Authors: Sue Apkon, MD and Danielle Cassidy, Pharm.D., BCPS

1. Clinical Review: Focused
Safety Considerations in the Use of Botulinum Toxins
in Children With Cerebral Palsy
Susan D. Apkon, MD, Danielle Cassidy, PharmD
The use of botulinum toxins to decrease spasticity in children with cerebral palsy has
become standard of care during the past decade. In 2008 reports of severe adverse events,
including death, were reported in children who received injections of these medications.
The following discussion focuses on the background of these reports, the response of the
U.S. Food and Drug Administration, as well as the safety profile and pharmacokinetics of
botulinum toxins. Finally, the authors will offer their perspective on the safe use of
botulinum toxins.
PM R 2010;2:282-284
INTRODUCTION
The safe and appropriate use of medications is paramount to the physician code of ethics.
Since 2008, physicians caring for children with cerebral palsy (CP) have been challenged by
information in the lay press regarding the safe and appropriate use of botulinum toxin in this
population of patients. In early 2008, reports of children with CP dying after the injection
of botulinum toxin made its way to newspapers and television, prompting physicians and
their patients to question the safety of this medication [1]. The following discussion focuses
on the background of those reports and the response of the U.S. Food and Drug Adminis-
tration (FDA). The safety profile and pharmacokinetics of botulinum toxins will be reviewed
as well as a summary of the authors’ recommendations on the safe use of botulinum toxins.
Anaerobic Clostridium botulinum produces 7 serotypes of neurotoxin, with Botulinum
toxin type A being the most potent and the first to be manufactured for commercial use
under the brand names of Botox (onabotulinumtoxinA; Allergan, Irvine, CA) and Dysport
(abobotulinumtoxinA; Ipsen Biopharm Ltd., Wrexham, UK). When injected intramuscu-
larly at therapeutic doses, botulinum toxins target receptor binding sites on the motor nerve
terminals, and upon internalization, inhibit the release of the neurotransmitter acetylcholine
into the neuromuscular junction. This action causes partial chemical denervation of the
muscle and results in a reduction of muscle activity. The pharmacologic affects of botulinum
toxins are temporary, as axonal sprouting and the formation of new neuromuscular
junctions may develop. These affects eventually regress as the function of the original
endplate is re-established over time [2].
The onset of muscle weakness usually occurs within 14 days of treatment and the
duration of action averages 3 to 6 months. Because of the eventual reversal of muscle
denervation, treatment frequency is usually determined on the basis of individual patient
response. Dosing intervals of less than 3 months are discouraged because of the risk for S.D.A. Department of Rehabilitation Medicine,
development of neutralizing antibodies, which can lead to treatment resistance or decrease University of Washington; and Department of
Rehabilitation Medicine, Seattle Children’s,
the overall effectiveness of botulinum toxins [3].
M/S W-9847, PO Box 5371, Seattle, WA.
The biological activity of the botulinum toxins is measured in units, with 1 unit of Address correspondence to S.D.A.; e-mail:
botulinum toxin corresponding to the lethal dose capable of killing 50% of a mouse Susan.apkon@seattlechildrens.org
Disclosure: nothing to disclose
population (ie, LD50) with the specific activity of Botox being 20 units per nanogram of
botulinum neurotoxin protein [4]. The units of biological activity between botulinum D.C. Investigational Drug Services & Antico-
agulation Clinical Pharmacist, The Children’s
products are not considered bioequivalent because of distinct manufacturing methods used Hospital, Denver, CO
for each formulation. A number of experimental attempts have been made to establish a Disclosure: nothing to disclose
dose conversion factor for each botulinum product. However, the conversion factors Submitted for publication December 22,
reported in published literature vary, and results from these studies continue to confirm that 2009; accepted February 17, 2010.
PM&R © 2010 by the American Academy of Physical Medicine and Rehabilitation
1934-1482/10/$36.00 Vol. 2, 282-284, April 2010
282
Printed in U.S.A. DOI: 10.1016/j.pmrj.2010.02.006

