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versión impresa ISSN 1130-0558
Rev Esp Cirug Oral y Maxilofac v.26 n.3 Madrid mayo.-jun. 2004
Botulinum toxin and its use in oral and maxillofacial pathology
Toxina botulínica y su empleo en la patología oral y maxilofacial
Abstract: Botilinum toxins are exotoxins of the bacteria that form the Clostridium botulinum spores and the causative agents of botulism. When injected into the muscle flaccid paralysis is produced. The clinical effect is directly related with the dose and is should be adjusted for each particular case. over the last twenty years that it has been in use, the botulinum toxin has shown itself to be a reliable drug. Current indications for the use of botulinum toxin include all those pathologies which are the results of muscle hyperfunction and autonomic dysfunction.
Keywords: Clostridium Botulinum; Botulinum toxin; Dystonia; Masseteric hypertrophy; Bruxism.
Resumen: Las toxinas botulínicas son exotoxinas de la bacteria formadora de esporas Clostridim botulinum y los agentes causantes del botulismo. Cuando se inyecta en el músculo produce una parálisis flácida. El efecto clínico está directamente relacionado con la dosis y debe ajustarse para cada caso concreto. La Toxina botulínica ha demostrado en los más de veinte años en que se está utilizando que es un fármaco seguro. Las indicaciones de la toxina botulínica en la actualidad incluyen todas aquellas patologías que resultan de la hiperfunción muscular y la disfunción autonómica.
Palabras clave: Clostridium Botulinum; Toxina botulínica; Distonía; Hipertrofia maseterina; Bruxismo.
Unidad de Cirugía Oral y Maxilofacial.
Fundación Jiménez Díaz, Madrid, España.
Fundación Jiménez Díaz
Avda. de los Reyes Católicos, 2
In 1895 for the first time the Clostridium Botulinum was isolated in Belgium by van Emengem. As there was a danger during the Second World War that the botulinum toxin could be used widely as a biological weapon, the US government appointed a group of scientists to study it in Fort Detrick in Maryland.1 They were the ones that were able to purify Subtype A (Botox) in its crystalline form and, by the same token, the English form Dysport was produced as a result of investigations into biological weapons. The first clinical application was described by Scott and cols. who were investigating with primates the possibility of non-surgical treatment for strabismus in 1977, and the first publication of its use as a therapeutic agent in humans took place in 1980.2 The use of the toxin for cosmetic purposes was observed by chance by the Carruthers husband and wife team who noted a reduction in the wrinkles of the glabella in a patient they had treated with blepharospasm. As a result of this they began to treat patients with purely cosmetic aims.3
Structure and pharmacology
Botulinum toxins are exotoxins of the bacteria that form the Clostridium Botulinum spores and the causative agents of botulism. Clinical diagnosis of botulism includes autonomic dysfunction (dryness of the mouth, nausea, paralytic ileus, postural hypertension and flaccid paralysis with no fever. It is a highly toxic substance, lethal doses being 10-9g/kg of weight. There are eight serotypes (A,B,C alpha, C beta, D,E,F and G). Of these A,B and E are those associated with botulism in humans. The serotypes are similar from a structural and functional point of view, however they have their own receptors, and their own intracellular enzymatic areas.
When injected into the muscle flaccid paralysis is produced. The toxin attaches itself to the cholinergic nerve terminations, it penetrates the cell by means of endocytosis aided by a receptor and it passes into the cytoplasm where it acts by separating one of the three proteins necessary for exocytosis of the acetylcholine. Depending on which serotype it is, it will act on a certain protein or on different bonds. This determines the duration of the effect of the different botulinum toxins. The BTA deactivates the SNAP-23 protein and BTB the VAMP.4,5 The muscle fibers then suffer functional denervation which results in flaccid paralysis. The effect starts 6-36 hours after the injection, and the maximum effect is 7-14 days later. In the space of 3-6 months muscular function is reestablished due to the formation of new axonal sprouting and neuromuscular unions. The clinical effect is directly related with the dose and it should be adjusted for each particular case. Long-term use does not seem to give rise to atrophy nor to permanent muscular degeneration.6
Botulinum toxin type A can be found on the market in two forms. BOTOX (Allergan) and Dysport (Ipsen Ltd., UK). Later a Toxin type B preparation was marketed, Myoblock (Elan Pharmaceuticals San Francisco Ca.) which has FDA approval for use in cervical dystonia.7 In the US the BTA toxin comes in 100U vials in the form of vacuum dried, purified crystalline toxin (Botox). A single unit is defined as the average lethal intraperitoneal dose for Swiss Webster mice (LD50).8 The average lethal dose in humans is 2800-3500U.
The European preparation of the Botulinum toxin type A Dysport, (Ipsen Ltd., previously Speywood pharmaceuticals, Maidenhead, UK) does not have an equivalent dose, due to there being a different method for purification. Generally, the dose required of Dysport for the same effect is two to five times greater than Botox.9 The reconstitution of the botulinum toxin type A (Botox) is carried out with saline with no preservatives. It should not be shaken, nor frozen as freezing causes denaturation of the solution. The volume of dilution varies, between 1 to 8 ml for every 100U. (Allergan Inc, prospectus for the use of Botox). The reconstituted solution should be kept at between 2 and 8°C, and using the solution within the first four hours is recommended.
