SPECIAL ARTICLE

Practice guideline update summary: Botulinum

neurotoxin for the treatment of blepharospasm, cervical
dystonia, adult spasticity, and headache
Report of the Guideline Development Subcommittee of the American
Academy of Neurology

David M. Simpson, MD ABSTRACT

Mark Hallett, MD Objective: To update the 2008 American Academy of Neurology (AAN) guidelines regarding bot-
Eric J. Ashman, MD ulinum neurotoxin for blepharospasm, cervical dystonia (CD), headache, and adult spasticity.
Cynthia L. Comella, MD
Methods: We searched the literature for relevant articles and classified them using 2004 AAN
Mark W. Green, MD
criteria.
Gary S. Gronseth, MD
Melissa J. Armstrong, Results and recommendations: Blepharospasm: OnabotulinumtoxinA (onaBoNT-A) and incobotuli-
MD numtoxinA (incoBoNT-A) are probably effective and should be considered (Level B). Abobotulinum-
David Gloss, MD toxinA (aboBoNT-A) is possibly effective and may be considered (Level C). CD: AboBoNT-A and
Sonja Potrebic, MD, PhD rimabotulinumtoxinB (rimaBoNT-B) are established as effective and should be offered (Level A),
Joseph Jankovic, MD and onaBoNT-A and incoBoNT-A are probably effective and should be considered (Level B). Adult
Barbara P. Karp, MD spasticity: AboBoNT-A, incoBoNT-A, and onaBoNT-A are established as effective and should be
Markus Naumann, MD offered (Level A), and rimaBoNT-B is probably effective and should be considered (Level B), for upper
Yuen T. So, MD, PhD limb spasticity. AboBoNT-A and onaBoNT-A are established as effective and should be offered
Stuart A. Yablon, MD (Level A) for lower-limb spasticity. Headache: OnaBoNT-A is established as effective and should
be offered to increase headache-free days (Level A) and is probably effective and should be consid-
ered to improve health-related quality of life (Level B) in chronic migraine. OnaBoNT-A is established
Correspondence to as ineffective and should not be offered for episodic migraine (Level A) and is probably ineffective for
American Academy of Neurology:
chronic tension-type headaches (Level B). Neurology® 2016;86:1818–1826
[email protected]

GLOSSARY
AAN 5 American Academy of Neurology; aboBoNT-A 5 abobotulinumtoxinA; AE 5 adverse event; BDI 5 Blepharospasm
Disability Index; BoNT 5 botulinum neurotoxin; CD 5 cervical dystonia; CI 5 confidence interval; CM 5 chronic migraine;
DAS 5 Disability Assessment Scale; EM 5 episodic migraine; incoBoNT-A 5 incobotulinumtoxinA; onaBoNT-A 5 onabotu-
linumtoxinA; QOL 5 quality of life; RD 5 risk difference; rimaBoNT-B 5 rimabotulinumtoxinB; RMT 5 randomized, masked
trials; TWSTRS 5 Toronto Western Spasmodic Torticollis Rating Scale; TZD 5 tizanidine.

This article summarizes information provided in the BoNT pharmacology is reviewed in the 2008
complete guideline, available on the Neurology® Web AAN guidelines.1–3 BoNT is commercially available
site at Neurology.org. Tables e-1 through e-6 and in 2 serotypes, A and B. There are 4 US Food and
appendices e-1 through e-5, cited in the full guideline Drug Administration2approved preparations of
(data supplement), as well as references e1 through e16, BoNT: onabotulinumtoxinA (onaBoNT-A), abobot-
cited in this summary, are available at Neurology.org. ulinumtoxinA (aboBoNT-A), incobotulinumtox-
In 2008, the American Academy of Neurology inA (incoBoNT-A), and rimabotulinumtoxinB
(AAN) published guidelines on the uses of botulinum (rimaBoNT-B) (table 1). The regulatory-
neurotoxin (BoNT).1–3 New research on 4 approved indications do not necessarily correspond
indications—blepharospasm, cervical dystonia (CD), to those in the evidence-based recommendations
spasticity, and headache—prompted this update. presented here.
Supplemental data
at Neurology.org
From the Department of Neurology (D.M.S., M.W.G.), Icahn School of Medicine at Mount Sinai, New York, NY; Human Motor Control Section
(M.H.), National Institute of Neurological Disorders and Stroke (B.P.K.), National Institutes of Health, Bethesda, MD; Department of Neurology
(E.J.A.), Bronson Neuroscience Center, Bronson Methodist Hospital, Kalamazoo, MI; Department of Neurological Sciences (C.L.C.), Rush
University Medical Center, Chicago, IL; Department of Neurology (G.S.G.), University of Kansas School of Medicine, Kansas City; Department of
Neurology (M.J.A.), University of Maryland, Baltimore; Department of Neurology (D.G.), Geisinger Health System, Danville, PA; Department of
Neurology (S.P.), Kaiser Permanente Los Angeles Medical Center, CA; Parkinson’s Disease Center and Movement Disorders Clinic (J.J.),
Department of Neurology, Baylor College of Medicine, Houston, TX; Department of Neurology and Clinical Neurophysiology (M.N.), Klinikum
Augsburg, Germany; Department of Neurology and Neurological Sciences (Y.T.S.), Stanford University, Palo Alto, CA; and Division of Physical
Medicine and Rehabilitation (S.A.Y.), University of Alberta, Edmonton, Canada.
Approved by the Guideline Development Subcommittee on November 16, 2013; by the Practice Committee on February 27, 2015; and by the
AAN Institute Board of Directors on January 19, 2016.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

