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1 History

Botulinum toxin (BT) is infamous as the compound with the highest toxic potency of any natural or man-made substance causing the clinical syndrome of botulism in man and animals. At the end of the 1970s, this perception began to change, when BT was first used by Alan B. Scott to treat strabismus in children [1, 2]. It soon became clear that this had established a completely novel therapeutic principle which could be used in various muscle hyperactivity syndromes. Subsequently BT was used in blepharospasm, hemifacial spasm and cervical dystonia, thus reaching neurology [3, 4]. Here its use exploded and soon numerous other medical specialties became involved. With its use in crocodile tears, pioneered by Manuel Meyer in Zurich, exocrine glands became a second principal target tissue for BT. Recently, BT’s use for treatment of pain syndromes was established [5]. For most of its indications, BT therapy is the therapy of choice [6]. For some, it has revolutionised therapy altogether. This, together with its exploding use in cosmetics, has generated an industry with annual sales in excess of three billion US dollars. BT’s use in dystonia, however, is still one of the most important indications for BT, both with respect to the amount of BT used and with respect to the therapeutic impact generated.

2 Pharmacology of Botulinum Toxin Drugs

2.1 Structure

As shown in Fig. 10.1, BT drugs consist of the BT component and of excipients. The BT component is formed by botulinum neurotoxin (BNT) and by non-toxic proteins also known as complexing proteins. BNT consists of a heavy amino acid chain with a molecular weight of 100 kD and a light amino acid chain with a molecular weight of 50 kD. BNT and complexing proteins form superstructures of different sizes [7]. In Xeomin®, the complexing proteins are removed during the manufacturing process [8].

Fig. 10.1
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Contents of therapeutic botulinum toxin preparations. HP haemagglutinating protein, NHP non-haemagglutinating protein

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2.2 Mode of Action

When a BT drug is injected into a target tissue, it is bound to glycoprotein structures located on the cholinergic nerve terminal. Subsequently, BNT’s light chain is internalised by using synaptic vesicle proteins and syntagmins of the neuron’s acetylcholine vesicle-recycling mechanism [9–12]. Intracellularly, BT cleaves different proteins of the acetylcholine transport protein cascade (soluble N-ethylmaleimide-sensitive fusion attachment protein receptor or SNARE proteins) transporting the acetylcholine vesicle towards the synaptic cleft [13]. Different BT types target different SNARE proteins. BT interrupts the synaptic transmission only temporarily. Structural neuronal changes or functional neuronal impairment other than the synaptic blockade itself cannot be detected. Recently, we therefore suggested classifying BT not as a neurotoxin but as a temporary neuromodulator [14]. BT can block cholinergic neuromuscular transmission but also the cholinergic autonomic innervation of the sweat glands, the tear glands, the salivary glands and the smooth muscles depending on the target tissue selected.

Apart from a direct action upon the striated muscle, BT can act upon the muscle spindle organ reducing its centripetal information traffic [15–17]. Whether this BT-induced blockade of the muscle spindle’s centripetal information is relevant to BT’s therapeutic action remains unclear [18, 19].

Although BT can produce numerous indirect central nervous system effects, direct central nervous system effects beyond the alpha motoneuron are a controversial issue [20, 21].

In addition to the blockade of the acetylcholine secretion, animal experiments indicate BT-induced blockade of transmitters involved in pain perception, pain transmission and pain processing [22–28]. This may be the basis of BT’s action on pain syndromes.

2.3 Time Course of Action

After intramuscular injection, initial BT effects can be detected within 2–3 days depending on the detection method used. BT reaches its maximal effect after about 2 weeks, maintains it and then gradually starts to decline after 2–2.5 months. BT injections into glandular tissue can exert prolonged effects of up to 6 or 9 months. BT’s action follows a dose-effect correlation [29]. An additional dose-duration correlation can also be assumed. Both correlations are valid only within certain limits. Although there may be interindividual variability of the duration of action, there is remarkable intraindividual reproducibility of the duration of action throughout years of continued treatment [30, 31].

