headache
In 2011, Linde et al published a double-blind, placebo-controlled crossover study that included 28 patients with treatment-resistant cervicogenic headache (Linde, 2011). Patients were randomized to botulinum toxin type A or placebo; there was at least an 8-week period between treatments. The trial did not find significant differences between active and placebo treatment in the primary outcome, reduction in the number of days with moderate-to-severe headache. Three other RCTs, published between 2000 and 2008, randomized patients with chronic, whiplash-related headache to botulinum toxin type A treatment or placebo (Braker, 2008; Freund, 2000; Padberg, 2007). One trial reported trends toward improvement with treatment for various outcomes; most were not statistically significant (Braker, 2008). Another reported no significant differences for several pain-related outcomes (Padberg, 2007). One trial reported a significant improvement in pain with treatment while the placebo group reported no improvement, but trial design was flawed because the placebo group reported less pain at baseline (Freund, 2000), A Cochrane review of treatment of mechanical neck disorders, published in 2007, included 6 RCTs (total N=273 patients) assessing botulinum toxin and placebo for chronic neck disorders with or without radicular findings or headache (Peloso, 2007). A meta-analysis of 4 studies (n=139 patients) for pain outcomes found no statistically significant results. Reviewers concluded that a range of doses did not show significant differences compared with placebo or other comparators.
 
Section Summary: Headache
For chronic migraine, a meta-analysis of RCTs found that onabotulinumtoxinA was more effective than placebo in reducing the number of chronic migraine episodes per month, although it was also associated with a significantly higher rate of treatment discontinuation due to adverse events than placebo. For patients with an episodic pattern of migraine (ie, <15 episodes per month), the published evidence does not suggest that botulinum toxin improves net health outcome for patients. For tension headache, RCTs and systematic reviews do not indicate that botulinum toxin improves outcomes. For other headache types, the evidence is inconclusive to confirm efficacy.
 
ESOPHAGEAL ACHALASIA
Esophageal achalasia is a primary motor disorder characterized by abnormal lower esophageal sphincter relaxation. A 2014 Cochrane review by Leyden et al identified 7 RCTs (total N=178 participants) on treatment of primary esophageal achalasia with botulinum toxin or endoscopic pneumatic dilation (Leyden, 2014). A pooled analysis of data from 5 trials did not find a statistically significant difference in the rate of initial remission with pneumatic dilation vs botulinum toxin injection (RR=1.11; 95% CI, 0.97 to 1.27). Remission at 6 and 12 months favored the pneumatic dilation group. No serious adverse events were reported after botulinum toxin injection; however, there were 3 cases of perforation after pneumatic dilation.
 
Section Summary: Esophageal Achalasia
A systematic review of RCTs reported similar initial remission rates of esophageal achalasia after botulinum toxin injection and pneumatic dilation. Pneumatic dilation was associated with higher longer term remission rates but is more invasive, and perforation has been reported.
 
SIALORRHEA
 
Sialorrhea (Drooling) Associated With Parkinson Disease
Several RCTs have evaluated botulinum toxin injections in patients with Parkinson disease. For example, in 2006, Lagalla et al randomized 32 patients with Parkinson disease to placebo or botulinum toxin type A; evaluation at 1 month postinjection resulted in significant improvements compared with placebo in drooling frequency, saliva output, and familial and social embarrassment (Lagalla, 2006). Dysphagia scores were not significantly improved. Moreover, Ondo et al (2004) randomized 16 patients with Parkinson disease to botulinum toxin type B or placebo (Ondo, 2004). The botulinum toxin group had significantly better outcomes than the placebo group at 1 month on 4 drooling outcomes. Groups did not differ on salivary gland imaging or on a dysphagia scale. Mancini et al (2003) assigned 20 patients with Parkinson disease to injections of either a saline placebo or botulinum toxin type A (Mancini, 2003). The treatment group had significantly better outcomes than the placebo group on a drooling scale at 1 week; the effect disappeared by 3 months.
 
Section Summary: Sialorrhea (Drooling) Associated With Parkinson Disease
RCTs have consistently found benefit of botulinum toxin injection on sialorrhea in patients with Parkinson disease.
 
