Neuromuscular Disorders
Neurogenetics and genetic and genomic testing
Dec. 09, 2024
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Botulinum toxin treatment of neurologic disorders …
- Updated 03.06.2024
- Released 05.27.2004
- Expires For CME 03.06.2027
Botulinum toxin treatment of neurologic disorders
Introduction
Overview
Botulinum toxins (BoNT) are widely used in clinical practice and their clinical application is ever expanding. Seven different serotypes of botulinum toxins are available on the market; however, only types A and B are available for clinical applications. There is interest to use other serotypes or modifications of these serotypes in order to change the duration of action of the toxin. In this review, the general aspect of botulinum toxins will be discussed and then each available toxin will be discussed in detail in regard to its clinical, therapeutic applications. This article will not delve into the cosmetic application of the toxins nor go into detail on non-FDA-approved indications.
Key points
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• There is an expansion/modification of current uses of botulinum toxins in noncosmetic applications as metered by durational effects. | |
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• Two distinct serotypes of botulinum toxins, types A and B, are commercially available for clinical and cosmetic applications. |
Historical note and terminology
In 1817, Christian Andreas Justinus Kerner first recognized that muscle paralysis due to food-born botulism was caused by botulinum toxin (22). He proposed that it could be used to treat abnormal spasms and movements; however, it took until 1973, when Alan Scott applied botulinum toxin injections into the extraocular muscles in monkeys to correct strabismus, to demonstrate this. The first publication of the therapeutic application of botulinum toxin dates to 1984 in the treatment of blepharospasm. Subsequently, multiple studies provided evidence of the benefit of botulinum toxin to treat a variety of neurologic, ophthalmologic, and urologic disorders and more (22). The name comes from the Latin word “botuls,” meaning sausage as Kerner called it “sausage poison” (32).
Clinical aspects
Description
There are two distinct serotypes of botulinum toxin, types A and B. There are four commercial botulinum toxin serotypes in the United States and a fifth in an investigational stage.
Botulinum toxin serotype A | |
• onabotulinumtoxinA (onaBoNT-A) | |
Botulinum toxin serotype B | |
• rimabotulinumtoxin B (rimaBoNT-B) | |
Botulinum toxin type A. The commercially available botulinum toxins-A in the United States include onabotulinumtoxinA (onaBoNT-A), abobotulinumtoxinA (aboBoNT-A), incobotulinumtoxinA (incoBoNT-A), daxibotulinumtoxinA, and prabotulinumtoxinA-xvfs.
The difference among the multiple types of botulinum toxin-A include potency, presence, or absence of nontoxic accessory proteins, dosing, storage, as well as FDA-approved indications (11; 13).
Prabotulinumtoxin A was most recently approved by the FDA in 2019 but is only indicated for cosmetic purposes and will not be discussed in this review. DaxibotulinumtoxinA is a novel botulinum toxin-A product that has cosmetic FDA approval for glabellar lines and is in clinical development for other aesthetic and therapeutic indications and has the potential to be the first long-acting neuromodulator (04; 08; 19).
HU-014 is a botulinum toxin A in clinical trials for an aesthetic indication, glabellar frown lines, and it will not be discussed further (35).
OnabotulinumtoxinA (onaBoNT-A). Botox® (Allergan plc, Dublin, Ireland) is the trade name for onaBoNT-A. Originally approved by the FDA in 1989 for clinical use, onaBoNT-A has now been approved by the FDA for all of the following conditions (05):
• strabismus and blepharospasm |
OnaBoNT-A has been available for clinical use the longest compared to the other toxin formulations discussed in this article. For this reason, OnaBoNT-A tends to be the toxin of choice amongst many providers in the United States (13).
OnaBoNT-A requires refrigeration at 2°C to 8°C and must be reconstituted in preservative-free normal saline prior to administration.
Almost all FDA-approved clinical indications for onaBoNT-A necessitate dosing every 3 months (05).
