The current status and use of botulinum toxins
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Correspondence: Professor A. Albanese, Istituto NazionaleNeurologico, Via Celoria 11, Milano 20133, Italy (tel.: 39 02 2394448; fax: 39 02 2394441; e-mail: email@example.com)
The current status and use of botulinum toxins
A. AlbaneseIstituto Nazionale Neurologico, Universita` Cattolica del Sacro Cuore, Via Celoria 11, Milano 20133, Italy
There are seven different serotypes of botulinum toxinavailable for study. Each serotype binds to receptorproteins at cholinergic terminals, although there maybe different receptor proteins for different serotypes,and each produces a blockade of cholinergic neuro-transmission in striated muscle (Martin, 1997; Schiavoet al., 1992; Blasi et al., 1993). The toxins also affectgamma motor neurones serving intrafusal fibres with-in muscle, thus influencing central neurotransmission(Filippi et al., 1993; Rosales et al., 1996; Modugnoet al., 1998), and affecting autonomic terminals onsmooth muscles (Albanese et al., 1995). Thereforethere are, potentially, a large number of uses for thesetoxins. The main current uses for the botulinum toxinsare reviewed here.
Mechanism of action
In dystonia and spasticity, to some extent, clinicalbenefit of the toxin parallels the muscle weakness pro-duced by chemical denervation. However, it is alsoclear that this benefit may outweigh the muscle weak-ness produced. In addition, significant spasticity mayremain, despite muscle weakness. Therefore peripheralweakening of the muscle does not explain all theeffects of the toxin: there must be some other mecha-nism that contributes to its efficacy. To some extent,this is explained by the fact that efficacy is improvedby increased uptake during increased muscle activity.Another possible factor is reduced alpha-motor neu-rone drive, caused by diminished muscle-spindle out-
put. Recently, it has also been shown that intracorticaland reciprocal inhibition are normalized in dystonia,probably in the aftermath of an alteration in sensoryinput from the injected region. Thus, a peripheralaction of the toxin is capable of changing the action ofthe brain in pathological states.
Treatment of dystonia
The direct cause of dystonia may be an overactivity inthe supplementary motor area, and a resulting corticaloverflow. Focal dystonia is the primary indication forbotulinum toxin in neurology. For patients with seg-mental or generalized dystonia, treatment isapproached as a collection of focal dystonias. Effectivetreatment is therefore dependent on tailoring injectionsaccording to the clinical presentation of a particularpatient. There are several key issues to be resolved inthe use of botulinum toxin to treat dystonia. The mostimportant current issues include the variability of clin-ical presentation and severity of disease in differentpatients; and variations in patients perception of thedisease, which may explain some dissatisfaction at theoutcome of treatment (Lindeboom et al., 1998). Thereis also a pressing need for validated scales that willallow the assessment of treatment efficacy in differentparts of the body, as this cannot be defined preciselyat present.
The key strategy in treating focal dystonia is to treatthe symptoms, not the aetiology of the disorder. Thus,many different types of dystonia (for example, tardive,primary, post-traumatic and peripherally induced dys-tonia) all respond well to botulinum toxin treatment(Brashear et al., 1998; Molho et al., 1998; Comellaet al., 1998; Sankhla et al., 1998). Patients sufferingfrom any of these conditions can simply be treatedaccording to their clinical pattern of disease presenta-tion, rather than the cause of their disorder.
2001 EFNS 3
Keywords:botulinum toxin, motor disorders
Botulinum toxin is now widely used in neurology for the treatment of disordersinvolving muscle hyperactivity. Focal dystonia is the primary indication, and the keyto effective treatment of dystonia is tailoring the treatment to the individuals pat-tern of muscle involvement; even complex and generalized dystonias are treated as acollection of focal disorders. The dystonias known to respond to botulinum-toxintherapy include cervical dystonia, blepharospasm, laryngeal dystonia, writers crampand anismus. Spasticity is another, growing, indication for the toxins. The treatmentof these disorders with botulinum toxins is reviewed here.
