Dystonia

Botulinum Toxin Type A for Dystonia

Injections of botulinum toxin type A (BoNT-A) have been used in the management of dystonia since the late 1980s. BOTOX® (onabotulinumtoxinA, Allergan, Inc.) was approved in the United States by the FDA in 1989 for use in patients ages 12 and above who were affected by strabismus, blepharospasm associated with dystonia–including benign essential blepharospasm–or disorders of the seventh cranial nerve. Since then, BoNT-A has been demonstrated to be safe and effective in the management of focal dystonias, as well as other disorders characterized by excessive involuntary muscle spasms.

On December 27, 2000, the FDA approved the use of BOTOX® for the treatment of cervical dystonia (CD). Injections of this product decrease the severity of abnormal head positioning and postures as well as associated neck pain. In 2009, the FDA approved another botulinum toxin type A product, Dysport® (abobotulinumtoxinA, Ipsen Ltd), for treatment of cervical dystonia. The appropriateness of BoNT-A–or of any dystonia therapy–relies on its ability to meet the goals of patients and caregivers as outlined in their comprehensive treatment plan.

Administration of botulinum toxin type A for the treatment of dystonia
A solution of BoNT-A is injected directly into several sites in the overactive, dystonic muscle. These sites are near the nerve terminals or that part of the nerve cell that actually stimulates the muscle to contract. BoNT-A works inside the nerve terminals to block the release of the neurotransmitter acetylcholine. This neurotransmitter serves to initiate or elicit muscle contractions. Some nerve terminals remain unaffected by BoNT-A; therefore, the injected muscle may still contract but with less force. One important benefit of BoNT-A is that the dose may be adjusted to provide the precise degree of weakness needed to overcome dystonia; however, some strength for normal function is preserved.

BoNT-A temporarily weakens dystonic muscles, thereby allowing for a more normal posture and function. The benefits that BoNT-A conveys to a particular patient depend on the location and relative degree of severity of the dystonic muscles being injected. In general, BoNT-A cannot be used alone to treat widespread or extremely severe generalized dystonia, as the drug dose required for this type of treatment would be too high. In these patients, BoNT-A may be used to target specific dystonic muscles, thereby improving particular aspects of care and function or relieving discomfort or pain. Many patients with painful muscle spasms report a reduction in pain after injection with BoNT-A.

Duration of botulinum toxin type A effects
The effects of treatment with BoNT-A are usually greatest for a two- to six- week period following injection. These effects usually fade after about three to six months. If necessary, reinjection of the drug is possible at that time. In order to decrease the possibility of antibody formation, reinjections are usually not administered before three months after the last injection.

Side effects of botulinum toxin type A
During the dose regulation process, physicians work closely with patients to optimize their therapy. Some patients may experience temporary, muscle weakness. This weakness is temporary and wears off. If patients experience muscle weakness, it is important to discuss this finding with their physicians as it may be a signal for a modification of the treatment approach. For example, muscle weakness may be lessened by reducing the dose of BoNT-A during the next injection. BoNT-A should be used with extreme caution in patients with neuromuscular disease such as myasthenia gravis or amyotrophic lateral sclerosis (ALS or motor neuron disease), or in those who receive therapy with drugs that thin the blood (anticoagulants), or certain antibiotics (aminoglycosides such as gentamicin [Garamycin®], kanamycin [Kantrex®], neomycin [Mycifradin®, Myciguent®, or NeoTab®], streptomycin [Streptomycin], or tobramycin [Tobrex® or Nebcin®]).

The decision to combine injections of BoNT-A with other forms of treatment for dystonia is an individual decision and based on many factors. This decision is reached after thorough clinical evaluation and consultation with the treating physician. In some patients receiving injections of BoNT-A, the dosage of other medications may be reduced. Certain oral medications as well as baclofen, which may be delivered directly next to the spinal column (intrathecally), may provide global muscle tone reduction, whereas BoNT-A injections may provide graded focal relief in selected muscles.

Injection of botulinum toxin type A
During the administration of BoNT-A, a relatively small needle is placed into the target muscle. In large or accessible muscles, confirmation of appropriate placement of the injection into the target muscle may be achieved by feeling the muscle. In small or deep muscle groups, electromyography (EMG) or electrical stimulation may be required to confirm appropriate placement.

Small muscles may be injected in only one or two sites. Larger muscles may require three to four injection sites. Most individuals are able to tolerate these small needle punctures; however, if necessary, local anesthetic cream or sedation may help ease discomfort or anxiety associated with injection. This may be particularly useful for children who are receiving injections.

Antibodies and botulinum toxin type A therapy
Antibodies are proteins produced by the immune system to help fight infections or dispose of other foreign agents that enter the body. In some individuals treated with BoNT-A, antibodies may develop, bind to the drug, and inactivate it. This renders BoNT ineffective in weakening muscle contractions associated with dystonia. It is estimated that approximately five percent of individuals with cervical dystonia who have been treated regularly with relatively higher doses of BoNT-A develop antibodies. Once a patient forms antibodies to a particular serotype of BoNT (immunoresistance), further injections of that particular serotype of BoNT are typically ineffective. Physicians should, therefore, use the smallest amount of BoNT-A necessary to achieve therapeutic benefit; extend the time interval between treatment sessions as long as possible (with at least three months between treatments); and, if possible, avoid the use of "booster" injections. A new, lower protein form of BOTOX®-A is available. It is theorized that lower protein may lead to lower rates of antibody formation (reduced immunogenicity). See E-MOVE Article: BoNT-A current bulk toxin vs. original (AAN report).

On occasion, a patient may not respond to therapy with BoNT-A. So-called "primary non-responders" are patients who do not respond to their first injection of BoNT. Secondary non-response may occur as the result of a technical problem, such as an inappropriate site of injection into the wrong muscle, a dose that is inadequate to provide a clinical effect, or disease progression. The toxin may weaken the muscle; however, the degree of relaxation may not provide symptomatic relief for the patient. In addition, some patients on combination therapies for segmental or generalized dystonias may fail to take their oral medications, leading to a general increase in symptoms (masking the local effects of BoNT-A). If failure to respond continues, it is possible that the patient has antibody-mediated resistance (immunoresistance).

It is important that patients work with their physicians to set appropriate treatment goals and tailor the course of treatment to meet these goals. There is no formal "recipe" that works for every patient. Each individual is unique and responds differently to BoNT-A therapy.