1818 © 2016 American Academy of Neurology

ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 superior to placebo (difference in change in Jankovic
Table 1 BoNT preparations and FDA-approved indications
Rating Score6 at week 6, 1.0, 95% confidence interval
BoNT preparation Brand name (manufacturer) FDA-approved indicationsa [CI] 0.5–1.4). Benefit lasted a median of 10.6 weeks.
OnabotulinumtoxinA Botox (Allergan, Inc., Irvine, CA) Blepharospasm, CD, upper A Class II placebo-controlled RMT7 observed that
extremity spasticity, lower aboBoNT-A (40 U, 80 U, or 120 U) improved dis-
extremity spasticity, CM
ability in a dose-related manner on active treatment as
AbobotulinumtoxinA Dysport (Ipsen Ltd., Paris, France) CD, upper extremity
spasticity measured by the Blepharospasm Disability Index8
IncobotulinumtoxinA Xeomin (Merz Pharmaceuticals, Blepharospasm, CD, upper
(BDI) (median change in BDI after 80 U 23.0,
Frankfurt, Germany) extremity spasticity 95% CI 24.0 to 21.0). Benefit lasted 12 weeks with
RimabotulinumtoxinB Myobloc Neurobloc (US CD 40 U and up to 16 weeks with 80 U or 120 U.
WorldMeds/Solstice Neurosciences,
Louisville, KY) A second Class I RMT comparing onaBoNT-A with
incoBoNT-A (1:1 dosing)9 found comparable magni-
Abbreviations: BoNT 5 botulinum neurotoxin; CD 5 cervical dystonia; CM 5 chronic
tude (change in BDI 22.0, p 5 0.148) and duration of
migraine; FDA 5 Food and Drug Administration.
a
FDA approvals relevant to this review. benefit (13 weeks) between BoNT preparations.
A second Class II RMT compared onaBoNT-A
and incoBoNT-A at the same dose with injections
There are important pharmacologic differences
to one eye with one drug and the other eye with
between BoNT preparations, including potency and
the other drug (injected side randomly assigned).
duration of action. Therefore, unlike the approach
No differences were found with multiple measures
taken in the previous guidelines, where BoNT was
over 5 treatment sessions.10
evaluated for safety and efficacy as a single class, in
Commonly reported adverse events (AEs) with
this update we assessed each formulation separately
BoNT injections included periorbital hematoma
for each indication. As a result, the level of support
(25%), ptosis (range of risk differences [RDs] 13%–
for efficacy in the conclusions and recommendations
54%), dry eyes (range of RDs 7.1%–13%), and
may be lower for the individual BoNT formulations
blurred vision (RD 42%).
than it would be had BoNT been considered as a
Four Class IV observational studies reported long-
class. Efficacy of BoNT is for symptomatic control,
term outcomes. Benefit from aboBoNT-A or
as there is no evidence for disease modification.
onaBoNT-A was sustained for at least 15 years in
DESCRIPTION OF THE ANALYTIC PROCESS The 128 patients,11 onaBoNT-A for 10 years in 83
AAN’s Guideline Development Subcommittee patients,12 and incoBoNT-A for 69 weeks in 82 pa-
(appendices e-1 and e-2) assembled an author panel, tients.13 In 288 patients arbitrarily assigned to toxin
balanced in regard to those with and those without formulation, similar degrees of benefit were sustained
potential conflicts, to develop the guideline following for at least 10 years (onaBoNT-A), 15 years (abo-
the processes described in the 2004 AAN guideline BoNT-A), and 5 years (incoBoNT-A).14
process manual.4 A nonconflicted panel member con- No studies meeting inclusion criteria were
firmed the rating of each study. found for rimabotulinumtoxin for treatment of
We performed a systematic review to identify rel- blepharospasm.
evant studies published since the prior guidelines. In Conclusions. OnaBoNT-A (2 Class II studies from
general, only randomized, masked trials (RMTs) were 2008 guideline) and incoBoNT-A (1 Class I study)
considered. To assess long-term outcomes, including are probably safe and effective, and aboBoNT-A
safety, we used evidence from nonrandomized trials. (1 Class II study) is possibly effective, for treating
Twenty-three articles on blepharospasm, 23 on blepharospasm. There is insufficient evidence to
CD, 86 on spasticity, and 28 on headache met inclu- determine the efficacy of rimaBoNT-B.
sion criteria. Table 2 summarizes the conclusions IncoBoNT-A and onaBoNT-A (1 Class I compar-
from this review. ative effectiveness study from the 2008 guideline and
2 more recent comparative effectiveness studies [Class
ANALYSIS OF EVIDENCE Blepharospasm. Blepharo- I and 1 Class II]) are equivalent in efficacy for treating
spasm is a dystonia that can cause disabling eyelid clo- blepharospasm. AboBoNT-A and onaBoNT-A
sure. The 2008 guideline2 concluded that BoNT as a (1 Class II study from the 2008 guideline) are possi-
class is probably safe and effective on the basis of 2 bly equivalent for treating blepharospasm.
Class II studies comparing onaBoNT-A with placebo, Recommendations. OnaBoNT-A and incoBoNT-A
1 Class II study comparing onaBoNT-A with injections should be considered (Level B), and
aboBoNT-A, and 1 Class I study comparing aboBoNT-A may be considered (Level C), as treat-
onaBoNT-A with incoBoNT-A. ment options for blepharospasm.
Since the 2008 publication, 1 Class I RMT found Clinical context. BoNT is considered the first-line
that incoBoNT-A (doses of up to 50 U/eye)5 was treatment of blepharospasm by most movement