2.4 Botulinum Toxin Drugs

BT drugs are either based upon BT type A, such as Botox® (onabotulinumtoxinA, Allergan Inc, Irvine, CA, USA), Dysport® (abobotulinumtoxinA, Ipsen Ltd, Slough, Berks, UK) and Xeomin® (incobotulinumtoxinA, Merz Pharmaceuticals, Frankfurt/M, Germany), or upon BT type B, such as NeuroBloc®/MYOBLOC® (rimabotulinumtoxinB, Solstice Neurosciences Inc, Malvern, PA, USA). Additional BT drugs are distributed in fringe markets (Fig. 10.2). As shown in Table 10.1, the properties of BT type A drugs are similar. Those of the BT type B drug are considerably different. Differences include antigenicity, adverse effect profiles, adverse effect frequency, injection site pain, storage conditions, mode of preparation, pharmacological stability and potency labelling. Although all BT drugs are based upon BT, they are not generics. They can be compared in principle and they can be interchanged in an ongoing therapy, but comparisons and interchanges have to be performed with caution. Current understanding suggests that Botox® and Xeomin® have identical therapeutic effects and adverse effect profiles [32, 33]. Their potency labelling is identical, making exchanges between both products particularly easy [34].

Fig. 10.2
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Some of the currently available botulinum toxin drugs

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Table 10.1 Properties of different botulinum toxin drugs
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With an improved specific biological activity, Xeomin® should have a reduced antigenicity as compared to conventional BT drugs [8].

Dysport® also has an identical therapeutic profile as Botox®. Its potency labelling is still a matter of debate. Currently, a conversion ratio between the mouse units measured by Allergan for Botox® and the mouse units measured by Ipsen for Dysport® of 1:2.5 must be assumed. NeuroBloc®/MYOBLOC®’s potency labelling can be compared to that of Botox® by using a conversion ratio 1:40. Its disadvantageous adverse effect profile and its problematic antigenicity will be discussed below. It can only be recommended for those dystonia patients with complete secondary therapy failure due to formation of antibodies against BT type A.

2.5 Antigenicity

Since BT consists of foreign proteins, antibodies can be formed against BNT and the non-toxic proteins. Antibodies formed against BNT (BNT-AB) block BT’s biological activity and, thus, produce antibody-induced therapy failure (ABTF). BNT-AB are therefore called blocking or neutralising antibodies. BNT-AB and BT are in a functional balance [35]. The therapeutic relevance of BNT-AB titres has to be considered. Antibodies formed against the non-toxic proteins do not interfere with BT’s biological activity and are called non-neutralising antibodies.

Risk factors for ABTF include the amount of BT applied at each injection series, the interinjection interval [36] and the immunological quality of the BT drug as described by their specific biological activity. The specific biological activity varies between different therapeutic preparations as shown in Table 10.1 [37–40]. A probable risk factor for ABTF is the reactivity of the immune system of the individual patient [41, 42]. Potential risk factors include the target tissue; the type of injection, i.e. intradermal, intramuscular or intraglandular injections; and female sex. Cumulative dose, treatment time and patient age have been excluded as risk factors. Recent analysis revealed that ABTF usually develops within the first 2–3 years of BT therapy [43]. After a treatment time of more than 5 years, ABTF becomes rare.

2.6 Safety Aspects and Adverse Effects

Based upon a broad therapeutic window and strictly local effects avoiding contact with excretion organs, BT excels with a remarkably advantageous adverse effect profile. Adverse effects can be classified as obligate, local or systemic. BT adverse effects occur in a typical time window after BT application. They usually start after 1 week and last for 1–2 weeks. Severity and duration of adverse effects depend on the BT dose applied, the target tissue and the adjacent tissues. Systemic spread of BT becomes clinically relevant only when BT doses applied are very high. BT transport through the blood-brain barrier is excluded by BT’s molecular size. The use of BT during pregnancy is contraindicated as a precautionary measure until further experience is gained. Extremely rarely, BT applications may trigger acute autoimmune reactions with brachial plexopathies or with dermatomyositis [44]. Caution is required when using BT in patients with pre-existing pareses, as in amyotrophic lateral sclerosis, myopathies and motor polyneuropathies, or in patients with impaired neuromuscular transmission, such as myasthenia gravis and Lambert-Eaton syndrome [45, 46]. Warnings not to use BT in patients receiving aminoglycoside antibiotics seem theoretical. With large numbers of patients being treated over prolonged periods of time, long-term experience is ample but does not indicate additional adverse effects [47].

