**1. Introduction**

Cerebral palsy (CP) is a nonprogressive encephalopathy that primarily affects motor system; in consequence, there is a defect in motor milestone development with a variable degree of severity and locomotor deformities. Therefore, CP is a complex entity with known and unknown causes [1].

exocytosis is a result of a nerve action potential arriving at the terminal membrane causing an influx of calcium ions through voltage-dependent channel and binding to the receptors on the postsynaptic neuron, causing a change in the electrical properties of that membrane, which finally results in the contraction of the muscle fiber. Calcium regulated the process of exocytosis which is considered a complicated process that involves the actions of proteins located on the vesicles in the cytosol and on the presynaptic membrane. The protein known as synapsin I binds to the synaptic vesicle to the cytoskeleton. Calcium-dependent process known as synapsin I phosphorylation leads to the release of the vesicle from the cytoskeleton and then is transported into the active zone, where it binds to the presynaptic membrane [10]. The synaptic vesicle contains other important proteins; synaptobrevin and syntaxin on the presynaptic membrane act as shelter that pulls the membranes together. On the other hand, synaptosome-associated protein 25, which is attached to the presynaptic membrane, binds to two molecules of syntaxin, which forms a complex [11]. Synaptobrevin binds to this complex and displaces one of the syntaxin molecules from the complex, which brings the synaptic vesicle and the presynaptic membrane into the proximity that is necessary for fusion and

Use of Botulinum Toxin A in Cerebral Palsy http://dx.doi.org/10.5772/intechopen.79551 97

From the above, we conclude that exocytosis is considered the primary mechanism for the release of acetylcholine, and this process is complicated and not fully investigated; however, it involved a lot of specific proteins. Therefore, any intervention with these proteins impaired acetylcholine release by exocytosis which results in presynaptic blocking, and this is what

Botulinum neurotoxin is indeed a remarkable protein produced by *Clostridium botulinum* [12]; there are at least seven serotypes of neurotoxin discovered till now: botulinum toxin A (BTX-A), botulinum toxin B (BTX-B), botulinum toxin C (BTX-C), botulinum toxin D (BTX-D), botulinum toxin E (BTX-E), botulinum toxin F (BTX-F), and botulinum toxin G (BTX-G), only first two are medically used. Neurotoxins share with same target to inhibit presynaptic acetylcholine release to synaptic cleft, but they are different in targeting protein, their duration of effect, and their potency [13, 14]. BTX-A displays their effect in relaxing the muscle propor-

The effect of BTX lasts for about 12–16 weeks; however, within 4 weeks soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex of protein has its turnover. Exocytosis resumes and new axonal sprouting is at the end plate to reestab-

Botulinum toxin drugs currently available (BTX drugs) are Botox (Allergan Inc., Irvine, CA, USA), Dysport® (Ipsen Ltd., Slough, Berkshire, UK), NeuroBloc/Myobloc (Solstice Neurosciences Inc., Malvern, PA, USA), and Xeomin (Merz Pharmaceuticals, Frankfurt/M, Germany). From 1989 to 1992, Botox's trade name was Oculinum®. In the USA and in some

exocytosis to take place [10].

tionally related to doses [15, 16].

lish conduction [17].

**2. Mechanism of action of botulinum toxin**

**2.1. Pharmacological aspects of botulinum toxin therapy**

happens with BTX.

Cerebral palsy (CP) is the most frequent cause of spasticity in children [2]. In the last 25 years, injecting botulinum toxin type A (BTX-A) has been proven as an effective medicine strategy to decrease hypertonia in CP child. Now used in most countries of five continents, it is a green light after 2 years of age adopted by most expertise; however, there is big difference in licensing from one country to another. Therefore, most of BTX-A use is labeled according to its trademark. Nowadays, BTX-A has a major role of the multidisciplinary treatment in spastic CP, in addition to physiotherapy, occupational therapy, speech therapy, casting, anklefoot orthoses (AFO), and knee-ankle-foot orthosis (KAFO) surgical application of intrathecal baclofen; selective dorsal rhizotomy (SDR); and different orthopedic interventions, with varying simple to complex intervention to achieve optimal reconstructive [3].

Within the current clinical management of CP in children, the use of BTX-A is recommended to improve function and to support motor development [4]. Botulinum toxin injection has an additional role on the decrease of pain associated with focal spasticity [5]. Actually, in muscular hypertonia, sever muscle contraction produces compromising vessel resulting in ischemia, ultimately agonizing nociceptive pain (ischemic muscular pain). Nevertheless, decrease of spasm by BTX injection improved blood flow, the ischemia markedly decreased, and pain subsided by muscular relaxation effect of BTX [6].

BTX had been discovered at the beginning of the nineteenth century as a poison. This poison is a protein, which is a product of *Clostridium botulinum* bacterium, a Gram-positive anaerobe. Meat is considered the primary source of this bacterium, from the name "botulus" which mean sausage, though it is present in different food types. The German physician Justinus Kerner in 1818 first wrote about poison that food-borne diseases who was described confidently in the middle-aged patient. The features of botulism have been known since ancient times around the time of Christ [7]. He then published a monograph on poisoning in 1820 in which he described the features, made many original observations, and commented on the possible causation, diagnosis, and treatment [8]. He concluded that a toxin produced by an infective agent was responsible for the features of paralysis of skeletal and smooth muscles. He published a second monograph in 1822, in which he laid out his hypotheses on BTX and described clinical evaluation of the problem through case histories of his patients and through post-mortem examination of patients with botulism [9].

#### **1.1. Physiology of neuromuscular transmission**

When we take neuromuscular junction (NMJ) in focus, it consists of the terminal branch of the motor neuron and the muscle fiber that innervates and synaptic cleft between. Acetylcholine is synthesized and stored in the synaptic vesicles that are released into the synaptic cleft by fusion with the presynaptic membrane, through the process called exocytosis. The process of exocytosis is a result of a nerve action potential arriving at the terminal membrane causing an influx of calcium ions through voltage-dependent channel and binding to the receptors on the postsynaptic neuron, causing a change in the electrical properties of that membrane, which finally results in the contraction of the muscle fiber. Calcium regulated the process of exocytosis which is considered a complicated process that involves the actions of proteins located on the vesicles in the cytosol and on the presynaptic membrane. The protein known as synapsin I binds to the synaptic vesicle to the cytoskeleton. Calcium-dependent process known as synapsin I phosphorylation leads to the release of the vesicle from the cytoskeleton and then is transported into the active zone, where it binds to the presynaptic membrane [10]. The synaptic vesicle contains other important proteins; synaptobrevin and syntaxin on the presynaptic membrane act as shelter that pulls the membranes together. On the other hand, synaptosome-associated protein 25, which is attached to the presynaptic membrane, binds to two molecules of syntaxin, which forms a complex [11]. Synaptobrevin binds to this complex and displaces one of the syntaxin molecules from the complex, which brings the synaptic vesicle and the presynaptic membrane into the proximity that is necessary for fusion and exocytosis to take place [10].

From the above, we conclude that exocytosis is considered the primary mechanism for the release of acetylcholine, and this process is complicated and not fully investigated; however, it involved a lot of specific proteins. Therefore, any intervention with these proteins impaired acetylcholine release by exocytosis which results in presynaptic blocking, and this is what happens with BTX.
