Medical Applications of Clostridia and Clostridial ToxinsView this Special Issue
Review Article | Open Access
Therapeutic Use of Botulinum Toxin in Neurorehabilitation
The botulinum toxins (BTX), type A and type B by blocking vesicle acetylcholine release at neuro-muscular and neuro-secretory junctions can result efficacious therapeutic agents for the treatment of numerous disorders in patients requiring neuro-rehabilitative intervention. Its use for the reduction of focal spasticity following stroke, brain injury, and cerebral palsy is provided. Although the reduction of spasticity is widely demonstrated with BTX type A injection, its impact on the improvement of dexterity and functional outcome remains controversial. The use of BTX for the rehabilitation of children with obstetrical brachial plexus palsy and in treating sialorrhea which can complicate the course of some severe neurological diseases such as amyotrophic lateral sclerosis and Parkinson's disease is also addressed. Adverse events and neutralizing antibodies formation after repeated BTX injections can occur. Since impaired neurological persons can have complex disabling feature, BTX treatment should be viewed as adjunct measure to other rehabilitative strategies that are based on the individual's residual ability and competence and targeted to achieve the best functional recovery. BTX therapy has high cost and transient effect, but its benefits outweigh these disadvantages. Future studies must clarify if this agent alone or adjunctive to other rehabilitative procedures works best on functional outcome.
Botulinum toxins are some of the most potent poisons present in nature produced by the anaerobic bacterium Clostridium Botulinum. Historically, these toxins were predominantly associated with a food-borne toxicosis producing a neurological life-threatening disease called “botulism”, characterized by a severe generalized muscular paralysis and cholinergic autonomic blockade. Currently, botulinum toxins have become established as efficacious therapeutic agents for the treatment of numerous medical disorders. Seven types of toxins have been harvested from clostridium, designated A through G, but only type A (BTX-A) and B (BTX-B) are commercially available and used in clinical practice. In 1989, the Food and Drug Administration approved BTX-A for the treatment of strabismus; since then, the growing use of this drug in several neurological disturbances has made it one of the most important advancements in the therapeutics of movement disorders such as muscular dystonia and dyskinesia. At the same time, botulinum toxin (BTX) either alone or adjunct to other measures has emerged as a new important therapeutic strategy for clinicians, treating a wide range of disturbances including gastroenterological and urological diseases as well as dermatological and cosmetic applications.
In the last decade, one of the main indications of BTX is the treatment of disorders characterized by muscular hyperactivity and excessive or inappropriate muscle contraction. Neurorehabilitative medicine treats these patients and ameliorates severe neurological impairments that have scarcely available therapeutic interventions. This paper presents both the consolidated applications of BTX in spasticity as well as in other disturbances in which it has been shown to be a useful therapeutic tool. Since in clinical practice, BTX-B is less used than BTX-A, and few researches studies have been published regarding its use, most of data presented pertain to BTX-A treatment.
2. Structure and Type of BTX
The active BTX molecule is formed by two chains weighing ~150.000 daltons, in which a heavy chain is linked by a disulfide bond to a light chain . The heavy chain is responsible for neuron-specific binding and internalization. Once internalized and within a vesicle, the light chain across the vesicle membrane is released into the neuronal cytoplasm, where it binds to a specific target protein involved in the docking and fusion of acetylcholine-containing vesicles to the internal portion of the cell membrane. These target proteins are collectively referred to as the SNARE complex. The BTX-A cleaves a protein termed SNAP-25, whereas BTX-B binds a different protein designed VAMP, also known as synaptobrevin . Both are responsible for vesicle acetylcholine release. The derangement of this process at the neuromuscular junctions cause clinical effects consisting in muscle weakness and paralysis. BTX-A and BTX-B are commercially available and used in clinical practice. To date, three formulation of BTX-A are commercialized and are marketed as Botox (Allergan, Inc., Irvine, Calif, USA), Dysport (Ipsen Ltd., Berkshire, UK) and Xeomin (Merz, Frankfurt, Germany), respectively. The preparations are manufactured by different processes, have different formulations and potencies, which are determined by different biological assays based on their clinical use. BTX-B is marketed by Solstice Neuroscience (Malvern, Pa, USA) as MyoBloc in the United States and NeuroBloc (Elan Pharmaceuticals, San Diego Calif, USA) in Europe. It is important to note that the potency of a single unit varies greatly among the commercial types. Although the potency of 1 U of Botox is roughly equal to 1 U of Xeomin, 3 U of Dysport, and 40 to 50 U of MyoBloc, it is very important to recognize that a simple ratio of dosing equivalencies cannot be applied . BTX-B is commercially packaged in vials of 10 mL containing 5.000 MU and 10.000 MU of neurotoxin. For muscle injections, botulinum toxins are diluted with 0.9% sodium chloride solution at variable volumes depending on the dose that the clinician plans to inject. BTX doses are generally adjusted according to factors such as severity of the hyperactive muscle, number of muscles involved, age, and previous response to BTX therapy. The duration of BTX effect is variable depending from several factors including type of neurotoxin, dose, site of injections, and clinical applications. In disease botulism, neurotoxin A produces longer paralysis than botulinum neurotoxin B consistent with human observations . Likewise, BTX-A has been shown to have a longer duration of effect in cervical dystonia compared with BTX-B . Botulinum types A and B have a similar duration of clinical action in treating drooling due to neurological diseases . In poststroke spasticity, the duration of action was not specifically addressed by the available studies although some trials suggested that efficacy of BTX-A may be appreciated 6 weeks after injection and for up to 9–12 weeks . BTX-B has a tendency to produce more autonomic side effects than BTX-A  and can have a more enduring action than BTX-A in specific clinical applications such as hyperidrosis and sialorrhea [9, 10].
In a neurorehabilitation setting, BTX is predominantly used for the treatment of spasticity and to prevent muscular contractures. Spasticity is defined as a velocity-dependent increased resistance to passive limb movement in people with upper motor neuron syndrome . Clinically, it is an involuntary motor disorder, characterized by hypertonic muscle tone with increased excitability of the muscle stretch reflex and increased tendon reflexes. Muscle weakness and limb paresis are associated to spasticity and contribute to the loss of motor dexterity and ability. Spasticity, if left untreated can hamper functional outcome by promoting persistent abnormal posture that, in turn, produces muscular-tendon contractures and bone deformity. Secondary complications arising from spasticity include impaired movement, hygiene, self-care, poor self-esteem, body image, pain, and pressure ulcers. Furthermore, patients with severe spasticity can develop poor social participation and quality of life (QOL) . Because of these clinical concerns and related high social costs , several therapeutic strategies have been proposed for the treatment of spasticity including surgical, medical, and rehabilitative procedures. However, spasticity is not always harmful and patients with a combination of muscle weakness and hypertonic muscles may rely on the increased tone to maintain their posture and aid standing or walking. It is important to point out that BTX use is indicated when the spasticity is focal or segmental and if it interferes with active or passive functioning. Treatment of muscle hyperactivity may be considered when the condition is disabling. The primary aim of the treatment of spastic muscles is to maintain length and allow normal positioning of the limbs to prevent secondary soft-tissue shortening. Generally, BTX treatment is carried out as an adjunct to other rehabilitative strategies that are based on an individualized, multidisciplinary programmes and targeted to achieve patient goals. Treatment plans must consider a tradeoff between reduction of spastic hypertonia and preservation of residual motor function . Although there is no consensus as to when BTX therapy should be initiated, or how long it should last, BTX-A injection is considered the hallmark or first line of medical treatment for focal/segmental spasticity . Conversely, BTX-B has been predominantly used as an alternative agent for patients who developed resistance to BTX-A . BTX-B has been used for the treatment of adult and child spasticity, but its effectiveness is unclear . Data in the literature are insufficient to recommend it for the treatment of children with spasticity . It is known that spasticity can follow several neurological diseases such as stroke, acquired brain injury, multiple sclerosis, cerebral palsy, and spinal cord injury. BTX use for the treatment of spasticity in some of those will be addressed.
