Botulinum Toxins

This LCD supplements but does not replace, modify or supersede existing Medicare applicable National Coverage Determinations (NCDs) or payment policy rules and regulations for botulinum toxins. Federal statute and subsequent Medicare regulations regarding provision and payment for medical services are lengthy. They are not repeated in this LCD. Neither Medicare payment policy rules nor this LCD replace, modify or supersede applicable state statutes regarding medical practice or other health practice professions acts, definitions and/or scopes of practice. All providers who report services for Medicare payment must fully understand and follow all existing laws, regulations and rules for Medicare payment for botulinum toxins and must properly submit only valid claims for them. Please review and understand them and apply the medical necessity provisions in the policy within the context of the manual rules. Relevant CMS manual instructions and policies may be found in the following Internet-Only Manuals (IOMs) published on the CMS Web site:

IOM Citations:

• CMS IOM Publication 100-02, Medicare Benefit Policy Manual,
• Chapter 15, Section 50 Drugs and Biologicals, Section 60 Services and Supplies Furnished Incident To a Physician’s/NPP’s Professional Service
• Chapter 16, Section 120 Cosmetic Surgery
• CMS IOM Publication 100-08, Medicare Program Integrity Manual,
• Chapter 13, Section 13.5.4 Reasonable and Necessary Provisions in LCDs

Social Security Act (Title XVIII) Standard References:

• Title XVIII of the Social Security Act, Section 1861(t). This section addresses drugs and biologicals definitions.
• Title XVIII of the Social Security Act, Section 1862(a)(1)(A) states that no Medicare payment shall be made for items or services which are not reasonable and necessary for the diagnosis or treatment of illness or injury.
• Title XVIII of the Social Security Act, Section 1862(a)(10) excludes coverage for cosmetic surgery.
• Title XVIII of the Social Security Act, Section 1873 addresses the designation of organization or publication by name within the Act relevant when referencing authoritative sources like drug compendia (e.g., Micromedex).

Clostridium botulinum toxin describes a family of neurotoxins produced by the anaerobic bacteria of the species C botulinum. There are 7 distinct serotypes of botulinum toxin: A, B, C, D, E, F, and G. All botulinum neurotoxin serotypes are understood to produce their clinical effect by blocking the release of the neurotransmitters, principally acetylcholine, from nerve endings.¹ There are 5 distinct serotype A botulinum toxin products, onabotulinumtoxinA (Botox), abobotulinumtoxinA (Dysport), incobotulinumtoxinA (Xeomin), prabotulinumtoxinA-xvfs (Jeuveau), and daxibotulinum toxin A (Daxxify) and 1 serotype B botulinum toxin product, rimabotulinumtoxinB (Myobloc) that have been approved by the FDA. PrabotulinumtoxinA-xvfs (Jeuveau) is indicated for cosmetic use only.²

Whether a botulinum toxin is produced from the same or different serotype producing strain, they undergo different manufacturing processes which yield differences in the size and weight of the molecules. Because of this, Botox, Dysport, Xeomin, Myobloc, and Daxxify, as well as other botulinum toxin products available internationally, are not interchangeable. They are chemically, pharmacologically, and clinically distinct.¹

For the purposes of this LCD, botulinum toxin injections (BTI) refers to the general use of these products as a whole. Each specific product will be discussed by name. BTI are commonly used to treat a wide variety of conditions in which the main therapeutic effect is to decrease undesired or excessive contraction of striated or smooth muscle. They produce a presynaptic neuromuscular blockade by preventing the release of acetylcholine from the nerve endings.¹ The resulting chemical denervation of muscle produces local paresis or paralysis and allows individual muscles to be weakened selectively.

Covered Indications

NOTE: The 5 botulinum therapies are not interchangeable and are only covered as listed below.

BOTULINUM TOXINS (Botox, Dysport, Xeomin, Myobloc, and Daxxify), will be considered reasonable and necessary when administered for treatment of FDA-labeled indications and off-label indications (as applicable) below:

1. FDA indications for onabotulinumtoxinA (Botox) as noted on the FDA website: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=103000 ³
2. Off-Label indications for onabotulinumtoxinA (Botox) are considered reasonable and necessary in patients for the following conditions:
• Esophageal achalasia in the following circumstances:
• Medically high-risk patients who cannot undergo other invasive treatments (peroral endoscopic myotomy [POEM], Heller myotomy, pneumatic dilation [PD])^4-12
• As a bridge for those awaiting more effective treatments such as Heller myotomy, PD, or POEM¹⁰
• During work-up and treatment planning of definitive treatments for achalasia^13,14
• Chronic anal fissure for patients with inadequate response to conservative or pharmacologic treatment¹⁵
• Essential hand tremor for patients with a high amplitude tremor that disrupts activities of daily living and have had inadequate response to oral pharmacotherapy such as propranolol and primidone¹⁶
• Focal hand and limb dystonia¹⁶
• Hemifacial spasm in adults (cranial nerve VII disorder)¹⁶
• Isolated oromandibular dystonia (also known as orofacial dystonia, isolated oromandibular dystonia, oromandibular dystonia, blepharospasm associated with orofacial dystonia, and Meige syndrome) in adults¹⁷
• Laryngeal dystonia (spastic dysphonia) for adductor type (ADSD)¹⁶
• Bothersome simple motor tics in adolescents and adults when the benefits of treatment outweigh the risks¹⁸
• Severely disabling or aggressive vocal tics in older adolescents and adults when the benefits of treatment outweigh the risks¹⁸
3. FDA indications for abobotulinumtoxinA (Dysport) as noted on the FDA website: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125274 ¹⁹
4. Off-label indications for abobotulinumtoxinA (Dysport) are considered reasonable and necessary in patients for the following conditions:
• Blepharospasm in adults^16,17
• Hemifacial spasm in adults (cranial nerve VII disorder)¹⁶
• Isolated oromandibular dystonia (also known as orofacial dystonia, isolated oromandibular dystonia, oromandibular dystonia, blepharospasm associated with orofacial dystonia, and Meige syndrome) in adults¹⁷
5. FDA indications for incobotulinumtoxinA (Xeomin) as noted on the FDA website: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125360 ²⁰
6. FDA indications for rimabotulinumtoxinB (Myobloc) as noted on the FDA website: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=103846 ²¹
7. FDA indications for daxibotulinumtoxinA-lanm (Daxxify) as noted on the FDA website: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=761127 .²²

Limitations

1. Localization procedures would not be expected and therefore considered not reasonable and necessary for easily targeted muscles.^17,23
2. Administration of onabotulinumtoxinA (Botox) for achalasia in the following circumstances is considered not reasonable and necessary:

• Patients with contraindications for Botox or upper endoscopy.²⁴
• Injection of botulinum toxin in the esophageal body.^6,8-10

3. Treatment of isolated lower limb dystonia and isolated exercise-associated lower limb dystonia is considered not reasonable and necessary.²⁵
4. Treatment of abductor spasmodic dysphonia is considered not reasonable and necessary.²⁶
5. Treatment of wrinkles, also called glabellar lines, smoker’s lines, crow’s feet, laugh lines, and aging neck, using botulinum toxins, are considered cosmetic procedures and not covered under Medicare.

Notice: Services performed for any given diagnosis must meet all of the indications and limitations stated in this LCD, the general requirements for medical necessity as stated in CMS payment policy manuals, any and all existing CMS national coverage determinations, and all Medicare payment rules.

Off-Label Indications Supported by Evidence-Based Guidelines

Botulinum toxin is used therapeutically to reduce pathologic muscle contraction. Health outcomes of interest are improved function and improved quality of life.