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 Table 2 Evidence-based conclusions and recommendations for the efficacy of various botulinum neurotoxin formulations by indication

Level Bb probably Level Cc possibly Level Ud insufficient Level Ae Level Bf

Indication Level Aa effective effective effective evidence ineffective ineffective

Blepharospasm OnabotulinumtoxinA, AbobotulinumtoxinA RimabotulinumtoxinB

incobotulinumtoxinA

Cervical dystonia AbobotulinumtoxinA, OnabotulinumtoxinA,

rimabotulinumtoxinB incobotulinumtoxinA

Upper limb AbobotulinumtoxinA, RimabotulinumtoxinB

spasticityg onabotulinumtoxinA,h
incobotulinumtoxinA

Lower limb OnabotulinumtoxinA, IncobotulinumtoxinA,

spasticity abobotulinumtoxinA rimabotulinumtoxinB

Chronic migraine OnabotulinumtoxinAi

Episodic migraine OnabotulinumtoxinA

Tension-type OnabotulinumtoxinA
headache

Abbreviations: aboBoNT-A 5 abobotulinumtoxinA; incoBoNT-A 5 incobotulinumtoxinA; onaBoNT-A 5 onabotulinumtoxinA; rimaBoNT-B 5

rimabotulinumtoxinB.
a
Level A recommendation for effectiveness signifies intervention should be offered.
b
Level B recommendation for effectiveness signifies intervention should be considered.
c
Level C recommendation for effectiveness signifies intervention may be considered.
d
Level U recommendation signifies insufficient evidence to support or refute effectiveness of intervention.
e
Level A recommendation for ineffectiveness signifies intervention should not be offered.
f
Level B recommendation for ineffectiveness signifies intervention should not be considered.
g
Evidence demonstrates efficacy in reducing spasticity but is inadequate to determine improvement in active function associated with limb spasticity.
h
Probably superior to tizanidine and exercise alone for reducing spasticity.
i
Established as effective for decreasing the number and severity of headaches; probably effective in improvement of health-related quality of life.