3.1. Poststroke Spasticity
Spasticity is a frequent motor disorder in adult patients with stroke and its incidence is variable ranging from 17% to 43% [19–21]. A bulk of trials have demonstrated the efficacy of BTX-A in reducing poststroke spasticity [22–24]. Improvement of hypertonic muscles has been reported both in upper [12, 25–28] and lower limbs [29–31] after BTX-A injections. Thus far, administration modalities, and standard muscle doses of BTX-A (either Botox or Dysport) have been proposed for the reduction of limb spasticity in adult patients with stroke. However, there is no clear evidence from the literature to guide optimal timing of interventions (e.g., early versus late), frequency of interventions, dilutions, injection sites, or doses. Current clinical recommendations for muscle-specific dosing in spasticity remain largely based on expert opinion, clinical experience, as well as the formulation of botulinum toxin being used. A mean BTX-A global dose ranging from 90 to 360 MU and from 350 to 1500 MU per intramuscular injection has been reported for upper spastic limbs when using Botox or Dysport, respectively. A BTX-A dose ranging from 100 to 400 MU and from 400 to 1500 MU for the two toxins, respectively, has been used in treating lower spastic limbs [7, 32]. According to the European Consensus on the use of BTX-A in adult spasticity, maximum doses should not exceed 1500 MU Dysport and 600 MU Botox per injection session . The magnitude of response is dose dependent [34, 35] even if the dosage is largely titrated by the practitioner based on individual patient response.
BTX-B has also been used in treating poststroke spasticity, but its efficacy in reducing spasticity has been questioned and, thus far remains unclear . A recent systematic review of BTX use in adult poststroke spasticity concluded that available data on BTX-B were insufficient to assess its effect on spasticity and that further controlled trials using BTX-B were necessary .
Although the reduction of spasticity is widely demonstrated with BTX-A treatment, its impact on the improvement of dexterity and functional outcome remains controversial. Some functional improvements may be seen after BTX injections, but global functional assessment methods do not consistently reflect these changes. Numerous studies have reported to attain prespecified goals [26, 36], active movement [37, 38], and gait . Conversely, other studies did not find any benefit on functional gain in patients with post-stroke spasticity after BTX-A treatment [12, 40–44]. Fridman et al.  reported kinematic parameters improvement of spastic upper arm in post-stroke patients after BTX-A injections. They speculated that the improvement in velocity and time required to perform some motor tasks could be translated to countless situations in a patient’s life, which is difficult to determine with objective functional scales. Likewise, Bensmail et al.  described improvement of kinematic parameters in upper spastic arm after BTX-A treatment but without significant changes in clinical outcomes. However, clinical practice shows that some patients benefit with improved motor function, but that predicting factors still have to be identified. Several reasons have been suggested to explain this contrasting finding. It is possible that spasticity does not contribute to limitation of function and that the underlying weakness is the only significant cause of activity limitation . Many recovering patients with stroke experience significant reductions in functioning, QOL, and family relationships. Improvements in QOL, caregiver burden, and patient functioning are key measures of success in any rehabilitation program. Furthermore, these patients can develop shoulder pain that interfere with the rehabilitative process and has been associated with poorer outcomes and prolonged hospital stays . BTX-A treatment of poststroke spasticity has been demonstrated to produce improvement of patients’ quality of life [12, 25] and pain relief .
3.2. Spastic Cerebral Palsy
Cerebral palsy (CP) is the most common nonprogressive cause of motor disturbance and disability in children. Even with improvements in medical technology and clinical practice, the overall rate of CP remains high, with 2 to 3 per 1000 live births . CP is the main cause of spasticity in children. Therapeutic management may include splinting/casting, passive stretching, facilitation of posture and movement, spasticity-reducing medication, and surgery. Many clinicians frequently face the dilemma of whether and how to medically treat spasticity in children with CP. When pharmacologic intervention is deemed appropriate, treatment decisions must first be based on accurate assessment using valid and reliable clinical instruments, and, even more importantly, measurable, achievable, and realistic treatment goals should be delineated. Successful use of BTX in children with CP was first reported in 1993 by Koman et al. . Since then, there has been a growing interest of the therapeutic effects of BTX-A, and many trials have investigated its effectiveness for treatment of spasticity in children and adults with CP [18, 51–55]. Likewise in poststroke spasticity, BTX-A has been effective in the reduction of spasticity of both upper [52, 56] and lower extremities [54, 57].
In the late 1990s, pediatric doses of BTX-A in the treatment of children with spastic CP ranged from 12 to 16 U/kg and from 15 to 25 U/Kg of body weight for Botox  and Dysport , respectively. These dosages have increased over time . Higher BTX-A doses of 15 to 22 U/kg and of 20 to 30 U/kg have also been used without serious adverse events for Botox  and Dysport [62, 63], respectively. Maximum doses of BTX-A should not exceed 300 U Botox and 900 U Dysport per injection session, respectively. Children typically receive higher doses per kilogram of body weight than adults and can develop more adverse events. BTX-A treatment is effective and safe, maintaining long-lasting effects after repeated injections. A recent review of relevant literature concerning the treatment of spasticity in children with CP recommended that the use of BTX-A should be offered as an effective and generally safe treatment to reduce localized/segmental spasticity in upper and lower extremities. The same review did not find sufficient data to support or refute the use of BTX-B . In this rehabilitation area, BTX-A is generally used as an adjunct to physiotherapy or other rehabilitative interventions such as casting or orthotics to obtain reduction of spasticity and functional improvement. A review by Ryll et al.  reported that BTX-A injections combined with usual care or physiotherapy can have a positive effect on walking in children with CP. Trials comparing BTX-A with usual care or physiotherapy showed evidence that functional outcomes improved at different follow-up times of 2 to 6 weeks [64, 65], 12 weeks , and 24 weeks [64, 66] when BTX-A injections were combined with usual care or physiotherapy compared to usual care or physiotherapy alone. Similarly, another recent systematic review found a high level of evidence supporting the use of BTX-A as an adjunct to managing upper limbs in children with spastic CP . However, several issues remain unsolved including timing, duration of BTX-A action, and its effectiveness in the long term. Furthermore, when BTX-A is used as adjunct to other measures, the type of physiotherapy that is best indicated, application, timing, and type of casting to obtain better results remain unclear.
3.3. Brain Injury
About 75% of patients with physical disability following severe brain injury (BI) will develop spasticity requiring specific treatment. Also, patients with focal spasticity due to BI can benefit from BTX treatment. Unlike poststroke spasticity, scarce data about the use of BTX in treating spasticity following traumatic BI have been reported. Generally, these studies used BTX-A and enrolled small or heterogeneous samples of patients including subjects with stroke and traumatic BI [67–70]. BTX-A injection was used as an adjunct to physiotherapy  or casting  strategies. However, all studies demonstrated the efficacy of BTX-A in reducing spasticity either in adults [23, 67–70] or children [71, 72].
4. BTX as Adjunct Therapy for Management of Spasticity
Treatment of spasticity incorporating BTX is usually part of an integrated multidisciplinary rehabilitation program. BTX is rarely a sole treatment, and it is generally used combined with physiotherapy or casting, particularly in children with spastic CP. Physiotherapy procedures associated with BTX-A treatment can be variable including stretching posture, constraint induced therapy, occupational therapy, and electrical stimulation [73–76]. A previously mentioned systematic review reported that a combination of BTX-A and occupational therapy for the treatment of spastic arm in children with CP is more effective than occupational therapy alone in reducing impairment, improving activity level outcomes, and goal achievement . Furthermore, the authors found a high level of evidence to support the use of BTX-A as an adjunct to managing upper limb spasticity in these children.
4.1. BTX and Casting/Orthotics
BTX is also used to prevent muscular contraction and to facilitate cast application or orthotics. Serial casting is a method used for reducing contractures due to spasticity and can be applied both to upper and lower limbs. BTX can facilitate this process by producing temporary weakness and relaxation of the targeted muscles, allowing them to be stretched more easily, thus reducing the neurogenic and biomechanical components of spasticity. Casting is the application of fiberglass and/or plaster to the spastic upper or lower limb to immobilize a joint and has been proposed for the treatment of spasticity following stroke, acquired brain injury and CP, in particular. This strategy has been recommended as a treatment option in the management of equinus in children with CP for many decades. Early researches reported that BTX is as effective as serial casting in improving dynamic function for children suffering with cerebral palsy [77–79]. Hence, there has been a growing interest of the therapeutic effects of BTX-A as adjunct to casting [80–82]. However, the effect of BTX-A combined with casting on the reduction of spasticity remain controversial and unclear [53, 80–82]. A systematic review of the effects of the casting on equinus of children with CP did not find any differences between groups comparing BTX-A plus casting or BTX-A alone versus casting .