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Botulinum toxin is the first-choice treatment for ble-pharospasm. The classical orbital injection is an effec-tive therapy, although that efficacy can be improved inmany patients by using, instead, a pretarsal injection(Aramideh et al., 1995; Albanese et al., 1996).Combined therapy with other procedures has also beenproposed as a means of improving efficacy. Eyelid pro-tractor myectomy (Chapman et al., 1999) or injectionof doxorubicin into the eyelid (Wirtschafter andMcLoon, 1998) are two such procedures that mayenhance treatment effects. Nevertheless, even withoutadjunctive treatment, botulinum toxin therapy is high-ly effective in this indication.
Botulinum toxin is also the first-choice therapy for theadductor form of laryngeal dystonia (Blitzer et al.,1998). There are two different treatment approachesfor reaching the thyroarytenoid muscle in this disorder:electromyography- (EMG-) guided percutaneous injec-tion and transoral injection under laryngoscopic con-trol. Both of these approaches are effective, so theiruse depends mainly on local treatment preferences.
Cervical dystonia is the most common form of focal dys-tonia, and botulinum toxin is the first-choice therapy.This is the only form of focal dystonia in which there hasbeen a direct comparison between botulinum toxin andoral treatments. Botulinum toxin has been shown to bemore effective than the anticholinergic, triexyphenydyl.
There are currently two, and will soon be three, dif-ferent botulinum toxins available for the treatment ofcervical dystonia. Two of these, Botox (Allergan) andDysport (Ipsen) are type A toxins, whereasNeuroBloc/MYOBLOC (Elan) is a type B toxin.Typical starting doses are: Dysport 500 U, Botox
200 U and NeuroBloc/MYOBLOC 10 000 U. Thesestarting doses differ because the toxin units used differ the amounts of toxin injected are much more similarthan the doses suggest. A remarkable differencebetween these toxins, which has implications for theirclinical use, is the fact that Elans botulinum toxin typeB is presented as a liquid formulation, whereas theothers are lyophilized or dry-powder formulations andmust therefore be reconstituted.
Individualization of therapyThe challenge in treating cervical dystonia is the vari-ety in its clinical presentation. This varies both
between patients and in a single patient over time(Dauer et al., 1998). In addition, the combination ofrapid and slow movement abnormalities can produce agreat variety of clinical presentations. Thus, treatmentmust not only be carefully adapted for each individualpatient, but the initial treatment pattern of injectionsmust also be adapted over time to follow the changesin patterns of muscle activity. It is important that thisis done, because failure to do so may lead to a lack oftherapeutic response over time. Muscles are selectedfor treatment by physical examination; the involve-ment of certain muscles is likely to result in particularclinical presentations (Table 1). Patients with uncom-plicated presentations are then treated clinically bydirect inspection of the injection site, without EMGguidance. EMG can, however, be used to allow moreprecise localization of muscles in uncomplicated dysto-nia, to detect specific activity in muscles when the pre-sentation is complex, or to locate specific deep musclesthat are more difficult to reach without EMG support.
Sub-optimal responsesLarge doses of toxin are used to treat cervical dysto-nia, therefore patients are at risk for the developmentof antitoxin antibodies. These have been demonstratedin a substantial minority of patients up to 10%(Green et al., 1994; Borodic et al., 1996; Zuber et al.,1993) and antibodies can be detected in about 30%of patients who develop secondary non-responsivenessto toxin therapy (Jankovic and Schwartz, 1995). Thepossibility of antibody production can be ruled out ifmuscle atrophy is observed in the injected area, or ifthe frontalis test demonstrates that the frontalis mus-cle can be paralysed (Brin, 1998; Hanna and Jankovic,1998). Otherwise, non-responding patients should beinvestigated for antibody production using biologicalassays.
In patients who do not respond well to therapy andare not producing neutralizing antibodies, this sec-ondary treatment failure may well result from changesin the pattern of muscle involvement, which, if treat-ment is not adapted, leads to inadequate efficacy. In
4 A. Albanese
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Table 1 Individual muscles responsible for symptoms of cervicaldystonia
Presentation Ipsilateral Contralateral
Torticollis Sternocleidomastoid Splenius capitisRetrocollis Splenius capitis Splenius capitis
Trapezius TrapeziusLaterocollis Splenius capitis Sternocleidomastoid
TrapeziusAnterocollis Sternocleidomastoid Sternocleidomastoid
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this case, efficacy can be improved by re-assessing thepatient and tailoring toxin injections precisely to theirclinical presentation. For patients in whom treatmentfailure is secondary to antibody production there isnow an alternative to their current therapy, which isswitching from type A toxin to a different serotype.Positive efficacy has been demonstrated in this indica-tion for serotypes B (Brin et al., 1999), C and F(Houser et al., 1998). Although serotypes C and Fremain experimental therapies, serotype B will soon beavailable as a commercial treatment.