disorder specialists.15 All 3 type A toxins appear to reported AE in the incoBoNT-A groups in this study
have similar efficacy and can continue to be effica- was dysphagia (23.4% in the 240 U dose group and
cious over long periods. 10.7% in the 120 U dose group).
Another placebo-controlled study (Class II) of
Cervical dystonia. CD is characterized by involuntary
onaBoNT-A (the original Botox formulation contain-
contractions of neck and upper shoulder muscles, re-
sulting in abnormal postures or movements (or both) ing 25 mg of neurotoxin complex protein per 100
of the neck, shoulder, and head.16 U)20 found that onaBoNT-A produced greater im-
The 2008 guideline2 concluded that BoNT is es- provements in the CD Severity Scale (21.81 vs
tablished as safe and effective for CD treatment on 20.31 points, p 5 0.012) and Global Assessment
the basis of 1 Class I trial of onaBoNT-A, 2 Class I Scale (61.7% vs 41.6% improved, p 5 0.022). Rhi-
trials of aboBoNT-A, and 3 Class I trials of nitis and treatment-related dysphagia were more fre-
rimaBoNT-B. Moreover, on the basis of a single Class quent with onaBoNT-A.
I study comparing aboBoNT-A with trihexyphenidyl, Five studies compared different formulations of
the guideline concluded that BoNT is probably more BoNT. The first 2 studies (Class I)21,22 randomized
efficacious and better tolerated than trihexyphenidyl. patients with CD to onaBoNT-A (1502250 U) or
Since the 2008 guideline publication, 1 placebo- rimaBoNT-B (10,000 U) and noted similar durations
controlled Class I study17 found that incoBoNT-A of effect and no significant difference in improved
(120 U, 240 U) improved Toronto Western Spas- TWSTRS scores at 4 weeks. Dysphagia occurred
modic Torticollis Rating Scale (TWSTRS)18 total more frequently in the rimaBoNT-B group in both
scores from baseline to week 4 (placebo 5 22.2, studies (48% vs 19% in the first study and 16% vs
120 U 5 29.9, and 240 U 5 210.9, p , 0.001). 14.5% in the second study).
A second study (Class II) comparing 2 doses of The third Class I study23 compared the effect of
incoBoNT-A (120 U or 240 U)19 demonstrated that onaBoNT-A 70–240 U with aboBoNT-A 240–720
both doses provided significant improvements in U and observed no difference in the improvement of
mean TWSTRS total scores, and in severity, disabil- posttreatment Tsui scores at 4 weeks (mean difference
ity, and pain subscores, from each injection session to 0.2, 95% CI 20.7 to 1.1, lower scores with
the respective 4-week follow-up visit. There was no aboBoNT-A). In a Class II 9-month randomized,
significant difference in efficacy between the 2 stud- double-blind, multicenter, noninferiority, 2-period
ied doses, although the study was not powered to crossover study with a 2.5:1 (aboBoNT-A:ona-
demonstrate such differences. The most frequently BoNT-A) protocol involving 103 patients with CD,

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 94 of whom completed the study, there were no sta- The guideline also concludes that BoNT is effective
tistically significant differences between aboBoNT-A in treating lower limb spasticity on the basis of 2 Class
and onaBoNT-A in mean changes in the Tsui scale I studies of aboBoNT-A and 1 Class I study of
(0.8 points favoring onaBoNT-A, 95% CI 20.1 to onaBoNT-A. Studies demonstrated that BoNT is
1.7), TWSTRS, global impression, or frequency of effective for reducing muscle tone and improving pas-
AEs from baseline to 4 weeks after each injection.24 In sive function (e.g., improved range of motion) and is
another comparison study (Class II), 46 patients with probably effective for improving active function
CD were enrolled in a double-blind, randomized, (1 Class I study of aboBoNT-A).
crossover trial of onaBoNT-A vs aboBoNT-A in 1:3 Upper extremity spasticity. AboBoNT-A. Four new Class
dose conversion ratios. There was no significant dif- I trials30–33 investigating aboBoNT-A demonstrated
ference between the 2 products at week 4, but at week significant reductions in upper limb tone as measured
12 there was a significantly shorter duration and by the modified Ashworth scale. These studies also