Furthermore, similar questions and doubts about the improvement of functional outcome were raised when BTX and casting was used for the treatment of spastic children with CP. Studies comparing BTX-A injections plus casting or BTX-A injections alone versus casting showed strong evidence for no effects on the functional outcomes in the application of BTX-A injections, casting alone, or a combination of both treatments  in children with CP. On the other hand, Yaşar et al.  recently observed that in chronic stroke patients, casting might be an appropriate intervention following BTX-A injection to prevent equinovarus deformity and to improve the quality of walking. Likewise, casting and application of orthotics might potentiate the effect of BTX treatment. Lai et al.  reported that in poststroke spastic patients, dynamic splinting after BTX injection increased the range of active elbow extension and suggested that it might be a useful adjunct procedure for optimizing BTX effects.
5. BTX Use without Spasticity
Neurological diseases can produce variable and complex impairments requiring tailored rehabilitation strategies. In a neurorehabilitation setting, clinicians have to approach numerous motor and nonmotor disorders other than spasticity. BTX use in specific neurological diseases and disorders with complex neurological dysfunction will be provided.
6. BTX and Focal Hand Dystonia
Focal hand dystonia (FHD) is a motor disturbance characterized by a task specific muscle spasms, in which learned or repetitive motor tasks (such as writing or playing a musical instrument) trigger muscle spasms and interfere with practiced motor execution, whereas other actions remain normal. FHD include a variety of disorders affecting many different skilled functions. Writer’s cramp and musician’s dystonia are the most common forms of idiopathic FHD . Writer’s cramp is characterized by involuntary, repetitive, or sustained contractions of finger, hand, or arm muscles that occur during writing and produce abnormal postures or movements that interfere with normal handwriting. Although the prevalence is relatively low, varying from 3 to 7/100 000, [85, 86], it may be responsible for considerable morbidity in terms of working impairment, pain, embarrassment, low self-esteem, and poor social interaction. Musician's dystonia is a task-specific movement disorder that manifests itself as a loss of voluntary motor control in extensively trained movements. Approximately 1% of all professional musicians develop musician's dystonia, and in many cases, the disorder terminates the careers of affected musicians . Therapeutic strategy proposed for the treatment of FHD including muscle relaxation techniques, physical and occupational therapy, and medical and surgical therapies have all been disappointing. Several researches have demonstrated that BTX injections into selected hand and forearm muscles provides the most effective relief in patients with these task-specific occupational dystonias [88–90]. Injection of BTX into the muscles responsible for the abnormal postures can be very effective and is often considered the first choice. A muscle dose ranging from 5 to 40 MU of BTX-A (Botox) and from 15 to 150 MU of BTX-A (Dysport) has been injected for writer’s cramp . There has also been a specific study showing utility for musician’s cramps . Patients can continue to respond to injections for many years. Lungu et al. recently reported that BTX-A treatment was safe and effective after more than a decade of treatment  in 20 patients with FHD. Of these, the musicians were more likely to wait longer between injections. The dose of BTX is based on the size of the muscle affected, the intensity of the spasm, and the number of muscles involved . Likewise, in other motor disorders, BTX can correct abnormal hand posture and relieve discomfort. However, the restoration of normal hand function can be difficult to achieve. Not only are some of the underlying dystonic defects, such as loss of speed and coordination, not fully addressed by the botulinum toxin injection, but the weakness that accompanies injection can be an additional source of hand disability. In some patients, the tradeoff between disability due to weakness from injection and disability due to the dystonia itself is not acceptable. The cyclic improvement with BTX injection and the worsening of the dystonia when the benefit wears off, does not allow for consistent sustained performance which is especially problematic for professional musicians .
7. BTX and Obstetrical Brachial Plexus Injury
Obstetric brachial plexus injury (OBPI) can be a dramatic sequela of dystocia or complicated delivery. A recent study showed an incidence of 1.3 per 1000 live births in the United States . A higher incidence, ranging from 3 to 4.6 per 1000 live births was found in Europe [97, 98]. Severe brachial plexus palsies can result in disabling due to impairment and imbalance of the muscular contraction in the paretic limb. In spite of physical therapy, some children continue to experience contractures and abnormal posture that hamper complete recovery. In the last decade, an increasing number of reports on the treatment of BTX-A for OBPI have been published [99–103]. BTX-A has been used to improve muscular imbalance of the internal rotator-adductor muscles of the shoulder, limited active elbow extension, and triceps cocontraction in combination with conservative treatment, including long-term physiotherapy, occupational therapy, and functional orthopaedic or plastic surgery. Furthermore, BTX-A as adjunct to serial casting has been successfully used in children with OBPI to improve muscular contracture, arm position, elbow extension, and dexterity in the paretic limb [99, 100]. However, a recent systematic review about the treatment indications of BTX-A in children with OBPI emphasized the need for randomized controlled trials to determine its benefits and efficacy in order to support the continued use of this intervention in managing muscle imbalance and muscle cocontraction in children with OBPI .
8. BTX in Sialorrhea
Since BTX also inhibits the release of presynaptic acetylcholine at the neurosecretory junctions of the salivary glands, it has been proposed as a possible efficacious pharmacological treatment for hypersalivation and sialorrhea, which can occur and complicate the course and management of some severe neurological diseases such as amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and CP. Indeed, numerous studies have demonstrated that BTX-A and BTX-B are effective and safe for the reduction of drooling in patients with ALS and PD [105–108]. The injected doses into salivary glands is variable depending on the disease, the BTX used, and the clinician’s experience. The mean global doses injected into salivary glands ranged from 55 U to 200 U (Botox) [109, 110] and from 250 U to 450 U (Dysport) [111, 112] for BTX-A and from 2500 to 4000 U for BTX-B [106, 108, 113]. A recent research study comparing the two toxins in controlling sialorrhea of ALS and PD patients reported that either 250 U BTX-A (Dysport) or 2500 U BTX-B (Neurobloc) have similar effectiveness and safety .
In children with CP, drooling and sialorrhea have an incidence of 10% to 37% . These symptoms can have a devastating effect on the family’s social relationships and the patient’s quality of life. Several studies have demonstrated that BTX-A can be used with success in controlling sialorrhea in children with CP [115, 116]. A mean dose of BTX-A (Botox) ranging from 2 to 22.5 U/kg of body weight per single gland has been injected [117–119]. BTX-B can also be a safe and effective therapy for the treatment of drooling in these children. A recent randomized trial comparing three doses of 1500 MU, 3000 MU, and 5000 MU BTX-B injection into the salivary glands with ultrasound guidance  reported that the 3000 MU injection of BTX-B significantly improved the frequency and severity of sialorrhea in those children. The lower dosage was ineffective, and the higher dosage produced no greater benefit and more side effects. It has been proposed that BTX-B is more effective and could have a more enduring effect than BTX-A on autonomic function [10, 106]. Indeed, autonomic side effects are sometimes observed far from the injection site (such as dry mouth) after treatment for axillary hyperhidrosis with BTX-B . As previously mentioned, BTX-B has a tendency to produce more autonomic adverse events than BTX-A [5, 8, 121, 122], mainly due to the hypothesized affinity for postganglionic neurons containing M3 receptors (such as those responsible for salivation) . However, the study of Guidubaldi et al. found that that BTX-B had a shorter latency than BTX-A and comparable duration . The most relevant finding was that BTX-B had a significantly shorter latency than BTX-A (3 versus. 6 days). The different latencies might be due to various characteristics of the two serotypes, perhaps diffusion and/or affinity for autonomic fibers.
9. BTX Use in Rare Rehabilitative Clinical Conditions
Neurologically disabled subjects can present with complex dysfunction and clinicians have to face unique and difficult to treat clinical conditions. BTX can be a useful therapeutic tool in some of these conditions. Anecdotal reports have been published concerning the use of BTX-A in specific rare conditions such as sustaining posture after surgery in patients with cervical disk herniation, secondary to dystonic cerebral palsy . BTX-A has been used to hasten the healing of lower lip ulcers due to oromandibular dyskinesia in a subject in a vegetative state following a severe subarachnoid hemorrhage . Likewise, BTX-A treatment was used to hasten the healing of a buttock pressure sore in a subject with severe spastic paraplegia following a traumatic spinal cord lesion. In this last case, several therapeutic agents were applied without success, since all efforts at healing the ulcer by topical medication were hampered by recurrent spasms involving the gluteal muscles and the ulcer region . Gluteal injections of 660 U BTX-A (Dysport) reduced the movement disorder and improved buttock ulcer healing.
