International 2015; volume 7:5886

Botulinum neurotoxin type A in Introduction Correspondence: Marco Antonio Araujo Leite, neurology: update Departamento de Neurologia, Universidade type A treatment has Federal Fluminense, Tavares de Macedo, 95, 902, Marco Orsini,1,2 Marco Antonio Araujo already made a dramatic impact on neurologic Icarai, Niterói, RJ, Brasil. E-mail: maarau- Leite,2 Tae Mo Chung,3 Wladimir Bocca,4 clinical practice to provide a new effective [email protected] Jano Alves de Souza,3 Olivia Gameiro de treatment and management of some diseases. Key words: botulinum toxin; neurology; rehabili- 3 5 It’s a bacterial endotoxin produced by Souza, Rayele Priscila Moreira, Victor tation. Hugo Bastos,5 Silmar Teixeira,5 Acary Clostridium botulinum during growth and Bulle Oliveira,4 Bruno da Silva Moraes,1 reproduction. According to the difference in Contributions: the authors contributed equally. toxin antigenic profiles, it is classified into André Palma Matta,2 Luis Jorge Jacinto5 seven serotypes namely type A, B, C, D, E, F Conflict of interest: the authors declare no poten- 1Centro Universitário Augusto Motta, and G. Type A, B, E and F are human toxic types tial conflict of interest. Bonsucesso, Rio de Janeiro; while type C and D are animal and poultry toxic 2Universidade Federal Fluminense, types.1 Botulinum toxin acts as the neuromus- Received for publication: 25 February 2015. Accepted for publication: 17 August 2015. Departamento de Neurologia, Niterói, cular junction to inhibit the release of neuro- transmitter, acetylcholine, presynaptically by Rio de Janeiro; 3Universidade de São This work is licensed under a Creative Commons the following steps: i) fast, specific and irre- Paulo - USP, São Paulo; 4Universidade Attribution NonCommercial 3.0 License (CC BY- versible binding to acceptors on presynaptic NC 3.0). Federal de São Paulo - UNIFESP, São nerve surface; ii) uptake of toxin into cell vesi- 5 Paulo, Universidade Federal do Piaui, cle; iii) translocation of toxin into cytosol ©Copyright M. Orsini et al., 2015 Parnaíba, Brasil across vesicle membrane, iv) toxin activates Licensee PAGEPress, Italy proteolysis which, in turn, blocks the release of Neurology International 2015; 7:5886 acetylcholine. In recent years, other possible doi:10.4081/ni.2015.5886 mechanisms of botulinum toxin have also been studied including its actions on afferent anonly imbalance between facilitatory and Abstract nerve, nociceptive sensory nerve and parasym- inhibitory input of alpha motor neurons lead- pathetic neuron. These studies serve as basis ing to motor system hyperexcitability. In other This paper reviews the current and most evidence that help develop innovative indica- words, is a motor disorder marked by the neurological (central , CNS) tions and new therapeutic applications.use increase of tonic stretch reflex-speed depend- uses of the botulinum neurotoxin type A. The Botulinum toxin (BT) is currently used in ent. In association with increased tonus, other signs of involvement of the pyramidal system effect of these toxins at neuromuscular junc- those entities characterized by excessive mus- as tendon hyperreflexia, clonus and presence tion lends themselves to neurological diseases cle contraction, including and spastic- ity. In addition, BT has been used to control of Babinski’s sign may occur. Patients affected of muscle overactivity, particularly abnormali- associated with increased muscle con- by spasticity commonly mention complaints ties of muscle control. There are seven traction in dystonia and spasticity, but also is such as muscle stiffness, impaired dexterity in serotypes of the toxin, each with a specific useful to control chronic pain not associated performing functional tasks, joint instability, activity at the molecular level. Currently, with muscle contraction, such as chronic daily painful muscle contractures, spasms, limited serotypes A (in two preparations) and B are . Finally, BT is useful in sialorrhea.2,3 range of motion and abnormal postures.4 available for clinical purpose, and they have Neurological disorders that trigger spastici- proved to be safe and effective for the treat- ty as , , Head Trauma, Assessment of spasticity in clinical ment of dystonia, spasticity, headache, and commercialSpinal Cord Trauma, Cerebral Palsy and some practice other CNS disorders in which muscle hyperac- motor neuron diseases (Spastic Paraparesis, In the assessment of spasticity, profiles, tivity gives rise to symptoms. Although initially Amyotrophic Lateral Sclerosis), can be man- measurements and indicators of evaluation thought to inhibit acetylcholine release only at aged by applying botulinum toxin. The mech- should be individualized and based on the the neuromuscular