lower efficacy of onaBoNT-A assessed by reduction measured functional outcomes. The first study30
in TWSTRS total score, suggesting that the optimal demonstrated no significant difference in quality of
conversion ratio between onaBoNT-A and life (QOL) but observed significantly greater global
aboBoNT-A is lower than 1:3.25 benefit in patients given BoNT. The second study31
Three long-term, prospective, open-label studies observed no significant difference between groups for
(Class IV)26–28 evaluated the clinical response of improved active arm function as measured by the
repeated injections of onaBoNT-A and found persis- Action Research Arm Test at 1 month (RD favoring
tent benefit for up to 2 years. the BoNT group 5.7%, 95% CI 23.5% to 14.6%).
Conclusions. AboBoNT-A (2 Class I studies reviewed However, participants treated with aboBoNT-A
in the 2008 guideline) and rimaBoNT-B (3 Class I showed improvement in upper limb muscle function
studies reviewed in the 2008 guideline) are established at 3 months as measured by the Motricity Index
as safe and effective for the treatment of CD. (mean change in index 3.5, 95% CI 0.1 to 6.8,
OnaBoNT-A (1 Class I study reviewed in the greater number of points in the intervention group).
2008 guideline, 1 more recent Class II study) and The third study32 demonstrated no significant change
incoBoNT-A (1 more recent Class I study) are prob- in functional assessment scores. The fourth, a more
ably safe and effective for the treatment of CD. recent study,33 showed improved response rate (.1
RimaBoNT-B and onaBoNT-A (2 Class I compar- point) on the principal target of treatment of the Dis-
ative effectiveness studies) are equivalent in efficacy for ability Assessment Scale (DAS), a measure of self-
treating CD. AboBoNT-A and onaBoNT-A (1 Class I reported disability, at 4 weeks among participants
study) are probably equivalent for treating CD. treated with 1,000 U of aboBoNT-A, but not with
Recommendations. AboBoNT-A and rimaBoNT-B 500 U or placebo (62% in 1,000 U, p 5 0.0018 vs
should be offered (Level A), and onaBoNT-A and placebo; 50% in 500 U, p 5 0.1279 vs placebo; and
incoBoNT-A should be considered (Level B), as op- 39.2% in placebo). The higher-dose BoNT-A group
tions for the treatment of CD. also demonstrated improved active range of motion in
the elbow, wrist, and fingers.
Clinical context. BoNT is accepted as first-line treat-
A fifth Class I study34 of patients with upper limb
ment for CD. Although the evidence levels may differ
spasticity focused on caregiver burden. This study
across BoNT serotypes and brands, all formulations
found that 67% of caregivers of patients receiving
have regulatory approval and are commonly used.
aboBoNT-A reported a $4-point reduction on the
There is an extensive clinical history of onaBoNT-A
carer burden scale as compared with 20% of care-
and incoBoNT-A use, but the lack of additional Class
givers of patients injected with saline (p 5 0.001).
I studies led to only a Level B recommendation.
OnaBoNT-A. Four studies (3 Class I,35–37 1 Class
Comparative trials indicate similar efficacy for
II38) demonstrated consistent efficacy in tone reduc-
rimaBoNT-B and onaBoNT-A, and for aboBoNT-A
tion in the upper limb from onaBoNT-A. Scores on
and onaBoNT-A, in the treatment of CD.
the DAS improved only in patients choosing
Spasticity in adults. A 2010 AAN guideline provides improved limb position35,38 and dressing36 as princi-
recommendations for BoNT treatment of spasticity pal treatment goals. One of the Class I studies37
in pediatric patient populations,29 and therefore this enrolled 21 patients and failed to demonstrate signif-
review discusses only adult spasticity. icant effects of BoNT on many functional outcomes.
The 2008 guideline1 concludes that BoNT is However, this study was underpowered to exclude
established as effective in the treatment of adult potentially important differences. In these studies
spasticity in the upper extremity on the basis of 6 onaBoNT-A was well tolerated, with no significant
Class I studies of aboBoNT-A, 4 Class I studies of difference observed in the overall AE incidence
onaBoNT-A, and 1 Class I study of rimaBoNT-B. between treatment and placebo groups.