(1) Strabismus. OnaBoNT-A is indicated for the treatment of strabismus and blepharospasm in individuals aged 12 years and older. One open-label study analyzed 677 patients who had received at least one Botox® injection. Of those individuals, 55% demonstrated improvement of 10 prism diopters or less 6 months or more postinjection (05). An earlier study by Carruthers and colleagues looked at 30 patients who were treated with either botulinum toxin or adjustable suture surgery (10). In this prospective, randomized clinical trial, the group who received onaBoNT-A demonstrated a 50.5% net change in prism diopters 6 months postinjection. The safety and efficacy of onaBoNT-A for children less than 12 years old are yet to be established by the FDA (10).
(2) Blepharospasm. The treatment for blepharospasm was one of the first approved indications for onaBoNT-A. An open-label study conducted by Arthurs and colleagues assessed the efficacy of onaBoNT-A in 27 individuals with blepharospasm (02). Almost all participants experienced significant improvement within 48 hours postinjection, with a peak effect occurring 1 to 2 weeks postinjection. There were no serious adverse effects reported (02; 05).
(3) Cervical dystonia. The safety and efficacy of onaBoNT-A have been shown in multiple clinical trials with individuals experiencing 70% to 90% reduction of symptoms. The mean dose of toxin in these studies was between 198 to 300 units, divided amongst the affected muscles. An open-label observational study, CD PROBE, was conducted in the U.S. and a total of 1046 patients received onaBoNT-A between January 12, 2009 and August 31, 2012. In individuals who underwent all assessments of the study, a statistically significant decrease in the Toronto Western Spasmodic Torticollis Rating Scale Total score was noted (mean score of 39.2 at baseline to 27.1 at final visit). Providers and patients alike reported vast improvements (95% improvement by CGI-C and 91.7% improvement by PGI-C) by the final assessment (21; 33; 05).
(4) Hyperhidrosis. In 2004, the FDA approved Botox® for the treatment of primary axillary hyperhidrosis—severe underarm sweating. Two clinical trials evaluated the safety and efficacy of onaBoNT-A for this use. One trial randomized individuals who had a score of 3 or 4 on the Hyperhidrosis Disease Severity Scale as well as produced 50 mg of sweat in a resting state over the course of 5 minutes. Study participants were randomized 1:1:1 to receive placebo treatment, 50 units of Botox®, or 75 units of Botox®. Assessments were performed at 4-week intervals. Response was defined as a 2-grade improvement on the Hyperhidrosis Disease Severity Scale. Sweat production was also measured with response being defined as a 50% decrease from baseline. About 50% of participants who received Botox® achieved response as measured by a decrease on the Hyperhidrosis Disease Severity Scale as compared to only 6% who received the placebo. Over 80% of participants who received onaBoNT-A were responders in terms of decrease in sweat production. Similarly, the second clinical trial reported a decrease in sweating by 50% or more in over 90% of the individuals who received onaBoNT-A (05).
(5) Upper and lower limb spasticity. OnaBoNT-A has demonstrated efficacy in adults with upper and lower limb spasticity in multiple clinical trials. OnaBoNT-A is recommended as a treatment option for upper and lower limb spasticity in clinical practice guidelines. Five clinical trials assessed the efficacy of onaBoNT-A for upper limb spasticity in individuals poststroke. Two of the five trials measured the efficacy of onaBoNT-A for thumb spasticity. The first three clinical trials included individuals who had a baseline Ashworth scale score of at least 3 in the wrist flexor and at least a 2 for finger flexor. The primary endpoint was wrist and finger flexor tone as measured with the Ashworth scale and compared to the baseline score. Individuals who received onaBoNT-A had a reduction in their Ashworth scale score, therefore, representing an improvement in their spasticity. Similarly, in the clinical trials directly assessing the change from baseline Ashworth Scale score for thumb spasticity, a reduction in Ashworth scale scores were noted in the onaBoNT-A groups. In terms of lower limb spasticity, a sixth clinical trial specifically evaluated the efficacy of onaBoNT-A for ankle spasticity in individuals poststroke. The primary endpoint was the change from baseline Modified Ashworth Scale score to the Modified Ashworth Scale score at weeks 4 and weeks 6 posttreatment with either onaBoNT-A or placebo. A statistically significant reduction in Modified Ashworth Scale was observed in individuals who received onaBoNT-A compared to placebo (33; 05).
