Botulinum Toxin Therapy in Children:

The use of botulinum toxin type A (BOTOX) for treating wrinkles has been well publicized. Cosmetic use of this agent is promoted in magazines and on television.

Botulinum toxin has also been used to treat medical ailments.¹ However, its use in children has received very little attention in general pediatric literature. Here we focus on clinical applications of botulinum toxin in children.

What Is Botulinum Toxin?

Before 1897, researchers used the term "botulism poisoning" to describe various illnesses that developed from tainted food. Most commonly, botulism poisoning was described after eating blood sausages. (The Greek word for sausage is botulus). In 1897, E. van Ermengem in Ghent, Belgium, described his research following a group of people who had eaten ham that had been submerged in salt water. They became ill and several died. This ham was then fed to animals including mice, cats, rabbits, and guinea pigs. Subsequent infection led to identification of the anaerobic bacillus, Clostridium botulinum.²

Subsequently, "true" botulism poisoning related to C botulinum infection was found to develop after ingestion of contaminated or improperly prepared food (most commonly in home-canned, low acid foods in which the botulinum toxin was not killed), as a result of wound infection, or from colonization in the GI tract of infants. In the United States, infant botulism is the most common form of botulism poisoning.¹ Limb paralysis, facial weakness, dysarthria, dysphagia, constipation, urinary retention, and dyspnea leading to respiratory failure are all clinical signs of botulism poisoning.

Each year in the United States, over 100 cases of botulism poisoning are known to occur. Approximately 25% of these poisonings are food-borne, over 70% are infant botulism, and the rest are wound-related.

There are 7 antigenically distinct botulinum toxin serotypes: A, B, C, D, E, F, and G. In humans, infection with serotypes A, B, E, and F causes botulism.³

In the late 1940s, Burgen and colleagues⁴ found that botulinum toxin blocks neuromuscular transmission. With this knowledge, researchers attempted to use the toxin as a therapeutic tool. An injectable form of botulinum toxin type A (BOTOX) was subsequently developed. A discussion of its mechanism of action appears in Box I.

Indications for BOTOX in Children

Although some physicians use both botulinum toxin types A and B, toxin A has been used the longest and still is the most commonly used toxin in children. BOTOX is not currently FDA-approved for most uses in pediatric patients.

In children, botulinum toxin type A is primarily used to treat spasticity and dystonia. Spasticity is a disorder of the neuromuscular system characterized by a velocity-dependent increase in muscle tone with excessive deep tendon reflexes. When spasticity restricts motion, disability can occur. Chronic spasticity often leads to muscle contracture, thereby preventing normal control of limb position and movement. Cerebral palsy is the most common cause of spasticity in pediatric patients.

Botulinum toxin type A is also used to treat spasticity caused by stroke, traumatic brain injury, and spinal cord injury. Other potential uses include treatment of torticollis and other cervical dystonias, blepharospasm, oromandibular dystonia, spasmodic dysphonia, and writer's cramp.

The goals of administering botulinum toxin type A injections in children who have spasticity associated with cerebral palsy or other conditions are to:

• Eliminate pain.

• Minimize contractures.

• Delay or prevent surgery.

• Maximize function.

The protocol for evaluation and treatment of the child with botulinum toxin type A includes assessment by a physician (usually a pediatric physiatrist, pediatric neurologist, or pediatric orthopedic surgeon), who--with input from therapists and family--sets goals to be achieved for therapy. Evaluation may include tone, range of motion, strength, and selective motor control and function. Alternative and adjunct treatments, such as serial casting, oral anti-spasticity medications (including baclofen [Lioresal], tizanidine [Zanaflex], diazepam [Valium], and dantrolene [Dantrium]), selective dorsal rhizotomy, and intrathecal baclofen administration need to be discussed with the team and family. In some patients these adjunct treatments are often required in addition to botulinum toxin type A.

Technique of Administration

Botulinum toxin type A is injected directly into the muscle (Box II). In large muscles, the injection is often done "blindly." In muscles that cannot be easily palpated or are difficult to locate, either an electromyogram (EMG) or electrical stimulation can be done to ensure appropriate needle placement and injection. Because an EMG requires the patient to activate the muscle when the needle is in place to assure proper placement, electrical stimulation may have an advantage during the treatment of children.

A child may appear to worsen transiently following botulinum toxin type A injections because as spasticity decreases, muscle weakness previously masked by spasticity may prevail. The child needs time to strengthen the antagonist and agonist muscles. It is critical that following injection of the selected muscles, the patient continues physical and occupational therapies to achieve the goals of treatment.