Based upon a conversion factor of 1:1, the adverse effect profiles of Xeomin® and of Botox® are identical [32, 33]. The adverse effect profile of BT type B drugs is substantially different from the adverse effect profile of therapeutic BT type A drugs. Whereas even low and intermediate BT-B doses frequently produce systemic autonomic adverse effects, frequency of motor adverse effects is similar after BT type B and BT type A [48]. Whereas BT type A has a relatively strong effect on the motor system and a relatively weak effect on the autonomic nervous system, this correlation is reversed in BT type B [49]. Because of its systemic autonomic adverse effects, BT type B should be used with caution in patients with pre-existing autonomic dysfunction or in connection with anticholinergics.

2.7 Therapeutic Profile

With the features described above, BT’s therapeutic profile can be summarised as shown in Table 10.2. BT can be used in muscles, exocrine glands and structures associated with pain. BT’s therapeutic effect follows a time course, which is remarkably reproducible in the individual patient, but shows some interindividual variability. When BT is injected into muscle tissue, it produces a peripheral paresis. This paresis manifests clinically after a few days, reaches its maximum after 1–2 weeks, is usually stable for 6–12 weeks and then gradually resolves over several weeks. The extent of the therapeutic effect is well controllable by the amount of BT applied. Adverse effects are benign and fully reversible. With BT type B, systemic anticholinergic adverse effects and ABTF are frequent.

Table 10.2 Therapeutic profile of botulinum toxin drugs
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3 Basic Principles of Botulinum Toxin Therapy

3.1 The Multilayer Concept of Dystonia Treatment

Dystonia is a chronic condition for which no causal therapy exists. In most cases, dystonia treatment therefore has to be multimodal and long term. Co-ordinating the efforts of interdisciplinary treatment teams over prolonged periods of time may be supported by special working groups such as IAB (Interdisziplinärer Arbeitskreis Bewegungsstörungen) [50].

Treatment of dystonia can best be described as a multilayer concept (Table 10.3). The basal layer includes antidystonic therapies. Here, BT therapy is pivotal. It is entirely symptomatic. Nevertheless, its use may change the long-term perspective of patients affected. In children, symptomatic suppression of dystonic muscle activity may enable certain motor developments otherwise prevented. In adults, it can avoid the development of complications otherwise potentially dominating the clinical picture. The use of BT therapy early in dystonia’s course therefore seems advisable. BT’s therapeutic effect may involve central mechanisms. Its predominant effects, however, are peripheral. Usually, BT therapy should be complemented by physiotherapy where stretching exercises that can increase and maintain joint mobility, training of antagonistic muscles that can improve functional capabilities and retraining the impaired patient’s self-perception in space are the main tasks [51]. BT therapy can easily be combined with other antidystonic treatment options, including oral antidystonic drugs, intrathecal baclofen and peripheral or central surgery including deep brain stimulation.

Table 10.3 The multilayer concept of comprehensive dystonia therapy
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The second layer includes adjuvant drugs such as analgesics and anxiolytics. They can become necessary when the effects of the antidystonic drugs are unsatisfactory. Relaxation exercises can break the vicious circle of motor induction in dystonia.

The third layer consists of adjuvant measures including adequate information for the patient and his/her family about the BT therapy as well as about the treated condition. Sharing a solid information base is a prerequisite for a stable patient-physician relationship, which seems particularly important since dystonia is a chronic condition. Patient support groups have a role to play here. Social support gives advice to the patient about available social benefits.