10. Adverse Events
Before performing BTX-A injections for therapeutic purposes, the expected risks and benefits for each patient must be carefully considered. Currently, dosages are largely titrated by the practitioner based on the previously mentioned criteria and the individual patient’s response. Reported adverse events associated with BTX are infrequent and predominantly concern the BTX-A formulation. Local and remote effects following BTX injections have been described. The former consisted in a reaction at the injection site, including pain, rush, and edema, whereas remote effects are due to diffusion of toxin and cause variable effects characterized by autonomic, regional, or systemic muscular weakness. Most adverse events after BTX treatment arise through weakness of the muscles injected or those nearby, which become weak through local spread of the toxin. Allergic or possible immune-mediated mechanisms have been proposed to be the cause of symptoms such as general malaise, fever, and skin rush.
Observed adverse events include nausea, urinary incontinence, falls, seizures, fever, dry mouth, and dysphagia . These disturbances have often been found in patients with preexisting comorbidities, for example, seizures in subjects with previous epileptic disorders. General malaise and “flu-like” symptoms have also been described . Generally, they are mild to moderate and transient. A pooled analysis including 792 patients concluded that nausea was the most frequent minor adverse event in poststroke patients treated with BTX-A, affecting 2.2% of cases . No serious adverse event was reported in a recent systematic review regarding BTX-A use in adults with poststroke spasticity . Conversely, because children receive higher doses per kilogram than adults, they can develop more adverse events. A variable incidence of side effects ranging from 4% to 7% has been reported [40, 128, 129]. In a previously mentioned paper, 28.5% of CP children who were injected with 5000 MU of BTX-B for sialorrhea developed generalized weakness and severe dysphagia requiring hospitalization and nasogastric tube feeding . A very infrequent systemic effect manifested was generalized weakness distant from the site of injection . A recent review of cases described in the literature indicates that risk of developing systemic effects does not seem to be related to dose based on body weight . It may be more likely that risk for this condition is related to the total injection dose and injection frequency. Doses greater than 600 units of Botox with follow-up injections occurring every 3 months may lead to an increased risk of developing severe adverse events. Repeated contralateral weakness and fatigue after high doses of BTX-A injection for poststroke spasticity have been also described .
11. Neutralizing Antibodies
BTX-A effects can be abolished by the development of neutralizing antibodies (NAbs). Antibody formation against BTX proteins is one of the reasons for therapy failure. Studies have demonstrated that antibodies-binding toxins, specifically in the region responsible for entry into neurons, neutralize or inactivate the toxin. In order to overcome therapy failure, injecting increased BTX doses with short injection intervals and using different BTX serotypes [133, 134] has been suggested. This phenomenon is reported with a variable incidence according to the treated disorder. In cerebral palsy, the incidence of NAbs has been reported in a range from 6% to 31% [128, 135, 136]. NAbs are rare in poststroke spasticity. In a sample of 235 poststroke patients with spasticity receiving a dose ranging from 100 to 400 MU of BTX-A, Yablon et al.  found <0.5% of NAbs. The development of NAbs are facilitated if repeated injections and high dosages of BTX are used independently from the treated disorder. However, NAbs are more frequent in patients with cervical dystonia compared to other hyperactive muscular disturbances. The development of NAbs has been also observed in subjects who underwent BTX injections for nonmotor disorders such as sialorrhea. Although no BTX-A resistance in the treatment of sialorrhea has yet been reported, this disappointing phenomenon has recently been described for BTX-B after repeated injection into the salivary glands .
Muscle selection is a key feature for the efficacy of BTX treatment, and the infiltration modalities are a further source of heterogeneity. BTX-A injections are more efficacious if the muscles are targeted by needle EMG or ultrasound guidance. There is evidence from dystonia that EMG targeting increases accuracy and improves outcome . However, when high doses are injected into sufficiently large muscles, as in spasticity, toxin diffusion compensates for this limitation. Salivary glands are generally injected by ultrasound guidance. A drawback for BTX therapy is its high cost and the transient nature of the toxin. In this respect, recent papers have reported that the clinical benefits of BTX-A treatment outweigh the apparent high costs of this intervention, showing it to be a cost-effective treatment [13, 42].
Botulinum toxin types A and B are valuable agents in the multiple therapeutic strategies that clinicians carry out in a neurorehabilitation setting. It is important to strive to attain the best clinical and functional benefit that improves the quality of care of patients undergoing rehabilitation. Since neurologically disabled subjects present complex dysfunction, prior to initiating BTX therapy, specific functional limitations, goals, and expected outcomes of treatment should be discussed with the patient and caregiver. Muscle selection and the order and priority of treatment should be tailored to the treatment of spasticity and muscular imbalance. BTX-A and BTX-B strategies should be viewed as adjunct measures based on the individual’s residual ability, and competence and tailored rehabilitation programs are needed to achieve the best functional outcome. Although BTX-A treatment has been demonstrated safe and effective in managing several neurological disorders, many questions still remain unsolved. Future studies should address if this agent alone or as an adjunct to other rehabilitative procedures optimizes functional outcome.
- B. R. das Gupta, “Structures of botulinum neurotoxin. Its functional domains and perspectives on the crystalline tipe A toxin,” in Therapy with Botulinum Toxin, J. Jankovic and M. Hallet, Eds., pp. 15–39, Marcel Dekker, New York, NY, USA, 1994.
- G. Schiavo, F. Benfenati, B. Poulain et al., “Tetanus and botulinum—B neurotoxins block neurotransmitter release by proteolytic cleavage of synapto-brevin,” Nature, vol. 359, no. 6398, pp. 832–835, 1992.
- A. Tilton, J. Vargus-Adams, and M. R. Delgado, “Pharmacologic treatment of spasticity in children,” Seminars in Pediatric Neurology, vol. 17, no. 4, pp. 261–267, 2010.
- J. E. Keller, “Recovery from botulinum neurotoxin poisoning in vivo,” Neuroscience, vol. 139, no. 2, pp. 629–637, 2006.
- C. L. Comella, J. Jankovic, K. M. Shannon et al., “Comparison of botulinum toxin serotypes A and B for the treatment of cervical dystonia,” Neurology, vol. 65, no. 9, pp. 1423–1429, 2005.
- A. Guidubaldi, A. Fasano, T. Ialongo et al., “Botulinum toxin A versus B in sialorrhea: a prospective, randomized, double-blind, crossover pilot study in patients with amyotrophic lateral sclerosis or Parkinson's disease,” Movement Disorders, vol. 26, no. 2, pp. 313–319, 2011.
- A. E. Elia, G. Filippini, D. Calandrella, and A. Albanese, “Botulinum neurotoxins for post-stroke spasticity in adults: a systematic review,” Movement Disorders, vol. 24, no. 6, pp. 801–812, 2009.
- D. Dressler and R. Eleopra, “Clinical use of non-a botulinum toxins: Botulinum toxin type B,” Neurotoxicity Research, vol. 9, no. 2-3, pp. 121–125, 2006.
- G. Lagalla, M. Millevolte, M. Capecci, L. Provinciali, and M. G. Ceravolo, “Long-lasting benefits of botulinum toxin type B in Parkinson's disease-related drooling,” Journal of Neurology, vol. 256, no. 4, pp. 563–567, 2009.
- M. Basciani, F. di Rienzo, A. Fontana, M. Copetti, F. Pellegrini, and D. Intiso, “Botulinum toxin type B for sialorrhea in children with cerebral palsy: a randomized trial comparing three doses,” Developmental Medicine & Child Neurology, vol. 53, no. 6, pp. 559–564, 2011.
- J. W. Lance, “Symposium synopsis,” in Spasticity: Disordered Motor Control, R. G. Feldman, R. R. Young, and W. P. Koella, Eds., pp. 485–494, Yearbook Medical, Chicago, Ill, USA, 1980.
- G. D. Caty, C. Detrembleur, C. Bleyenheuft, T. Deltombe, and T. M. Lejeune, “Effect of upper limb botulinum toxin injections on impairment, activity, participation, and quality of life among stroke patients,” Stroke, vol. 40, no. 7, pp. 2589–2591, 2009.
- A. Esquenazi, “Improvements in healthcare and cost benefits associated with botulinum toxin treatment of spasticity and muscle overactivity,” European Journal of Neurology, vol. 13, no. 4, supplement 4, pp. 27–34, 2006.
- H. Woldag and H. Hummelsheim, “Is the reduction of spasticity by botulinum toxin A beneficial for the recovery of motor function of arm and hand in stroke patients?” European Neurology, vol. 50, no. 3, pp. 165–171, 2003.
- G. Sheean, “Botulinum toxin should be first-line treatment for poststroke spasticity,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 80, no. 4, p. 359, 2009.