Other dystonia indications
In writers cramp, the approach to treatment is similarto that used in clinical dystonia. The affected musclesare identified by physical examination. However, EMGguidance is always used to target the injection.Anismus is also a form of focal dystonia (of the pubo-rectalis muscle) in which botulinum toxin is effective.Anismus may be a primary condition or an off-typedystonia of Parkinsons disease. Both primary (Mariaet al., 2000) and secondary (Albanese et al., 1997)forms of the condition respond well to botulinum-toxin therapy.
Treatment of spasticity
Spasticity is a form of hypertonia, which is the resis-tance felt when moving a limb passively. Spasticity isdefined as a velocity-dependent increase of the tonicstretch reflex, with exaggerated tendon jerks. Otherfeatures that contribute significantly to the resistanceto passive movements include co-contraction and bio-mechanical changes. Together, these combine to formthe clinical picture of spastic paresis. The diagnosis ofspastic paresis is different from that of dystonia, asthere are not only positive signs (flexor spasm,increased tendon reflexes, spasticity) but also negativesigns (weakness, lack of dexterity, paresis) of the dis-order. Botulinum toxin is effective in treating the pos-itive signs but not the negative ones. Therefore atherapeutic strategy should be selected and designed tocorrect positive signs without exacerbating the negativesigns of the disease.
Limb spasticity in adults
Several open trials and four double-blind trials of bot-ulinum toxin in adults have shown that this therapy iseffective in reducing resistance to passive movementsin both the upper and lower limbs. There are alsoreports that other sequelae of spasticity that are sig-nificant to the patients (for example, pain, need for
care, the resting posture of the limb) have beenimproved by toxin therapy. Thus, all the signs com-monly associated with spastic paresis that are difficultfor the patient to cope with are improved by treatmentwith botulinum toxin. Nevertheless, the practical con-sequences of therapy are less clear, as there is littleconclusive evidence that the reduction in hypertoniaproduced by botulinum toxin treatment results in animprovement in active functional movements.
Several studies of botulinum toxin have been per-formed in this indication, generally in children (Corryet al., 1997, 1998; Thompson et al., 1998; Wissel et al.,1999). Improvements in several aspects of the disorderhave been demonstrated following this therapy(Table 2). The goals of treatment for cerebral palsy arevaried, and include: the treatment of focal dystonia;reduction of spasticity; modifications of early patternsof axial asymmetry that may impair later developmentof the spine and hips; modification of the effects ofspasticity on soft tissue and bone; mimicking theeffects of later surgery; providing a therapeutic win-dow for physical interventions (Russman et al., 1997).Thus, cerebral palsy comprises a complex set of indi-cations that require a goal-directed strategy.
In both spasticity and cerebral palsy, botulinum toxinis not a therapy that is given in isolation. It can andshould be combined with other strategies, such as cast-ing, electrical stimulation, ongoing physiotherapy,orthoses and continuing oral medication.
Chemical denervation with botulinum toxin is widelyused in the clinic to correct movement disorders asso-
The current status and use of botulinum toxins 5
2001 EFNS European Journal of Neurology 8 (Suppl. 4), 37
Table 2 Improvements demonstrated in the treatment of cerebralpalsy with botulinum toxin
Clinical issue Improvement Reference
Dynamic deformities Gait Koman et al.Spasticity (1994); (2000)
Dynamic contracture Clinical examination Cosgrove et al.of lower limb Gait analysis (1994)
Dynamic deformities Skilled hand movements Denislic and Meh of hand and foot Foot posture (1995)
Spasticity and athetosis Pain Gooch and Sandell of limbs Ease of care (1996)
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ciated with dystonia and spasticity. In addition, it canbe used to treat hyperhidrosis, facial lines and anal fis-sure. There are many other possible indications for thistherapy, such that the field continues to grow.
This work was supported by Elan Pharmaceuticals.The author has no conflicts of interest to disclose.
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