The American Academy of Neurology (AAN) has produced a clinical practice guideline process manual that includes a discussion regarding elements of recommendations and levels of evidence (see tables below).²⁷

Note: When there is insufficient evidence to support an inference for the use of an intervention (i.e., the balance of benefits and harms is unknown), a Level U is appropriate. A Level U indicates that the available evidence is insufficient to support or refute the efficacy of an intervention.²⁷

Achalasia
Achalasia is a relatively rare primary motor esophageal disorder, characterized by incomplete relaxation of the gastroesophageal junction coupled with the absence of organized peristalsis along the esophageal body. The gold standard for diagnosing achalasia is high-resolution esophageal manometry. The treatment options for patients with achalasia aim to improve symptoms by reducing the functional obstruction at the level of the gastroesophageal junction. Though this is an off-label use, endoscopic injections of Botox into 4 quadrants of the LES temporarily reduces lower esophageal sphincter (LES) pressure by inhibiting the release of acetylcholine from nerve endings.^4-10

FCSO performed a literature search in PubMed and Google Scholar for the past 10 years with terms including “achalasia” and “botulinum toxin”. FCSO also participated in a multi-MAC Contractor Advisory Committee (CAC) meeting in October 2023 with CAC panelists experienced in BTI and included additional articles selected by them. Also, 4 society guidelines and 5 additional systematic reviews (SR) were included in the analysis.

Intra-sphincteric BTI is effective for esophageal achalasia treatment but is limited by its short-term efficacy. Four society guidelines (from the American Society for Gastrointestinal Endoscopy [ASGE],⁶ the International Society for Diseases of the Esophagus [ISDE],¹⁰ the American College of Gastroenterology [ACG],⁸ and the European Society of Gastrointestinal Endoscopy [ESGE])⁹ support the use of BTI as a treatment for achalasia only in patients who are not candidates for alternative invasive therapies, such as PD, laparoscopic Heller myotomy (LHM), or POEM. Four additional SR and meta-analyses comparing the use of BTI with alternative treatments have found that while BTI may provide short-term symptom relief and is associated with low complication rates, its results are inferior in both medium- and long-term symptom relief compared to all other non-pharmacological alternatives.^4,11,12,28

The 2018 ISDE achalasia guidelines also recommend the use of BTI as a bridge for those awaiting more effective treatments such as LHM, PD, or POEM.¹⁰

The use of BTI during work-up and treatment planning of definitive treatments for achalasia is recommended by CAC panelists and Katzka et al.¹³

In non-achalasia esophageal motility disorders, the evidence of BTI is inconsistent, but the CAC panelists support its use. Additionally, the ESGE guidelines provide recommendations for the use of BTI in these disorders.⁹

BTI in achalasia is safe overall.^10-12 Patients with contraindications for upper endoscopy should not undergo BTI for this indication.²⁴ BTI in the esophageal body is not recommended in the treatment of idiopathic achalasia.¹⁰ Frequency intervals of Botox vary. ESGE guidelines found that although the initial (1 month) response rate is high (>75%), the therapeutic effect of repeated treatments substantially reduces over time and about half of patients required further injections at intervals of 6 – 24 months with some reporting long lasting effects when repeating BTI after a month.⁹

A Cochrane database review of 7 studies included 178 patients and discovered no significant difference in remission between PD and BTI treatment within 4 weeks of the initial intervention.¹² Four studies included in the review had 12 month data with remission in 55 of 75 PD patients compared with 27 of 72 BTI patients (risk ratio of 1.88 [95% confidence interval (CI) 1.35 to 2.61, P=0.0002]). These outcomes provide strong evidence that PD is more successful than botulinum toxin in the long term for patients with achalasia.

Chronic Anal Fissure

Anal fissure is a superficial tear in the skin of the anal canal. This condition is common in those with a history of hard stools, low fiber diet, trauma, or previous anal surgery. The fissures can be acute, lasting less than 6 weeks, or chronic, lasting more than 6 weeks. Current evidenced-based recommendations indicate chronic anal fissure should be treated with topical medications like calcium channel blockers or nitrates. In situations where patients do not respond to conservative or pharmacologic treatment, local injections of botulinum toxin have been shown to be as effective in healing fissures and are therefore recommended as an alternative treatment. Thus, consistent with evidence-based guidelines, coverage has been extended for Botox as an off-label treatment option for chronic anal fissure in patients with inadequate response to conservative or pharmacologic treatment.¹⁵

FCSO received and reviewed 7 studies supporting the use of Dysport for the treatment of chronic anal fissures. These included 3 randomized controlled trials (RCTs),^31-33 3 prospective observational studies,^34-36 and 1 retrospective observational study.³⁷ However, these studies did not provide a sufficient level of evidence for coverage of Dysport for the treatment of chronic anal fissures.

Blepharospasm

For the purposes of this LCD, benign essential blepharospasm (referred to herein as blepharospasm) is a focal dystonia involving the involuntary closure of the eyelids. The orbicularis oculi muscles spasm creating sustained or intermittent muscle contractions resulting in mild blinking or sustained forced closure of the eyes. To diagnose a patient with blepharospasm, clinicians can observe for involuntary contraction of the orbicularis oculi and other muscles involved in eyelid closure, which can range from sporadic and mildly irritating to functionally blinding.

Studies show Botox and Xeomin may be comparable for the treatment of blepharospasm following dose modification. Studies also show that Botox and Dysport may be equivalent for the treatment of blepharospasm. Dysport has backing in the IBM Micromedex compendium DrugDex for off-label treatment of blepharospasm in adults.²⁶ Accordingly, coverage has been extended for off-label use of Dysport for the treatment of blepharospasm in adults.

FCSO received a reconsideration request to expand coverage for Myobloc to include the treatment of benign essential blepharospasm in patients refractory to Botox. A single prospective case series publication was submitted for reconsideration of the LCD to expand coverage.³⁸ An additional search of PubMed revealed 10 studies. Four studies only briefly mentioned botulinum toxin type B and possible use for blepharospasm but do not examine its use in depth; 1 study examined the cosmetic use of botulinum toxin type B, and another study focused on the use of zinc with botulinum toxins. There were 4 other studies that do mention or analyze Myobloc’s use in some capacity, but all 4 studies establish reasons not to cover Myobloc for blepharospasm.^17,39,40 The review by Jankovic et al states that Myobloc for blepharospasm treatment has an insufficient level of evidence to establish its efficacy and use in the treatment of blepharospasm.⁴¹ Hellman et al notes that Myobloc is available in a solution which is acidic and can result in more painful injections, dry mouth, and constipation than type A botulinum toxins.³⁹ The prevalence of use and level of evidence regarding botulinum toxin type B is much smaller than that of botulinum toxin type A preparations. Hellman et al also point out that botulinum toxin type B often produces more painful injections. Overall, the available evidence both from the submitted literature and FCSO independent review was found to be of low certainty, offering insufficient support for the inclusion of Myobloc in the treatment of blepharospasm.

Hemifacial Spasm

The literature indicates botulinum neurotoxin may be considered as a treatment for hemifacial spasm with minimal side effects. Studies show Botox and Dysport, after dosage modification, may be equal in effectiveness.²⁶ Subsequently, coverage has been extended for Botox and Dysport as an off-label treatment of hemifacial spasm in adults.

Focal Hand and Limb Dystonia

Focal hand dystonia (FHD) is a disabling task-specific movement disorder, that can generalize across tasks and be present at rest. It is also referred to as writer’s cramp, musician’s dystonia, and other occupational hand dystonias. A patient’s history and clinical examination are both critical for its diagnosis and for identification of dystonic muscles.