3.2 Dosing

BT therapy is a local therapy. Dosing, therefore, depends on two elements, i.e. the number of dystonic muscles requiring treatment (target muscles) and the degree of their dystonic involvement. Given the enormous variability of dystonia with respect to localisation and intensity, communication of total doses per patient is only relevant with respect to systemic adverse effects. Recently, it has been demonstrated that Xeomin® in total doses of up to 840 MU is free of motor or autonomic systemic adverse effects [33]. Indirect evidence suggests the similar safety margins for Botox® [33]. Frequently this dose range is not exploited. Within the individual target muscles, broad consensus emerged amongst physicians over the last years about appropriate dose ranges. Within these dose ranges, the individual dose has to be selected according to the degree of dystonic involvement. Additionally, some general dose modifiers (Table 10.4) should be used to adapt BT doses to the individual strength of the patient’s target muscles. When neuromuscular transmission is impaired or when underlying paresis is present, BT dosages may need to be reduced.

Table 10.4 Factors predicting the individual strength of the patient’s target muscles. These factors, when present, modify the botulinum toxin dose within the recommended dose ranges
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3.3 Planning of Botulinum Toxin Therapy

Planning of BT therapy is based upon identification of target muscles and their degree of dystonic involvement. This information may be obtained clinically by analysing the dystonic movements or postures. Based upon physiological activation patterns, dystonic muscles can be deduced. However, with unphysiological co-activation of antagonistic muscles as a key feature of dystonia, this clinical approach has limitations. An additional problem is compensatory muscle activity and preventive postures may be difficult to identify. The clinical approach does not allow determination of the degree of dystonic involvement. A superior way of planning of BT therapy is based upon electromyography [52]. Needle electromyography allows precise target muscle identification. It also allows comparison between maximal voluntary muscle activation and dystonic muscle activity for calculation of the dystonic involvement. Still, identification of compensatory muscle activation may be a problem. However, recordings of prolonged periods of electromyographic activity often allow distinction between dystonic and compensatory muscle activity. Target muscle selection by estimation of muscle hypertrophy using tomographic imaging techniques is inadequate, since muscle hypertrophy is not a necessary feature of dystonia and precise measurement of hypertrophy would require muscle relaxation which dystonia patients usually cannot maintain. At the end of the planning process stands the injection scheme describing the target muscles with their respective BT doses. This injection scheme is a prediction of the patient’s therapeutic response. Subsequent injection series will usually improve the injection scheme. Recommendations not to exceed certain initial total doses and to very gradually build them up are counterproductive and risk the patient’s compliance. Once the optimal injection scheme is established, it should be adhered to unless there is evidence of major changes of the treated symptomatology.

3.4 Intramuscular Placement of Botulinum Toxin Drugs

Placement of the BT drug into the target muscle can be done clinically by palpation (ideally under voluntary activation of the target muscle), by using surface landmarks or by back-tracing the muscle tendons. To identify individual finger muscles, repetitive active or passive finger movements may allow improved palpation of the target muscles. In target muscles, in which this is difficult, such as the iliopsoas or the piriformis muscles, or when selective injection of individual finger muscles is required, electromyographic guidance using a special injection needle may become necessary. Simultaneous electric stimulation may be of additional help. General use of electromyography to place BT drugs is not necessary. Whether electromyography-guided BT placement would allow a dose reduction needs to be demonstrated. Tomographic imaging has also been suggested to improve drug placement. Since magnetic imaging may be disturbed by the presence of the injection needle, x-ray tomography has been applied. However, application of substantial radiation doses is problematic for chronic treatment. Ultrasound techniques seem to be more helpful, especially in children who may be uncooperative and particularly pain sensitive [53].

The effects of dilution and number of injection sites within a given target muscle have not been well studied so far. It is believed that increased dilution increases diffusion. The injection volumes at each injection site should be manageable. In our experience, injection volumes of 0.5–1.0 ml and 0.1–0.3 ml in facial muscles seem reasonable.