- M. P. Barnes, D. Best, L. Kidd et al., “The use of botulinum toxin type-B in the treatment of patients who have become unresponsive to botulinum toxin type-A—initial experiences,” European Journal of Neurology, vol. 12, no. 12, pp. 947–955, 2005.
- A. Brashear, A. L. McAfee, E. R. Kuhn, and J. Fyffe, “Botulinum toxin type B in upper-limb poststroke spasticity: a double-blind, placebo-controlled trial,” Archives of Physical Medicine and Rehabilitation, vol. 85, no. 5, pp. 705–709, 2004.
- M. R. Delgado, D. Hirtz, M. Aisen et al., “Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society practice parameter: pharmacologic treatment of spasticity in children and adolescents with cerebral palsy (an evidence-based review): report of the quality standards subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society,” Neurology, vol. 74, no. 4, pp. 336–343, 2010.
- D. K. Sommerfeld, E. U. B. Eek, A. K. Svensson, L. W. Holmqvist, and M. H. von Arbin, “Spasticity after Stroke: its occurrence and association with motor impairments and activity limitations,” Stroke, vol. 35, no. 1, pp. 134–139, 2004.
- E. Lundstrom, A. Terent, and J. Borg, “Prevalence of disabling spasticity 1 year after first-ever stroke,” European Journal of Neurology, vol. 15, no. 6, pp. 533–539, 2008.
- P. P. Urban, T. Wolf, M. Uebele et al., “Occurence and clinical predictors of spasticity after ischemic stroke,” Stroke, vol. 41, no. 9, pp. 2016–2020, 2010.
- R. Kaji, Y. Osako, K. Suyama, T. Maeda, Y. Uechi, and M. Iwasaki, “Botulinum toxin type A in post-stroke upper limb spasticity,” Current Medical Research and Opinion, vol. 26, no. 8, pp. 1983–1992, 2010.
- D. M. Simpson, A. Blitzer, A. Brashear et al., “Assessment: Botulinum neurotoxin for the treatment of movement disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology,” Neurology, vol. 70, no. 19, pp. 1699–1706, 2008.
- R. L. Rosales and A. S. Chua-Yap, “Evidence-based systematic review on the efficacy and safety of botulinum toxin-A therapy in post-stroke spasticity,” Journal of Neural Transmission, vol. 115, no. 4, pp. 617–623, 2008.
- E. P. Elovic, A. Brashear, D. Kaelin et al., “Repeated treatments with botulinum toxin type A produce sustained decreases in the limitations associated With focal upper-limb poststroke spasticity for caregivers and patients,” Archives of Physical Medicine and Rehabilitation, vol. 89, no. 5, pp. 799–806, 2008.
- P. McCrory, L. Turner-Stokes, I. J. Baguley et al., “Botulinum toxin a for treatment of upper limb spasticity following stroke: a multi-centre randomized placebo-controlled study of the effects on quality of life and other person-centred outcomes,” Journal of Rehabilitation Medicine, vol. 41, no. 7, pp. 536–544, 2009.
- M. F. Gordon, A. Brashear, E. Elovic et al., “Repeated dosing of botulinum toxin type A for upper limb spasticity following stroke,” Neurology, vol. 63, no. 10, pp. 1971–1973, 2004.
- R. Kaji, Y. Osako, K. Suyama, T. Maeda, Y. Uechi, and M. Iwasaki, “Botulinum toxin type A in post-stroke lower limb spasticity: a multicenter, double-blind, placebo-controlled trial,” Journal of Neurology, vol. 257, no. 8, pp. 1330–1337, 2010.
- S. J. Pittock, A. P. Moore, O. Hardiman et al., “A double-blind randomised placebo-controlled evaluation of three doses of botulinum toxin type A (Dysport) in the treatment of spastic equinovarus deformity after stroke,” Cerebrovascular Diseases, vol. 15, no. 4, pp. 289–300, 2003.
- C. Bleyenheuft, S. Cockx, G. Caty, G. Stoquart, T. Lejeune, and C. Detrembleur, “The effect of botulinum toxin injections on gait control in spastic stroke patients presenting with a stiff-knee gait,” Gait and Posture, vol. 30, no. 2, pp. 168–172, 2009.
- G. D. Caty, C. Detrembleur, C. Bleyenheuft, and T. M. Lejeune, “Reliability of lower limb kinematics, mechanics and energetics during gait in patients after stroke,” Journal of Rehabilitation Medicine, vol. 41, no. 7, pp. 588–590, 2009.
- S. Ozcakir and K. Sivrioglu, “Botulinum toxin in poststroke spasticity,” Clinical Medicine and Research, vol. 5, no. 2, pp. 132–138, 2007.
- J. Wissel, A. B. Ward, P. Erztgaard et al., “European consensus table on the use of botulinum toxin type a in adult spasticity,” Journal of Rehabilitation Medicine, vol. 41, no. 1, pp. 13–25, 2009.
- S. J. Smith, E. Ellis, S. White, and A. P. Moore, “A double-blind placebo-controlled study of botulinum toxin in upper limb spasticity after stroke or head injury,” Clinical Rehabilitation, vol. 14, no. 1, pp. 5–13, 2000.
- S. A. Yablon, M. F. Brin, A. M. Vandenburgh et al., “Dose response with onabotulinumtoxinA for post-stroke spasticity: a pooled data analysis,” Movement Disorders, vol. 26, no. 2, pp. 209–215, 2011.
- A. Brashear, M. F. Gordon, E. Elovic et al., “Intramuscular injection of botulinum toxin for the treatment of wrist and finger spasticity after a stroke,” New England Journal of Medicine, vol. 347, no. 6, pp. 395–400, 2002.
- H. P. Francis, D. T. Wade, L. Turner-Stokes, R. S. Kingswell, C. S. Dott, and E. A. Coxon, “Does reducing spasticity translate into functional benefit? An exploratory meta-analysis,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 75, no. 11, pp. 1547–1551, 2004.
- G. Sheean, N. A. Lannin, L. Turner-Stokes, B. Rawicki, and B. J. Snow, “Botulinum toxin assessment, intervention and after-care for upper limb hypertonicity in adults: international consensus statement,” European Journal of Neurology, vol. 17, supplement 2, pp. 74–93, 2010.
- J. V. G. Robertson, D. Pradon, D. Bensmail, C. Fermanian, B. Bussel, and N. Roche, “Relevance of botulinum toxin injection and nerve block of rectus femoris to kinematic and functional parameters of stiff knee gait in hemiplegic adults,” Gait and Posture, vol. 29, no. 1, pp. 108–112, 2009.
- A. M. O. Bakheit, S. Pittock, A. P. Moore et al., “A randomized, double-blind, placebo-controlled study of the efficacy and safety of botulinum toxin type A in upper limb spasticity in patients with stroke,” European Journal of Neurology, vol. 8, no. 6, pp. 559–565, 2001.
- M. K. Childers, A. Brashear, P. Jozefczyk et al., “Dose-dependent response to intramuscular botulinum toxin type a for upper-limb spasticity in patients after a stroke,” Archives of Physical Medicine and Rehabilitation, vol. 85, no. 7, pp. 1063–1069, 2004.
- L. Shaw, H. Rodgers, C. Price et al., “BoTULS: a multicentre randomised controlled trial to evaluate the clinical effectiveness and cost-effectiveness of treating upper limb spasticity due to stroke with botulinum toxin type A,” Health Technology Assessment, vol. 14, no. 26, pp. 1–113, 2010.
- L. Turner-Stokes, I. J. Baguley, S. De Graaff et al., “Goal attainment scaling in the evaluation of treatment of upper limb spasticity with botulinum toxin: a secondary analysis from a double-blind placebo-controlled randomized clinical trial,” Journal of Rehabilitation Medicine, vol. 42, no. 1, pp. 81–89, 2010.
- D. Bensmail, J. V. G. Robertson, C. Fermanian, and A. Roby-Brami, “Botulinum toxin to treat upper-limb spasticity in hemiparetic patients: analysis of function and kinematics of reaching movements,” Neurorehabilitation and Neural Repair, vol. 24, no. 3, pp. 273–281, 2010.
- E. A. Fridman, M. Crespo, S. G. Argüello et al., “Kinematic improvement following Botulinum Toxin-A injection in upper-limb spasticity due to stroke,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 81, no. 4, pp. 423–427, 2010.
- L. Ada, C. Canning, and T. Dwyer, “Effect of muscle length on strength and dexterity after stroke,” Clinical Rehabilitation, vol. 14, no. 1, pp. 55–61, 2000.
