Compliance with the provisions in this LCD may be monitored and addressed
through post payment data analysis and subsequent medical review audits.

**History/Background and/or General Information**

Clostridium botulinum toxin describes a family of neurotoxins produced by the
anaerobic bacteria of the species C. botulinum. There are seven 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 four distinct serotype A botulinum toxin products,
onabotulinumtoxinA (Botox), abobotulinumtoxinA (Dysport),
incobotulinumtoxinA (Xeomin), and prabotulinumtoxinA-xvfs (Jeuveau), and one
serotype B botulinum toxin product, rimabotulinumtoxinB (Myobloc) that have
been approved by the U.S. Food and Drug Administration (FDA). Jeuveau is
indicated for cosmetic use only.2

Whether a botulinum toxin is produced from the same or a 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 and Myobloc, as well as other botulinum toxin products
available internationally, are not interchangeable. They are chemically,
pharmacologically and clinically distinct.1

Botulinum toxin injections 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 (involuntary) 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.

The overall coverage of drugs is addressed in the CMS IOM Publication 100-02,
_Medicare Benefit Policy Manual_ , Chapter 15, Sections 50.4.1 and 50.4.2 and
includes coverage for FDA-approved drugs and unlabeled use of a drug.

**Covered Indications**

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

Botulinum toxins (Botox, Dysport, Xeomin and Myobloc), will be considered
medically reasonable and necessary when administered for treatment of FDA-
labeled indications and Off-label indications (as applicable) below:

  1. FDA3 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](https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=103000)

  2. Off-Label indications for onabotulinumtoxinA (Botox) may be considered medically reasonable and necessary in patients for the following conditions: 
    * Esophageal achalasia in adults who are considered poor surgical candidates4
    * Chronic anal fissure for patients with inadequate response to conservative or pharmacologic treatment5
    * 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 primidone6
    * Focal limb dystonia6
    * Hemifacial spasm in adults (cranial nerve VII disorder)6
    * Isolated oromandibular dystonia in adults7
    * Laryngeal dystonia (spastic dysphonia) for adductor type (ADSD)6
    * Bothersome simple motor tics in adolescents and adults when the benefits of treatment outweigh the risks8
    * Severely disabling or aggressive vocal tics in older adolescents and adults when the benefits of treatment outweigh the risks8

  3. FDA9 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](https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125274)

  4. Off-label indications for abobotulinumtoxinA (Dysport) may be considered medically reasonable and necessary in patients for the following conditions:

  *     * Blepharospasm in adults6,7
    * Hemifacial spasm in adults (cranial nerve VII disorder)6
    * Isolated oromandibular dystonia in adults7

  5. FDA10 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](https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125360)

  6. FDA11 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](https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=103846)

**Limitations**

  1. Localization procedures would not be expected for easily targeted muscles and, therefore, would not be considered medically reasonable and necessary.7

  2. Cosmetic procedures are not a covered benefit under Medicare.

  *     * Treatment of wrinkles, also referred to as glabellar lines, smoker's lines, crow's feet, laugh lines and aging neck, using botulinum toxins is considered to be a cosmetic procedure, and is 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.

**Gastrointestinal**

**Achalasia**  
The American College of Gastroenterology has provided evidence based clinical
practice guidelines for the diagnosis and management of achalasia. Achalasia
is a condition where the muscles in the lower part of the esophagus do not
relax and prevent the passage of food. Botulinum toxin has a strong
recommendation based on moderate quality evidence in patients who are not
candidates for pneumatic dilation (PD) or surgical myotomy.4 Serious side
effects are rare. In comparative effectiveness studies, PD was found to be
superior to botulinum toxin, demonstrating PD is more effective in the long
term, and therefore only patients who are not candidates for pneumatic
dilation, or surgical myotomy, are eligible for botulinum toxin.

**Technical Assessments**  
A Cochrane database review of 6 studies included 178 patients and discovered
no significant difference in remission between PD and botulinum toxin
treatment within 4 weeks of the initial intervention. Three studies included
in the review had 12-month data with remission in 33 of 47 PD patients
compared with 11 of 43 botulinum toxin patients (relative risk of 2.67, 95%
confidence interval 1.58-4.52). 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 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 adaptation 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 2013.5 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 al.5 released the American College of Gastroenterology practice
guideline for management of benign anorectal disorders which discuss the
definitions, diagnostic criteria, differential diagnoses, and treatments of a
set of benign disorders of anorectal function and/or structure. Studies5 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.