The treatment options for FHD aim to improve symptoms by reducing the signals that cause muscle spasms. Botulinum toxin injections in FHD require guidance either by ultrasound or by electromyography with or without electrostimulation.⁴² Botulinum toxin injections dosing in FHD is highly individualized due to different activity types, levels, and multiple potential target muscles with varying BTI doses and intervals.⁴³ Currently, no effective alternative medical or proven surgical therapies have been established for FHD.^44-49

A literature search was performed in PubMed and Google scholar for the past 10 years with terms including “focal hand dystonia” and “botulinum toxin”. Additionally, a multi-MAC CAC meeting was held in October 2023 with CAC panelists and included additional articles selected by them. The CAC panelists concluded that BTI should be offered as a first-line treatment for focal hand dystonia. We included a total of 6 studies in our analysis. (Class I and II strength of recommendations).²⁷ They all support the use of BTI as a first line treatment of FHD. Therefore, in the management of FHD, injection of Botox is considered reasonable and necessary as an FDA off-label use consisting of focal injections of the toxin into the muscles responsible for the abnormal postures.

The efficacy of BTI use in isolated lower limb dystonia and isolated exercise-associated lower limb dystonia has a class III level of scientific evidence,²⁵ therefore, coverage of off-label use of BTI is not extended for this indication.

FCSO  received a comment requesting to expand coverage for Dysport to include the treatment of Focal Hand and Limb Dystonias (specifically Writer’s Cramp, Focal Task Dystonia, and Musician’s Dystonia). Ten studies were submitted by commenters for the expansion of coverage of the LCD.^50-59 Five studies were left out of the analysis because they looked at dosage changes,⁵¹ electromyography (EMG) testing for injections,⁵⁹ and somatosensory evoked potential (SEP) tools for focal dystonias.⁵⁷ These topics are outside the scope of this reconsideration. The study by Somma-Mauvais et al was presented in French, and FCSO only reviews studies published in the English language.⁵⁶ Additionally, the study by Koelman et al was submitted only as an abstract. A request for the full-text version was made, but it was not provided by the commenter.⁵⁸ In summary, FCSO has determined that there is insufficient evidence (based on the small sample sizes, relatively short follow-up, and adverse effects seen in clinical studies) to support the coverage of Dysport for Focal Hand and Limb Dystonias.

Laryngeal Dystonia

Laryngeal dystonia (spasmodic dysphonia) is a disorder which causes the vocal cords to spasm subsequently causing the voice to sound tight, strained, or breathy. This disorder commonly presents as adductor type spasmodic dysphonia (ADSD) where the vocal cords stiffen and do not open appropriately causing a strained voice, or less commonly as abductor type spasmodic dysphonia (ABSD) where the vocal cords inappropriately remain open causing a weak, breathy voice. Studies show botulinum neurotoxin should be recommended as a treatment option for adductor spasmodic dysphonia (ADSD); however, there is inadequate evidence to support the effectiveness of botulinum neurotoxin in abductor spasmodic dysphonia (ABSD). Presently no effective alternative medical or surgical therapies have been established for spasmodic dysphonia. Botox has support in the IBM Micromedex compendium DrugDex for off-label treatment of spastic dysphonia in adults.²⁶ Consistent with evidence-based guidelines, coverage has been extended for Botox as an off-label treatment of ADSD.

FCSO received a comment requesting to expand coverage for Dysport for the treatment of spasmodic dysphonia and laryngeal dystonia. A total of 6 pieces of evidence were submitted for spasmodic and laryngeal dysphonia including 4 observational studies, 1 narrative review with case reports, and 1 review.^60-65 Studies excluded from analysis focused on botulinum toxin administration procedures,⁶¹ injection techniques and dosage,^62,63 and diagnosis/assessment methods which is beyond the scope of this policy.⁶⁵ A detailed discussion of these studies is provided in the Analysis of Evidence section, which explains the rationale for determining that the literature is insufficient to conclude Dysport is an effective treatment for these spasmodic dysphonia and laryngeal dystonia.

Essential Hand Tremor

Tremors, an involuntary movement of a body part with relatively constant frequency, is the most common movement disorder. It usually presents as a bilateral tremor of the hands. Evidence-based guidelines from Simpson et al indicate botulinum neurotoxin injection of forearm muscles may be helpful in reducing the tremor amplitude in patients with a high amplitude essential hand tremor that disrupts activities of daily living and have had an inadequate response to oral agents including propranolol and primidone.¹⁶ Therefore, consistent with these evidence-based guidelines, coverage has been extended for Botox as an off-label treatment for essential hand tremor for patients with a high amplitude tremor that disrupts activities of daily living and who have had an inadequate response to oral pharmacotherapy such as propranolol and primidone.

The contractor received 1 abstract supporting the use of Dysport for the treatment of essential hand tremor.⁶⁶ Full text of the article was requested from the submitter but was not received; and, as this text was abstract only and outside the scope of this reconsideration, it was not included in the analysis of evidence.

Oromandibular Dystonia

Oromandibular dystonia (OMD) is a rare neurological movement disorder characterized by involuntary and often forceful contractions of the muscles of the jaw and tongue. Oromandibular dystonia is described by several different terminologies. Those include, orofacial dystonia, isolated oromandibular dystonia, oromandibular dystonia, blepharospasm associated with orofacial dystonia, and Meige syndrome.⁶⁷ Oromandibular dystonia can present along with involuntary muscle spasms and contractions of the muscles around the eyes (blepharospasm) and is known as Meige Syndrome.⁶⁸ Overall, half of all blepharospasm subjects experience symptoms to different parts of the body over a period of 5 years.⁶⁹

Oromandibular dystonia has various treatment choices consisting of botulinum toxin therapy, medication, and surgical intervention. Medications, like anticholinergics (trihexyphenidyl and benztropine), benzodiazepines, VMAT2 inhibitors (tetrabenazine), levodopa, and baclofen have been utilized with varying success. The effectiveness of medication therapy is limited and does not show the same level of value when compared to BTI. Oral medication treatments are also restricted by systemic side effects not typically experienced with botulinum toxin.

The current AAN practice guidelines for botulinum toxins show support for Botox and Dysport for the treatment of OMD.⁴⁰ A systematic literature review conducted by Hassell et al identified relevant literature regarding the use of botulinum toxin type A (BoNT/A) and type B (BoNT/B) for blepharospasm, oromandibular dystonia, and Meige syndrome.¹⁷ In addition to the literature, Botox has support in the IBM Micromedex compendium DrugDex for off-label treatment of isolated oromandibular dystonia in adults.²⁶ Thus, consistent with evidence-based guidelines, coverage has been extended for Botox and Dysport as an off-label treatment for isolated OMD in adults.

Chronic Motor Tics and Disabling or Aggressive Vocal Tics

Chronic motor and vocal tics, sudden and uncontrolled repetitive movement or sound, also referred to as Gilles de la Tourette syndrome or Tourette disorder, is characterized by tics that begin in childhood. The treatment of tics must be personalized and based on collaborative determinations among patients, caregivers, and clinicians. Many individuals with tic disorders have psychiatric comorbidities, which require clinicians to set treatment priorities. The management of comorbid conditions is of chief concern in determining treatment options for tics in individuals with Tourette’s Syndrome. Medications, behavioral therapy, and neurostimulation have been shown to significantly decrease tics; however, these treatments seldom fully terminate tics.²⁶ Evidence-based guidelines from Pringsheim et al indicate: 1) OnabotulinumtoxinA (Botox) injections are recommended for the treatment of adolescents and adults with localized and bothersome simple motor tics when the benefits of treatment outweigh the risks; and 2) OnabotulinumtoxinA (Botox) injections are recommended for the treatment of older adolescents and adults with severely disabling or aggressive vocal tics when the benefits of treatment outweigh the risks.¹⁸ In addition to the current guidelines, the IBM Micromedex compendium DrugDex²⁶ lends support for Botox as an off-label treatment of Gilles de la Tourette syndrome in adults. Therefore, coverage has been extended for Botox as an off-label treatment consistent with current evidence-based guidelines.