Adverse effects and complications
Over the last twenty years that it has been in use, the botulinum toxin has shown itself to be a reliable drug, although there are at least three articles reporting the appearance of a botulism-like syndrome.10-12
Among the systemic effects produced by the botulinum toxin, flue-like symptoms are frequent (nausea, fatigue, separated skin rashes). Lately, thirst has been associated with these treatments, although the effect is more intense with the B toxin than with the A.13 Another effect of toxin at a separated is that the emptying of the gallbladder slows down, and on some occasions bilary colic has been reported.14
In the area of the injection pain, erythema, ecchymosis, or hyperesthesia of short duration frequently appear. The diffusion of the toxin and the paralysis of adjacent muscle groups is the most common adverse effect. In order to minimize these problems, the use of concentrated dilutions and multiple injections are recommended, as well as taking maximum care as to the location and depth of the injection. In any event, the adverse effect as well as the therapeutic effect is reversible.
Botulinum toxin treatment is not advised if there is a neuromuscular illness (myasthenia, Eaton Lambert syndrome) or treatment with aminoglycoside, penicillamine, quinine, and calcium channel blockers, as these can increase the effects.
Acquired resistance to botulinum toxin is extremely well known. It appears in 3-5% of patients treated for cervical dystonia. This is due to the appearance of circulating antibodies that seem to develop depending on the length of treatment, dose reached and repetition of the treatment after short intervals. In general a maximum dose of 100 u per session is recommended, together with a three-month interval between sessions. In cases of resistance to the A Toxin, some patients initially respond to treatment with the B Toxin. After several sessions resistance is also developed which is because of the development of antibodies against the new serotype or crossed antigenicity.15
Current indications for the use of botulinum toxin include all those pathologies which are the result of muscle hyperfunction and autonomic dysfunction. In 1989 it received FDA approval for the treatment of strabismus, blepharospasm and alterations VII carnial nerve. In April 2002 Botulinum toxin A was approved by the FDA16 for cosmetic treatment of the glabella, and this year its use in cosmetic treatment has been approved in Spain.
The first applications of the botulinum toxin in our specialty have been in the treatment of patients with focal dystonia (orbicularis oculi, facial, oromandibular and myoclonus of the palate dystonia).
Oromandibular dystonia Depending on the type of movement generated in each case of dystonia, treatment is directed at the group of muscles implicated (oral aperture, oral closure, lingual protrusion, etc.) Generally, injecting the anterior bellies of digastric and lingual muscles is avoided today as the paralysis of lingual muscles leads to dysphagia and dysarthria.17 Injecting the internal pterygoid, temporal and masseter muscles is done directly given their large volume. This is not the case with the external pterygoid muscles which are more difficult to locate. Identification using electromyography is recommended. The onset of velopharyngeal insufficiency because of diffusion of the toxin should be minimized. (Figs. 1 and 2)
Cervical and facial dystonia
One of the first treatments to be accepted was for its use in blepharospasm. In order to minimize the secondary effects in blepharospasm treatment, the injection should be kept outside the orbit border so as not to affect the function of the lacrimal gland, the pumping function of the lacrimal system, the lid elevator muscle nor the oculomotor muscles.
Similarly it has been used in the treatment of hemifacial spasms, in adherences that appears during recuperation of facial paresis and, extensively, in the treatment of torticollis. In this pathology the toxin is effective only if there is anatomical and neurophysiological knowledge of the muscles involved. Included are the sternocleidmastoideus, trapezius, semispinalis capitis, splenius capitis, scapula elevator and minor paraspinal muscles.1
The botulinum type A toxin has been used, since first described by Carruthers, for the treatment of facial wrinkles. Its use has extended particularly in the treatment of forehead wrinkles, in the glabella area, external lines of the canthus (crows feet), as well as for modifying the position of the eyebrows. It is less used in the middle and lower third of the face where it has been used to change the nasolabial angle, for creating the effect of a fuller top lip, and for the treatment of peribuccal lines among other applications.18,19
Application in this area was first described in 1994, and from then its use has extended astonishingly, especially in Korea.20,21,22
Pathology of the temporomandibular joint
In the literature there are more and more applications of botulinum toxin for the treatment of masticatory myalgias, bruxism, recurrent dislocation of the jaw.23
At the beginning of the 1990s decade Binder noted that patients with migraines or tension headaches that had received botulinum toxin for cosmetic purposes, experienced relief or disappearance.24 These findings were later endorsed by clinical trials.
Acetylcholine is not only the principal neurotransmitter of the muscles but also of the peripheral parasympathetic system. In this sense it has been used in salivation and sweating modulations. It is effective in the treatment of Frey syndrome and it gives alleviation to those patients suffering neurological problems (ELA; Parkinsons, cerebral paralysis) with hypersialorrhea.27 In the same fashion it has also been introduced for the treatment of hyperhidrosis and rhinorrhea.28
Among the more novel indications is the obtaining of more aesthetic scarring by reducing the tension of the wound on injecting the edges with toxin.29
The fundamental limitations of the botulinum toxin are due to the average duration of its therapeutic effect. Treatment of chronic pathologies requires the repetition of treatment every three months throughout the patients lifetime, which is not only bothersome but it also favors the appearance of resistances. The desirable future of these therapies requires obtaining preparations with effects of differing length. It is hoped that the effects of these preparations will, in time, be of longer duration.
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