(6) Migraine headache. In 2010, Botox® gained FDA approval as a treatment for chronic migraines. Individuals diagnosed with chronic migraine have headaches on 15 or more days per month over the course of 3 or more months. At least 8 of the 15 headache days per month, the headache meets criteria for a migraine. The main clinical trial that studied the safety and efficacy of onaBoNT-A for chronic migraine was Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT). A total of 1384 patients participated in the trials with the primary endpoint being the reduction in headache days at the 24-week mark. At baseline, participants suffered on average 19 to 20 headache days per month. Acute headache treatments were permitted but other forms of prophylaxis were excluded. Individuals who received onaBoNT-A had an average reduction of eight to nine headache days per month compared to six or seven in the placebo group (15; 05).
(7) Overactive bladder. One of the latest FDA-approved indications for onaBoNT-A came in 2013 when Botox® was approved for treatment of overactive bladder. OnaBoNT-A is injected into the detrusor muscle to allow for muscle relaxation, allowing the bladder to increase its storage of urine and prevent urinary frequency, urgency, and incontinence. Individuals who either are unable to take oral anticholinergic agents or have failed these agents may be considered for Botox® injection. Two 24-week placebo-controlled, randomized, clinical trials were conducted to evaluate the efficacy of onaBoNT-A in terms of improvement in daily urinary incontinent episodes. Both studies were observed to significantly reduce daily episodes of incontinence. Nearly half of the individuals who received onaBoNT-A experienced a greater than or equal to 75% reduction in urinary incontinent episodes (05).
AbobutulinumtoxinA (aboBoNT-A).
Dysport® (Ipsen) is the trade name for aboBoNT-A. The FDA has approved the application of aboBoNT-A for the following conditions: cervical dystonia, glabellar lines, upper limb spasticity in adults, and lower limb spasticity in pediatric patients aged 2 years of age or older.
AboBoNT-A was available in Europe years prior to when it was approved in the United States.
Similar to onaBoNT-A, aboboNT-A requires refrigeration at 2°C to 8°C and must be reconstituted in preservative-free normal saline prior to administration.
The typical dosing interval for aboBoNT-A is also about every 3 months (11; 13; 16).
(1) Cervical dystonia. AboBoNT-A was approved by the FDA in 2009 for the treatment of adults with cervical dystonia and is now recommended as a treatment option for individuals with this condition by clinical practice guidelines. The first U.S. clinical trial of aboBoNT-A assessed the safety and efficacy of the toxin in patients with cervical dystonia. AboBoNT-A had been available and utilized in Europe in patients with cervical dystonia for over a decade prior to this clinical trial, so this study attempted to replicate the findings from the European study done years earlier. Individuals with a Toronto Western Spasmodic Torticollis Rating Scale of greater than or equal to 30, a severity score greater than or equal to 15, a disability score greater than or equal to 3, and a pain score greater than or equal to 1 were eligible for inclusion in the study. The primary efficacy endpoint was a reduction in the Toronto Western Spasmodic Torticollis Rating Scale total score at week 4 as compared to baseline. Individuals who received aboBoNT-A had a significant reduction in their Toronto Western Spasmodic Torticollis Rating Scale total score at weeks 4, 8, and 12 as compared to the placebo group. A second clinical trial also found a statistically significant reduction in the Toronto Western Spasmodic Torticollis Rating Scale total in individuals who received aboBoNT-A as compared to placebo (37; 36; 33; 16).
(2) Upper and lower limb spasticity adults. In 2015, Dysport® was FDA-approved for upper limb spasticity in patients and received an expanded indication for lower limb spasticity in adults in 2017. The safety and efficacy of aboBoNT-A for upper limb spasticity was evaluated in a placebo-controlled clinical trial of 238 patients after stroke or traumatic brain injury. Individuals included in the study had a Modified Ashworth Scale of greater than or equal to 2 (toxin naïve) or greater than or equal to 3 (toxin nonnaïve). The coprimary efficacy endpoints were muscle tone as measured by Modified Ashworth Scale and the physician global assessment at week 4. There was a statistically significant reduction in muscle tone at week 4 in the Dysport® group compared to placebo. Additionally, physicians noted a significant improvement in patient response to treatment at week 4 in the Dysport® group as compared to placebo. Similarly, a clinical trial to evaluate the efficacy of Dysport® in lower limb spasticity assessed the reduction in the Modified Ashworth Scale at week 4 in an affected ankle joint. A statistically significant reduction in Modified Ashworth Scale was noted by week 4 in the Dysport® group as compared to the placebo group (16).