junction, botulinumNon toxins anism of action is complex, mainly acting on International Classification of Functioning, are now recognized to inhibit acetylcholine terminal neuromuscular junction, but also Disability and Health (ICF) of the World Health release at autonomic cholinergic nerve termi- exhibiting properties, probably Organization (WHO).5 The Modified Ashworth nals, as well as peripheral release of neuro- through inhibition of pain Scale is undoubtedly the most widely used 1 transmitters involved in pain regulation. Its release. Note: In addition to the direct action instrument for the assessment of spasticity effects are transient and nondestructive, and on striated muscle, botulinum toxin may act in due to its reliability and reproducibility. With the body of the muscle spindle and reduce cen- largely limited to the area in which it is admin- it, the passive movement of the segment eval- tripetal conduction of information.2 istered. These effects are also graded accord- uated is performed aiming to quantify the ing to the dose, allowing individualized treat- degree of resistance to movement. The scale is ordinal, with values ranging from 0 to 4.6 The ment of patients and disorders. It may also Barthel index and the Functional prove to be useful in the control of autonomic Injections of botulinum toxin Independence Measure (FIM) are used to dysfunction and sialorrhea. In over 20 years of in spasticity measure the level of functional independence use in humans, botulinum toxin has accumu- of patients in their basic and instrumental lated a considerable safety record, and in many activities of daily living.7,8 cases represents relief for thousands of Understanding the pathophysiolo- Currently the gait labs are able to assess in patients unaided by other therapy. gy of spasticity greater detail the performance of patients (post-application of botulinum toxin) by dis- Spasticity is triggered on the occurrence of tance traveled, speed and amplitude of steps.

[Neurology International 2015; 7:5886] [page 31] Review

The analysis must be carried through stan- der linked to botulin neurotoxin therapy use, dardization of physical examination and gait Botulinum toxin use in spasticity mainly in hemiplegia and spastic diplegia pattern records in two-dimensional video forms. Clinical use of BoNT-A provides many recording. They should, if available in the serv- Stroke different benefits, including a better control in pain, muscle spasms, functional recovery and ices, be applied the three-dimensional kine- In these patients the pattern of spasticity is prevention of severe contractures.20 Children matic and kinetic records, the dynamic elec- predominant in the flexor muscles of the upper tromyography, baropodography and measure- limbs, with posture in adduction and internal with chronic non progressive childhood 9 ment of energy consumption during gait. rotation of the shoulder, elbow flexion, prona- were evaluated in many differ- tion of the wrist and finger flexion. In the ent studies about performance of BoNT-A Types off botulinum toxin type A, lower limbs, spasticity predominates in the injections for spasticity in the lower and upper 21,22 points of application, ways of dilu- extensor muscles, with extension and internal limbs. A recent meta-analysis was per- formed and disclosed a short-term effective tion and long term effects rotation of the hip, knee extension, plantar flexion and foot inversion. This characteristic result for lower limb muscle tone, in passive Currently, the therapeutic preparations of posture receives the name of Wernicke-Mann ankle range of motion and gait speed, and a the most common TB type A for the treatment attitude.14,15 We alert that in some cases, such late-onset effectiveness on gross motor func- of patients with neurological injuries are pattern is not present. Therefore, before any tion measures for lower limbs.22 These cases Botox® (Alergan Inc., Irvine, CA, EUA) and/or procedure, a careful/judicious review should were studied after BoNT-A injections in ankle Dysport® (Ipsen Ltd., Slough, Berks, RU, be performed. Such doses may vary according flexors (including soleus and gastrocnemius), USA). There are other types of therapeutic to the bibliography used. knee flexors and hip adductors. Despite the preparations not commented in this chapter. fact that lower limb involvement is more com- We alert that doses are not interchangeable Spastic paraparesis mon in cerebral palsy, in some cases spastic between the different preparations of botu- Although patients with neuromuscular dis- quadriparesisis an important clinical finding linum toxin type A. Furthermore, they vary eases such as, for example, in spastic para- and should care attention. according