Botulinum toxin refers to a potent toxin that is used in the treatment of non-neurologic and neurologic conditions. Its efficacy was first shown in blepharospasm, and the US Food and Drug Administration approved it. Botulinum toxin has been used for medical reasons, but some patients do not respond to Botulinum toxin because of the creation of neutralizing or blocking antibodies. The use of Botulinum toxin has created demand across healthcare departments around the globe. Therefore, the FDA has approved many formulations of Botulinum toxin to cater to the increasing need. Although the FDA has only approved two types (type A and B) of Botulinum toxin, there are eight different types. Botulinum toxin is used in patients with muscle pain, excessive secretions, and involuntary muscle pain. This informative essay describes the history and development of Botulinum toxin, the structure and the types of botulinum toxin, and the development of antibodies of Botulinum toxin.
History of Treatment and Development of Botulinum Toxin
FDA first approved botulinum toxin in 1989. Eight major types of Botulinum toxin exist, but only types A and B are used for clinical purposes. Type A and B are considered the most effective because they take a longer time to their action. The core of the toxin contains a heavy chain (100 kDa) and a light chain (50 kDa) bonded together by a disulphide bond. Type A toxin is produced by Dysport from Ipsen and Allergan Inc. and Xeomin from Merz pharma (Choudhury et al., 2021). United States World Meds manufacture type B. Justinus Kerner first discovered the use of Botulinum toxin in the medical field. He found that this toxin can treat autonomic dysfunctions and hyperkinetic movement disorders. He used a sample of 155 and 76 patients to study the effects of botulinum toxins, where he found that fat poison caused the patients’ illnesses. After investigating the patients’ weaknesses, he noticed that the fat toxin could treat the reduction of body secretions and dry mouth. Since then, botulin toxin has been used to treat significant movement disorders.
Botulinum toxin has been widely used in medical practice to treat dystonia. Dystonia is a neurologic syndrome characterized by repetitive muscle contractions, patterned and involuntary sustained muscle contractions that cade abnormal postures or spasmodic and twisting movements—currently, the primary medical practice of botulinum toxin in the treatment of dystonic symptoms. The toxin also treats blepharospasm (Choudhury et al., 2021). Frequent eye blinks and closure of the eyes characterize this condition. The treatment of blepharospasm by anticholinergic medications was proven to be effective. However, it requires higher doses which may lead to confusion and memory loss, mainly when applied to older people. Several patients with blepharospasm were tested on the effectiveness of botulinum toxin. Botox showed a positive response in treating blepharospasm, where 2000 patients were treated in 1990. The FDA approved the treatment of blepharospasm in 1989, considering the positive clinical observations, although there was no class I and II blinded studies (Choudhury et al., 2021). Based on accumulated literature, botulinum toxin shows an effective rate of over 90% when used to treat blepharospasm. The effective injections show that botulinum toxins accurately treat secondary and essential blepharospasm. An experience collected over 26 years shows that botulinum’s efficacy level has not changed since its introduction in medical practice.
Moreover, botulinum toxins are also used in the treatment of hemifacial spasms. The history shows that hemifacial spasm has regional and semiology similarities with blepharospasm and therefore treated with botulinum toxins. This condition is characterized by one-side eye focus. It is caused by ecstatic or anomalous blood vessels encroaching as the facial nerve exits the brain stem. The condition can also be treated with clonazepam and anticonvulsants, but they involve the risk of severe morbidity. The effectiveness of this condition with type A botulinum toxins was first discovered in 1984 with an experiment done on three patients (Anandan & Jankovic, 2021). Another open observation was conducted in 1985 on fifteen patients, and the toxin showed a high efficacy rate. After repeating the observations with many patients, the FDA approved the botulinum toxin treatment on patients with hemifacial spasms in 1989. Toxin A experiments were done adequately compared to type B and C toxins. However, their level of efficacy is also considered appropriate for treating hemifacial spasms. The observations of type B and C efficacy levels lacked the data on level II studies. They are therefore associated with limitations like high patient dropouts, single-blind design, fewer patients’ participation, and lack of concealment. Toxin A is considered the most effective for treating HFS, with many patients reporting 75% symptom improvement (Anandan & Jankovic, 2021).