The quality of evidence in the literature is insufficient to support BTI for the treatment of defecatory disorders (DD), chronic proctalgia, phonic tics, head tremor, and voice tremor. Further research is needed to clarify the utility and efficacy of botulinum toxin therapy for these conditions.¹⁶

BTI can improve quality of life through reducing muscle rigidity and contraction and is a treatment for voluntary and involuntary muscle dysfunction. Reduction of painful contractions is important for an improved quality of life.

Dosing and frequency are important considerations. While botulinum toxins have a wide therapeutic window, all botulinum toxin products have a black box warning about the potential for distant spread of toxin effect. These symptoms can occur hours to weeks after administration. Symptoms may include swallowing and breathing difficulties which can be life threatening and can lead to death. The risk of symptoms is probably greatest in children treated for spasticity, but symptoms can also occur in adults, particularly in those patients who have an underlying condition that would predispose them to these symptoms.^3,19-21 Therefore, the lowest effective dose that produces the desired clinical effect should be used. Treatment effect can last from 12 to 16 weeks, with labeled use suggesting a minimum interval of 12 weeks. Dosing frequency should be at the longest interval that produces the desired clinical effect.

Medical utilization of botulinum toxins has increased in the past 30 years with an extensive track record of safety and efficacy.¹ The mechanism of action is well understood. However, the benefits of botulinum toxin must be balanced with the risk. Professional societies have evidence-based guideline recommendations to assist providers in maximizing patient outcomes.

There are important differences between the botulinum toxin preparations that include potency and duration of effect. They are chemically, pharmacologically, and clinically distinct and are not interchangeable.

Achalasia

BTI in the Treatment of Achalasia

Society Guidelines:

Of these guidelines, 3 were based on results of SRs (2020 ASGE, 2018 ISDE, 2020 ESGE) and 1 was a position statement (ACG).^6,8-10 The guidelines based on SRs encompassed open label trials involving small numbers of participants, attributable to the rarity of achalasia and the invasiveness of treatments. Each guideline employed its own chosen methodology (for instance GRADE, Delphi process, etc.) which are broadly recognized and utilized in guideline formation and evidence review.

The ASGE guideline on the management of achalasia 2020,⁶ 2018 ISDE achalasia guidelines,¹⁰ ACG Clinical Guidelines: Diagnosis and Management of Achalasia, 2020,⁸ and ESGE Guideline 2020,⁹ all support BTI into the distal esophageal sphincter as an effective short-term treatment for achalasia, in medically high-risk patients who are not candidates for other invasive therapies.

ASGE guidelines were based on a SR and meta-analysis by Khashab et al of 22 uncontrolled studies published from inception to October 2017,⁶ in 730 achalasia patients who were treated with Botox injection. Clinical success, defined by an Eckardt score of less than or equal to 3, was achieved in 77% (95% CI, 72%-81%; I ² value 35; P=0.04) over a follow-up period ranging from 1 to 6 months. There was a statistically significant decrease in average LES pressure from 38.23 mmHg (range, 34.40-42.06) before the procedure to 23.30 mmHg (range, 20.79-25.81) after BTI (P <0.01). At 12 months, clinical success rates were 73.3% (55/75) and 37.5% (27/72), for PD and BTI respectively (risk ratio, 1.88; 95% CI, 1.35-2.61; P=0.0002). Serious adverse events were uncommon, with transient chest pain reported after 4.4% of injections. The authors recommended against the use of BTI as definitive therapy for achalasia patients (Assessing the Methodological Quality of Systematic Reviews-2 AMSTAR-2 moderate quality of evidence or moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different).

The ESGE performed a systematic review (see Weusten SR below) and Delphi consensus and aligned with previous recommendations.⁹ They additionally made specific dosing recommendations of 100 units of Botox or equivalent of the toxin diluted in preservative-free saline that is injected in aliquots of 0.5–1mL using an injection needle in forward view just above the squamocolumnar junction in at least 4 quadrants. This was a strong recommendation and high quality of evidence, with the level of agreement 100%. A multicenter randomized trial with injection of 50, 100, and 200 units of Botox resulted in similar short-term results in LES pressure 1 month after injection⁵ and in a SR review, a dose of 100 units of Botox was used most frequently supporting this dosing recommendation.⁷⁰

The 2018 ISDE achalasia guidelines were based on Zaninotto et al SR (see below),¹⁰ and the strength of recommendation was graded according to the Grading of Recommendations Assessment and Evaluation (GRADE). Based on a moderate GRADE rating of the evidence, the authors support Botox injection for patients who are unfit for surgery or as a bridge to more effective therapies, such as surgery or endoscopic dilation.

The ACG Clinical Guidelines performed a literature review and generated consensus-based recommendations using a modified Delphi process.⁸ They recommend BTI as first-line therapy for patients with achalasia that are unfit for definitive therapies compared with other less-effective pharmacological therapies.

Systematic Reviews:

Recent SR and meta-analyses comparing the use of BTI with alternative treatments have found that, while BTI may provide short-term symptom relief and is associated with low complication rates, its results are inferior in both the medium- and long-term compared to all other non-pharmacological alternatives.

Andolfi et al conducted a SR of articles published between 2008 and 2018 comparing the effect of different invasive treatments on symptomatic outcomes across achalasia subtypes.⁴ Their search strategy included PubMed and MEDLINE only. They included 20 studies (1575 participants) reporting clinical outcomes after BTI, PD, LHM and POEM based on manometric subtypes. The authors performed a meta-analysis. Three studies reported data on botulinum toxin (58 patients). Botulinum toxin injection was the treatment modality with the worse outcomes (18% for type I, 59% for type II, and 21% for type III). Approximately half of the patients needed further injections at intervals of 6–24 months.

Gong et al conducted a SR comparing the efficacy of 9 interventional treatments (BTI, PD, BTI + PD, LHM + Toupet, LHM + anterior wrap [D], APOEM, traditional posterior POEM, double-scope POEM, and waterjet assisted [JPOEM]) for achalasia.¹¹ The authors included 27 RCTs published from 1990 to December 2020 with 2278 achalasia patients (BTI [n=158], BTI + PD [n=72]) in a meta-analysis. The primary outcome was comparison of the induction of clinical remission after 1 year follow-up. Results indicated that APOEM was the most effective (rank 1, 50%) strategy to significantly relieve achalasia symptoms, while BTI ranked last (rank 9,99%), although BTI had the highest safety profile.