Sialorrhea (Drooling) Not Associated With Parkinson Disease
Several systematic reviews have evaluated botulinum toxin for treating sialorrhea in people with conditions other than Parkinson disease. In 2014, Squires et al reviewed the research on botulinum toxin injections for drooling in patients with amyotrophic lateral sclerosis/motor neuron disease (Squires, 2014). Reviewers included RCTs and controlled and uncontrolled observational studies. They identified 12 studies, of which 8 had no control groups. There were 2 small RCTs, each with fewer than 20 patients. Sample sizes in the non-RCTs ranged from 5 to 26 patients. Due to heterogeneity, study findings were not pooled. Only one of the 2 RCTs reported drooling outcomes; it found a significantly greater reduction in saliva volume with botulinum toxin than with placebo at 2 weeks.
 
In 2012, Rodwell et al published a systematic review evaluating botulinum toxin injections in the salivary gland to treat sialorrhea in children with cerebral palsy and neurodevelopment disability (Rodwell, 2012). Reviewers identified 5 RCTs; sample sizes in individual trials ranged from 6 to 48 participants. One of the RCTs (N=6) was terminated due to adverse events. In a pooled analysis of data 4 weeks postintervention in 3 RCTs, the mean score on the Drooling Frequency and Severity Scale was significantly lower in children who received botulinum toxin injections than a control intervention (MD = -2.71 points; 95% CI, -4.82 to -0.60; p<0.001). The clinical significance of this difference in Drooling Frequency and Severity Scale scores is not clear. Data were not pooled for other outcomes. The systematic review also identified 11 prospective case series. The rate of adverse events associated with botulinum toxin injection in the RCTs and case series ranged from 2% to 41%. Dysphagia occurred in 2 (33%) of the 6 participants in an RCT terminated early and in 2 (2%) of 126 patients in a case series. There was 1 reported chest infection, 1 case of aspiration pneumonia, and, in 1 case series, 6 (5%) of 126 patients experienced an increased frequency of pulmonary infections. In 7 studies, there were reports of patients with difficulty swallowing and/or chewing following botulinum toxin treatment.
 
The largest RCT on botulinum toxin for treating sialorrhea in children with cerebral palsy was published in 2008 by Reid et al (Reid, 2008). Forty-eight children with cerebral palsy (n=31) and other neurologic disorders (n=17) were randomized to a single injection of botulinum toxin type A 25 U compared with no treatment. Drooling was assessed by using the Drooling Impact Scale. Scores differed significantly between groups at 1 month, and a beneficial effect of botulinum toxin injection remained at 6 months. Gonzalez et al (2017) reported the results of an RCT in which 40 adults with cerebral palsy were randomized to onabotulinumtoxinA or observation (Gonzalez, 2017). The trial had greater than 80% power to detect a 39% difference in the proportion of patients who achieve at least a 50% reduction in drooling quotient. The primary efficacy outcome was drooling quotient. This quotient, measured as a proportion, is a semi-quantitative method that assesses the presence of newly formed saliva on the lips every 15 seconds with 40 observations in 10 minutes, expressed as a percentage based on the ratio between the number of observed drooling episodes and the total number of observations. The proportion of patients who achieved at least a 50% reduction in drooling quotient in the treated group vs control after 8 weeks and 80 weeks was 45% vs 0.0% (p=0.001) and 20% vs 0% (p=0.106). While the treatment effect was large, the trial did not use a placebo group and was unblinded.
 
A 2013 retrospective review focused on the long-term safety of botulinum toxin type A injection for treating sialorrhea in children (Chan, 2013). Reviewers included 69 children; 47 (68%) had cerebral palsy. Children received their first injection of botulinum toxin type A at a mean age of 9.9 years; mean follow-up was 3.1 years. During the study period, the children received a total of 120 botulinum toxin injections. Complications occurred in 19 (28%) of 69 children and in 23 (19%) of 120 injections. Fifteen of 23 complications were minor, including 6 cases of dysphagia. There were 8 major complications: 3 cases of aspiration pneumonia, 2 cases of severe dysphagia, and 3 cases of loss of motor control of the head. Complications were associated with 5 hospitalizations and 2 cases of nasogastric tube placement.
 
Section Summary: Sialorrhea (Drooling) Not Associated With Parkinson Disease
Although there is evidence of improvement in drooling scales following botulinum toxin injections in children with cerebral palsy, the clinical significance is uncertain, and there are concerns about the safety of injecting botulinum toxin into the salivary gland in this population. The evidence on botulinum toxin for treating sialorrhea in patients with amyotrophic lateral sclerosis/motor neuron disease is inconclusive due to the paucity of controlled studies, small sample sizes of available studies, and limited reporting of drooling outcomes.
 