(3) Lower limb spasticity pediatrics. Dysport® is the only toxin currently approved for the treatment of pediatric spasticity. One clinical trial evaluated the safety and efficacy of Dysport® in children aged 2 to 17 years with equinus foot deformity due to cerebral palsy. Children in the study were ambulatory and had a baseline score of 2 or more on the Modified Ashworth Scale. The coprimary efficacy endpoints were the change in Modified Ashworth Scale from baseline in the ankle plantar flexor and the physician’s global assessment at week 4. All children who received Dysport® had a statistically significant reduction in their Modified Ashworth Scale by week 4. Additionally, physicians noted a statistically significant greater improvement in the children who received Dysport® as compared to the placebo group at week 4 (14; 16).
IncobotulinumtoxinA (incoBoNT-A).
Xeomin® (Merz) is the trade name for incoBoNT-A. IncoBoNT-A is the most recent BoNT-A to come to the market in the United States. The FDA has approved the application of incoBoNT-A for the following conditions: upper limb spasticity, cervical dystonia, chronic sialorrhea, blepharospasm, and glabellar lines.
IncoBoNT-A was manufactured free of potentially immunogenic proteins from clostridia origin in an attempt to reduce immunogenicity.
Unlike the other BoNT-A, incoBoNT-A may be stored at room temperature prior to reconstitution with preservative-free normal saline.
Patients tend to require dosing for therapeutic indications once every 3 months (11; 38; 13). In the TRUDOSE and TRUDOSE II multicenter retrospective international studies of patients switched from onaBoNT-A to incoBoNT-A for administrative or financial reasons, there was no single fixed dose ratio between the toxins (26).
(1) Upper limb spasticity. IncoBoNT-A gained FDA approval for the treatment of upper limb spasticity in adults in 2015. Two clinical trials were conducted to evaluate the safety and efficacy of incoBoNT-A for this indication. Study participants included adults post-stroke. The coprimary efficacy endpoint for the first clinical trial was a change in the Ashworth Scale score at week 4 (spasticity measured in the elbow flexors, wrist flexors, finger flexors, and thumb muscles) and the Investigator’s Global Impression of Change Scale at week 4. There was a statistically significant difference in the Ashworth Scale score in the individuals who received Xeomin® as compared to placebo. Likewise, Global Impression of Change Scale scores represented a greater improvement in patient functioning in individuals who received Xeomin® compared to those who received placebo (38; 17).
(2) Cervical dystonia. Similar to the other toxins, incoBoNT-A is FDA-approved for the treatment of cervical dystonia. One prospective, double-blind, placebo-controlled, randomized clinical trial of 233 patients with cervical dystonia aimed to assess the safety and efficacy of incoBoNT-A. The primary outcome was the change in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) from baseline to weeks 4 after treatment. Individuals included in the study had to have a total TWSTRS score of 20 or greater, with a TWSTRS severity score of 10 or greater, TWSTRS disability score of 3 or greater, and TWSTRS pain score of 1 or greater. This study reflected a significant reduction in the TWSTRS total score in individuals who received treatment with incoBoNT compared to placebo (12; 38).
(3) Blepharospasm. Xeomin® is an effective treatment for blepharospasm. A clinical trial assessed the safety and efficacy of incoBoNT-A for this indication. One hundred and nine patients were randomized 2 to 1 to either Xeomin® or placebo. Study participants included adults with bilateral benign essential blepharospasm who had previously received treatment with Botox®. Additionally, participants had to have a Jankovic Rating Scale severity subscore of greater than or equal to 2. The Jankovic Rating Scale measures the intensity and frequency of eyelid spasms. The primary efficacy endpoint for the study was a change in the Jankovic Rating Scale score from baseline to week 6 of treatment. Individuals who received treatment with Xeomin® demonstrated a statistically significant reduction in Jankovic Rating Scale score compared to the placebo group (24; 38).