to the selected muscles. The main paresis due to multiple causes, are considered A recent randomized double-blind clinical dose modifiers are muscle mass, degree of as relative contraindication to the use of botu- trial was also performed to evaluate the safety spasticity (Ashworth Scale) and results in ear- only linum toxin, some may benefit from therapy. and efficacy of BoNT-A in different degrees of lier applications. Unpreserved physiological The major problem in these patients is the upper extremity spasticity and showed short- solution (sodium chloride 0.9%) is used for presence of chronic and progressive weakness term improvements in function with a well-tol- dilution. The number of points of application is of the muscles of the lower limbs, often caus- erated and safe profile, irrespective of the indi- dependent on the morphology of muscle ing the pattern of extensor spasticity to beuse use- vidual spasticity pattern or degree.21 There are groups and is usually based on: i) the surface ful to the performing of certain functional many protocols of multiple injection sessions anatomy; ii) electromyography; iii) electrical activities. When treatment of spasticity is real- described in the literature without a clear ben- stimulation; iv) ultrasound (deeper mus- ly necessary, the therapeutic target is the efit from one to the others. There is also no cle).10,11 adductor muscles of the lower limbs. The appli- evidence that low or high doses improve spas- The onset of botulinum toxin efficacy cation of botulinum toxin may facilitate the ticity in significantly different degrees. ranged from few days to few weeks after injec- gait patterns and assist patients in hygiene, tion. Toxin induces muscle paralysis and clin- changes in position, transfers and other tasks. ically atrophy. Efficacy duration lasts for 2-4 The dose varies according to the degree of months or even longer. Muscle shows response spasticity and therapeutic target.16 Other neurological diseases to botulinum toxin treatment for a long time and/or clinical manifestations except when formation of neutralizing anti- Amyotrophic lateral sclerosis body occurs. It is noteworthy that the efficacy commercial In amyotrophic lateral sclerosis (ALS), Injections of botulinum toxin type A of botulinum toxin could be maximized when countless studies demonstrate the effective- combining with physiotherapy and orthopedic ness of botulinum toxin injection for the man- in cervical dystonia devices, such as, orthoses. Some factors may agement of sialorrhea, dysphagia and pain.17,18 Most patients with cervical dystonia present limit the benefits of botulinum toxin,Non which The therapy can also be used with caution in with cosmetic, social and pain complaints fre- are: the absence of a rehabilitation program or those cases where spasticity is accentuated, quently originate a common search for medical inappropriate treatment after the application; impairing caregivers in performing activities care. Although it can occur in association with the presence of fixed contractures; patients related to hygiene and changes in position complex phenotypes with cognitive impairments and antibodies (XXX). It is important to emphasize that there (including hemifacial spasms, ble- against botulinum toxin are some of them.12 are cases of patients with ALS who developed pharospasms, Meige syndrome, or mandibular Spasticity may also prevent severe muscle generalized weakness after focal botulinum dystonia and spasmodic dysphonia), most atrophy manage loss of bone mass and edema, toxin injection.19 Professionals should be care- cases present isolated cervical dystonia pic- as well as the risk of deep venous thrombosis. ful in the evaluation and in the possible dam- ture, even the fracture cases. Clinical trials As a result, these factors must be analyzed ages after application. As previously men- have been conducted since the 1980 and thoroughly before application. Conditions such tioned, the presence of spasticity can be a use- almost always provided important evidence as bedsores, urinary tract infection, deep vein ful strategy for implementing certain functions regarding disease symptom improvement after thrombosis, fecal impaction, emotional stress, in patients with ALS. botulinum toxin use as a long-term efficient fractures, and dislocations among others may and safety therapeutic method. However, there cause a momentary increase of spasticity. After Chronic childhood encephalopathy is little data regarding the role of the long-term clinical resolution of these problems, the Cerebral palsy as an acquired or genetic- effects of the injections on neuroplasticity and patients present spontaneous attenuation of related condition is the most common isolated peripheral and central neuromodulatory mech- the tonus without any intervention.13 cause of spasticity and the most studied disor- anism sexist.23-25

