Click here for list of medical indications
By D.E.Hobson BSc. M.D. FRCP(C)
The indications for the clinical use of botulinum toxin (BTX) type A (table 1), a toxin that can safely and consistently weaken muscles, continue to grow in number. The
toxin's effect at presynaptic neuromuscular junction terminals is to cleave the protein complex (SNAP-25) binding site of acetyl-choline containing vesicles, thereby
preventing acetyl-choline release (1). BTX also blocks the autonomic postganglionic terminals from releasing acetylcholine. Although the latter fact had been confirmed in
1950's the clinical implications are only now being discovered (2).
BTX is available in a crystallized, lyophilized form that is kept frozen in vials containing 100 units (1 unit is the LD 50 in mice). There is significant vial to vial variability in
clinical potency (range of effective units can be 70-130). Prior to injection, depending on the site to be treated, 1 to 4 milliliters of normal saline without preservative are
added to a vial. As the toxin diffuses 1 to 2 centimeters in muscle, several injections per muscle may be required for full benefit to be seen. Depending on the location
being injected (e.g. vocal cord) an EMG guided technique can be used. After injection, although some patients will claim instant relief, the clinical effect on muscle
strength will begin in 2 to 3 days and cause maximal benefit by 7 to 10 days. The weakness is associated with muscle atrophy. The duration of action ranges from 10 to 20
weeks (usually 3 months). Recovery to normal function occurs as the permanently dysfunctional nerve terminals are replaced as a result of sprouting (3). The treatment is repeated 3 to 4 times per year.
Dr. Allan Scott brought the most powerful toxin in the world (by weight) from the laboratory into the realm of clinical medicine in 1977 to control strabismus (4). At that
stage he was already aware of this toxin's potential for use in disorders of excessive muscle contraction including a variety of movement disorders (5).
Use in Movement disorders:
Blepharospasm, Hemifacial Spasm:
Botulinum has become the treatment of choice for involuntary facial spasms with response rates of 90% for blepharospasm (6) and hemifacial spasm. The exact doses and
sites injected vary from one "injector" to another. Typical side effects include local bruising, ptosis, and dry or irritated eyes. Diplopia is rare. BTX is very successful in
controlling obicularis oculi spasms. In those patients with associated lower face involvement, injecting the periorbital region may be enough to stop the lower face
movement. If not, cheek muscles are also injected. In some patients though, control over cheek movement can only be achieved with resultant facial droop. If this
happens when treating hemi-facial spasm the face can be made symmetric by injecting the opposite side. If satisfactory control of hemi-facial spasm cannot be achieved
without disfiguring weakness the patient would be tried on oral medication or referred for surgical decompression of the facial nerve.
Cervical Dystonia (spasmodic torticollis):
Cervical dystonia was the second type of focal dystonia BTX was approved for. Although injection sites, toxin dilution, doses, and the use of EMG guidance vary
considerably between centers, it is clear that this therapy is far superior to that achieved with previously available medication. The patient can, on average, expect 90%
improvement in pain, and a 70% improvement in the involuntary movement (7). Pure rotational forms are the most responsive. Anterocollis is difficult to treat. The toxin, if
injected into neck flexors, diffuses to adjacent pharyngeal muscles and may create speech and swallowing difficulty.
In general doses between 150 – 300 units are required (1½ – 3 vials). With these doses there is a risk (10% of patients after 5 years) of blocking antibodydevelopment.
Antibodies render the patient permanently immune to the toxin (8).
Jaw closure dystonia including bruxism, related dental problems, and associated pain can be controlled with BTX injections into the maseter and temporalis muscles
bilaterally. In more severe forms weakening the internal pterygoids will also be required. On average reported improvement is 45% (9). Jaw opening dystonia,
particularly with side to side deviation, is more difficult to treat (average response 37-44% improvement) (9). The external pterygoid, mylohyoid, geniohyoid and digastric
muscles are the main jaw openers. These muscles need to be identified by EMG prior to injection.
Stuttering, voice tremor, abductor breathing, and abductor breathing dystonia, have all been shown to respond to BTX (10). By far the most responsive disorder is
adductor spasmodic dysphonia. Under EMG guidance small doses of BTX are injected either unilaterally or bilaterally into the vocal cord abductors. Often the patient will
experience a "breathy" voice prior to maximal benefit. The duration of benefit tends to last 4-5 months (slightly longer than in the above indications).
The most studied form of limb dystonia is writer's cramp. The main challenge is to suppress the involuntary movement without interfering with normal function. This limits
success to "simple" forms with only a few main dystonic muscles involved. Given their complex nature only 25% will respond significantly (11).
Many task-specific, and other limb dystonias have responded to BTX. The pattern of injection must be individualized, and guided by EMG. Painful dystonic spasms in
nonfunctional limbs often respond well as subsequent weakness is not problematic. Foot inversion dystonia can be reduced by injection of the tibialis posterior (other agonistic muscles may also need injecting).