Dosing and Outcomes

The WE MOVE Spasticity Study Group (www.wemove.org) has suggested a maximum dose of 3 to 6 units/kg for large muscles and 1 to 2 units/kg for small muscles in children. More commonly included muscles include the gastrocnemius and the medial and lateral hamstrings in the lower extremities. The suggested dose for the gastrocnemius and medial hamstrings is 3 to 6 units/kg; 2 to 3 units/kg is the recommended dose for the lateral hamstrings.^5,6

The number of injections depends on the muscle size. The WE MOVE study group also suggested that the maximum total dose (for all muscles) given at one time should not exceed 12 units/kg or 400 units. Nevertheless, some physicians use as much as 30 units/kg or up to 800 units. At our institution, we commonly use 15 to 18 units/kg for a maximum total dose at a single visit.

In some centers, EMLA cream, fluoromethane, or ethyl chloride spray is used to anesthetize the area before the toxin is injected.

An age limit for the use of botulinum toxin type A has not been established, although the product has been used safely in infants as young as 1 month.⁵

Clinical effects can be seen as early as 5 to 7 days after injection. With aggressive physical and occupational therapies and home stretching exercises, improvements in spasticity, range of motion, and function occur. These effects typically last for 3 to 4 months. The effects depend, at least in part, on the degree of spasticity and on compliance with the subsequent therapy program. In those families in which compliance is suboptimal, benefit may be short-lived.

Botulinum toxin type A can be re-administered when effects wane. In the initial studies on adults, neutralizing antibodies developed after repeated injections in a small number of patients. If antibodies do develop, patients may become nonresponsive to further injections. To minimize the potential for the development of neutralizing antibodies, use the smallest possible effective dose and inject it no sooner than every 3 months. However, as the protein load in botulinum toxin type A has been reduced, resistance has also decreased.

Contraindications and Precautions

There are several contraindications to the use of botulinum toxin type A in children. Botulinum toxin type A causes muscle relaxation. It does not correct a fixed contracture, however, and should be used in this setting only for such reasons as pain reduction. This therapy is not appropriate for children with diffuse hypertonia but rather should be used for focal treatment. Botulinum toxin type A should be used cautiously (if at all) in patients with myasthenia gravis and motor-neuron disease. Injection of botulinum toxin type A into an infected muscle is contraindicated.

Use caution when botulinum toxin type A is co-administered with an aminoglycoside or other agent that interferes with neuromuscular transmission. The effects of the toxin may be potentiated.

Botulinum toxin type A is currently considered a pregnancy category C drug. In some animals, the product has produced severe maternal toxicity, reductions in fetal weight, and fetal malformations. No well-controlled studies have been done in pregnant women.

Adverse Effects

Botulinum toxin type A has relatively few frequent side effects. A small percentage of patients have reported flu-like symptoms or fever that lasts several days. Rash (including erythema multiforme, urticaria, and psoriasiform eruption), pruritus, and allergic reactions (both at the injection site and systemically) have been reported, although whether these are causally related to botulinum toxin is unknown.⁶ Localized pain, tenderness, and bruising, which may occur within the first week following injection, are generally transient. Rarely, ptosis has occurred, even when the neurotoxin is injected far from the face.⁶ In addition, dysphagia, headache, and neck discomfort have been reported after treatment of cervical dystonias.⁶ The authors have seen cases of temporary urinary incontinence after injection of the adductor muscles. Weakness of muscles adjacent to those injected may develop because of spread of the toxin.

If too much botulinum toxin type A is injected into a muscle, excessive weakness and temporary loss of function may occur. No studies have been conducted of the long-term consequences of the toxin's use.

Rare reports of death following treatment with botulinum toxin type A have been reported. These have sometimes been associated with dysphagia, pneumonia, anaphylaxis, and other significant disability.⁶ Myocardial infarction and arrhythmia have also been reported, although the exact relationship of these events to the botulism toxin injection has not been established.⁶

References:

REFERENCES:

1. Jankovic J, Brin MF. Botulinum toxin: historical perspective and potential new indications.

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3. Davis L. Botulism toxin. From poison to medicine.

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4. Burgen AS, Dickens F, Zatman LJ. The action of botulism toxin on the neuro-muscular junction.

J Physiol.

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5. Russman B, Tilton A, Gormley M Jr. Cerebral palsy: a rational approach to a treatment protocol, and the role of botulinum toxin in treatment. In: Mayer NH, Simpson DM, eds.

Spasticity: Etiology, Evaluation, Management, and the Role of Botulinum Toxin.

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6.BOTOX (Botulinum Toxin Type A) Purified Neurotoxin Complex [package insert]. Irvine, Calif: Allergan, Inc; 2004.
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Spasticity: Etiology, Evaluation, Management, and the Role of Botulinum Toxin.

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