Another disorder treated by botulinum toxin is cervical dystonia. This disorder exists in different forms, are women are the most affected. These forms include the posterior bent, anterior bent, lateral tilt, and torticollis. This list ranges from the lowest percentage of disorder to the highest percentage. Torticollis is mainly shown by head tilt on one side. Before the approval of botulinum toxins, this disease was treated using benztropine and trihexyphenidyl. However, these anticholinergic drugs were associated with limitations such as visual hallucinations, delusions, and memory loss. The first observation was done on 12 patients by Tsui and his co-workers in 1985 and 1986 (Anandan & Jankovic, 2021). The injection of botulinum toxins improved neck pain and head movement. After ten years, the class II and III studies showed that botulinum toxins were influential in treating CD symptoms. Class I study was Also done in 1997, showing improved CD symptoms. Among other disorders that botulinum toxins treat are task-specific dystonia, spasmodic dysphonia, tremor, essential tremor, rest tremor, tics, and Tourette syndrome.
Furthermore, botulinum toxins are historically used to treat uncommon movement disorders. One of these disorders is the spinal myoclonus. This is caused by the spinal cord segment(s) dysfunction or lesion. This results from causes of demyelination, infection, trauma, and tumor. It involves discomfort in one leg or significant leg pain. Some treatments used before applying botulinum toxins are valproic acid and clonazepam, but they helped very few patients (Anandan & Jankovic, 2021). OnabotulinumtoxinA was first applied on a 16-year-old female who had paralyzed the right leg. She was injected with botulinum toxin, and the effect lasted for five months. It showed a significant reduction of movements and pain relief in the paralyzed leg. Botulinum toxins also significantly affect the treatment of moving fingers, painless hands, painful hands, moving toes, and painful and painless legs. The observation was first done in 1971. The study was revolutionized and improved in 2007 by Papapetropoulos and Singer (Matak et al.,2019). The botulinum toxins showed an improvement making the pain painless hands painful and increasing the movement of the toes. The history of botulinum as a therapeutic agent has developed from 1817 to 1822, a study that Kerner did. Several physicians and professionals had since developed the study of botulinum until 1989, when the FDA approved its use in medical practices, where it has helped multiple patients recover from the above-described disorders.
Structure and Types of Botulinum Toxins
Clostridium argentinensis, clostridium barati, clostridium butyrricum, clostridium botulinum, and anaerobic bacteria produce botulinum toxins. All the types of botulinum toxins exist in two peptide chains. However, the amino acids contained in these types are different in content. The whole protein contains three domains that function differently according to their molecular levels. The C-terminal is responsible for attaching the toxin to the receptor site, and the N-terminal, on the other hand, performs translocation. The light chain acts as a catalyst, and a natural layer of proteins surrounds the entire toxin molecule. The motor end plate guides the botulinum toxin action. This is the junction that lies between muscle fibre and motor neurons. Motor axons terminals release acetylcholine. This happens when the motor neuron generates the action potential. Therefore, this action makes the muscle fibres contract (Matak, et al.,2019). Different types of botulinum toxins are used to treat several human disorders. The technology is rising rapidly, and the botulinum toxins are now genetically engineered. The toxic-pharmacological properties of botulinum toxins are now changeable, and they can be used for several purposes in medical practice. The non-toxic botulinum toxins are used in the manufacture of toxoids and vaccines. Through data screening and analysis, several proteins containing the same properties and structures of botulinum toxins have been discovered. These types of botulinum toxins are known as non-clostridial botulinum toxins.
Another type of botulinum toxin discovered based on healthcare needs is chimeric botulinum toxins. These toxins are formed through a process known as engineer chimeric proteins. These were first produced in 2008 using BoNT/AE and E. coli codon. These formed two chimeric proteins, which showed the same functions as botulin toxins. However, the type of paralysis on these chimeric proteins was different from the original toxin. It took much longer to treat the head migraine and initiate movement of body parts. This duration is affected by HC and LC, which define their roles. Another type of botulinum toxins was created with target specificity modified. The action of the toxin was modified by changing the sequence of amino acids. DNA technology was also applied to initiate this process. The modification also targets the receptor proteins in line with the clinical needs. This process can be performed through the mutation of LC combined with BoNT/C1 (Matak et al.,2019). Moreover, the types of Botulin Toxins are also groped in alphabetical numbers and their treatment. For instance, type A is used to treat muscle spasms, excessive sweating, and wrinkles. Type B is used to treat muscle spasticity and spasms. Type C, on the other hand, is used to treat similar disorders in type A. Lastly, types E and D treats muscle spasticity, muscle spasms, and wrinkles.