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Injections of botulinum toxin type A existence of some relevant neuromuscular dis- the World Health Organization International in tension headache and orders (like neuromuscular junction diseases, Classification of Functioning, Disability and including autoimmune acquired myasthenia Health (ICF), which describes the effects of Many studies regarding the clinical thera- gravis and Eaton-Lambert syndrome), social any health condition on: body functions and peutic use of botulinum toxin for prophylactic and psychological instability (as there is no structures, impairment; ability to perform treatment of migraine, chronic daily headache, proper social support in cases of lack of suc- tasks, activities; involvement in society (citi- chronic or persistent tension-type headache cess), pregnancy, lactating females, skin or zenship), participation. For spasticity manage- and chronic cervicogenic headache have been muscle local infection, and the history of ment, the treatment goals must aim to promo- performed. However, a few provide conclusive adverse effects linked to previous toxin use. te improvements on impairments but also in and definitive data of its efficacy and reliable The most common relative contra indication is task performance: mobility, carrying, moving use. Most important clinical data have been a fixed contracture of an involved joint to be and handling objects, or, self care and domes- originated in studies regarding its use for injected. Recent botulinum neurotox applica- tic life activities, decrease in care-burden, faci- chronic migraine and, at some extention it can tion in less than 3 months is also a relative litate handling/physical therapies and positio- be applied to the different groups of contra indication as the common finding of ning, maintaining joint range of motion, avoi- .26 In cases of refractory chronic neutralizing antibodies comes more evident in ding skin complications, improving cosmetics migraine and in patients which discontinued such condition. Important attention must be and self-esteem. It’s been well documented oral prophylactics, there is increasing evi- carried in cases with severe late-stage motor that spastic muscles suffer structural changes, dence that toxin injection can provide impor- neuron disease or polyneuropathies.23,30 As the so-called non neurogenic components of tant therapeutic improvement. The most rele- previously disclosed in this text, therapeutic spasticity. That’s why, if untreated, it can lead vant studies showed that botulinum toxin A use of drugs affecting the neuromuscular to fixed contractures and permanent restric- use was associated with moderate benefit in transmission should also be avoided, unless tion of joint movement, resulting in rapidly chronic daily headaches and chronic extremely necessary representing thus, a rela- progressive limb deformity. , without an evidence of fewer tive contra indication. episodic migraine occurrence or a decrease in chronic tension-type headache episodes per Physical medicine and rehabilita- month. Despite the well-tolerated and low Differentialonly diagnosis adverse effect profile in cases of headache, few tion after application of botulinum medical centers have experienced teams in toxin type A Severe spasticity is often difficult to diffe- technical application and provide adequate Different definitions of spasticity have been rentiate from fixed contractures. General 23,27 patient outcomes. published, nevertheless it’s very importantuse to anesthesia, intravenous sedation or local keep in mind that, what patients really present nerve blocks can be used to differentiate these Injections of botulinum toxin type A is not pure spasticity but a number of types of two conditions. These interventions tempora- in sialorrhoea muscle hyperactivity that co-exist and some- rily switch off’muscle hyperactivity and hence, Inherited and acquired neuromuscular and times are not easy to differentiate. According allow an evaluation of the degree of contractu- neurodegenerative causes of dysphagia are to the most recent and worldwide recognized re present. frequently related to severe compromise of guidelines, patients with spasticity should be quality. Pulmonary infections and sialorrhea treated by multidisciplinary teams that are represents one of the most devastating symp- knowledgeable and experienced in the field, toms linked to swallowing disorders.23,28 The and the treatment should be individualized Assessement of spasticity benefits from clinical use of botulinum toxin