Currently, a consensus has not been reached on dosage, exact site of
administration, number of injections, or effectiveness. Greater doses may
increase healing and are considered as safe as lower doses. The effects of
botulinum toxin may be potentiated by topical nitrate medications in patients
with refractory anal fissure. Botulinum toxin 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 botulinum toxin injection therapy.

Other benign anorectal disorders which include defecatory disorders, fecal
incontinence and chronic proctalgia lack evidence for botulinum toxin
administration.

**Neurology**  
The American Academy of Neurology (AAN)12 has produced a clinical practice
guideline process manual that includes a discussion regarding elements of
recommendations and levels of evidence (see tables below).

**Level (Quality) of Evidence**  
  
---  
  
**Level A (High)**

|

**Level B (Moderate)**

|

**Level C (Low)**  
  
  * High quality evidence from more than 1 random controlled trial (RCT)
  * Meta-analyses of high-quality RCTs
  * Several high-quality studies with consistent results





|

  * Moderate quality evidence from 1 or more RCTs
  * Meta-analyses of moderate quality RCTs
  * Moderate quality evidence from 1 or more well designed nonrandomized studies or meta-analyses of such studies



|

  * Randomized or nonrandomized observational or registry studies with limitations of design
  * Meta-analyses of such studies
  * Consensus of expert opinion
  * Case studies
  * Practice guidelines
  * Reviews





  
  
**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.12  
  


**Class (Strength) of Recommendation**

**Measures the Risk of Bias**  
  
---  
  
Class I Studies (Strong)





|

Studies are judged to have a low risk of bias; randomization of patients is
effectively balanced between treatment and comparison groups for important
confounding baseline differences.  
  
Treatment is recommended/is indicated/useful/effective/beneficial.  
  
Class IIa Studies (Moderate)

|

Studies have a moderate risk of bias; patients in different treatment groups
match on all known baseline confounders.  
  
Recommendation is reasonable/can be useful/effective/beneficial.  
  
Class IIb Studies (Weak)

|

Studies have a moderate to high risk of bias; patients in different treatment
groups may not match on all important confounders.  
  
Additional studies needed. Usefulness/effectiveness is
unknown/unclear/uncertain or not well established.  
  
Class III Studies (No Benefit)

|

Studies have a moderately high risk of bias; patients in different treatment
groups do not match on all important confounders.  
  
Therapy is not recommended/not useful/effective and may be harmful.12  
  


**Blepharospasm**  
The American Academy of Neurology has provided recommendations for the use of
botulinum neurotoxin in blepharospasm based on the following studies:

One Class II and one Class III study6 compared two different serotype A
botulinum neurotoxins (Botox and Dysport). 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 two 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 two 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.

The conclusion for these studies indicate Botox and Xeomin have level B
evidence, Dysport has level C evidence. 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.

**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 technique.

A Class II study6 comprised of 11 patients was a prospective, blinded trial
with four arms: a random dose based on clinical experience of between 2.5 and
10 units of BoNT-A (Botox), half the dose, double the dose, and saline
placebo. Patients went through the four treatment arms in random order.
Utilization of a clinical scale to rate videotapes and a patient subjective
scale, 84% had objective improvement with a minimum of one of the active doses
with a tendency for an improved response with higher dose; only one
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.

A Class III study6, a double-blind, prospective, parallel design including
only four participants per group used individualized therapy (dose range 2.5
to 40 units) with BoNT-A (Botox) in the active arm. In addition, 93 patients
studied in an open label fashion were reported. More improvement was shown on
a clinical scale with BoNT than with a saline placebo. Improvement continued
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 study6 contrasted Botox and Dysport in a parallel design
without placebo control or blinded raters. 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
two products. Therapeutic effects lasted 2.6-3.0 months.

The conclusion for these studies signifies botulinum neurotoxin may be
considered as a treatment for hemifacial spasm. Botox and Dysport have level
C evidence and after dosage modification, are comparable in effectiveness.

**Focal limb dystonia**  
Focal hand dystonia is also referred to as writer's cramp, other occupational
hand dystonia, and non-task-specific hand dystonia. Currently, no effective
alternative medical or proven surgical therapies have been established for
focal limb dystonia.