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 Using goal attainment scaling scores as the pri- Lower extremity spasticity. One placebo-controlled
e4
mary endpoint measure, another Class I study (pro- Class I study published since the 2008 guideline
spective, double-blind) randomized participants to examined aboBoNT-A use in multiple sclerosis and
1 of 2 groups: onaBoNT-A plus standard of care or observed reduced pain in both legs in patients ran-
placebo plus standard of care. No difference was domized to aboBoNT-A (RD proportion of patients
found between groups with respect to achievement reporting decreased pain at 12 weeks 29.9%, 95% CI
of principal and secondary active functional goals. 10.9%–46%). Three Class I studies of onaBoNT-A
Significantly more patients achieved their secondary in the treatment of adult lower limb spasticitye52e7
passive goal with onaBoNT-A plus standard of care demonstrated significant reduction in tone but found
vs placebo plus standard of care at week 24, but not inconsistent results in regard to functional measures.
at week 12 or week 52.39 The literature search did not identify studies meet-
IncoBoNT-A. Two new Class I trials40,e1 showed sig- ing inclusion criteria addressing the efficacy of
nificant improvement in tone reduction with incoBoNT-A or rimaBoNT-B for adult lower limb
incoBoNT-A. In the first trial, incoBoNT-A pro- spasticity.
duced a greater proportion of participants with Conclusions. AboBoNT-A and onaBoNT-A are es-
$1-point improvement in the Ashworth scale score tablished as safe and effective for the reduction of
at 4 weeks (odds ratio 3.97, 95% CI 1.9–8.3). In the adult lower limb spasticity (multiple Class I studies).
second study, participants treated with incoBoNT-A Data are inadequate to determine the efficacy of
demonstrated larger reductions in Ashworth scale incoBoNT-A or rimaBoNT-B for improvement of
scores of muscle groups in the primary target clinical active function in adult lower limb spasticity.
pattern (20.9 with incoBoNT-A vs 20.5 with pla- Data are inadequate to determine the efficacy
cebo, p , 0.001) as well as a greater proportion with of aboBoNT-A, onaBoNT-A, incoBoNT-A, or
.1-point improvement (69.6% vs 37.5%, respec- rimaBoNT-B for improvement of active function
tively). Both studies also showed that incoBoNT-A associated with adult lower-limb spasticity (no studies
produced greater response in all domains of the DAS available or inconsistent results dependent on specific
and global assessment of benefit. The open-label outcome from multiple Class I studies).
extension study of the first trial showed persistence Recommendations. For focal manifestations of adult
of benefit without detection of neutralizing spasticity involving the lower limb that warrant treat-
antibodies.e2 ment, onaBoNT-A and aboBoNT-A should be
RimaBoNT-B. In a newer Class I study,e3 patients offered (Level A) as treatment options.
were randomized to 1 of 2 doses of rimaBoNT-B or There is insufficient evidence to support or refute
placebo. Patients randomized to either BoNT dose a benefit of incoBoNT-A or rimaBoNT-B for treat-
had improved active elbow extension vs placebo ment of adult lower limb spasticity.
(18.3°, 95% CI 1.1°–15.5°). There was no signifi- Comparative studies. In a Class I study of patients
cant change as compared with placebo in upper limb with adult upper limb spasticity, onaBoNT-A was
function as measured by the Modified Frenchay superior to tizanidine (TZD) for improving wrist
Scale. and finger flexor tone, whereas TZD showed no ben-
Conclusions. AboBoNT-A, incoBoNT-A, and efit over placebo. Notably, the high incidence of AEs
onaBoNT-A are established as safe and effective for with TZD limited dose titration (90.5% of patients
the reduction of adult upper limb spasticity and receiving TZD experienced one or more AEs).35
improvement of passive function (multiple Class I Conclusions. OnaBoNT-A is probably superior to
studies for all preparations). TZD for reducing upper extremity tone (1 Class I
RimaBoNT-B is probably safe and effective for the study) in adult spasticity.
reduction of adult upper limb spasticity (1 Class I Recommendations. OnaBoNT-A should be consid-
study). ered as a treatment option before TZD for treating
Data are inadequate to determine the efficacy adult upper extremity spasticity (Level B).
of aboBoNT-A, onaBoNT-A, incoBoNT-A, or Techniques to optimize response to BoNT. Two Class I
rimaBoNT-B for improvement of active function studiese8,e9 demonstrated that high-volume injections
associated with adult upper limb spasticity (Class I of onaBoNT-A and endplate targeting into proximal
studies, inconsistent results dependent on active func- upper extremity muscles are probably effective strat-
tional outcome). egies for enhancing tone reduction in adult spasticity.
Recommendations. For focal manifestations of adult One Class II studye10 compared 3 different tech-
spasticity involving the upper limb, aboBoNT-A, in- niques for guiding BoNT injection placement (man-
coBoNT-A, and onaBoNT-A should be offered ual needle placement, electrical stimulation, and
(Level A), and rimaBoNT-B should be considered ultrasonography) and did not find consistent out-
(Level B), as treatment options. comes favoring one technique.