ANAL APPLICATIONS
 
Internal Anal Sphincter Achalasia
Internal anal sphincter (IAS) achalasia is a defecation disorder in which the internal anal sphincter is unable to relax. Symptoms include severe constipation and soiling. A meta-analysis of studies on treatment of IAS achalasia was published in 2012 by Friedmacher and Puri (Friedmacher, 2012). Reviewers did not identify any RCTs of Botox treatment. Two prospective case series and 14 retrospective case series (total N=395 patients) of IAS achalasia were identified. Most patients (229/395 [58%]) in the series were treated with posterior IAS myectomy and 166 (42%) were treated with intrasphincteric botulinum toxin injection. A meta-analysis of data from the observational studies found that regular bowel movements were more frequent after myectomy (odds ratio [OR], 0.53; 95% CI, 0.29 to 0.99; p=0.04). Moreover, the rate of transient fecal incontinence was significantly higher after botulinum toxin injection (OR=0.07; 95% CI, 0.01 to 0.54; p<0.01) and the rate of subsequent surgical intervention was higher after botulinum toxin injection (OR=0.18; 95% CI, 0.07 to 0.44; p<0.001). Other outcomes, including continued use of laxatives or rectal enemas and overall complication rates, did not differ between treatments. Emile et al (2016) reported the results of a systematic review that included 7 studies comprising 189 patients with a follow-up period greater than 6 months in each of the individual studies (Emile, 2016). Of the 7 included studies, 2 were RCTs and remaining were comparative and observational studies. Both RCTs were single site from the same author group and conducted in Egypt, enrolling 15 and 24 patients, respectively (Farid, 2009; Farid, 2009). Improvement was defined as patients returning to their normal habits. The first RCT used biofeedback and the other used surgery as the comparator. In the first RCT, 50% of individuals in the biofeedback group reported improvement initially at 1 month but it dropped down to 25% by the end of year. The respective proportions of patients in the botulinum toxin arm were 70.8% and 33.3%. In the second RCT, surgery led to improved outcomes in all patients at 1 month but that percentage dropped to 66.6% at 1 year. The respective proportions of patients in the botulinum toxin arm were 87% and 40%. While these results suggest temporary improvement, methodologic limitations, including small sample size, lack of blinded assessment, and use of validated outcome measure, limit the interpretation of these RCTs.
 
Section Summary: Internal Anal Sphincter Achalasia
There is a lack of good quality RCTs evaluating botulinum toxin injection as a treatment of IAS achalasia. A meta-analysis of observational data and a systematic review suggested that posterior IAS myectomy results in greater improvement in health outcomes than botulinum toxin injections.
 
Anal Fissure
Chronic anal fissure is a tear in the lower half of the anal canal that is maintained by contraction of the IAS and is treated surgically with an internal sphincterotomy. Because the anal sphincter contraction could be characterized as a dystonia, botulinum toxin is a logical medical approach.
 
In 1998, Maria et al randomized 30 patients with chronic anal fissure to 2 injections of botulinum toxin type A, on either side of the fissure, or 2 injections of saline (Maria, 1998). After 2 months, 11 (73%) patients in the treated group and 2 (13%) patients in the control group had healed fissures (p=0.003); 13 (87%) patients in the treated group and 4 (26%) in the control group had symptomatic relief (p=0.003). Four patients in the treated group were later retreated. No relapses occurred during an average of 16 months of follow-up. Nitroglycerin ointment has also been used to successfully treat anal fissure. In 1999, Brisinda et al in Italy compared the results of nitroglycerin ointment with botulinum toxin type A in a randomized trial of 50 patients (Brisinda, 1999). After 2 months, 96% of the fissures were healed in the botulinum group compared with 60% in the nitroglycerin group. Brisinda et al conducted a second, similar trial in 2007 and reported 92% healing rates for botulinum toxin type A and 70% for nitroglycerin ointment (p<0.001) (Brisinda, 2007). Another trial by Brisinda et al (2004) found that 2 botulinum type A formulations (onabotulinumtoxinA, abobotulinumtoxinA) used to treat anal fissures were similar in terms of efficacy and tolerability (Brisinda, 2004). Others have reported both supportive (De Nardi, 2006) and contradictory (Fruehauf, 2006) data from randomized trials comparing the same treatments. RCTs of botulinum toxin vs sphincterotomy, and a meta-analysis of these studies, have reported significantly better healing rates with sphincterotomy, but authors concluded that botulinum toxin was a viable first option for patients who are not good surgical candidates or who want to minimize the likelihood of incontinence (Iswariah, 2005; Nasr, 2010, Chen, 2014).
 