A Class I trial6 randomized 40 study participants with writer's cramp in a
double-blind design for botulinum neurotoxin (BoNT) or an equal amount of
saline placebo. Clinical assessment was utilized in selecting the muscle to be
injected. Study participants with insufficient or no response were offered a
second injection one month later. The chief outcome measure was the patient's
indicated request to continue injection therapy. In patients randomized to
BoNT, 70% requested to maintain treatment in comparison to 32% of those who
received a placebo (p = 0.03). Patients injected with BoNT also had
considerable improvement in comparison to patients who had been given a
placebo 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. The only side effects
reported were temporary weakness and pain at the injection site.

One Class II trial, a prospective, double-blind, crossover study6 comprised 17
study participants with several forms of limb dystonia, including lower
extremity (3 patients) and secondary dystonia (4 patients). Study participants
were given a series of four injections in arbitrary order, one with a dose of
BoNT that the investigators judged to be "optimal," one at half the optimal
dose, one at double the dose, and one with saline placebo. Per a patient
subjective scale, 82% of patients who received BoNT experienced improvement
compared to 6% (one patient) who received placebo. Using physician rating of
videotapes, 59% of patients experienced improvement with active treatment and
38% with placebo (not significant). A dose-response association for
improvement was not evident. A considerable degree of inter-observer
inconsistency was shown, which was attributed to an inadequate outcome
evaluation. The principal side effect after BoNT injections was focal weakness
(53%) with increased probability with higher doses. Weakness was experienced
with 13% of placebo injections and additional adverse effects involved muscle
stiffness, pain, and malaise.

Another Class II study6 utilized a placebo-controlled, double-blind, crossover
design for 20 individuals with writer's cramp. Clinical assessment was
utilized in selecting the muscle to be injected and the dose of BoNT-A was
founded on investigator experience. Outcome evaluations included assessment of
writing speed, accuracy, writing samples, and patients' subjective report.
There was substantial improvement with BoNT therapy 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 one
participant. This study only evaluated the first active therapy session for
study participants; therefore, the therapeutic effects achieved were not
optimal.

An additional Class II trial6 was a double-blind, placebo-controlled,
crossover design with 10 study participants with focal hand dystonia. Muscles
and BoNT-A (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 six had improved videotape ratings with BoNT in
comparison with placebo. Weakness was noted in the injected muscles of 80% of
study participants with active treatment.

Three Class II studies6 assessed technical issues of BoNT administration. In
one trial, a blinded, randomized, crossover design was utilized to contrast
continuous muscle activation to immobilization immediately following BoNT
injection. 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 different Class II study,
participants were randomized to one of two 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 established on surface anatomy,
37% were localized in the targeted muscle.

The therapy for focal limb dystonia with BoNT is challenging, especially in
reaching adequate neuromuscular blockade to relieve dystonic movements without
initiating excessive muscle weakness.

The conclusion for these studies signifies Botox has level B evidence and
should be considered as a treatment option for focal limb dystonia.

**Laryngeal dystonia**  
Laryngeal dystonia (spasmodic dysphonia) commonly presents as adductor type
(ADSD) and less commonly as abductor type (ABSD). The voice of an individual
with ADSD is described as strained or strangled, while ABSD generates a weak
and breathy voice. Currently, no effective alternative medical or surgical
therapies have been established for spasmodic dysphonia.

One Class I trial6 of botulinum neurotoxin (BoNT) for 13 study participants
with ADSD, a double-blind, randomized, parallel group study, compared seven
patients who received BoNT with six patients who received saline. Outcome
measures comprised instrumental quantitative measures of voice function and
patient ratings. Substantial benefit was achieved in the study participants
who received BoNT (p = 0.01).

One Class III trial6 discovered that adding voice therapy after BoNT therapy
in ADSD patients extended improvements from the BoNT treatment. Another study
discovered that resting the voice for 30 minutes following the BoNT injection
extended the therapeutic effects of BoNT. One Class III study of 15
participants with ABSD did not observe a noteworthy distinction between using
percutaneous or endoscopic injection technique.

The conclusion for these studies signifies Botox has level B evidence and
should be recommended as a treatment option for adductor spasmodic dysphonia
(ADSD); however, there is inadequate evidence to support the effectiveness for
botulinum neurotoxin in abductor spasmodic dysphonia (ABSD).

**Chronic 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,6 the muscles involved in the motor
and phonic tics were injected with botulinum neurotoxin (BoNT) 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
length of improvement was 3.4 months (up to 10.5). 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 BoNT (average improvement 70.6%).