Leyden et al conducted a Cochrane SR and meta-analysis comparing the efficacy and safety of 2 endoscopic treatments, PD, and Botox injections.¹² They included 7 RCTs with 178 patients published from 1946 through March 2014. The authors examined symptom remission rates within the first month, at 6 months, and at 12 months. Based on the AMSTAR-2 critical appraisal tool, the overall confidence in the result of this meta-analysis was deemed to be “high”. The overall methodological quality of the studies was good although the risk of bias was high. Only 1 of the studies included was double blinded. There was no significant difference between PD and Botox injection arms in clinical success rates or LES pressures within 4 weeks of the initial intervention (risk ratio of remission, 1.11; 95% CI, 0.97-1.27) with a weighted mean difference for PD of –0.77 (95% CI, –2.44 to 0.91; P=0.37). Clinical success rates beyond 4 weeks were available for 3 studies at 6 months, and 4 studies at 12 months. At 6 months, clinical success was achieved in 80.7% of patients (46/57) who underwent PD as compared with 51.8% of patients (29/56) who underwent Botox injection (risk ratio, 1.57; 95% CI, 1.19-2.08; P=0.0015). At 12 months, clinical success rates were 73.3% (55/75) and 37.5% (27/72), respectively (risk ratio, 1.88; 95% CI, 1.35-2.61; P=0.0002). There were no adverse events in the botulinum injection arm (total of 151 injection procedures), whereas perforation occurred in 3 cases (total of 188 PD procedures) in the PD arm.

This data demonstrates that PD is a more effective long-term (>6 months) endoscopic treatment option compared with Botox injection for patients with achalasia.

Shiu et al conducted a SR and meta-analysis of RCTs published between January 2000 and June 2021 to compare the efficacy of 8 treatments for achalasia.²⁸ Twenty-four studies involved 1987 participants for analysis. LHM+Dor (OR 2.29, 95% CI: 1.50–3.49) all showed significantly greater efficacy and were at least twice as effective as the reference group with only BTI (OR 0.33, 95% CI: 0.17–0.63) showing significantly lower efficacy. The medians (IQRs) for short-term clinical success rates (%) of APOEM, Posterior POEM, LHM+Toupet, BTI+PD, LHM+Dor, PD, and BTI were 91.1 (IQR, 84.4–95.4), 92.1 (IQR, 87.0–93.0), 93.9 (IQR, 90.2–97.0), 85.4 (IQR, 84.4–86.5), 86.7 (IQR, 79.7–88.7), 66.35 (IQR, 56.0–77.7), and 53.3 (IQR, 37.5–60.0), respectively.

Zaninotto et al conducted a SR with interdisciplinary and international authors to establish best evidence-based principles for the diagnosis and management of achalasia.¹⁰ The authors included 466 articles in their analysis. Regarding BTI results, the authors found that BTI has a high safety profile with mild adverse events (heartburn or chest pain) observed in less than 10% of patients treated. At 2 year follow up, only 34% of BTI patients versus 87.5% of the Heller patients were asymptomatic. Similarly, 4 randomized trials and a Cochrane meta-analysis comparing BTI with PD consistently reported a higher cumulative rate of remission rate at 1 year after treatment after PD. Based on the moderate GRADE rating of the evidence, the authors recommended against BTI as an effective therapy (control of symptoms) for achalasia in patients fit for surgery (LHM or PD).

Repeated BTI may be successful if there are contraindications to invasive, but more durable treatments. The authors also found that BTI efficacy may decrease over time.

Weusten et al conducted a SR of the technical aspects of the endoscopic management of gastrointestinal motility disorders (including achalasia).⁹ Evidence levels and recommendation strengths were assessed using the GRADE system. This is based on a moderate GRADE rating of the evidence.

BTI in the Work-Up and Treatment Planning of Achalasia

Although the literature is sparse with small sample studies, expert consensus supports that Botox injections may be used during work-up and planning of definitive treatments for achalasia.¹⁴ Katzka DA et al followed a retrospective cohort of 11 patients evaluating BTI in patients with: 1) symptoms consistent with achalasia but insufficient manometric criteria to make the diagnosis; 2) complex clinical situations in which there were factors in addition to achalasia that may be contributing to the patient’s symptoms and that required different treatment; 3) atypical manifestations of achalasia; 4) advanced achalasia in which it was unclear that sphincter-directed therapy (vs esophagectomy) would be of benefit; and 5) after Heller myotomy.¹³ Based on the analysis of evidence, this policy will provide coverage for off-label use of Botox injections for the treatment of achalasia.

Chronic Anal Fissure

Anal fissure is defined as an ulcer-like, longitudinal tear in the midline of the anal canal, distal to the dentate line. Treatments for anal fissure lean heavily on adaptations from the American Society of Colon and Rectal Surgeons Practice Parameters from the most recent published guidelines in 2010 and 2011 and are supplemented with subsequent publications through 2023.⁷¹ Generally, treatment for chronic anal fissure is targeted at reducing the sphincter spasms caused by this condition. Recommended therapy includes topical medications like calcium channel blockers or nitrates. For patients who do not respond to conservative or pharmacologic treatment, local injections of botulinum toxin are strongly recommended for relief of painful spasms. Surgery (internal anal sphincterotomy) is recommended for medically refractory situations.

Wald et al¹⁵ released the ACG practice guideline for management of benign anorectal disorders which discusses the definitions, diagnostic criteria, differential diagnoses, and treatments of a set of benign disorders of anorectal function and/or structure. Studies show that injection of botulinum toxin into the internal anal sphincter allows healing in 60% to 80% of fissures, and at a greater rate than a placebo. Usual side effects include temporary incontinence of flatus in up to 18%, and of stool in 5%. Relapse may occur in up to 42%; however, patients have shown similar outcomes to initial therapy.

BTI is reserved for patients who fail pharmacologic treatment with nitrates or calcium channel blockers. Lateral internal sphincterotomy (LIS) is recommended for patients who have failed BTI therapy.

The studies submitted supporting the use of Dysport in the treatment of chronic anal fissures included 3 RCTs,^31-33 3 prospective observational studies,^34-36 and 1 retrospective observational study.³⁷ All the submitted studies were conducted with European and young (<50 years old on average) populations and, therefore, were not reflective of the Medicare population.

The randomized studies submitted had similar limitations including small sample sizes, insufficient methodology descriptions for randomization, recruitment/enrollment, patient populations, and analyses, and a lack of blinding.^31-33 The observational studies also had notable limitations including small sample sizes and a lack of comparators or insufficient description of treatment allocations.^34-37 Overall, the studies provided to FCSO resulted in a low certainty of evidence supporting the use of Dysport for the treatment of chronic anal fissures. Thus, FCSO considers the use of Dysport for this indication to be not reasonable and necessary.

Blepharospasm

The AAN has provided recommendations for the use of botulinum neurotoxin in blepharospasm based on the following studies:

One Class II and 1 Class III study compared 2 different serotype A botulinum neurotoxins (Botox and Dysport).^72,73 In the Class II study, 212 participants were assessed in a crossover design using a 4:1 dose ratio of Dysport to Botox. The primary clinical outcome, duration of effect, was similar for the 2 botulinum neurotoxins. The Class III trial, a parallel design of 42 patients without blinded raters, used a dose ratio of 4:1. Duration of action was the primary clinical outcome, and this outcome and others including number of booster doses needed, latency of effect, clinical efficacy, and adverse reactions were comparable for the 2 botulinum toxin products. A Class I trial performed a comparison of Xeomin and Botox injecting equal doses in 300 study participants (256 participants finished the trial). Results showed identical effectiveness and side effects.¹⁶ Additionally, the 2016 guidelines produced by AAN found no studies meeting the inclusion criteria for Myobloc for the treatment of blepharospasm (randomized trials and non-randomized trials with long term outcomes). The AAN guidelines state that there is insufficient evidence to support the effectiveness of Myobloc for blepharospasm.⁴⁰ Upon preponderance of the submitted and identified literature detailed in the Summary of Evidence, FCSO has determined that evidence is insufficient to support the use of Myobloc for blepharospasm.