A 2012 systematic review identified 2 RCTs comparing botulinum toxin with placebo, 1 RCT comparing botulinum toxin with lidocaine pomme, 5 RCTs comparing botulinum toxin with nitrates, and 8 RCTs comparing botulinum toxin with surgery (Yiannakopoulou, 2012). A meta-analysis was not performed due to heterogeneity among studies. The author noted that the studies tended to be small and of short duration, and that superiority of botulinum toxin over surgery had not been demonstrated. However, because this minimally invasive option can be repeated, it is a reasonable option prior to surgery.
 
Section Summary: Anal Fissure
There is evidence on botulinum toxin for treatment of anal fissure from numerous small RCTs. Botulinum toxin has not been found to have better outcomes than surgery, but studies have found that healing rates after botulinum toxin are reasonably high and that it is a less invasive than surgery.
 
UROLOGIC APPLICATIONS
 
Overactive Bladder and Neurogenic Detrusor Overactivity
Several meta-analyses of RCTs have been published on overactive bladder and neurogenic detrusor overactivity (Cui, 2013; Cui 2015; Duthie, 2011). Drake et al (2017) reported on the results of a network meta-analysis of 56 RCTs that compared the efficacy of onabotulinumtoxinA, mirabegron, and anticholinergics in adults with idiopathic overactive bladder (Drake, 2017). While all treatments were more efficacious than placebo after 12 weeks, patients who received onabotulinumtoxinA (100 U) reported the greatest reductions in urinary incontinence episodes, urgency episodes, and micturition frequency, and the highest odds of achieving decreases of 100% and 50% or greater from baseline in urinary incontinence episodes per day. The exclusion of studies with a high risk of bias had little impact on the conclusions. Freemantle et al (2016) also reported on the results of a network meta-analysis of 19 RCTs comparing any licensed dose of onabotulinumtoxinA, mirabegron, anticholinergic drugs, or placebo (Freemantle, 2016). Both onabotulinumtoxinA and mirabegron were more efficacious than placebo at reducing the frequency of urinary incontinence, urgency, urination, and nocturia. OnabotulinumtoxinA was more efficacious than mirabegron (50 mg and 25 mg) in completely resolving daily episodes of urinary incontinence and urgency and in reducing the frequency of urinary incontinence, urgency, and urination.
 
A 2016 network meta-analysis by Cheng et al assessed a total of 1915 patients with neurogenic detrusor overactivity from 6 RCTs (Cheng, 2016). Using the mean number of urinary incontinence episodes per week as the primary outcome measure, reviewers reported that treatment with onabotulinumtoxinA 200 U and 300 U compared with placebo reduced the mean number of urinary incontinence episodes at week 6 by 10.72 (95% CI, -13.4 to -8.04; p<0.001) and -11.42 (95% CI, -13.91 to -8.93; p<0.001), respectively. Treatment with onabotulinumtoxinA was associated greater frequency of urinary tract infections (RR=1.47; 95% CI, 1.29 to 1.67; p<0.001), urinary retention (RR=5.58, 95% CI, 3.53 to 8.83; p<0.001), hematuria (RR=1.70; 95% CI, 1.01 to 2.85; p=0.05), and muscle weakness (RR=2.59; 95% CI, 1.36 to 4.91; p=0.004).
 
