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Botulinum Toxin (BOTOX (R)), Dystonia Treatment

Author: Tarakad S Ramachandran, MBBS, FRCP(C), FACP, Professor of Neurology, Clinical Professor of Medicine, Clinical Professor of Family Medicine, Clinical Professor of Neurosurgery, State University of New York Upstate Medical University; Chair, Department of Neurology, Crouse Irving Memorial Hospital
Coauthor(s): Fiona M Molloy, MD, Clinic Director, Department of Neurology, National Institute of Neurological Disorders and Stroke
Contributor Information and Disclosures

Updated: Dec 4, 2008

Introduction

Introduction

Dystonia is a disorder characterized by involuntary sustained muscle contractions resulting in twisting and repetitive movements or abnormal postures. Despite an incomplete understanding of the neurological mechanisms underlying dystonia, relief of dystonic posturing and associated pain and discomfort has improved markedly since the introduction of botulinum toxin (BTX) therapy in the late 1980s, so much so, it has become the standard therapy for focal dystonias.

BTX is one of the most potent biologic substances known. The 7 distinct serotypes, A, B, C, D, E, F, and G, are of similar sizes and structures. However, the serotypes differ in their potency, duration of action, and cellular target sites. Types A and B have been shown to be safe and effective in double-blind clinical trials for the treatment of dystonia. One formulation of BTX-A is marketed worldwide under the name BOTOX® (Allergan Inc.) and another in Europe as Dysport (Speywood, UK). BOTOX® was approved in December 1989 by the US Food and Drug Administration (FDA) for "the treatment of strabismus, blepharospasm, and focal spasms including hemifacial spasm" and more recently for the treatment of cervical dystonia. A formulation of BTX-B was approved in December 2000 by the FDA for treatment of cervical dystonia, and will be marketed under the name Myobloc in the United States and Neurobloc in Europe (Elan Pharmaceuticals).

The clinician must recognize that the various commercial formulations of BTX differ in the dosages used clinically owing to differences in potency and diffusion (see next 2 sections).

Botulinum toxin type A

BTX proteins have been studied since the early 1900s, initially to gain an understanding of botulism, a form of food poisoning. Later, they were studied because of the unique and specific muscle paralysis induced by minute amounts of the toxins. During the past 30 years of work on the use of the toxin for human treatment, selective procedures for the production, purification, and dispensing of the toxin have been developed to make it suitable for injection. Today BTX-A is employed and considered safe and effective for treatment of movement disorders and spasticity. One of the more common movement disorders treated with BTX-A is focal dystonia, the most frequently occurring types of which include cervical dystonia, blepharospasm, hand dystonia, oromandibular dystonia, occupational dystonia, and laryngeal dystonia.

The administration of BTX therapy for the focal dystonias requires a thorough understanding of the toxin itself, preparation of various dilutions, and practical knowledge of typical dosages and anatomy, along with basic electromyographic skills. The optimal dose of botulinum toxin (BTX) is the least amount of BTX needed to achieve a predetermined outcome (eg, decreased muscle tone, improved range of motion, improvement of certain active function, improved hygiene) without causing an adverse effect, weakness.¹

BTX type A has the property of Ach release at the neuromuscular junction. Following local injection into muscles, the toxin enters the nerve terminal via endocytosis, interacts with intracellular proteins (soluble N -ethyl-maleimide sensitive factor attachment protein receptor [SNARE] proteins), and inhibits the vesicular release of the Ach neurotransmitter at the neuromuscular junction.^2,3 This chemical denervation results in paralysis of the striated muscles, which usually peaks 2 weeks after the injection. Because of the molecular turnover within the neuromuscular junction and neuronal sprouting, neuronal activity begins to return at 3 months, with restoration of complete function at approximately 6 months.⁴

Many factors affect the dose of botulinum toxin including severity and chronicity of the disease, number of muscles involved, previous response, concurrent other medical therapy used, and also the experience of the person performing the injection. Smaller doses are used in children, proportionate to the body mass.

Structure

BTX is synthesized as a single-chain peptide with a molecular mass of 150 kilodaltons. This form has relatively little potency as a neuromuscular blocking agent, and activation requires a 2-step modification in the tertiary structure of the protein. This process converts the single-chain neurotoxin to a di-chain neurotoxin comprising a 100,000-dalton heavy chain (HC) linked by a disulfide bond to a 50,000-dalton light chain (LC). BTX acts at the neuromuscular junction where it exerts its effect by inhibiting the release of ACH from the presynaptic nerve terminal.

ACH is contained in vesicles, and several proteins (VAMP, SNAP-25, and syntaxin) are required to mediate fusion of these vesicles with the axon terminal membrane. BTX binds to the presynaptic terminal via the HC. The toxin is then internalized and the HC and LC are separated. The LC from BTX-A cleaves SNAP-25, the LCs from serotypes B and F cleave VAMP, and that from serotype C cleaves syntaxin. This disrupts ACH release and subsequent neuromuscular transmission, resulting in weakness of the injected muscle.

Medications used to treat focal dystonia

• Botulinum toxin injections
• Benzodiazepines
  • Clonazepam
  • Lorazepam
  • Diazepam
• Baclofen
• Anticholinergics
  • Trihexyphenidyl
  • Benztropine
• Dopamine-depleting agents
  • Tetrabenazine
  • Clozapine

Indications

Applications of botulinum toxin injections

• Focal dystonia
  • Focal limb dystonia
    • Blepharospasm
    • Cervical dystonia (torticollis)
    • Oromandibular-facial-lingual dystonia
  • Hemifacial spasm
  • Myoclonus
  • Dystonic tics
  • Tremors
  • Bruxism
  • Spasticity

Treatment of focal dystonia with BTX is designed to improve the patient's posture and function and to relieve associated pain. As BTX-A has been studied most intensely and used most widely, this section outlines its structure, origin, and mechanism of action.

The toxin inhibits release of acetylcholine (ACH), a neurotransmitter responsible for activation of muscle contraction. Administration of the toxin results in weakness in the injected muscle. Some nerve terminals are not affected by the toxin, allowing the injected dystonic muscle to contract, but with less force. This weakness allows for improved posture and function of the dystonic muscle(s). The degree of weakness depends on the dose, and the duration of weakness is further dependent on the serotype employed.

Contraindications

Contraindications

No absolute contraindications to the use of BTX-A are known. Relative contraindications include myasthenia gravis or motor neuron disease. Patients who are pregnant or lactating may not be appropriate candidates for BTX therapy.

Relative contraindications for clinical application of botulinum toxin

• Pregnancy and lactation
• Neuromuscular disease (eg, myasthenia gravis, Eaton-Lambert syndrome)
• Motor neuron disease
• Concurrent use of aminoglycosides

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