After demonstrating success for many focal facial dyskinesias, it followed that stereotypic movements of other types should also respond. A remarkable observation was
made while treating tics with BTX. The "urge" preceding the tic often disappears. Even relatively small BTX doses may suppress the urge enough to resolve severe
retrocollic tics. Unfortunately in the occasional patient the ability to "tic" stops but the urge remains (an obviously unsuccessful result).
Reports of use of BTX in a variety of head and hand tremors exist (see table 1) (12,13). The most responsive type is a side to side essential head tremor. Injecting the
splenius capitus, and levator scapulae bilaterally result in marked reduction of tremor amplitude. The success in treating arm tremors is often limited by dysfunctional
weakness. When the main component of the tremor is wrist flexion/extension weakening the flexor and extensor carpi ulnaris and carpi radialis may provide significant relief.
In addition to controlling hyperkinetic movement disorders there are increasing options for those patients with rigid akinetic disorders. Parkinsonian patients with "off"
period focal dystonia (e.g. blepharospasm, dystonic foot inversion) are proven indications (14). Non-dystonic painful rigidity may also respond to BTX (15). Other
potential therapeutic indications for BTX in Parkinson's Disease include (see table 1): anismus, severe constipation (16), vocal stuttering, apraxia of eyelid opening, and
gait freezing (17). Most recently BTX has been reported to have potential in treating problematic drooling though it's autonomic effects (18).
The therapeutic wonders of this poison have certainly made a major impact within the realm of movement disorders during the "Decade of the Brain". The unfortunate
patients whose benefits have been cut short by antibodies to BTX type A await the further development and approval of other BTX serotypes.
- Blais J Chapman ER Link E et al. Botulinum neurotoxin A selectively cleaves the synaptic protien SNAP-25. Nature 1993;365:160-163.
- Schnider P Binder M Auff E et al. Double-Blind trial of botulinum type A toxin for the treatment of focal hyperhydrosis of the palms. Br J Dermatology 1997;136:548-552.
- Borodic G Ferrante R Pearce L et al. Pharmacology and histology of the therapeutic application of botulinum toxin, in: Therapy with Botulinum Toxin, Jankovic J Hallat M (eds.) Marcel Dekker, Inc. 1994:119-157
- Scott A, Botulinum toxin injection into extraocular muscles as an alternative to strabismsus surgery. Ophthalmology 1980;87:1044-1049.
- Scott, AB. Forward, in: Therapy with Botulinum Toxin, Jankovic, J. Hallat, M. (eds.) Marcel Dekker, Inc. 1994:vii-ix.
- Dutton J. Acute and chronic effects of botulinum toxin in the management of Bleparospasm, in: Therapy with Botulinum Toxin, Jankovic, J. Hallat, M. (eds.) Marcel Dekker, Inc. 1994:199-209
- Greene P Kang U Fahn S et al. Double-blind, placebo-controlled trial of botulinum toxin injections for the treatment of spasmodic torticollis. Neurology 1990;40:1213-1218.
- Zuber N Derecondo J Rondet P. Botulinum toxin antibodies in dystonic patients treated with type A botulinum toxin. Neurology 1993;43: 1715-1718.
- Brin M Blitzer A Hermans S et al. Oromandibular dystonia: treatment of 96 patients with botulinum toxin type A. in: Therapy with Botulinum Toxin, Jankovic, J. Hallat, M. (eds.) Marcel Dekker, Inc. 1994:429-436.
- Brin M. Botulinum toxin: new and expanded indications. Euro J Neuro 1997;4(suppl 2):S54-S65.
- Tsuii J Bhatt M Calne S et al. Botulinum toxin in treatment of writers cramp: A double-blind study. Neurology 1993; 43: 183-185.
- Wissel J Masuhr F Schelosky L et al. Quantitative assessment of botulinum toxin treatment in 43 patients with head tremor. Mov Disord. 1997;12(5): 722-726.
- Jankovic J Schwartz K Clemence W et al. A randomized, double-blind, placebo-controlled study to evaluate botulinum toxin type A in essential hand tremor. Mov Disord. 1996;11(3):250-256.
- Limousin P. Treatment of dystonia occurring in parkinsonian syndromes by botulinum toxin. Eur Neurol. 1997;37(1):66-67.
- Polo K. Botulinum toxin-A improves the rigidity of progressive supranuclear palsy. Ann Neurology. 1994;35(2):237-239.
- Albanese A Maria G Bentivoglio A et al. Severe constipation in Parkinson's disease
- relieved by botulinum toxin. Mov Disord. 1997;12(5):764-766.
- Giladi N Honigman S. Botulinum toxin injections to one leg alleviate freezing of gait in a patient with Parkinson's disease. Mov Disord. 1997;12(6):1085-1086.
- 18 Bushara KO. Sialorrhea in amyotrophic lateral sclerosis: a hypothesis of a new treatment botulinum toxin A injections of the parotid glands. Med Hypotheses. 1997;48(4):337-339.