In 2015, Cui et al identified 6 double-blind RCTs comparing botulinum toxin type A with placebo for treating patients with idiopathic overactive bladder (Cui, 2015). In a pooled analysis of 3 studies, patients treated with botulinum toxin were significantly more likely to be incontinence-free at the end of the study (OR=4.89; 95% CI, 3.11 to 7.70). Moreover, a pooled analysis of 5 studies found significantly greater reduction in the number of incontinence episodes per day in the group treated with botulinum toxin (SMD = -1.68; 95% CI, -2.06 to -1.31). Previously, in 2011, Duthie et al published a Cochrane review of RCTs evaluating botulinum toxin injections for patients with idiopathic or neurogenic overactive bladder (Duthie, 2011). Reviewers identified 19 trials that compared treatment using botulinum toxin with placebo or another intervention. Two studies included botulinum toxin type B; the remainder included botulinum toxin type A. Outcomes varied, which made it difficult to pool trial findings. A pooled analysis of 3 trials found change in urinary frequency episodes at 4 to 6 weeks reported a significantly better outcome with botulinum toxin injection than with placebo (pooled MD = -6.50; 95% CI, -8.92 to -4.07). A pooled analysis of 3 trials on change in incontinence episodes at 4 to 6 weeks also found a significantly greater improvement with botulinum toxin (MD = -1.58; 95% CI, -2.16 to -1.01).
 
Other systematic reviews have included both controlled and uncontrolled studies. A 2013 systematic review by Soljanik identified 28 studies evaluating onabotulinumtoxinA for the treatment of neurogenic detrusor overactivity or neurogenic overactive bladder; 6 studies were RCTs (Soljanki, 2013). The reviewer reported that studies with comparative data found superior outcomes with onabotulinumtoxinA compared with placebo. Data from the RCTs were not pooled. Serious adverse events were not reported. However, adverse events after intradetrusor botulinum toxin injection included postvoid residual urine (50%), urinary retention (23.7%), and urinary tract infection (UTI; 16.7%). Also in 2013, Mehta et al identified 14 studies evaluating botulinum toxin type A for treating neurogenic detrusor overactivity after spinal cord injury; only one was an RCT (Mehta, 2013). Studies tended to have large effect sizes (>0.8) for outcomes including bladder capacity and reflex detrusor volume. Rates of incontinence episodes decreased after treatment with botulinum toxin type A from 23% to 1.3% per day. Previously in 2008, Karsenty et al identified 18 studies evaluating botulinum toxin type A to treat patients who were refractory to anticholinergics (Karsenty, 2008). Most studies reported statistically significant improvements in clinical and urodynamic outcomes, without major adverse events.
 
Representative large, double-blind RCTs are described below.
 
Nitti et al (2017) reported the results of open-label RCT in which 557 patients with overactive bladder, 3 or more urgency urinary incontinence episodes in 3 days, and 8 or more micturitions per day inadequately managed with anticholinergics were randomized to onabotulinumtoxinA 100 U or placebo (Nitti, 2017). Coprimary end points were the change from baseline in the number of urinary incontinence episodes per day and the proportion of patients with a positive response on the treatment benefit scale at posttreatment week 12. OnabotulinumtoxinA significantly decreased the daily frequency of urinary incontinence episodes vs placebo (-2.65 vs -0.87, p<0.001) and 22.9% vs 6.5% of patients became completely continent. A larger proportion of onabotulinumtoxinA than placebo-treated patients reported a positive response on the Treatment Benefit Scale (60.8% vs 29.2%, p<0.001). Uncomplicated UTI was the most common adverse event.
 
Amundsen et al (2016) reported the findings of a multicenter open-label RCT that assigned 381 women with refractory urgency urinary incontinence to cystoscopic intradetrusor injection of onabotulinumtoxinA (n=192) or sacral neuromodulation (n=189) (Amundsen, 2016). The primary outcome measure was change in the mean number of daily urgency urinary incontinence episodes from baseline to 6 months as measured with monthly 3-day diaries. Per protocol, analysis of data from 364 women showed that onabotulinumtoxinA group had statistically significant greater reduction in the primary outcome compared with sacral neuromodulation group (-3.9 vs -3.3 episodes per day, p=0.01). However, the mean difference of 0.63 (95% CI, 0.13 to 1.14) was of uncertain clinical importance. Additionally, urinary tract infections (35% vs 11%; risk difference, -23%; 95% CI, -33% to -13%; p<0.001, respectively) and need for transient self-catheterization (8% and 2% at 1 and 6 months in the onabotulinumtoxinA group) were higher in the onabotulinumtoxinA group vs sacral neuromodulation group.
 