3.5 Monitoring of the Therapeutic Effect

Usually the therapeutic effect of BT therapy is evaluated punctually at 2–4 weeks after application. Apart from subjective scores reflecting overall outcome or dystonic pain, various objective dystonia rating scales, such as the Tsui Scale [54], the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) [55] or the Burke-Fahn-Marsden Scale [56], have been introduced. The disadvantage of these scales is that they do not describe the dynamics of BT therapy, i.e. the time it takes for the therapeutic effect to build up and the time when it is waning. In order to construct the integral of the therapeutic effect, a new treatment calendar was recently introduced [57], (Fig. 10.3).

Fig. 10.3
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Patient diary to monitor the effects of botulinum toxin therapy over time

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4 Specific Indications for Botulinum Toxin Therapy in Dystonia

4.1 Cranial Dystonias

Cranial dystonias can affect periocular muscles, mandibular muscles and perioral muscles. Rarely, scalp muscles or periauricular muscles are affected [58]. BT therapy can be used in all of these conditions successfully, either when they occur in isolation or when they occur in various combinations. Cranial target muscles with their recommended doses are shown in Tables 10.5 and 10.6. In periocular dystonia producing the classical clinical picture of blepharospasm, BT is injected into the orbicularis oculi muscle responsible for eyelid closure [3, 59]. Additional target muscles include the procerus and the corrugator supercilii muscles which form the horizontal and vertical nasal root folds and narrow the eyebrows. They may produce tension but do not have much influence on eyelid function. The nasalis muscle forms the longitudinal nasal dorsum fold and can be injected when the patient complains of irritation especially when wearing glasses. The frontalis muscle is an accessory eyelid-opening muscle and, therefore, should not be injected in blepharospasm contrary to occasional belief. Doses, dilutions and injection points for the treatment of blepharospasm vary considerably, whereas results and adverse effects are surprisingly similar. Adverse effects include ptosis, double vision, lagophthalmus and hematoma. They are rare and transient. Ptosis can almost certainly be avoided by sparing the medial part of the upper eyelid. Some patients with blepharospasm, especially those with progressive supranuclear palsy, have a varying degree of additional apraxia of eyelid opening [60], i.e. a supranuclear impairment of the eyelid-opening mechanism. In those patients, additional BT injections close to the rim of the eyelid are helpful [61]. If this strategy does not produce satisfactory results, a bilateral suspension operation connecting the upper eyelid to the frontalis muscle by a subcutaneous non-resorbable thread is helpful [62]. In mild cases, a wire spring attached to a spectacle frame can produce similar effects.

Table 10.5 Recommended botulinum toxin doses in cranial muscles
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Table 10.6 Recommended botulinum toxin doses in mandibular muscles
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In perioral dystonia, muscles above the oral orifice should generally be injected with special caution in order to avoid drooping of the mouth. BT injections into the upper lip may produce paraesthesias for unknown reasons. The risorius muscle can be injected safely 2 cm lateral to the corner of the mouth, whereas injections into the depressor labii inferioris bear the risk of instability of the lower lip.

In mandibular dystonia, jaw-opening and jaw-closing forms can be distinguished [63]. Combined activation of opening and closing muscles, however, is not infrequent. Additional jaw movements include jaw protrusion and lateral shifts of the jaw. Jaw closing is caused by activation of the masseter, the temporalis and – to a minor extent – the medial pterygoid muscles. Jaw opening is the result of activation of the lateral pterygoid muscle and the suprahyoid muscles forming the muscular floor of the cavity of the mouth. Protrusion and lateral shifts are caused by the pterygoid muscles, mainly the lateral ones. Whereas treatment of the jaw-closing type produces excellent results with only rare adverse effects, treatment of the jaw-opening type is less rewarding. Our experience indicates that BT injections into the pterygoid muscles through the incisura mandibulae together with injections of the suprahyoid muscles seem to work best in this situation. Attempts to inject the lateral and the medial pterygoid muscles individually would cause major technical problems and discomfort for the patient. Local spread and frequent co-activation of both muscles question the logic of this approach.