A class II trial6 with 18 study participants with simple motor tics achieved a
39% decrease in the number of tics per minute in 2 weeks following BoNT
injection in comparison to a 6% rise in the placebo participants (p=0.004).
Also, a 0.46 decrease in "urge scores" with BoNT 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 BoNT 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 BoNT in phonic tics (one
Class IV study).

Pringsheim et al8 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. 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.  
  
Comprehensive Behavioral Intervention for Tics (CBIT) is recommended as an
initial treatment option for individuals with tics causing psychosocial or
physical impairment provided that the individual is motivated to participate
in treatment (Level B). Other behavioral interventions may be recommended if
CBIT is not available, such as exposure and response prevention (Level C).  
  
The literature shows that botulinum toxin injections with onabotulinumtoxinA
are probably more likely than a placebo to reduce tic severity in adolescents
and adults. Botulinum toxin injections may also improve premonitory urges.
OnabotulinumtoxinA 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 this study 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
(Level C). 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 (Level C). In addition,
providers must advise patients with tics that treatment with botulinum toxin
may cause temporary weakness and hypophonia.

**Essential hand tremor**  
Tremor, an involuntary, rhythmic movement generated by alternating or
synchronous contractions of antagonistic muscles is a common movement
disorder. While propranolol and primidone normally improve mild or moderate
essential tremor, pharmacotherapy is typically not adequate to control a high-
amplitude tremor that disrupts activities of daily living. In patients with
disabling tremor, local injection of botulinum neurotoxin (BoNT) may be
utilized prior to contemplating more aggressive intervention such as thalamic
deep brain stimulation.

A Class II placebo-controlled trial6 assessed 25 study participants with hand
tremor of 2 (moderate) to 4 (severe) on the tremor severity rating scale.
Patients were randomized to be given either 50 units of BoNT-A (Botox) or
placebo injections into the wrist flexors and extensors of the dominant limb.
If study participants failed to respond to the first injection, another
injection of 100 units could be administered 4 weeks later. Rest, postural,
and kinetic tremor were assessed at 2 to 4-week intervals over a 16-week
period, using tremor severity rating scales, accelerometry, and evaluations of
improvement and disability. There was substantial improvement on the tremor
severity rating scale 4 weeks following injection in participants treated with
BoNT as compared to placebo, and this improvement was maintained for the
length of the study. Four weeks following injection, 75% of BoNT-treated study
participants versus 27% of placebo-treated patients (p < 0.05) conveyed mild
to moderate improvement. While trends were observed for some elements,
functional rating scales did not improve. Postural accelerometry measurements
revealed a 30% decrease in amplitude in 9 of 12 BoNT-treated patients and in 1
of 9 placebo-treated patients (p < 0.05). While all patients treated with BoNT
reported some degree of finger weakness, no severe, irreversible, or
unexpected adverse events transpired.

Comparable results occurred in another Class II multicenter, double-blind,
controlled study6 that used a comparable protocol and included 133 study
participants with essential tremor. Participants were randomized to have 50 or
100 units of Botox injected into wrist flexors and extensors and were then
followed for 4 months. The trial revealed substantial improvement in postural
tremor, however only minimal improvement in kinetic tremor and functional
evaluations.

The study design of both Class II studies restricts their applicability to
clinical practice. Both studies utilized a rigid treatment protocol that
employed a fixed BoNT dose and a predetermined set of muscles. In practice,
dosages and injected muscles are frequently tailored for a patient based on
their tremor pattern.

A Class II study6 of only 10 patients with head tremor failed to demonstrate a
statistically significant benefit in BoNT-treated patients. Two Class IV open-
label studies in voice tremor showed modest improvement from baseline in
objective acoustic and subjective measures following unilateral or bilateral
BoNT injection.

The conclusion for these studies indicates BoNT injection of forearm muscles
may be helpful in reducing the tremor amplitude in patients with essential
hand tremor. The benefits must be considered in conjunction with the common
adverse effect of muscle weakness associated with BoNT injection. Existing
data is insufficient to draw a conclusion on the use of BoNT in the treatment
of head and voice tremor. Botox has level C evidence and should be considered
as a treatment option for essential hand tremor in patients with a high
amplitude tremor that disrupts activities of daily living and have had an
inadequate response to oral agents including propranolol and primidone.