In 2013, Nitti et al published data from an industry-supported study that included 557 patients with overactive bladder and urinary incontinence inadequately controlled by anticholinergics (Nitti, 2013). Patients were randomized to an intradetrusor injection of onabotulinumtoxinA 100 U or placebo. At the 12-week follow-up, there was a statistically significantly greater improvement in the daily frequency of urinary incontinence episodes in the group that received botulinum toxin (-2.65) than in the placebo group (0.87; p<0.001). The other primary end point was the proportion of patients with a positive response at week 12 using the Treatment Benefit Scale. A significantly larger proportion of patients in the botulinum toxin group than in the placebo group reported a treatment benefit (60.8% vs 29.2%, p<0.001). A total of 22.9% of patients in the botulinum toxin group and 6.5% of patients in the placebo group became completely continent. In the first 12 weeks after injection, UTIs occurred in 43 (15.5%) of 278 patients in the botulinum toxin group and 16 (5.9%) of 272 patients in the placebo group. Urinary retention was reported by 15 (5.4%) patients in the botulinum toxin group and 1 (0.4%) patient in the placebo group. Between-group p values were not reported for adverse events. A 2014 prespecified subanalysis of data from this RCT and another placebo-controlled trial (Chapple et al, 2013) evaluated the efficacy of onabotulinumtoxinA by number of anticholinergic therapies used (Sievert, 2014). Patients had used a mean of 2.4 anticholinergic therapies before enrolling in the study. At week 12, reduction in the daily number of urinary incontinence episodes was significantly lower in the onabotulinumtoxinA group than in the control group, whether or not 1, 2, 3, or more prior anticholinergics had been used. Mean reduction in daily incontinence episodes for patients with 1 prior anticholinergic was 2.82 in the onabotulinumtoxinA group and 1.52 in the placebo group (p<0.001); with 3 or more prior anticholinergics, it was 2.92 and 0.73, respectively (p<0.001).
 
A 2012 industry-supported RCT by Ginsberg et al included 416 patients with neurogenic detrusor activity associated with multiple sclerosis or spinal cord injury(Ginsberg, 2012). Patients were randomized to injections with onabotulinumtoxinA 200 U, onabotulinumtoxinA 300 U, or placebo. Decrease in the mean number of weekly incontinence episodes at week 6, the primary end point, was significantly greater in both active treatment groups (-21 in the 200-U group, -23 in the 300-U group) than in the placebo group (-9; p<0.001). Urinary retention was a common adverse event. Among patients who did not catheterize at baseline, 35% in the 200-U group, 42% were in the 300-U group, and 10% were on placebo-initiated catheterization. A total of 329 (79%) of 416 patients completed the 52-week study; however, outcomes like the number of weekly incontinence episodes were not reported at 52 weeks.
 
Section Summary: Overactive Bladder and Neurogenic Detrusor Overactivity
Numerous RCTs, as well as observational data, have reported improvements in outcomes following botulinum toxin treatment in patients with neurogenic detrusor overactivity or overactive bladder unresponsive to anticholinergic medication. Despite the risk of adverse events, including urinary retention and UTI, evidence suggests that botulinum toxin improves the net health outcome.
 
Other Urologic Issues
 
Detrusor Sphincter Dyssynergia
In 2002, de Seze et al studied 13 patients with chronic urinary retention due to detrusor sphincter dyssynergia from spinal cord disease (traumatic injury, multiple sclerosis, congenital malformations) who were randomized to perineal botulinum toxin type A or lidocaine injections into the external urethral sphincter (deSeze, 2002). In the botulinum group, there was a significant decrease in the primary outcome of postvoid residual volume compared with no change in the control group (lidocaine injection). Improvements were also seen in satisfaction scores and other urodynamic outcomes.
 
Systematic reviews have addressed treating detrusor sphincter dyssynergia with botulinum toxin injection. In 2012, Mehta et al conducted a meta-analysis on botulinum toxin injection as a treatment of detrusor external sphincter dysfunction and incomplete voiding after spinal cord injury (Mehta, 2012). Reviewers identified 2 RCTs and multiple uncontrolled studies. The RCTs included the de Seze study (discussed above) and a second study of 5 patients. A 2006 systematic review by Karsenty et al reviewed trials of botulinum toxin type A injected into the urethral sphincter to treat different types of lower urinary tract dysfunction, grouped into neurogenic detrusor sphincter dyssynergia and non-neurogenic obstructive sphincter dysfunction (Karsenty, 2006). In the former group, reviewers cited 10 small studies (N range, 3-53 patients; 3 studies included patients in both categories). Most patients were quadriplegic men unable to self-catheterize or patients (of both genders) with multiple sclerosis. All studies except two were case reports or case series; the two exceptions were controlled studies and were included in the Mehta meta-analysis. The authors of both reviews noted that, while most of the available studies have reported improvements with botulinum toxin injections, there are few published studies, and those published have small sample sizes.
 