4.2 Pharyngolaryngeal Dystonia

Tonic or clonic dystonia of the pharynx can produce dysphagia and dyspnea [64]. They can occur spontaneously or in an action-induced fashion. BT injections into the posterior pharynx can easily be placed transorally and are effective. Doses range between 20 and 40 MU of Botox®. Laryngeal dystonia produces the clinical picture of spasmodic dysphonia, either in the adductor form with a strained-strangled voice or in the much less frequent abductor form with hypophonia [65]. In adductor forms, 2.5–10 MU of Botox® is administered into the thyroarytenoid (vocalis) muscle. Unilateral application appears to produce less adverse effects than when the same amount is distributed over both sides. In abductor forms, 2.5–10 MU of Botox® is administered into the posterior cricoarytenoid muscle unilaterally in order to avoid dyspnea. BT application can be performed perorally or transcutaneously using electromyographic guidance. The transoral approach allows detection of additional dystonic muscle activities in the pharynx or the larynx and, therefore, seems to be the superior method.

For the patient and for the physician, BT therapy of spasmodic dysphonia represents a highly satisfying indication [66]. Practically all patients benefit from BT therapy and the degree of improvement is astonishing. In many cases, almost normal speech patterns can be regained. In patients with abductor forms, the treatment results are less favourable. Adverse effects include difficulties with swallowing liquids or solid food. BT therapy can also induce weakness of coughing and some pain at the injection side. In treatment of adductor forms, hoarseness, breathiness of voice and hypophonia can occur, while in treatment of abductor forms, dyspnea may result.

Spasmodic laryngeal dyspnea describes spontaneously occurring or respiration-induced muscle hyperactivity of laryngeal muscles [67]. This condition is very rare and may influence both glottic and supraglottic muscles and can also be treated with BT therapy.

4.3 Cervical Dystonia

Cervical dystonia induces deviation of the neck and the head. Frequently shoulder elevation occurs. Whereas the neck can only be flexed and extended on a sagittal plane or frontal plane and rotated on a horizontal plane throughout its entire structure employing numerous interspinal joints, the head is flexed and extended on a sagittal plane, tilted on a frontal plane and rotated on a horizontal plane by using the singular atlanto-occipital joint with the dens as an additional stabilisator. Head and neck deviations can best be described by the scheme shown in Table 10.7. The scheme allows an easy and semiquantitative, although comprehensive, description of the head and neck deviations elicited by cervical dystonia.

Table 10.7 Description of head and neck deviation in cervical dystonia
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Isolated occurrence of head or neck deviations is rare. Most patients suffer from complex combinations of head deviations.

Head rotation occurs always together with neck rotation. It is caused by activation of the ipsilateral splenius capitis, the contralateral sternocleidomastoid muscle and the ipsilateral trapezius/semispinalis capitis muscle complex. Deep posterior neck muscles arising from the atlas and the axis including the obliquus capitis inferior, the rectus capitis posterior major and the rectus capitis posterior minor muscles are strong ipsilateral head rotators. The levator scapulae muscle is an additional but weaker ipsilateral head rotator. In head and neck rotation, the role of the sternocleidomastoid is often overestimated, whereas the role of the splenius capitis and the deep posterior neck muscles is often underestimated.

Head flexion is caused by activation of the supra- and infrahyoid muscles. Neck flexion is produced by the scaleni and deep anterior neck muscles including the longus colli, the longus capitis and the rectus capitis anterior muscles. Head extension originates from bilateral activation splenius capitis and the deep posterior neck muscles, and neck extension from bilateral activation of the trapezius/semispinalis capitis muscle complex. Lateral head flexion originates from ipsilateral activation of the sternocleidomastoid and the splenius capitis, and lateral neck flexion from ipsilateral activation of the scaleni, the levator scapulae and the trapezius/semispinalis capitis muscle complex. Protrusion is the consequence of neck flexion together with head extension, and retrusion of neck extension together with head flexion.