**Oromandibular Dystonia**  
Hassel and Charles7 conducted a systematic literature review to give a summary
of the history of oromandibular dystonia, botulinum neurotoxin (BoNT), and the
utilization of BoNT to treat this focal cranial dystonia. Oromandibular
dystonia (OMD) has various treatment choices consisting of BoNT therapy,
medication, and surgical intervention. Botulinum neurotoxin is commonly
recognized as a first-line therapy.

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

For the treatment of OMD, OnaBoNT/A (Botox) and aboBoNT/A (Dysport) carry
the highest evidence (level of evidence C for both). While IncoBoNT/A
(Xeomin) and RimaBoNT/B (Myobloc) have insufficient evidence to support
therapy for OMD (level of evidence U for both).

Botulinum toxin 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 fairly wide therapeutic window, all botulinum toxin products have a black
box warning regarding 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.9,10,11 Therefore, the lowest effective dose that produces the
desired clinical effect should be used. Treatment effect can last from twelve
to sixteen weeks, with labeled use suggesting a minimum interval of twelve
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**  
Current evidence based guidelines indicate that botulinum toxin therapy for
achalasia is confined to circumstances where pneumatic dilation (PD) and
surgical myotomy are not considered suitable options due to inherent patient-
related risks. In addition to the current guidelines, the IBM Micromedex
compendium DrugDex lends support for Botox as an off-label treatment of
achalasia in adults.13 Therefore, off-label coverage has been extended for
Botox consistent with current evidence based guidelines.

**Chronic anal fissure**  
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, off-label coverage
has been extended for Botox as a treatment option for chronic anal fissure in
patients with inadequate response to conservative or pharmacologic treatment.

**Blepharospasm**  
Studies show Botox and Xeomin may be comparable for the treatment of
blepharospasm following dose modification. Studies signify 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.13 Accordingly, off-label coverage has been extended
for Dysport for the treatment of blepharospasm in adults.

**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. Botox and
Dysport have additional support in the IBM Micromedex compendium DrugDex
for off-label treatment of hemifacial spasm in adults.13 Subsequently, off-
label coverage has been extended for Botox and Dysport as a treatment of
hemifacial spasm in adults.

**Focal limb dystonia**  
Currently, no effective alternative medical or proven surgical therapies have
been established for focal limb dystonia. Studies signify botulinum neurotoxin
should be considered as a treatment option for focal hand dystonia, also
referred to as writer's cramp. Therefore, consistent with evidence based
guidelines, off-label coverage has been extended for Botox as a treatment of
focal limb dystonia.

**Laryngeal dystonia**  
Laryngeal dystonia (spasmodic dysphonia) commonly presents as adductor type
(ADSD) and less commonly as abductor type of spasmodic dysphonia (ABSD).
Presently, no effective alternative medical or surgical therapies have been
established for spasmodic dysphonia. 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 for
botulinum neurotoxin in abductor spasmodic dysphonia (ABSD). Botox has
support in the IBM Micromedex compendium DrugDex for off-label treatment of
spastic dysphonia in adults.13 Consequently, consistent with evidence based
guidelines, off-label coverage has been extended for Botox.

**Essential hand tremor**  
Studies 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.
Therefore, consistent with evidence based guidelines, off-label coverage has
been extended for Botox as a treatment for essential hand tremor for patients
with a high amplitude tremor that disrupts activities of daily living and have
had an inadequate response to oral pharmacotherapy such as propranolol and
primidone.

**Oromandibular dystonia (OMD)**  
Oromandibular dystonia (OMD) 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 botulinum toxin. Oral
medication treatments are also restricted by systemic side effects that are
not typically experienced with botulinum toxin.

Current practice guidelines for botulinum toxins show support for Botox and
Dysport for the treatment of OMD. In addition to the literature, Botox has
support in the IBM Micromedex compendium DrugDex for off-label treatment of
isolated oromandibular dystonia in adults.13 Thus, consistent with evidence
based guidelines, off-label coverage has been extended for Botox and Dysport
as a treatment for isolated oromandibular dystonia in adults.

**Motor tics and disabling or aggressive vocal 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. Evidence based guidelines 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. In addition to the current guidelines, the IBM Micromedex compendium
DrugDex13 lends support for Botox as an off-label treatment of Gilles de la
Tourette's syndrome in adults. Therefore, off-label coverage has been extended
for Botox consistent with current evidence based guidelines.

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