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 Conclusions. Both high-volume, low-potency injec- with BoNT injections met inclusion criteria. There
tions of onaBoNT-A and endplate targeting into also are no studies comparing different BoNT sero-
proximal upper extremity muscles are probably effec- types in headache.
tive strategies for enhancing tone reduction in adult AEs of onaBoNT-A included neck pain and mus-
spasticity (1 Class I study for each technique). cle weakness.
There is insufficient evidence to support or refute Conclusions. OnaBoNT-A is established as safe and
the superiority of specific techniques for guiding effective for reducing the number of headache days in
BoNT injection placement (inconsistent outcomes CM (2 Class I studies) and probably effective for
from 1 Class II study). improving health-related QOL (1 Class I study).
Recommendations. Both high-volume, low-potency There is insufficient evidence to compare the
injections of onaBoNT-A and endplate targeting of effectiveness of BoNT with that of oral prophylactic
onaBoNT-A into proximal upper extremity muscles topiramate. No Class I or II studies of other formula-
should be considered to enhance tone reduction in tions of BoNT in CM have been published.
spasticity (Level B). Recommendations. OnaBoNT-A should be offered
Clinical context. Although BoNT can reduce as a treatment option to patients with CM to increase
increased tone in spasticity, the impact of BoNT injec- the number of headache-free days (Level A) and
tions on functional outcomes is mixed, suggesting that should be considered to reduce headache impact on
potential functional gains are highly patient-specific. health-related QOL (Level B).
Because of the lack of comparative trials, there is insuf- Clinical context. Although the reduction of headache
ficient evidence to indicate that any one of the BoNT days with onaBoNT-A was statistically superior to
formulations is superior to the others. placebo in 2 Class I studies, the magnitude of the dif-
Headache. Chronic migraine. Chronic migraine (CM)
ference is small (1.7 and 2.3).
Episodic migraine. The 2008 guideline conclusion,3
refers to migraine attacks occurring 15 days or more
monthly for at least 3 months, with attacks lasting based on 2 Class I and 2 Class II studies, indicates
4 hours or more.e11 Episodic migraine (EM) refers onaBoNT-A injection is probably ineffective for treat-
to migraine with a lesser frequency of attack. The ment of EM. One Class I studye16 published since the
2008 guideline found inconsistent results from 4 2008 guideline compared onaBoNT-A at doses of 75
Class II studies comparing onaBoNT-A with placebo, U, 150 U, and 225 U with placebo, using 3 treatment
resulting in insufficient evidence to support or refute cycles 3 months apart. OnaBoNT-A was ineffective for
a benefit of BoNT for treatment of CM.3 reducing migraine frequency from baseline to day 180.
Conclusion. OnaBoNT-A is ineffective for the treat-
Comparison of BoNT with placebo. Two Class I placebo-
controlled studiese12,e13 published since the 2008 ment of EM (3 Class I studies, 2 from the 2008
guideline met inclusion criteria. In one study,e12 report).
Recommendation. OnaBoNT-A should not be
onaBoNT-A was ineffective for changes from baseline
for total headache episodes but was effective for the offered as a treatment for EM (Level A).
Tension-type headache. No new studies were identi-
secondary endpoint of change in frequency of total
headache days/28 days (mean intergroup difference fied that would have changed the conclusion of the
21.4 days, 95% CI 22.4 to 20.40). In the second 2008 guideline.3 BoNT injection is probably ineffec-
study,e13 onaBoNT-A was effective for reducing total tive for treating chronic tension-type headaches
headache days/28 days from baseline to weeks 21–24 (2 Class I studies).
posttreatment. Nine fewer headache days were seen in
AUTHOR CONTRIBUTIONS
the BoNT-A group, with 6.7 in the placebo group (p ,
David M. Simpson: study concept and design, acquisition of data, anal-
0.001). In both studies the placebo response was high. ysis or interpretation of data, drafting/revising the manuscript, critical
Several follow-up reports describing pooled analyses revision of the manuscript for important intellectual content, study super-
of both Class I studies have been published. One Class vision. Mark Hallett: study concept and design, acquisition of data, anal-
ysis or interpretation of data, drafting/revising the manuscript, critical
I follow-up reporte14 described significant reduction in revision of the manuscript for important intellectual content, study super-
headache impact and improvement in health-related vision. Eric J. Ashman: acquisition of data, analysis or interpretation of
QOL after 24 weeks of double-blind treatment (pro- data, drafting/revising the manuscript, critical revision of the manuscript
for important intellectual content. Cynthia L. Comella: acquisition of
portion of patients with severe Headache Impact Test
data, analysis or interpretation of data, drafting/revising the manuscript,
scores 67.6% of patients given BoNT vs 78.2% of critical revision of the manuscript for important intellectual content.
patients given placebo, p , 0.001). Mark W. Green: acquisition of data, analysis or interpretation of data,
Comparison of BoNT with other headache preventive treat- drafting/revising the manuscript, critical revision of the manuscript for
important intellectual content. Gary S. Gronseth: study concept and
ments. One Class III studye15 demonstrated similar effi-
design, acquisition of data, analysis or interpretation of data, drafting/
cacy for onaBoNT-A and topiramate in CM. No revising the manuscript, critical revision of the manuscript for important
other studies comparing oral preventive medications intellectual content. Melissa J. Armstrong: acquisition of data, analysis or