Planning of BT therapy for cervical dystonia includes careful examination of the spontaneous head position, the head position under motor and stress activation, the slow active head movement and passive head mobility. When dystonia occurs in waves or when it can be suppressed by gestes antagonistes, the time course of a dystonic build-up helps to identify compensatory muscle activity. Slow active movements can identify trigger postures and therefore potential preventive postures. Testing for pre-existent dysphagia identifies patients in which BT application into anterior neck muscles should be performed with caution.

Target muscles and recommended BT doses for cervical muscles are shown in Table 10.8.

Table 10.8 Recommended botulinum toxin doses for cervical muscles
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Dystonic pain as the leading complaint in most patients with cervical dystonia can almost always be markedly reduced by BT therapy. Residual pain may be caused by secondary degenerative processes or by radicular irritation. Head posture can also be improved substantially. Often, patients report the effects of the first BT applications enthusiastically, most likely due to the contrast to the sometimes prolonged period of insufficient treatment. Especially in the treatment of cervical dystonia, additional physiotherapy following the above-discussed guidelines is necessary [51]. Certain forms of cervical dystonia respond less favourably to BT therapy. Especially head flexion and neck flexion is difficult to treat when deep anterior neck muscles are involved, but also, alternating types of cervical dystonia may present a therapeutic challenge. In tremor types, sometimes reduced BT doses seem to be helpful.

The most common adverse effect of BT therapy of cervical dystonia is dysphagia. Depending on the definition of dysphagia and the effort to search for it, their incidence varies greatly. Applying current treatment standards, certainly less than 5 % of patients experience dysphagia constantly after each injection series. Mild dysphagia may be more frequent. Another adverse effect is head instability, especially due to impaired head and neck extension. When these adverse effects occur, their duration is usually limited to 1 or 2 weeks. Injection of the scaleni muscles can produce needle contacts with brachial plexus nerve fibres eliciting short-lasting electric sensations especially when injections are placed too close to Erb’s point.

4.4 Arm Dystonia

Arm dystonia can be divided into action-induced forms and spontaneous forms. Action-induced forms occur only during certain activities which can sometimes be highly specific. Spontaneous forms are not associated with specific activities, although they may be increased by unspecific physical activity. Writer’s cramp is the most common action-induced dystonia [68]. Other highly specific and sometimes peculiar activities can also trigger dystonia, such as playing musical instruments or performing sports. Especially, when these activities are performed under professional conditions, dystonia can result, thus explaining the term occupational cramp.

In writer’s cramp, a wrist flexor and a wrist extensor type can be distinguished. Additionally, elbow and shoulder muscles may be involved. However, abnormal elbow and shoulder postures may be compensatory in order to change the writing position and to reduce dystonia. Planning of BT therapy for writer’s cramp is based on careful examination of the clinical symptomatology. Electromyography is rarely contributory, since normal writing usually generates widespread muscle activation which can hardly be distinguished from dystonic muscle activity. Sometimes, asking the patient to write with the contralateral hand produces the dystonic pattern in the dominant hand without contamination of normal or compensatory muscle activity.

Target muscles and recommended BT doses for arm dystonia are shown in Table 10.9. Results of BT therapy of writer’s cramp are limited, because of narrow therapeutic windows of the potential target muscles [69]. This is a problem especially in the finger extensors. Apart from this, writer’s cramp frequently affects a large number of forearm muscles. BT therapy targeting all of these muscles would induce major paretic adverse effects. Additionally, distinction between physiological and dystonic muscle activity and identification of compensatory muscle activity may be difficult. Our experience indicates that even after several modifications of the injection scheme, only about half of the patients benefit from BT therapy and continue treatment. Results are better when the finger muscles are not involved, i.e. when the symptomatology is restricted to the wrist or elbow muscles. When finger muscles are involved, the outcome is better when individual finger muscles and when finger flexors rather than finger extensors are dystonic. If the symptomatology is restricted to individual finger muscles, electromyography possibly with additional electric stimulation may facilitate BT placement. If BT therapy is not successful in treatment of writer’s cramp, the patient can shift writing to the contralateral hand. About half of the patients can permanently use the contralateral hand for writing, whereas the other half develops writer’s cramp in this hand as well within 1 or 2 years. Increased use of keyboards is also one option to circumvent writer’s cramp. Retraining exercises may also become a therapeutic option in the future [70].