and is to include different modalities or tech- have been widely proved to improve drooling niques of physical medicine and rehabilita- To assess spastic patients we must resort to a severity in neuromuscular patients with mod- commercialtion. number of different tools, according to our erate and severe dysphagia and sialorrhea,29 This is not a universally accepted definition expertise, human and technical resources and especially in cases of of Spasticity and different authors have pro- experience. Fundamental are: i) clinical scales: (like Amyotrophic lateral sclerosis) and when posed others: Muscle hyperactivity, Reversible modified Ashworth scale (muscle tone), Tardieu 31,32 applied in association with differentNon therapeu- muscle hypertonia, to name a couple of scale (velocity dependent component), clonus, tic options, such as topical and oral anticholin- them. It’s presentation can be variable, spasm frequency scale, associate reaction rating ergic drugs and phonotherapy. It is also clear depending on the extent, topography and time scale, pendulum test, tonic inhibition; ii) neu- in cases of dysphagia that the higher the dose since occurrence of the lesion(s). Whatever rophysiological methods, EMG, H-reflex; iii) bio- injected in the parotid and submandibular the form of presentation is, it’s due to involun- mechanical methods: goniometry,muscle resis- glands, the stronger the effects and the more tary muscle hyperactivity and frequently leads tance. Of course we must evaluate more than common the side effects. There is no evidence to pain, abnormal postures and impaired func- just the spasticity aspect of a neurologic patient, tion. Even when it’s due to static lesions, loca- of the most appropriate techniques and esthet- before we can design a treatment strategy. The tion and severity of spasticity may change over ic drugs. global assement should include also: i) gonio- time. Therefore, the patient needs to be metry, muscle strength, selective residual motor Absolute and relative contraindica- assessed repeatedly and management should control; ii) quantifying symptoms: visual/nume- be adjusted accordingly. rical Analogic Scales, Lickert Scales, Shoulder Q, tions to the use of botulinum toxin Spin; iii) Functional Scales: 1) Upper Limbs: 9- type A hole peg test; Frenchay arm test; PRS; Fugl- Although its relative well-tolerated and safe- Meyer; ARMA; Action Research Arm Test; ty therapeutic use, physicians must be aware Spasticity management Rivermead Motor Assessment; Stream. 2) Lower of the most important absolute and relative Limbs: Stream, Berg Balance scale,10m walk contraindications of botulinum toxin type A To try and describe thoroughly the effects of test, timed up&go test, 6’ walk test, Functional use. Absolute contraindications include the spasticity on a person’s life, we should resort to Ambulatory Categories.3) Global Functioning:

[Neurology International 2015; 7:5886] [page 33] Review

Barthel; Functional Independence Measure; pate in the physical /cognitive rehabilitation Motricity Index; Goal Attainment Scale; QoL sca- Management of spasticity program. Botulinum neurotoxin A is therefore les; International Classification of Functionality best suited for the treatment of spasticity in and Health; Disability A assessment Scale 4) Spasticity must be approached and managed patients suffering from spasticity due to cere- Instrumented Analysis: gait and movement by a multidisciplinary specialized team and bral lesions/conditions. laboratories, dynamic poly-EMG telemetric sys- using a customized multimodal treatment tems, baropodography systems, accelerometer plan, designed to pursuit the goals defined in based activity measurement systems, robotic consensus with the patient and/or care takers. evaluation and training devices for upper limb, Ideally, in most cases, it should include inputs Treating spasticity with botu- lower limb, balance/postural control. It’s by using from the following items. linum neurotoxin A: final con- the adequate combination of all these evaluation Physiotherapy: proprioceptive neuromuscu- lar facilitation, balance training, gait training, siderations tools/methods for each patient, in each visit/eva- muscle strengthening, muscle stretching, luation, that we can get the best possible infor- hydrotherapy, functional electrical stimulation The efficacy in reducing muscle tone and mation, so as to derive a customized multidisci- (FES). the safety profile of BoNT-A, has been largely plinary and multimodal treatment plan, which Occupational therapy: perceptive-cognitive demonstrated and are nowadays considered may include botulinum neurotoxin A. training, training in domestic daily activities, level A evidence. There are currently different