Neurology 86 May 10, 2016 1823

ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 interpretation of data, drafting/revising the manuscript, critical revision of regarding the information. AAN specifically disclaims any warranties of mer-
the manuscript for important intellectual content. David Gloss: acquisi- chantability or fitness for a particular use or purpose. AAN assumes no
tion of data, analysis or interpretation of data, drafting/revising the man- responsibility for any injury or damage to persons or property arising out
uscript, critical revision of the manuscript for important intellectual of or related to any use of this information or for any errors or omissions.
content. Sonja Potrebic: acquisition of data, analysis or interpretation
of data, drafting/revising the manuscript, critical revision of the manu-
script for important intellectual content. Joseph Jankovic: acquisition of
CONFLICT OF INTEREST
data, analysis or interpretation of data, drafting/revising the manuscript, The American Academy of Neurology is committed to producing inde-
critical revision of the manuscript for important intellectual content. Bar- pendent, critical, and truthful clinical practice guidelines (CPGs). Signif-
bara P. Karp: acquisition of data, analysis or interpretation of data, draft- icant efforts are made to minimize the potential for conflicts of interest to
ing/revising the manuscript, critical revision of the manuscript for influence the recommendations of this CPG. To the extent possible, the
important intellectual content. Markus Naumann: acquisition of data, AAN keeps separate those who have a financial stake in the success or fail-
analysis or interpretation of data, drafting/revising the manuscript, critical ure of the products appraised in the CPGs and the developers of the
revision of the manuscript for important intellectual content. Yuen T. So: guidelines. Conflict of interest forms were obtained from all authors
acquisition of data, analysis or interpretation of data, drafting/revising the and reviewed by an oversight committee prior to project initiation.
manuscript, critical revision of the manuscript for important intellectual AAN limits the participation of authors with substantial conflicts of inter-
content. Stuart A. Yablon: acquisition of data, analysis or interpretation est. The AAN forbids commercial participation in, or funding of, guide-
of data, drafting/revising the manuscript, critical revision of the manu- line projects. Drafts of the guideline have been reviewed by at least 3
script for important intellectual content. AAN committees, a network of neurologists, Neurology peer reviewers,
and representatives from related fields. The AAN Guideline Author Con-
flict of Interest Policy can be viewed at www.aan.com. For complete
ACKNOWLEDGMENT
information on this process, access the 2004 AAN process manual.4
The authors thank Erin Hagen, Julie Cox, and Thomas Getchius for edi-
torial assistance.
Received June 8, 2015. Accepted in final form December 21, 2015.
STUDY FUNDING
REFERENCES
This guideline was developed with financial support from the American
Academy of Neurology. Authors who serve as AAN subcommittee mem- 1. Simpson M, Gracies JM, Graham HK, et al; for the Ther-
bers or methodologists (E.J.A., G.S.G., M.J.A., D.G., S.P.) were reim- apeutics and Technology Assessment Subcommittee of the
bursed by the AAN for expenses related to travel to subcommittee American Academy of Neurology. Assessment: botulinum
meetings where drafts of manuscripts were reviewed. neurotoxin for the treatment of spasticity (an evidence-
based review): report of the Therapeutics and Technology
DISCLOSURE Assessment Subcommittee of the American Academy of
D. Simpson has received research grants from and served as a consultant Neurology. Neurology 2008;70:1691–1698.
for Allergan Inc., Ipsen Ltd., Merz Pharmaceuticals, and Acorda Thera- 2. Simpson M, Blitzer A, Brashear A, et al; for the Thera-
peutics. M. Hallett serves as a chair of the Neurotoxin Institute Advisory peutics and Technology Assessment Subcommittee of the
Council and has received research grants from Allergan Inc. and Merz American Academy of Neurology. Assessment: botulinum
Pharmaceuticals. E. Ashman served as a paid editor for Neurology® from neurotoxin for the treatment of movement disorders (an
2011 to 2013. C. Comella has received research grants from and has
evidence-based review): report of the Therapeutics and
served as a consultant for Allergan Inc., Ipsen Ltd., Merz Pharmaceut-
Technology Assessment Subcommittee of the American
icals, and Revance Pharmaceuticals. M. Green and G. Gronseth report no
disclosures relevant to the manuscript. M. Armstrong serves on the Level
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of Evidence Review Team for Neurology (not compensated financially) 3. Naumann M, So Y, Argoff CE, et al; for the Therapeutics
and serves as an evidence-based methodologist for the AAN. She has no and Technology Assessment Subcommittee of the Ameri-
conflicts of interest related to the topic of this guideline. D. Gloss and S. can Academy of Neurology. Assessment: botulinum toxin
Potrebic report no disclosures relevant to the manuscript. J. Jankovic has in the treatment of autonomic disorders and pain (an
received research grants from and served as a consultant for Allergan Inc., evidence-based review): report of the Therapeutics and
Ipsen Ltd., and Merz Pharmaceuticals. B. Karp has received a research Technology Assessment Subcommittee of the American
grant from Allergan Inc. M. Naumann has served as a consultant for Academy of Neurology. Neurology 2008;70:1707–1714.
Allergan Inc. and Ipsen Ltd. Y. So reports no disclosures relevant to the
4. American Academy of Neurology. Clinical Practice Guide-
manuscript. S. Yablon has served as a consultant for Allergan Inc., Ipsen
lines Process Manual, 2004 ed. St. Paul, MN: The Amer-
Ltd., Medtronic Inc., and Merz Pharmaceuticals. Go to Neurology.org
for full disclosures.
ican Academy of Neurology; 2004. Available at: https://
www.aan.com/Guidelines/Home/UnderDevelopment.
Accessed August 1, 2011.
DISCLAIMER
Clinical practice guidelines, practice advisories, systematic reviews, and
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considered inclusive of all proper treatments, methods of care, or as a 6. Jankovic J, Orman J. Botulinum A toxin for cranial-
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between the time information is developed and when it is published or 7. Truong D, Comella C, Fernandez HH, Ondo WG; Dys-
read); (3) addresses only the question(s) specifically identified; (4) does
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tended to substitute for the independent professional judgment of the
treating provider, as the information does not account for individual var-
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1824 Neurology 86 May 10, 2016

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ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Practice guideline update summary: Botulinum neurotoxin for the treatment of
blepharospasm, cervical dystonia, adult spasticity, and headache: Report of the
Guideline Development Subcommittee of the American Academy of Neurology
David M. Simpson, Mark Hallett, Eric J. Ashman, et al.
Neurology 2016;86;1818-1826 Published Online before print April 18, 2016
DOI 10.1212/WNL.0000000000002560

This information is current as of April 18, 2016

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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since
1951, it is now a weekly with 48 issues per year. Copyright © 2016 American Academy of Neurology. All
rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.