Section Summary: Detrusor Sphincter Dyssynergia
There is a lack of adequately powered, scientifically rigorous RCTs to establish the efficacy of botulinum toxin in patients with detrusor sphincter dyssynergia.
 
Benign Prostatic Hyperplasia
The use of botulinum toxin to treat symptoms of benign prostatic hyperplasia (BPH) is premised in part on a static component related to prostate size and a dynamic component related to the contraction of smooth muscle within the gland. Botulinum therapy addresses this latter component. In 2012, Marchal et al published a systematic review on use of botulinum toxin to treat BPH (Marchal, 2012). Reviewers identified 25 studies, including controlled and uncontrolled studies and abstracts in journal supplements. There were 6 RCTs; three were published as full articles and three were published as abstracts (two RCTs were included in a meta-analysis). Reviewers reported that the mean postvoiding residue, both in pre- and posttreatment, did not differ significantly; pooled results were not reported for between-group outcomes. One of the RCTs, by Maria et al (2003), reported on 30 patients with BPH randomized to intraprostatic botulinum toxin type A or saline injection (Maria, 2003). Inclusion criteria were moderate-to-severe symptoms of BPH based on the American Urological Association score and a mean peak urinary flow rate of no more than 15 mL per second with a void volume of 150 mL or less. After 2 months, the American Urological Association symptom score decreased by 65% among those receiving botulinum toxin compared with no significant change in the control group. Mean peak urinary flow rate was significantly increased in the treatment group.
 
Section Summary: Benign Prostatic Hyperplasia
Given the prevalence of BPH, larger trials with good methodology that compare the role of botulinum toxin with other medical and surgical therapies for treating BPH are warranted before conclusions can be drawn about the impact of this technology on health outcomes.
 
 

CPT/HCPCS:
31513Laryngoscopy, indirect; with vocal cord injection
31570Laryngoscopy, direct, with injection into vocal cord(s), therapeutic;
31571Laryngoscopy, direct, with injection into vocal cord(s), therapeutic; with operating microscope or telescope
43201Esophagoscopy, flexible, transoral; with directed submucosal injection(s), any substance
43236Esophagogastroduodenoscopy, flexible, transoral; with directed submucosal injection(s), any substance
46505Chemodenervation of internal anal sphincter
52287Cystourethroscopy, with injection(s) for chemodenervation of the bladder
53899Unlisted procedure, urinary system
64612Chemodenervation of muscle(s); muscle(s) innervated by facial nerve, unilateral (eg, for blepharospasm, hemifacial spasm)
64615Chemodenervation of muscle(s); muscle(s) innervated by facial, trigeminal, cervical spinal and accessory nerves, bilateral (eg, for chronic migraine)
64616Chemodenervation of muscle(s); neck muscle(s), excluding muscles of the larynx, unilateral (eg, for cervical dystonia, spasmodic torticollis)
64642Chemodenervation of one extremity; 1-4 muscle(s)
64643Chemodenervation of one extremity; each additional extremity, 1-4 muscle(s) (List separately in addition to code for primary procedure)
64644Chemodenervation of one extremity; 5 or more muscles
64645Chemodenervation of one extremity; each additional extremity, 5 or more muscles (List separately in addition to code for primary procedure)
64646Chemodenervation of trunk muscle(s); 1-5 muscle(s)
64647Chemodenervation of trunk muscle(s); 6 or more muscles
64999Unlisted procedure, nervous system
67345Chemodenervation of extraocular muscle
92265Needle oculoelectromyography, 1 or more extraocular muscles, 1 or both eyes, with interpretation and report
95869Needle electromyography; thoracic paraspinal muscles (excluding T1 or T12)
95873Electrical stimulation for guidance in conjunction with chemodenervation (List separately in addition to code for primary procedure)
95874Needle electromyography for guidance in conjunction with chemodenervation (List separately in addition to code for primary procedure)
J0585Injection, onabotulinumtoxinA, 1 unit
J0586Injection, abobotulinumtoxinA, 5 units
J0587Injection, rimabotulinumtoxinB, 100 units
J0588Injection, incobotulinumtoxinA, 1 unit
S2341Chemodenervation of adductor muscle(s) of vocal cord

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