The conclusion for these studies indicates Botox and Xeomin have level B evidence, Dysport has level C evidence (see table above). These studies signify that following dose modifications, Botox and Xeomin may be equal and Botox and Dysport may be comparable for the treatment of blepharospasm. Dysport has backing in the IBM Micromedex compendium DrugDex for off-label treatment of blepharospasm in adults.²⁶ Evidence supports the use of Botox, Dysport, and Xeomin as reasonable and necessary for the treatment of blepharospasm; therefore, coverage is granted by this policy.

Hemifacial Spasm

Hemifacial spasm is illustrated by a combination of unilateral clonic and tonic spasms of the muscles innervated by the facial nerve. Treatment choices include oral pharmacologic treatments (including carbamazepine, baclofen, and benzodiazepine) that have limited effectiveness, and microvascular decompression of the facial nerve, which is a highly invasive procedure.

A Class II study comprised of 11 patients was a prospective, blinded trial with 4 arms: a random dose based on clinical experience of between 2.5 and 10 units of Botox, half the dose, double the dose, and saline placebo.⁷⁴ Patients went through the 4 treatment arms in random order. With utilization of a clinical scale to rate videotapes and a patient subjective scale, 84% had objective improvement with a minimum of 1 of the active doses with a tendency for an improved response with a higher dose; only 1 participant improved on placebo. Seventy-nine percent described subjective improvement lasting an average of 2.8 months with active treatment. The principal side effect was weakness of the face, generally mild (97%). Other side effects included bruising, diplopia, ptosis, and headache.

Another class III study with a double-blind, prospective, parallel design included only 4 participants per group using individualized therapy (dose range 2.5 to 40 units) with Botox in the active arm.⁷⁵ In addition, 93 patients studied in an open label fashion were reported. More improvement was shown on a clinical scale with BTI than with a saline placebo. Improvement continued for an average of 3.8 months. Side effects, reported in 63% of participants, were usually mild and involved dry eye, mouth droop, and ptosis.

One Class II study contrasted Botox and Dysport in a parallel design without placebo control or blinded raters.⁷³ A dose ratio of 4:1 was used for Dysport to Botox. The primary clinical outcome (duration of action) and other clinical outcomes (number of booster doses needed, latency of effect, clinical efficacy, and frequency of adverse reactions) were comparable for the 2 products. Therapeutic effects lasted 2.6–3.0 months.¹⁶

The conclusion of these studies signifies BTI may be considered as an off-label treatment for hemifacial spasm. Botox and Dysport have level C evidence and after dosage modification, are equivalent in effectiveness.²⁶ Therefore, Botox and Dysport will be considered reasonable and necessary for the treatment of hemifacial spasm.

Focal Hand and Limb Dystonia

A Class I trial randomized 40 study participants with writer’s cramp in a double-blind design for BTI or an equal amount of saline placebo.⁵² The primary outcome measure was the patient’s indicated request to continue injection therapy. In patients randomized to BTI, 70% requested to maintain treatment in comparison to 31.6% of those who received a placebo (P= 0.03). Patients injected with BTI also had considerable improvement in secondary clinical outcome measures including a visual analog scale, symptoms severity scale, writer’s cramp rating scale, and assessment of writing speed, but not in the functional status scale compared to patients who were given a placebo. The only adverse effects reported were temporary weakness and pain at the injection site.

A Class II study utilized a placebo-controlled, double-blind, crossover design for 20 individuals with writer’s cramp.⁷⁶ Clinical assessment was utilized in selecting the muscle to be injected and the dose of botulinum toxin type A was founded on investigator experience. Outcome evaluations included assessment of writing speed, accuracy, writing samples, and patients’ subjective report of pain. There was substantial improvement with BTI in the objective measures, but not in patients’ own evaluations. The only adverse effect was focal weakness, although this was severe enough to worsen pen control in 1 participant. This study only evaluated the first active therapy session for study participants; therefore, the therapeutic effects achieved were not optimal.

A Class II trial was a double-blind, placebo-controlled, crossover design with 10 study participants with focal hand dystonia.⁷⁷ Targeted muscles and Botox doses were selected and optimized during a time of open treatment before the trial. Outcome measures were based on study participant’s subjective ratings and observer ratings of videotapes taken during actions relevant to the individual dystonia. Eight participants had improved subjective ratings and 6 had improved videotape ratings with Botox injection in comparison with placebo. Weakness was noted in the injected muscles of 80% of study participants with active treatment.

Three Class II studies assessed technical issues of Botox administration. In 1 trial, a blinded, randomized, crossover design was utilized to contrast continuous muscle activation to immobilization immediately following Botox injection.⁷⁸ Blinded assessment of handgrip strength and writing showed a substantial increase in focal weakness with continuous muscle activity, but no subjective or objective improvement in writing. In a similar study,⁷⁹ participants were randomized to 1 of 2 muscle localization methods: electromyography (EMG) recording or electrical stimulation. Injections guided by both techniques were similarly effective in producing weakness in the target muscle. In a third trial, the precision of muscle localization with and without EMG was assessed. In needle placements without EMG, only 37% were localized in the targeted muscle.⁴²

Five publications assessed the use of Dysport for treating writer’s cramp and musician’s dystonia. Among these, 1 was a retrospective observational study,⁵⁰ 3 were prospective observational studies,^53-55 and 2 were RCTs.⁵²

A retrospective chart review published in 2005 investigated the safety and efficacy of Dysport in 88 consecutive patients with musician’s dystonia in Germany.⁵⁰ A baseline assessment using a 6 point scale (worse, no improvement, mild, moderate, marked improvement, remission) was done to rate musicians’ playing abilities and a follow-up assessment at a mean of 36 months was completed to examine improvements after BTI were given. Musicians rated their playing ability vs. skill level prior to onset of dystonic symptoms as 53±23% before, and 67±23% during treatment with Dysport (P<0.005).⁵⁰ After treatment, 58 patients experienced a benefit with 38 finding noticeable improvement. However, 26 patients felt they had no response to treatment. The study had several limitations including a lack of standardized assessment for musician’s dystonia, small sample size, and use of subjective outcome measures.

Additionally, 1 RCT examined the use of Dysport for the treatment of writer’s cramp.⁵² In a 2007 publication, Kruisdijk et al reported the results of a double-blind, RCT with follow-up at 12 weeks comparing patients that received Dysport vs. placebo. Forty patients with a mean age of 45.63 years in the placebo group and 47.60 years in the Dysport group who were BTI naïve and had idiopathic writer’s cramp were included. The primary endpoint was the patient’s choice at week 12 to continue with treatment. Fourteen (70%) patients in the Dysport group and 6 (31.6%) in placebo group (P=0.03) continued treatment after 12 weeks. The secondary endpoint was an improvement of patient condition based on clinical rating scales. There were significant improvement effects in the Dysport group compared with placebo on Visual Analog Scale (VAS; P=0.01), symptom severity scale (P=0.02), and the Writer’s Cramp Rating Scale (P=0.04) .⁵² Two types of adverse events were reported: weakness in the hand (18 patients in the Dysport group and 2 patients in the placebo group) and pain at the injection site (3 patients in placebo group and 1 patient in the Dysport group).⁵² However, the study had several limitations including small sample size, patients expressing dissatisfaction with treatment, and short follow-up period.