- I. Lindgren, A. C. Jonsson, B. Norrving, and A. Lindgren, “Shoulder pain after stroke: a prospective population-based study,” Stroke, vol. 38, no. 2, pp. 343–348, 2007.
- J. Y. Lim, J. H. Koh, and N. J. Paik, “Intramuscular botulinum toxin-A reduces hemiplegic shoulder pain: a randomized, double-blind, comparative study versus intraarticular triamcinolone acetonide,” Stroke, vol. 39, no. 1, pp. 126–131, 2008.
- I. Krägeloh-Mann and C. Cans, “Cerebral palsy update,” Brain and Development, vol. 31, no. 7, pp. 537–544, 2009.
- L. A. Koman, J. F. Mooney, B. Smith, A. Goodman, and T. Mulvaney, “Management of cerebral palsy with botulinum-A toxin: preliminary investigation,” Journal of Pediatric Orthopaedics, vol. 13, no. 4, pp. 489–495, 1993.
- M. B. Lukban, R. L. Rosales, and D. Dressler, “Effectiveness of botulinum toxin A for upper and lower limb spasticity in children with cerebral palsy: a summary of evidence,” Journal of Neural Transmission, vol. 116, no. 3, pp. 319–331, 2009.
- C. A. Olesch, S. Greaves, C. Imms, S. M. Reid, and H. K. Graham, “Repeat botulinum toxin-A injections in the upper limb of children with hemiplegia: a randomized controlled trial,” Developmental Medicine and Child Neurology, vol. 52, no. 1, pp. 79–86, 2010.
- K. Tedroff, F. Granath, H. Forssberg, and Y. Haglund-Akerlind, “Long-term effects of botulinum toxin A in children with cerebral palsy,” Developmental Medicine and Child Neurology, vol. 51, no. 2, pp. 120–127, 2009.
- U. Ryll, C. Bastiaenen, R. de Bie, and B. Staal, “Effects of leg muscle botulinum toxin A injections on walking in children with spasticity-related cerebral palsy: a systematic review,” Developmental Medicine and Child Neurology, vol. 53, no. 3, pp. 210–216, 2011.
- G. Maanum, R. Jahnsen, J. K. Stanghelle, L. Sandvik, and A. Keller, “Effects of botulinum toxin A in ambulant adults with spastic cerebral palsy: a randomized double-blind placebo controlled-trial,” Journal of Rehabilitation Medicine, vol. 43, no. 4, pp. 338–347, 2011.
- B. J. Hoare, M. A. Wallen, C. Imms, E. Villanueva, H. B. Rawicki, and L. Carey, “Botulinum toxin A as an adjunct to treatment in the management of the upper limb in children with spastic cerebral palsy (UPDATE),” Cochrane Database of Systematic Reviews, no. 1, Article ID CD003469, 2010.
- K. Kim, H. I. Shin, B. S. Kwon, S. J. Kim, I. Y. Jung, and M. S. Bang, “Neuronox versus BOTOX for spastic equinus gait in children with cerebral palsy: a randomized, double-blinded, controlled multicentre clinical trial,” Developmental Medicine and Child Neurology, vol. 53, no. 3, pp. 239–244, 2011.
- M. E. Gormley, D. Gaebler-Spira, and M. R. Delgado, “Use of botulinum toxin type A in pediatric patients with cerebral palsy: a three-center retrospective chart review,” Journal of Child Neurology, vol. 16, no. 2, pp. 113–118, 2001.
- L. J. Carr, A. P. Cosgrove, P. Gringras, and B. G. R. Neville, “Position paper on the use of botulinum toxin in cerebral palsy,” Archives of Disease in Childhood, vol. 79, no. 3, pp. 271–273, 1998.
- P. J. Flett, “Rehabilitation of spasticity and related problems in childhood cerebral palsy,” Journal of Paediatrics and Child Health, vol. 39, no. 1, pp. 6–14, 2003.
- E. M. Goldstein, “Safety of high-dose botulinum toxin type A therapy for the treatment of pediatric spasticity,” Journal of Child Neurology, vol. 21, no. 3, pp. 189–192, 2006.
- R. Baker, M. Jasinski, I. Maciag-Tymecka et al., “Botulinum toxin treatment of spasticity in diplegic cerebral palsy: a randomized, double-blind, placebo-controlled, dose-ranging study,” Developmental Medicine and Child Neurology, vol. 44, no. 10, pp. 666–675, 2002.
- E. Unlu, A. Cevikol, B. Bal, E. Gonen, O. Celik, and G. Kose, “Multilevel botulinum toxin type a as a treatment for spasticity in children with cerebral palsy: a retrospective study,” Clinics, vol. 65, no. 6, pp. 613–619, 2010.
- V. A. Scholtes, A. J. Dallmeijer, D. L. Knol et al., “Effect of multilevel botulinum toxin A and comprehensive rehabilitation on gait in cerebral palsy,” Pediatric Neurology, vol. 36, no. 1, pp. 30–39, 2007.
- D. Steenbeek, A. Meester-Delver, J. G. Becher, and G. J. Lankhorst, “The effect of botulinum toxin type A treatment of the lower extremity on the level of functional abilities in children with cerebral palsy: evaluation with goal attainment scaling,” Clinical Rehabilitation, vol. 19, no. 3, pp. 274–282, 2005.
- V. A. Scholtes, A. J. Dallmeijer, D. L. Knol et al., “The combined effect of lower-limb multilevel botulinum toxin type A and comprehensive rehabilitation on mobility in children with cerebral palsy: a randomized clinical trial,” Archives of Physical Medicine and Rehabilitation, vol. 87, no. 12, pp. 1551–1558, 2006.
- D. Verplancke, S. Snape, C. F. Salisbury, P. W. Jones, and A. B. Ward, “A randomized controlled trial of botulinum toxin on lower limb spasticity following acute acquired severe brain injury,” Clinical Rehabilitation, vol. 19, no. 2, pp. 117–125, 2005.
- U. Bergfeldt, K. Borg, K. Kullander, and P. Julin, “Focal spasticity therapy with botulinum toxin: effects on function, activities of daily living and pain in 100 adult patients,” Journal of Rehabilitation Medicine, vol. 38, no. 3, pp. 166–171, 2006.
- G. Pavesi, R. Brianti, D. Medici, P. Mammi, A. Mazzucchi, and D. Mancia, “Botulinum toxin type A in the treatment of upper limb spasticity among patients with traumatic brain injury,” Journal of Neurology Neurosurgery and Psychiatry, vol. 64, no. 3, pp. 419–420, 1998.
- J. Fock, M. P. Galea, B. C. Stillman, B. Rawicki, and M. Clark, “Functional outcome following Botulinum toxin A injection to reduce spastic equinus in adults with traumatic brain injury,” Brain Injury, vol. 18, no. 1, pp. 57–63, 2004.
- E. Guettard, E. Roze, G. Abada et al., “Management of spasticity and dystonia in children with acquired brain injury with rehabilitation and botulinum toxin A,” Developmental Neurorehabilitation, vol. 12, no. 3, pp. 128–138, 2009.
- J. van Rhijn, G. Molenaers, and B. Ceulemans, “Botulinum toxin type A in the treatment of children and adolescents with an acquired brain injury,” Brain Injury, vol. 19, no. 5, pp. 331–335, 2005.
- S. Hesse, F. Reiter, M. Konrad, and M. T. Jahnke, “Botulinum toxin type A and short-term electrical stimulation in the treatment of upper limb flexor spasticity after stroke: a randomized, double-blind, placebo-controlled trial,” Clinical Rehabilitation, vol. 12, no. 5, pp. 381–388, 1998.
- C. A. Johnson, D. E. Wood, I. D. Swain, A. M. Tromans, P. Strike, and J. H. Burridge, “A pilot study to investigate the combined use of botulinum neurotoxin type A and functional electrical stimulation, with physiotherapy, in the treatment of spastic dropped foot in subacute stroke,” Artificial Organs, vol. 26, no. 3, pp. 263–266, 2002.
- S. J. Page, E. Elovic, P. Levine, and S. A. Sisto, “Modified constraint-induced therapy and botulinum toxin A: a promising combination,” American Journal of Physical Medicine and Rehabilitation, vol. 82, no. 1, pp. 76–80, 2003.
- R. N. Russo, M. Crotty, M. D. Miller, S. Murchland, P. Flett, and E. Haan, “Upper-limb botulinum toxin A injection and occupational therapy in children with hemiplegic cerebral palsy identified from a population register: a single-blind, randomized, controlled trial,” Pediatrics, vol. 119, no. 5, pp. 1149–1158, 2007.