training for leisure activities, technical aids, formulations of BoNT-A in different markets games, computer, orthotic fitting and training, around the world. The units of BoNT-A prepa- wrist and hand mostly, fitting/training on rations are not the same and they are not Goal setting and treatment wheelchair positioning and driving. interchangeable. Hence, doses are specific to planning Activities of daily living (occupational thera- each preparation, are not interchangeable py/rehabilitation nurses): hygiene, self- with each other or with other preparations of botulinum toxin and should not be the basis of Before initiating treatment/management of care/grooming, dressing, bed mobility, trans- efficacy comparisons. Each brand has provided a spastic patient we need to establish treat- fers (t. board, t.disk, t. elevator), support bars. Orthotist: Provision of equipment, such as: tablesonly with dose recommendations for the ment goals. This is a complex, but rather com- removable splints to support joints and limbs approved indications and for the different pensatory process, that is easy to implement in in positions as physiologic as possible. muscles. everyday clinical practice, either for inpatients Serial casting (doctor + nurse or physiothe- The adverse event profiles have also been or outpatients of a specialized spasticity clinic. rapist/occupational therapist): the joint isuse pla- widely published, some of the most frequent A few steps are fundamental: firstly, from the ced in a plaster cast to prevent contractures being: muscle weakness, headache, flu-like anamnesis we find out what the main pro- and excessive muscle stiffness, sometimes symptoms, blurred vision, dry mouth, reduced blems of the patient are that are related to used immediately after botulinum neurotoxin sweating, constipation/diarrhea, vomiting, uri- spasticity. Secondly, we select from these pro- injections. nary incontinence, dysphagia, and gait distur- blems, those that may be managed by the treat- All these professionals, as well as psycholo- bances, accidental injuries due to falls, ment including botulinum neurotoxin, and we gists and social workers play a crucial role in pain/soreness/swelling/bruising or bleeding at inform the patient what we can do, what providing education/advice/advocacy/empo- the puncture site. Most importantly, it’s been he/she should commit to do as well, and what werment to patients and care takers affected clearly shown that they are rare, transient and the expected outcomes are. Then, if the by a congenital or acquired condition affecting mostly self-limited. patient is interested, these become treatment the central nervous system, of which resulted When treating a patient, by definition uni- goals. Goals are therefore identified on an impairment with spasticity. que, one major challenge to the physician is to individual basis, negotiated by the rehabilita- commercial be able to interprete/translate clinical patterns tion team with the patient and/or care takers, into a list of muscles contributing to the obser- and written down according to SMART rules: ved pattern and then prioritize the ones to be Specific, Measurable, Achievable, Realistic and Treatment strategies injected, according to the predefined treat- Timed. It is recommended to set oneNon primary ment goals for that injection cycle. There are goal and a few secondary goals, which ideally Patients should be under the care of a mul- muscle tables with recommendations for the shouldn’t be more than 2-3, for the sake of tidisciplinary team, in a specialized neuro- most frequent patterns, which are easily avai- lable in different trustworthy sources (for having both professionals and patient/care rehabilitation center, and the team must be example, www.mdvu.org). Anesthetic blocks taker focused and motivated. Once the time set experienced in evaluation and treatment of spasticity. Multiple modalities for spasticity with lidocaine or bupivacaine can be useful for follow-up and evaluation of treatment out- management should ideally be available and be tools, as can dynamic poly-emg. comes is reached, health professional team used, including: physical agents, physiothera- Once the right muscles to inject and the and patient should recur to the set SMART py, occupational therapy, casts, orthosis, apart right dose per muscle have been decided, the goals and determine if they were achieved and from the pharmacological and eventually sur- next step is the injection technique. An accu- to which extent. This is better accomplished gical treatments. rate technique should guarantee that the toxin with the use of the GAS (Goal Attainment Pharmacological treatments may include is injected in the right muscle and in the vici- Scale). GAS