Three prospective studies also assessed the use of Dysport as a treatment modality for writer’s cramp.^53-55 A prospective controlled study by Wissel et al included 31 patients with a mean age of 34.8 years old at the onset of writer’s cramp. The study measured the magnitude of treatment effect after injection using a subjective grading scale filled out by patients. The scale ranged from 0% to 100% (20% = no, 20% to < 60% = moderate, and 60%-100% = marked improvement).⁵³ It was found that 76% of treatment sessions produced subjective improvement of greater than 20% and a significant improvement in writing speed (measured using computer-based analysis, 1.96±0.84 Hz vs. baseline 1.6±0.74; P<0.05). However, the study had several limitations including small sample size, large range of follow-up which varied greatly, and a non-U.S. based study population based in Germany and Austria which may not be reflective of the U.S. Medicare population. A second prospective open-label study by Turjanski et al examined 45 patients with occupational cramps treated using 30-440 units of Dysport.⁵⁴ Patients used self-assessment scales to rate their degree of improvement in writing and amelioration of pain. The study found an onset of improvement after a mean of 8±5 days, and a mean duration of effect in 3±2 months.⁵⁴ The study noted several adverse events including weakness in injected muscles, local pain, skin hematoma, and finger weakness.⁵⁴ It is also important to note that 29 patients discontinued treatment at some point after the initial Dysport injection. Limitations of this study included small sample size (n=45), a large portion of patients were lost to follow-up and/or discontinued treatment, and the use of subjective scales for assessment. Finally, a prospective study by Djebbari et al investigated what factors could predict improvement for 47 patients with writer’s cramp between January 1998 and December 2002 treated using Dysport. Authors found a significant improvement in severity and disability scores for patients on the Burke-Fahn-Marsden scale (P<0.0001) and a subjective benefit rated through self-assessment was seen in 73% of patients.⁵⁵ There was found to be minimal improvement in the primary writing tremor. There was a correlation between the self-assessment score and the Burke-Fahn-Marsden score. The study showed a general improvement of writer’s cramp symptoms with BTI. However, the study did have several limitations including lack of control or comparator group, small sample size, and the use of single-center population located at a French hospital which may not be reflective of the U.S. Medicare population. Overall, while Dysport may offer some benefit to patients with writer’s cramp, the available evidence is of low certainty and indicates a potential for harm. As such, there is insufficient evidence to support Dysport as a frontline treatment for patients with focal hand dystonias.

Because FHD is a rare and heterogenous disease, studies had small sample sizes and different BTI dosing schemes. Most studies used subjective scales involving either patient or clinician ratings. None of the scales have been rigorously evaluated for clinical utility or validity. Whether studies involved treatments or pathophysiologic assays, there was a heterogeneous choice of rating scales used with no clear standard. As a result, the collective interpretive value of those studies is limited because the results are confounded by measurement effects.

The coverage determination for treating FHD with BTI is challenging due to the limited and uncertain evidence regarding its clinical effectiveness. The available literature does not provide sufficient clarity to support or refute the use of BTI for this condition. However, given the lack of alternative treatment options for patients with FHD and the limited available evidence, this contractor places appropriate weight on the expert opinion of CAC panelists who have endorsed BTI as a first-line treatment for FHD. Accordingly, the use of Botox will be considered reasonable and necessary for this indication.

Laryngeal Dystonia

One Class I trial studied the effects of Botox injection for 13 study participants with ADSD, a double-blind, randomized, parallel group study, compared 7 patients who received Botox injection with 6 patients who received saline.⁶² Outcome measures included instrumental quantitative measures of voice function and patient ratings. Substantial benefit was achieved in the study participants who received Botox injections (P=0.01).

One Class III trial discovered that adding voice therapy after BTI therapy in ADSD patients extended improvements from the BTI treatment.⁸⁰ One Class III study of 15 participants with ABSD did not observe a noteworthy distinction between using percutaneous or endoscopic injection technique.⁸¹

The conclusion for these studies signifies Botox has level B evidence and should be recommended as a treatment option for ADSD; however, there is inadequate evidence to support the effectiveness for BTI use in ABSD.

FCSO received a comment requesting to expand coverage for Dysport to include the treatment of Spasmodic Dysphonia/Laryngeal Dystonia. Two pieces of evidence were submitted for spasmodic and laryngeal dysphonia including 1 retrospective observational study and 1 prospective observational study.^60,64

The study by Elmiyeh et al examined the effects of Dysport in managing ADSD. A retrospective analysis was conducted using the records of 68 patients (mean age 54.4 years in the unilateral injection group and 55.2 years in bilateral injections) who were treated with Dysport at a hospital located in London.⁶⁰ Overall, 272 Dysport injections were performed, 116 of which were unilateral and 156 were bilateral. The study found that 94% of injections were successful with a voice score of 2 (slight improvement) or higher. A lower dose of Dysport for unilateral injection episodes was used compared to those reported by others and still produced comparable results and side-effect profiles.⁶⁰ Per study protocol, a duration of side-effects greater than 2 weeks was considered unacceptable. In terms of side effects, the bilateral injections caused longer duration of dysphagia, total voice loss, and breathiness, while unilateral injections had a slightly longer period of coughing.⁶⁰ A total of 13 injection episodes, 7 bilateral and 6 unilateral, in 8 patients caused breathiness for more than 2 weeks.⁶⁰ The study had several limitations including generalizability issues using a non-U.S. population (UK) with a mean age of 55 years which may not be reflective of the Medicare population, recall bias causing under or over-reporting of voice scores, and outcomes/injection intervals influenced by patient opinions/circumstances.

The prospective study by Whurr et al observed 31 patients with spasmodic dysphonia (mean age 57 years) undergoing bilateral injections to the thyroarytenoid with Dysport.⁶⁴ Improved voice was reported in 96% of patients with the median duration of peak effect being 5 weeks (n=24, range 1-12 weeks).⁶⁴ All 31 patients continued treatment every 2-4 months for up to 3 years with continued benefit. Multiple temporary adverse effects were reported by 8 of 22 patients (25%) including dysphagia for fluid (n=5), weak cough (n=2), and slight pain at site of injection (n=2).⁶⁴ The study included several important limitations including lack of placebo control group, lack of post-injection assessments and recording during peak effect, and a small sample size.

Overall, although studies show that Dysport may benefit patients with laryngeal dystonia/spasmodic dysphonia, based on the limitations presented above and paucity of literature, there is a low certainty of evidence to support Dysport as a treatment for patients with focal dystonia. Thus, FCSO considers Dysport injections not reasonable and necessary for the treatment of laryngeal dystonia/spasmodic dysphonia.

Essential Hand Tremor

Tremor, an involuntary rhythmic movement caused by alternating or synchronous contractions of opposing muscles, is a common movement disorder. While pharmaceutical interventions may provide relief for mild or moderate essential tremors, they often fall short for severe tremors that interfere with daily activities. For patients with debilitating tremors, injecting botulinum toxin locally may be considered before more invasive treatments such as thalamic deep brain stimulation.¹⁶

In a Class II placebo-controlled trial,⁸² 25 participants with moderate to severe hand tremors were randomly assigned to receive either 50 units of Botox or a placebo in wrist muscles of their dominant limb. If the initial injection showed no improvement, a second 100-unit injection could be given after 4 weeks. Over 16 weeks, tremor severity was assessed using rating scales, accelerometry, and disability evaluations every 2 to 4 weeks. Participants treated with BTI showed significant improvement in tremor severity compared to those who received placebo, which persisted throughout the study. Four weeks after injection, 75% of BTI-treated participants reported mild to moderate improvement, compared to 27% in the placebo group (P<0.05). Accelerometry measurements indicated a 30% decrease in tremor amplitude in 9 out of 12 BTI-treated patients versus 1 out of 9 in the placebo group (P<0.05). Although BTI caused mild finger weakness in all patients, no severe, irreversible, or unexpected adverse effects were reported.