2. PM&R Vol. 2, Iss. 4, 2010 283
each product differs in terms of unit potencies, efficacy, verse reactions. The petition was a response to reports of hospi-
diffusion, duration of action, and side effects. talization and death of 16 people injected with botulinum toxin,
In 1989 the FDA approved the use of botulinum toxin A including children with CP who had botulinum toxin injected
(Botox) in the treatment of strabismus and blepharospasm. into their lower limbs for control of spasticity.
Approval of Botox for cervical dystonia, primary axillary hyper- The FDA embarked on a systematic review of the literature,
hidrosis, and glabellar lines was obtained in the subsequent postmarketing Adverse Event Reporting System Database, and
decade. Approval of other botulinum toxin formulations was the clinical studies submitted by the manufacturers of the dif-
granted in 2000 (botulinum toxin B; Myobloc) and in 2009 ferent types of botulinum toxins. A search of Adverse Event
(botulinum toxin A; Dysport). In March 2010, the FDA granted Reporting System Database revealed 9 deaths in pediatric pa-
approval for the use of OnabotulinumtoxinA (Botox) for use in tients younger than 16 years of age, with cause of death listed as
adults with upper extremity spasticity due to stroke. Despite cardiorespiratory arrest (n 4), seizure (n 2), fatal arrhyth-
the absence of FDA approval in children, use of botulinum mia (n 1), pneumonia (n 1), and stroke (n 1). Dose
toxins is standard practice in the treatment of spasticity in ranges for serious systemic adverse reactions were reported for
children with CP [5]. Of interest, botulinum toxins have been Botox from 6.25 to 32 units/kg and for Myobloc from 388 to
approved for use in children with CP in Canada, Australia, 625 units/kg. It must be emphasized that all of the children who
and other countries. died reportedly had underlying neuromuscular problems. For
Many researchers have reported the efficacy of the botuli- privacy reasons, the complete details about the circumstances
num toxins over the past decade. Benefits have included a surrounding each of the deaths were not released; however,
decrease in spasticity and improvement in range of motion administration of at least one very high dose (32 units/kg) was
and function [6-12]. In 2000, a consensus statement was reported. This dose is well beyond what has been recommended
published by 15 experienced clinicians and scientists high- in the pediatric literature.
lighting patient selection, dosing guidelines, and injection Additional serious adverse events in pediatric patients
techniques for both upper and lower extremities in children were found in review of the medical literature and included
with CP [13]. The authors stressed the importance of select- systemic weakness requiring mechanical ventilation and se-
ing 1 or 2 muscle groups in the lower limbs and focusing on vere dysphagia requiring gastrostomy feeding [16-22]. Re-
treating dynamic tone in the upper limbs. In addition, the use view of adverse events in the adult population identified 225
of up to 12 units/kg up to a maximum dose of 300 units was case reports that were highly suggestive of distant spread of
recommended. To reduce the risk of secondary unrespon- botulinum toxin leading to recognizable signs and symptoms
siveness caused by the development of neutralizing antibod- of botulism. Doses in adult patients ranged from 100 to 700
ies, the consensus was to inject no more frequently than every units of Botox and 10,000 to 20,000 units of Myobloc.
3 months. Additional recommendations focused on the tar- In April 2009 the FDA issued a report on their review of their
geted dilution, which was a concentration of 100 units in 1 or investigation. The FDA obtained enough evidence that war-
2 mL of normal saline. A subsequent review article [14] in ranted a number of changes that would create an impact on the
which investigators summarized 22 articles published be- prescribing information [23]. The manufacturers of the 3 li-
tween 1993 and 2003 reported that the maximum total dose censed botulinum toxins had to strengthen the warnings in the
injected was 400 units with a maximum dose of 29 units/kg, product labeling and include a Boxed Warning highlighting
and concentrations varying from 50 to 500 units/mL, with the possibility of distant spread of the toxin, potentially
the most common being 100 units/mL. Both of these articles causing life-threatening events. They also had to implement a
described the potential for side effects related to spread of the risk evaluation and mitigation strategy that included a Med-
medication to distant sites. Injectors were implored to con- ication Guide to be provided to patients to help them under-
sider this spread of medication when selecting the appropri- stand the risks and benefits of the injections, as well as a
ate dose and concentration to be used. “Dear Health Care Professional” letter emphasizing the risks.
In January 2008, the consumer group Public Citizen Finally, the FDA required a change in the names of the 3
Health Research Group submitted a petition to the FDA botulinum toxins as a way to highlight the difference in
requesting the agency provide regulatory action regarding potency units of each of the products and remind physicians
the spread of botulinum toxin from the site that was inten- that they cannot compare or convert doses. The FDA an-
tionally injected to a distant site resulting in systemic signs of nounced the new names as OnabotulinumtoxinA (Botox),
botulism [15]. This letter requested the FDA send a warning AbobotulinumtoxinA (Dysport), and RimabotulinumtoxinB
letter directly to physicians alerting them to the problems (Myobloc.) The FDA also urged physicians to be aware that
associated with the toxin, including cases of hospitalization children treated for spasticity are at greatest risk for the
and death. Additionally, the petition asked the FDA to label systemic symptoms. Toxin spread has occurred at doses used
the products with a “black box” warning, the strongest warning to treat cervical dystonia, and even at lower doses, swallow-
the agency can make, and require physicians to give patients a ing and breathing problems can be life-threatening. In addi-
medication guide warning them of possible symptoms of ad- tion, the FDA noted that no serious adverse events caused by

3. 284 Apkon and Cassidy SAFETY AND BOTULINUM TOXINS IN CHILDREN WITH CP
distant spread have been reported with dermatologic use or mittee of the American Academy of Neurology and the Practice Com-
for blepharospasm or strabismus at approved doses. Finally, mittee of the Child Neurology Society. Neurology;74:336-343.
6. Ade-Hall RA, Moore AP. Botulinum toxin type A in the treatment of
the FDA is recommending ongoing monitoring of relevant lower limb spasticity in cerebral palsy. Cochrane Database Syst Rev
safety data. 2000:CD001408.
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children with cerebral palsy: A comprehensive evaluation. Pediatrics
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