- I. S. Corry, A. P. Cosgrove, C. M. Duffy et al., “Botulinum toxin A as an alternative to serial casting in the conservative management of equinus in cerebral palsy,” Developmental Medicine and Child Neurology, vol. 37, pp. 20–21, 1995.
- I. S. Corry, A. P. Cosgrove, C. M. Duffy, S. McNeill, T. C. Taylor, and H. K. Graham, “Botulinum toxin a compared with stretching casts in the treatment of spastic equinus: a randomised prospective trial,” Journal of Pediatric Orthopaedics, vol. 18, no. 3, pp. 304–311, 1998.
- P. J. Flett, L. M. Stern, H. Waddy, T. M. Connell, J. D. Seeger, and S. K. Gibson, “Botulinum toxin a versus fixed cast stretching for dynamic calf tightness in cerebral palsy,” Journal of Paediatrics and Child Health, vol. 35, no. 1, pp. 71–77, 1999.
- R. M. Kay, S. A. Rethlefsen, A. Fern-Buneo, T. A. L. Wren, and D. L. Skaggs, “Botulinum toxin as an adjunct to serial casting treatment in children with cerebral palsy,” Journal of Bone and Joint Surgery. Series A, vol. 86, no. 11, pp. 2377–2384, 2004.
- A. M. Blackmore, E. Boettcher-Hunt, M. Jordan, and M. D. Y. Chan, “A systematic review of the effects of casting on equinus in children with cerebral palsy: an evidence report of the AACPDM,” Developmental Medicine and Child Neurology, vol. 49, no. 10, pp. 781–790, 2007.
- E. Yaşar, F. Tok, I. Safaz, B. Balaban, B. Yilmaz, and R. Alaca, “The efficacy of serial casting after botulinum toxin type A injection in improving equinovarus deformity in patients with chronic stroke,” Brain Injury, vol. 24, no. 5, pp. 736–739, 2010.
- J. M. Lai, G. E. Francisco, and F. B. Willis, “Dynamic splinting after treatment with botulinum toxin type-A: a randomized controlled pilot study,” Advances in Therapy, vol. 26, no. 2, pp. 241–248, 2009.
- L. G. Cohen and M. Hallett, “Hand cramps: clinical features and electromyographic patterns in a focal dystonia,” Neurology, vol. 38, no. 7, pp. 1005–1012, 1988.
- The Epidemiological Study of Dystonia in Europe (ESDE) Collaborative Group, “A prevalence study of primary dystonia in eight European countries,” Journal of Neurology, vol. 247, no. 10, pp. 787–792, 2000.
- A. G. Butler, P. O. Duffey, M. R. Hawthorne, and M. P. Barnes, “An epidemiologic survey of dystonia within the entire population of northeast England over the past nine years,” Advances in Neurology, vol. 94, pp. 95–99, 2004.
- E. Altenmüller and H. C. Jabusch, “Focal dystonia in musicians: phenomenology, pathophysiology, triggering factors, and treatment,” Medical Problems of Performing Artists, vol. 25, no. 1, pp. 3–9, 2010.
- B. I. Karp, R. A. Cole, L. G. Cohen, S. Grill, J. S. Lou, and M. Hallett, “Long-term botulinum toxin treatment of focal hand dystonia,” Neurology, vol. 44, no. 1, pp. 70–76, 1994.
- R. Cole, M. Hallett, and L. G. Cohen, “Double-blind trial of botulinum toxin for treatment of focal hand dystonia,” Movement Disorders, vol. 10, no. 4, pp. 466–471, 1995.
- S. Schuele, H. C. Jabusch, R. J. Lederman, and E. Altenmüller, “Botulinum toxin injections in the treatment of musician's dystonia,” Neurology, vol. 64, no. 2, pp. 341–343, 2005.
- C. P. Das, D. Dressler, and M. Hallett, “Botulinum toxin therapy of writer's cramp,” European Journal of Neurology, vol. 13, no. 1, supplement 1, pp. 55–59, 2006.
- R. A. Cole, L. G. Cohen, and M. Hallett, “Treatment of musician’s cramp with botulinum toxin,” Medical Problems of Performing Artists, vol. 6, pp. 137–143, 1991.
- C. Lungu, B. I. Karp, K. Alter, R. Zolbrod, and M. Hallett, “Long-term follow-up of botulinum toxin therapy for focal hand dystonia: outcome at 10 years or more,” Movement Disorders, vol. 26, no. 4, pp. 750–753, 2011.
- M. Hallett, R. Benecke, A. Blitzer, and C. L. Comella, “Treatment of focal dystonias with botulinum neurotoxin,” Toxicon, vol. 54, no. 5, pp. 628–633, 2009.
- B. I. Karp, “Botulinum toxin treatment of occupational and focal hand dystonia,” Movement Disorders, vol. 19, no. 8, supplement 8, pp. S116–S119, 2004.
- S. L. Foad, C. T. Mehlman, and J. Ying, “The epidemiology of neonatal brachial plexus palsy in the United States,” Journal of Bone and Joint Surgery. Series A, vol. 90, no. 6, pp. 1258–1264, 2008.
- B. Backe, E. B. Magnussen, O. J. Johansen, G. Sellaeg, and H. Russwurm, “Obstetric brachial plexus palsy: a birth injury not explained by the known risk factors,” Acta Obstetricia et Gynecologica Scandinavica, vol. 87, no. 10, pp. 1027–1032, 2008.
- A. F. Hoeksma, H. Wolf, and S. L. Oei, “Obstetrical brachial plexus injuries: incidence, natural course and shoulder contracture,” Clinical Rehabilitation, vol. 14, no. 5, pp. 523–526, 2000.
- M. T. Desiato and B. Risina, “The role of botulinum toxin in the neuro-rehabilitation of young patients with brachial plexus birth palsy,” Pediatric Rehabilitation, vol. 4, no. 1, pp. 29–36, 2001.
- R. Hierner, J. D. Rollnik, A. C. Berger, and R. Dengler, “Botulinum toxin type a for the treatment of biceps/triceps co-contraction in obstetrical brachial plexus lesions—preliminary results after a follow-up of 18 months,” European Journal of Plastic Surgery, vol. 24, no. 1, pp. 2–6, 2001.
- M. Basciani and D. Intiso, “Botulinum toxin type-A and plaster cast treatment in children with upper brachial plexus palsy,” Pediatric Rehabilitation, vol. 9, no. 2, pp. 165–170, 2006.
- C. DeMatteo, J. R. Bain, V. Galea, and D. Gjertsen, “Botulinum toxin as an adjunct to motor learning therapy and surgery for obstetrical brachial plexus injury,” Developmental Medicine and Child Neurology, vol. 48, no. 4, pp. 245–252, 2006.
- A. E. Price, P. DiTaranto, I. Yaylali, M. A. Tidwell, and J. A. I. Grossman, “Botulinum toxin type A as an adjunct to the surgical treatment of the medial rotation deformity of the shoulder in birth injuries of the brachial plexus,” Journal of Bone and Joint Surgery. Series B, vol. 89, no. 3, pp. 327–329, 2007.
- D. Gobets, H. Beckerman, V. D. Groot, M. H. Van Doorn-Loogman, and J. G. Becher, “Indications and effects of botulinum toxin A for obstetric brachial plexus injury: a systematic literature review,” Developmental Medicine and Child Neurology, vol. 52, no. 6, pp. 517–528, 2010.
- A. Lipp, T. Trottenberg, T. Schink, A. Kupsch, and G. Arnold, “A randomized trial of botulinum toxin A for treatment of drooling,” Neurology, vol. 61, no. 9, pp. 1279–1281, 2003.
- G. Lagalla, M. Millevolte, M. Capecci, L. Provinciali, and M. G. Ceravolo, “Long-lasting benefits of botulinum toxin type B in Parkinson's disease-related drooling,” Journal of Neurology, vol. 256, no. 4, pp. 563–567, 2009.
- J. Costa, M. L. Rocha, J. Ferreira, T. Evangelista, M. Coelho, and M. de Carvalho, “Botulinum toxin type-B improves sialorrhea and quality of life in bulbaronset amyotrophic lateral sclerosis,” Journal of Neurology, vol. 255, no. 4, pp. 545–550, 2008.
- C. E. Jackson, G. Gronseth, J. Rosenfeld et al., “Randomized double-blind study of botulinum toxin type B for sialorrhea in ALS patients,” Muscle and Nerve, vol. 39, no. 2, pp. 137–143, 2009.