Botulinum Toxin Antibodies and their Detection
The body’s immune system produces the antibodies of botulinum to control the effect of botulinum toxin in the body. The Clostridium botulinum bacterium produces the effect of botulinum toxicity, and the body responds by producing antibodies. This is because the botulinum toxin contains toxic substances that might lead to death, paralysis, and breathing difficulties. The botulinum toxin antibodies work by attaching themselves to the toxin, protecting it from mixing with the muscles and nerves in the body (Bellows & Jankovic, 2019). The antibodies in action then assist in reducing the botulism symptoms. They take an essential role in the treatment of several medical conditions. They help treat facial wrinkles, overactive bladder, muscle spasms, and chronic migraines. The antibodies can be taken orally or administered directly to the muscles. They are available in oral and injectable forms. The injectable antibodies are used to provide localized and more targeted action. In summary, the antibodies are used to improve the treatment of the botulism band and eliminate its symptoms in the patient.
The nurse and other healthcare professionals measure the level of IgM and IgG to detect the presence of the antibodies. These measurements are taken from the patient’s serum. The method used to detect botulinum toxin antibodies is called the enzyme-linked immunosorbent assay. A specific antibody is used to coat a plate placed in wells to detect the antibody in the sample of the patient’s serum. Incubation of the plate is performed to allow the antibodies to attach to the plate coated with the specific antibodies. Once the incubation period is over, another antibody is added to permit the antibodies to bind with IgM and IgG from the serum sample. A spectrophotometer detects the second antibody (Bellows & Jankovic, 2019). The antibodies are evaluated by comparing the proportion of the enzyme to the botulinum toxin antibodies put in the sample. The purpose of detecting the antibodies is for effective treatment and also diagnosis of botulism. When the antibodies are detected in the patient’s body, it shows that they have been exposed to the botulinum toxin, and the best treatment measures should be implemented. If the results are negative, the patient is free from botulinum toxin. Other tests that can be done to detect antibodies include western blots and immunofluorescence assays. Although the methods are different, they all produce similar results.
In conclusion, Botulinum toxin was first approved by FDA in 1989. Eight major types of Botulinum toxin exist, but only types A and B are used for clinical purposes. Type A and B are considered the most effective because they take a longer time to their action. The core of the toxin contains a heavy chain (100 kDa) and a light chain (50 kDa) bonded together by a disulfide bond. Type A toxin is produced by Dysport from Ipsen and Allergan Inc. and Xeomin from Merz pharma. United States World Meds manufacture type B. Justinus Kerner first discovered the use of Botulinum toxin in the medical field. Clostridium argentinensis, clostridium barati, clostridium butyrricum, clostridium botulinum, and anaerobic bacteria produce botulinum toxins. All the types of botulinum toxins exist in two peptide chains. However, the amino acids contained in these types are different in content. The whole protein contains three domains that function differently according to their molecular levels. The body’s immune system produces the antibodies of botulinum to control the effect of botulinum toxin in the body. The Clostridium botulinum bacterium has the effect of botulinum toxicity, and the body responds by producing antibodies. The nurse and other healthcare professionals measure the level of IgM and IgG to detect the presence of the antibodies. These measurements are taken from the patient’s serum. The method used to detect botulinum toxin antibodies is called the enzyme-linked immunosorbent assay.
References
Anandan, C., & Jankovic, J. (2021). Botulinum toxin in movement disorders: an update. Toxins, 13(1), 42. https://www.mdpi.com/2072-6651/13/1/42
Bellows, S., & Jankovic, J. (2019). Immunogenicity associated with botulinum toxin treatment. Toxins, 11(9), 491. https://www.mdpi.com/2072-6651/11/9/491
Choudhury, S., Baker, M. R., Chatterjee, S., & Kumar, H. (2021). Botulinum toxin: an update on pharmacology and newer products in development. Toxins, 13(1), 58. https://www.mdpi.com/2072-6651/13/1/58
Matak, I., Bölcskei, K., Bach-Rojecky, L., & Helyes, Z. (2019). Mechanisms of botulinum toxin type A action on pain. Toxins, 11(8), 459. https://www.mdpi.com/2072-6651/11/8/459
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