(4) Chronic sialorrhea. The most recent FDA approval for all of the toxins presented includes the approval of incoBoNT-A for chronic sialorrhea, which occurred on July 3, 2018. This approval came based on results from a phase 3 clinical trial. This trial assessed the safety and efficacy of incoBoNT-A in adults with chronic sialorrhea secondary to a neurologic condition or injury. The coprimary endpoints were the change in unstimulated Salivary Flow Rate and Global Impression of Change Scale at week 4 after treatment. Individuals who received Xeomin® 100-unit dosing demonstrated a statistically significant reduction in unstimulated Salivary Flow Rate. The Xeomin® group also had a significant improvement in the Global Impression of Change Scale (38).
DaxibotulinumtoxinA (investigational).
DaxibotulinumtoxinA is a novel BoNT-A product that is FDA-approved for glabellar lines and is in clinical development for additional aesthetic and therapeutic indications and has the potential to be the first long-acting neuromodulator (04; 08; 19).
It is a purified 150 kDaBoNT-A (RTT150) that is devoid of accessory proteins and formulated with a proprietary stabilizing excipient peptide (RTP004) in a lyophilized powder.
The peptide has a backbone of lysines that carry a positive charge that results in the peptide binding electrostatically to the negatively charged core neurotoxin. The peptide permits the product to be formulated without human serum albumin and helps ensure that daxibotulinumtoxinA is room temperature stable prior to reconstitution.
Preliminary assessments suggest that injectable daxibotulinumtoxinA at doses up to 450 U is well tolerated and may offer prolonged efficacy in the treatment of cervical dystonia (19). The median duration of response (time until > 20% of the improvement in TWSTRS-total score achieved at week 4 was no longer retained or retreatment was needed) was 25.3 weeks (95% CI, 20.14-26.14 weeks).
There were no serious adverse events and there was no apparent dose-related increase in the incidence of adverse events. The most common treatment-related adverse events were dysphagia (14%) and injection site erythema (8%). Further studies involving larger numbers of patients are now warranted and underway.
Botulinum toxin type B.
There is only one commercially available botulinum toxin-B in the United States, rimabotulinumtoxin B (rimaBoNT-B).
Rimabotulinumtoxin B (rimaBoNT-B).
Myobloc® (Solstice Neuroscience) is the trade name for rimaBoNT-B. RimaBoNT-B is the only botulinum toxin type B available in the United States. The FDA has approved rimaBoNT-B for cervical dystonia.
Unlike the other toxins presented in this article, rimaBoNT-B is the only toxin in a liquid formulation. The liquid formulation has an acidic pH and causes a stinging pain at the site of injection (11; 13).
It seems to be more effective at neuroglandular junctions, lending itself well to off-label use for sialorrhea.
(1) Cervical dystonia. Myobloc® is currently only FDA-approved for cervical dystonia and unlike the other toxins discussed, it is the only botulinum toxin type B. Myobloc® was FDA-approved for cervical dystonia in 2000. Two clinical trials assessed the safety and efficacy of rimabotulinumtoxin B for this indication. One of the clinical trials included individuals with an adequate response to toxin type A whereas the other trial included individuals who had lost responsiveness to toxin type A. The primary efficacy endpoint for both trials was reduction in the Toronto Western Spasmodic Torticollis Rating Scale total score at week 4 after treatment. Individuals who received active treatment with Myobloc® regardless of toxin A responsiveness had a statistically significant improvement in their total Toronto Western Spasmodic Torticollis Rating Scale score by week 4 compared to the placebo group (06; 07; 29).