Similar findings were observed in another Class II multicenter, double-blind study involving 133 participants with essential tremor.⁸³ Participants received either 50 or 100 units of Botox injected into wrist muscles and were followed for 4 months. While postural tremor showed substantial improvement, kinetic tremor and functional assessments saw only minor enhancements.

Additional studies, including a systematic review published in 2019,⁸⁴ provide further support for the use of Botox in the treatment of patients with essential hand tremor for whom conservative treatment options were unsuccessful.

Based on the studies described, as well as evidence-based guidelines, Botox is reasonable and necessary for the treatment of essential hand tremors.^{16, 82, 83, 84}

Oromandibular Dystonia (OMD)

Hassel and Charles conducted a systematic literature review to give a summary of the history of oromandibular dystonia, botulinum toxin, and its utilization to treat this focal cranial dystonia.¹⁷ Oromandibular dystonia has various treatment choices consisting of botulinum toxin therapy, medication, and surgical intervention. Botulinum toxin is commonly recognized as a first-line therapy. This review examines literature describing the use of Botox, Dysport, Myobloc, and Xeomin for oromandibular dystonia.

The effectiveness of medication therapy is limited and does not show the same level of value when compared to botulinum toxin. Oral medication treatments are also restricted by systemic side effects not typically experienced with botulinum toxin. Benzodiazepine use is also problematic due to potential tolerance and addiction.

The authors conclude that for the treatment of OMD, Botox and Dysport carry the highest evidence (level of evidence C for both) and therefore this contractor supports them as reasonable and necessary for OMD. However, Xeomin and Myobloc have insufficient evidence to support therapy for OMD (level of evidence U for both); as a result, they cannot be considered reasonable and necessary for this indication.¹⁷

Chronic Motor Tics and Disabling or Aggressive Vocal Tics

Tics, generally linked with Tourette syndrome, are characterized as short, sporadic movements (motor tics) or sounds (vocal or phonic tics), generally led by a premonitory sensation. Current treatment includes anti-dopaminergic drugs (neuroleptics) which are normally successful for multifocal tics. However, the side effects are considered unfavorable especially in individuals with focal tics like blinking, blepharospasm, head jerking, neck twisting, and loud vocalizations, including the involuntary and repetitive use of obscene language.

In preliminary open label Class IV trials,¹⁶ the muscles involved in the motor and phonic tics were injected with botulinum toxin and showed an adequate to significant decrease in the strength and occurrence of the tics, and almost full elimination of the premonitory sensation. In a Class IV trial of 35 study participants treated in 115 sessions for bothersome or incapacitating tics, the average peak effect response was 2.8 (range: 0=no effect, 4=marked improvement in both severity and function). The average duration of improvement was 3.4 months (up to 10.5).⁸⁵ The dormancy to start of improvement was 3.8 days (up to 10). Twenty-one participants out of 25 (84%) with significant premonitory sensory symptoms obtained noticeable relief of these symptoms with BTI (average improvement 70.6%).

A class II trial with 18 study participants with simple motor tics achieved a 39% decrease in the number of tics per minute in 2 weeks following BTI in comparison to a 6% rise in the placebo participants (P=0.004).⁸⁶ Also, a 0.46 decrease in “urge scores” with BTI in comparison to a 0.49 rise in the placebo participants (P=0.02). This underpowered study was unable to reveal sufficient differences in measured variables like severity score, tic suppression, pain, and patient global impression. The maximum results derived from BTI may not have been realized at 2 weeks. Also, it was noted that the study participants did not score themselves as considerably compromised because of their tics, so their symptoms may have been reasonably mild at baseline.

The conclusion for these studies indicates Botox has level C evidence and may be effective for the treatment of motor tics (one Class II study). There is insufficient data to conclude the effectiveness of BTI in phonic tics (one Class IV study).

Pringsheim et al provided a systematic review of the literature to make recommendations on the assessment and management of tics in individuals with Tourette syndrome (TS) and chronic tic disorders.¹⁸ A multidisciplinary panel consisting of 9 physicians, 2 psychologists, and 2 patient representatives developed practice recommendations, integrating findings from a systematic review and following an Institute of Medicine–compliant process to ensure transparency and patient engagement. Recommendations were supported by structured rationales, integrating evidence from the systematic review, related evidence, principles of care, and inferences from evidence.

The systematic review integrates the evidence supporting the effectiveness and detriments of medical, behavioral, and neurostimulation treatments for tics. The treatment of tics must be personalized and based on collaborative determinations among patients, caregivers, and clinicians. Many individuals with tic disorders have psychiatric comorbidities, which require clinicians to set treatment priorities. The management of comorbid conditions is of chief concern in determining treatment options for tics in individuals with TS. Medications, behavioral therapy, and neurostimulation have been shown to significantly decrease tics; however, these treatments seldom fully terminate tics.

The literature shows that injection with Botox are more likely than a placebo to reduce tic severity in adolescents and adults. BTI may also improve premonitory urges.¹⁸ Botox is associated with greater rates of weakness relative to placebo. Also, a common side effect of injecting botulinum toxin in the laryngeal muscles for vocal tics is hypophonia. Botulinum toxin effects generally last for 12-16 weeks, after which injections would need to be repeated.

Recommendations based on the guidelines from Pringsheim et al include: 1) Botulinum toxin injections are recommended for the treatment of adolescents and adults with localized and bothersome simple motor tics when the benefits of treatment outweigh the risks; 2) Botulinum toxin injections are recommended for the treatment of older adolescents and adults with severely disabling or aggressive vocal tics when the benefits of treatment outweigh the risks.¹⁸ In addition, providers must advise patients with tics that treatment with botulinum toxin may cause temporary weakness and hypophonia. Based upon the evidence and consensus-based recommendations, Botox is considered reasonable and necessary for this indication when the benefits outweigh the risks.

Please refer to the related Local Coverage Article: Billing and Coding: Botulinum Toxins (A57715) for documentation requirements, utilization parameters and all coding information as applicable.

N/A

This bibliography presents those sources that were obtained during the development of this policy. The Contractor is not responsible for the continuing viability of Website addresses listed below.

1. Walker TJ, Dayan SH. Comparison and overview of currently available neurotoxins. J Clin Aesthet Dermatol. Feb 2014;7(2):31-9.
2. US Food and Drug Administration. U.S. Food and Drug Administration (FDA) prescribing information for Jeuveau®. Accessed June 19, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761085s001lbl.pdf
3. US Food and Drug Administration. U.S. Food and Drug Administration (FDA) prescribing information for Botox®. Accessed May 10, 2020. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=103000
4. Andolfi C, Fisichella PM. Meta-analysis of clinical outcome after treatment for achalasia based on manometric subtypes. Br J Surg. Mar 2019;106(4):332-341. doi:10.1002/bjs.11049
5. Annese V, Bassotti G, Coccia G, et al. A multicentre randomised study of intrasphincteric botulinum toxin in patients with oesophageal achalasia. GISMAD Achalasia Study Group. Gut. May 2000;46(5):597-600. doi:10.1136/gut.46.5.597
6. Khashab MA, Vela MF, Thosani N, et al. ASGE guideline on the management of achalasia. Gastrointest Endosc. Feb 2020;91(2):213-227 e6. doi:10.1016/j.gie.2019.04.231
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