Table 10.9 Recommended botulinum toxin doses for arm muscles
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Treatment of other action-induced arm dystonias, especially when they are occupational, is even more problematic, since the motor performance expected by the patient is usually so high that it cannot be met, either due to dystonic residues or due to therapy-induced paresis [71].

Spontaneous induced arm dystonia usually occurs as part of a spasticity-dystonia syndrome or as idiopathic dystonia. Typical postures include finger flexion, thumb flexion, wrist flexion, elbow flexion and shoulder adduction or shoulder abduction. In spasticity-dystonia syndrome, treatment is focused on pain, prevention of contractures and eased care. Functional improvement may result but is often restricted by the underlying paresis.

4.5 Leg Dystonia

Leg dystonia can occur in idiopathic as well as in symptomatic dystonia, mostly as part of a spasticity-dystonia syndrome due to stroke or cerebral palsy. Action-induced forms would be extremely rare. Typical postures include hip adduction; knee flexion; equinovarus posture, i.e. the combination of ankle plantar flexion, foot supination and toe flexion; ankle plantar flexion; and toe flexion. Hip adduction is caused by activation of the adductor muscle group (adductor magnus, minimus, longus, brevis and gracilis muscles), knee flexion by activation of the hamstrings (semimembranosus, semitendinosus, biceps femoris muscles) and equinovarus posture by activation of the tibialis posterior, triceps surae, flexor hallucis and digitorum longus muscles. Ankle plantar flexion is the result of activation of triceps surae, peroneus longus and brevis and flexor digitorum longus muscles, and toe flexion of the activation of the flexor digitorum longus and brevis muscles.

Target muscles and recommended BT doses for leg dystonia are shown in Table 10.10.

Table 10.10 Recommended botulinum toxin doses for leg muscles
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Hip adduction, ankle plantar flexion and equinovarus postures respond well to BT therapy. BT doses, however, may be high, especially when bilateral injections are necessary. BT therapy for knee extension bears the risk of knee weakness, especially in patients with additional paresis as in spasticity-dystonia syndrome after stroke. Toe and great toe flexion often requires combined treatment of short and long toe and great toe flexors.

4.6 Segmental Dystonia and Generalised Dystonia

BT therapy of extended dystonic symptomatologies usually requires selection of those target muscles which play a major role in functional impairment, pain and prevention of complications. Less relevant target muscles may need to be left untreated in order not to exceed total BT doses which are safe with respect to toxicological and immunological adverse effects. Paravertebral muscles require 40–60 MU Botox® per segment per side, the rectus abdominis 40–80 MU Botox® per segment per side and the abdominal wall muscle complex (obliquus internus abdominis, obliquus externus abdominis and transversus abdominis muscles) 80–200 MU Botox® per side.

Toxicological and immunological safety margins have been discussed above. When safety margins are exploited to their full extent, BT therapy can improve even extended symptomatologies substantially. In patients requiring excess BT doses, deep brain stimulation may offer a treatment alternative. Combinations of BT therapy and deep brain therapy or intrathecal baclofen are possible.

5 Outlook

BT therapy presents a novel therapeutic concept. It has revolutionised many medical fields. In dystonia, for the first time, it offers help to a large numbers of patients with focal dystonia [72]. In segmental and generalised dystonia, high BT doses are necessary. Emerging experience demonstrates that high BT doses are immunologically and toxicologically safe [73–75]. The recent introduction of low-antigenicity BT drugs may allow booster injections for rapid dose adaptation, reduced interinjection intervals for an improved dynamic adjustment and increased BT dose for treatment of extended BT symptomatologies [76, 77]. High-affinity BT drugs may improve antigenicity even further. They may reduce the threshold for systemic toxicology so that higher total BT doses may be applied.