- M. Porta, M. Gamba, G. Bertacchi, and P. Vaj, “Treatment of sialorrhoea with ultrasound guided botulinum toxin type A injection in patients with neurological disorders,” Journal of Neurology Neurosurgery and Psychiatry, vol. 70, no. 4, pp. 538–540, 2001.
- G. Lagalla, M. Millevolte, M. Capecci, L. Provinciali, and M. G. Ceravolo, “Botulinum toxin type A for drooling in Parkinson's disease: a double-blind, randomized, placebo-controlled study,” Movement Disorders, vol. 21, no. 5, pp. 704–707, 2006.
- A. C. Nóbrega, B. Rodrigues, A. C. Torres, A. Enzo, and A. Melo, “Does botulinum toxin decrease frequency and severity of sialorrhea in Parkinson's disease?” Journal of the Neurological Sciences, vol. 253, no. 1-2, pp. 85–87, 2007.
- F. Mancini, R. R. Zangaglia, S. Cristina et al., “Double-blind, placebo-controlled study to evaluate the efficacy and safety of botulinum toxin type A in the treatment of drooling Parkinsonism,” Movement Disorders, vol. 18, no. 6, pp. 685–688, 2003.
- W. G. Ondo, C. Hunter, and W. Moore, “A double-blind placebo-controlled trial of botulinum toxin B for sialorrhea in Parkinson's disease,” Neurology, vol. 62, no. 1, pp. 37–40, 2004.
- S. J. Bachrach, R. S. Walter, and K. Trzcinski, “Use of glycopyrrolate and other anticholinergic medications for sialorrhea in children with cerebral palsy,” Clinical Pediatrics, vol. 37, no. 8, pp. 485–490, 1998.
- S. M. Reid, B. R. Johnstone, C. Westbury, B. Rawicki, and D. S. Reddihough, “Randomized trial of botulinum toxin injections into the salivary glands to reduce drooling in children with neurological disorders,” Developmental Medicine and Child Neurology, vol. 50, no. 2, pp. 123–128, 2008.
- A. H. Alrefai, S. K. Aburahma, and Y. S. Khader, “Treatment of sialorrhea in children with Cerebral Palsy: a double-blind placebo controlled trial,” Clinical Neurology and Neurosurgery, vol. 111, no. 1, pp. 79–82, 2009.
- J. E. Bothwell, K. Clarke, J. M. Dooley et al., “Botulinum toxin A as a treatment for excessive drooling in children,” Pediatric Neurology, vol. 27, no. 1, pp. 18–22, 2002.
- M. Ellies, S. Rohrbach-Volland, C. Arglebe, B. Wilken, R. Laskawi, and F. Hanefeld, “Successful management of drooling with botulinum toxin A in neurologically disabled children,” Neuropediatrics, vol. 33, no. 6, pp. 327–330, 2002.
- Y. C. Lin, J. Y. Shieh, M. L. Cheng, and P. Y. Yang, “Botulinum toxin type a for control of drooling in Asian patients with cerebral palsy,” Neurology, vol. 70, no. 4, pp. 316–318, 2008.
- D. Dressler, F. Adib Saberi, and R. Benecke, “Botulinum toxin type B for treatment of axillar hyperhidrosis,” Journal of Neurology, vol. 249, no. 12, pp. 1729–1732, 2002.
- A. M. Lang, “A preliminary comparison of the efficacy and tolerability of botulinum toxin serotypes A and B in the treatment of myofascial pain syndrome: a retrospective, open-label chart review,” Clinical Therapeutics, vol. 25, no. 8, pp. 2268–2278, 2003.
- R. Tintner, R. Gross, U. F. Winzer, K. A. Smalky, and J. Jankovic, “Autonomic function after botulinum toxin type A or B: a double-blind, randomized trial,” Neurology, vol. 65, no. 5, pp. 765–767, 2005.
- J. C. Arezzo, “NeuroBloc/Myobloc: unique features and findings,” Toxicon, vol. 54, no. 5, pp. 690–696, 2009.
- M. Basciani, D. Intiso, R. P. Cioffi, and P. Tonali, “Preoperative treatment with botulinum a toxin in patients with cervical disk herniation secondary to dystonic cerebral palsy,” Neurological Sciences, vol. 21, no. 1, p. 63, 2000.
- D. Intiso, M. Basciani, F. Di Rienzo, M. Tolfa, G. Grimaldi, and P. Fiore, “Botulinum toxin type A in the healing of ulcer following oro-mandibular dyskinesia in a patient in a vegetative state,” Journal of Rehabilitation Medicine, vol. 40, no. 4, pp. 315–316, 2008.
- D. Intiso and M. Basciani, “Botulinum toxin type A in the healing of a chronic buttock ulcer in a patient with spastic paraplegia after spinal cord injury,” Journal of Rehabilitation Medicine, vol. 41, no. 13, pp. 1100–1102, 2009.
- C. C. Turkel, B. Bowen, J. Liu, and M. F. Brin, “Pooled analysis of the safety of botulinum toxin type A in the treatment of poststroke spasticity,” Archives of Physical Medicine and Rehabilitation, vol. 87, no. 6, pp. 786–792, 2006.
- A. W. Willis, B. Crowner, J. E. Brunstrom, A. Kissel, and B. A. Racette, “High dose botulinum toxin A for the treatment of lower extremity hypertonicity in children with cerebral palsy,” Developmental Medicine and Child Neurology, vol. 49, no. 11, pp. 818–822, 2007.
- C. Albavera-Hernández, J. M. Rodríguez, and A. J. Idrovo, “Safety of botulinum toxin type A among children with spasticity secondary to cerebral palsy: a systematic review of randomized clinical trials,” Clinical Rehabilitation, vol. 23, no. 5, pp. 394–407, 2009.
- K. Howell, P. Selber, H. K. Graham, and D. Reddihough, “Botulinum neurotoxin A: an unusual systemic effect,” Journal of Paediatrics and Child Health, vol. 43, no. 6, pp. 499–501, 2007.
- B. E. Crowner, D. Torres-Russotto, A. R. Carter, and B. A. Racette, “Systemic weakness after therapeutic injections of botulinum toxin A: a case series and review of the literature,” Clinical Neuropharmacology, vol. 33, no. 5, pp. 243–247, 2010.
- E. Varghese-Kroll and E. P. Elovic, “Contralateral weakness and fatigue after high-dose botulinum toxin injection for management of post-stroke spasticity,” American Journal of Physical Medicine and Rehabilitation, pp. 495–499, 2009.
- M. P. Barnes, D. Best, L. Kidd et al., “The use of botulinum toxin type-B in the treatment of patients who have become unresponsive to botulinum toxin type-A—initial experiences,” European Journal of Neurology, vol. 12, no. 12, pp. 947–955, 2005.
- S. A. Factor, E. S. Molho, S. Evans, and P. J. Feustel, “Efficacy and safety of repeated doses of botulinum toxin type B in type A resistant and responsive cervical dystonia,” Movement Disorders, vol. 20, no. 9, pp. 1152–1160, 2005.
- J. Herrmann, K. Geth, V. Mall et al., “Clinical impact of antibody formation to botulinum toxin A in children,” Annals of Neurology, vol. 55, no. 5, pp. 732–735, 2004.
- L. A. Koman, A. Brashear, S. Rosenfeld et al., “Botulinum toxin type A neuromuscular blockade in the treatment of equinus foot deformity in cerebral palsy: a multicenter, open-label clinical trial,” Pediatrics, vol. 108, no. 5, pp. 1062–1071, 2001.
- S. A. Yablon, A. Brashear, M. F. Gordon et al., “Formation of neutralizing antibodies in patients receiving botulinum toxin type a for treatment of poststroke spasticity: a pooled-data analysis of three clinical trials,” Clinical Therapeutics, vol. 29, no. 4, pp. 683–690, 2007.
- S. Berweck, A. S. Schroeder, S. H. Lee, H. Bigalke, and F. Heinen, “Secondary non-response due to antibody formation in a child after three injections of botulinum toxin B into the salivary glands,” Developmental Medicine and Child Neurology, vol. 49, no. 1, pp. 62–64, 2007.
- C. Cordivari, V. P. Misra, A. Vincent, S. Catania, K. P. Bhatia, and A. J. Lees, “Secondary nonresponsiveness to botulinum toxin A in cervical dystonia: the role of electromyogram-guided injections, botulinum toxin A antibody assay, and the extensor digitorum brevis test,” Movement Disorders, vol. 21, no. 10, pp. 1737–1741, 2006.
Copyright © 2012 Domenico Intiso. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.