is mostly a method for scoring the systemic medication, which may have some nity of the greater concentration of motor end- degree of success in reaching goals during or degree of efficacy in these patients. plates in each muscle. Several techniques are after some kind of intervention. Patients have Nevertheless, the side effects, which are dele- used around the globe, from simple anatomical personalized measurements for their specific terious to the functioning of the affected cen- landmarks and EMG maps, to what is nowa- expected outcomes, but the degree of achieve- tral nervous system, are largely limited to the days considered the best practice in most gui- ment is scored in a standardized way, in order maximal doses that can be used. In fact, high delines, which is the use of one or more targe- to allow statistical analysis. doses may affect the patients’ ability to partici- ting techniques. The most popular to date are

[page 34] [Neurology International 2015; 7:5886] Review still, EMG and electrical stimulation, but ultra- 5. Wissel J, Ward AB, Erztgaard P, et al. 19. Mezaki T, Kaji R, Kohara N, et al. sound and ultra-sound associated to any of the Consensus table on the use of botulinum Development of general weakness in a previously mentioned is becoming more and toxin type A in adult spasticity. J Rehabil patient with amyotrophic lateral sclerosis more popular amongst the most experienced Med 2009;41:13-25. after focal botulinum toxin injection. and research prone injectors. These physi- 6. Mayer NH, Simpson DM. Patient Neurology 1996;46:845-6. cians/scientists claim, and literature is begin- encounter forms and rating scales. 20. Koussoulakos S. Botulinum neurotoxina: ning to show, that efficacy can be increased Appendix. Spasticity examination rating the ugly duckling. Eur Neurol 2009;61:331- with lower doses, therefore less cost and less scales. In: Mayer NH, Simpson DM, eds. 42. risks of adverse events. Spasticity: etiology, evaluation, manage- When we think about getting the best ment, and the role of botulinum toxin. 21. Koman LA, Smith BP, Williams R, et al. results from the treatment, muscle activity New York: Wemove; 2002. Upper extremity spasticity in children with must also be considered. It has a direct 7. Mahoney FI, Barthel DW. Functional evalu- cerebral palsy: a randomized, double-blind, influence on the response to BoNT-A, as we ation: Barthel index. Md State Med J placebo-controlled study of the short-term see a greater degree of nerve block at the more 1965;14:61-5. out comes of treatment with botulinum A activated muscles. The higher the level of mus- 8. Keith RA, Granger CV, Hamilton BB, toxin. J Hand Surg Am 2013;38:435-46. cle activity, the higher the increase in BoNT-A Sherwin FS. The functional independence 22. Koog YH, Min BI. Effects of botulinum cellular absorption, thus affecting the amount measure: a new tool for rehabilitation. Adv toxin A on calf muscles in children with of neuromuscular blockade. Hence, it’s recom- Clin Rehabil 1987;1:6-18. cerebral palsy: a systematic review. Clin mended that the injected muscles be mobili- 9. Graham HK, Selber P. Musculoskelectal Rehabil 2010;24:685-700. zed/stretched immediately before and 20-30 aspects of cerebral palsy. J Bone Joint Surg 23. Chen S. Clinical uses of botulinum neuro- minutes after the injection. Br 2003;85:157-66. toxins: current indications, limitations This is a medication used in spasticity treat- 10. Davis TL, Brodsky MA, Carter VA, et al. and future developments. Toxins ment for more than 20 years, and yet, relevant Consensus statement on the use of botu- 2012;4:913-39. questions are still lacking consensual answers linum neurotoxin to treat spasticity in from available scientific literature and key opi- adults. Available from: http://www.pharm- 24. Ramirez-Castaneda J, Jankovic J. Long nion leaders around the world. Namely, how scope.com/system/files/PTJ3111666.pdf. onlyterm efficacy and safety of botulinum much does this treatment modality improve 11. Jankovic J, Brin MF. Botulinum toxin: his- toxin injections in dystonia. Toxins functionality in a way that can influence acti- torical perspective and potential indica- 2013;5:249-66. vities performance, or reduce care taker need, tions. Muscle Nerve Suppl 1997;6:S129-45. 25. Ramirez-Castaneda J, Jankovic J. Long- or improve social participation, or quality of 12. Truong D, Dressler D, Hallett M. Manualuse of term efficacy, safety, and side effect profile life ? When should treatment be started and botulinum toxin therapy. Cambridge: of botulinum toxin in dystonia: a 20-year stopped? Who are the golden responders? And, Cambridge University Press; 2009. p 267. follow-up. 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