Table 1. Recommended Doses of Botulinum Toxin Products for the FDA-Approved Therapeutic Indications
Agent | Indication | Dose |
OnabotulinumtoxinA | Axillary hyperhidrosis | 50 U per axilla. |
Blepharospasm | 1.25-2.5 U into the muscles of the upper and lower eyelid (three injection sites) per affected eye. | |
Strabismus | 1.25-5 U into each of three sites per affected eye; dose based on severity of deviation. Total dose should not exceed 25 U per single treatment. | |
Cervical dystonia | 15-150 U per affected muscle based on patient’s head/neck/shoulder position, pain localization, muscle hypertrophy; lower dose is recommended for toxin-naïve patients; repeat treatment no more frequently than every 12 weeks. Mean dose 236 units, range of 198 units to 300 units. | |
Chronic migraine prophylaxis | Total dose 155 U divided among seven muscles (total of 31 sites) in head/neck muscles; repeat treatment every 12 weeks. Total dose generally should not exceed 360 U per 3 months. | |
Upper limb spasticity | 75-400 U divided among the selected muscles. | |
Lower limb spasticity | The recommended dose for lower limb spasticity is 300-400 U. | |
Neurogenic detrusor | Total dose of 200 U divided across 30 injection sites in the detrusor muscle (approximately 6.7 U/site); repeat treatment every 42-48 weeks. | |
Overactive bladder | The recommend dose is 100 U for overactive bladder and is the maximum recommended dose. | |
AbobotulinumtoxinA | Cervical dystonia | Total dose of 500 U divided among affected muscles; repeat treatment every 12-16 weeks; titrate dose in 250 U increments to desired clinical response up to 1000 U. |
Upper limb spasticity | 500 U and 1000 U were divided among selected muscles in the pivotal clinical trial. | |
Lower limb spasticity in pediatrics | 10 to 15 units/kg for unilateral lower limb or 20 to 30 units/kg for bilateral lower limb injections. Maximum of 1000 U. | |
IncobotulinumtoxinA | Blepharospasm | 1.25-2.5 U per injection site. For patients previously treated with ONA, INCO dose is the same as previous dose of ONA. |
Cervical dystonia | 120-240 U divided among affected muscles; repeat treatment no more frequently than every 12 weeks. | |
Upper Limb Spasticity | Up to 400 units; repeat no more frequently than every 12 weeks. | |
Sialorrhea | Recommended total dose is 100 U per treatment consisting of 30 U per parotid gland and 20 U per submandibular gland, no sooner than every 16 weeks. | |
RimabotulinumtoxinB | Cervical dystonia | Initial recommended dose 2500-5000 U; may be titrated to up 10,000 U based on patient’s response; repeat treatment every 12-16 weeks. |
Table 2. Clinical Application of the Botulinum Toxins
Achalasia | Anal fissure | Benign prostatic hyperplasia | Blepharospasm* | Chronic anal fissures | Cervical dystonia* | Esophageal dysmotility | Facial esthetics* |
Hemifacial spasms | Hyperhidrosis* | Limb dystonia | Lingual dystonia | Lumbosacral pain & spasms | Migraine* | Myofascial pain | Nystagmus |
Oromandibular | Overactive bladder* | Palatal myoclonus | Pain syndromes | Pelvic floor spasm | Sialorrhea* | Spasticity of upper and lower limb* | Spasmodic dysphonia |
Strabismus* | Stuttering | Temporomandibular joint disorders | Tendinopathies | Tics | Tremors | Vaginismus | Writer’s cramp |
Restless legs syndrome | Bruxism | Tardive dyskinesia | Levodopa-induced dyskinesia | Jaw opening dystonia | Would healing | ||
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Indications
The clinical utility for the botulinum toxins is ever expanding. Currently, the FDA-approved indications amongst botulinum toxins type A and B include blepharospasm, cervical dystonia, hyperhidrosis, chronic migraine, overactive bladder, sialorrhea, strabismus, upper and lower limb spasticity, and improvement of glabellar lines. Outside of FDA-approved indications, a number of studies have evaluated the use of the botulinum toxins for a number of other conditions. Some studies have found benefit with the use of the botulinum toxins in individuals with bruxism, jaw opening dystonia, tics, severe symptoms of restless legs syndrome, pain, tremors, and wound healing (21; 20; 18; 19; 28; 19). Randomized double blind trial of splenius capitis injections for head tremor showed effect over placebo at 18 weeks post injection but with side effects in about half of treated patients including neck weakness, dysphagia, headache, and cervicalgia (27). Botulinum toxins are also being researched for potential benefit in neuropathic pain conditions such as trigeminal neuralgia (34).
Adverse effects
In 2009, the FDA released the updated version of the safety warning on botulinum toxins with emphasis on the lack of interchangeability among toxins due to a difference in units.
Another concern of this safety report was about the spread of the toxin to other body parts and the possibility of unwanted effects as extreme as respiratory failure and death.
Botulinum toxins have the potential to develop immunogenicity. The concern regarding immunogenicity is important, especially with long-term use and multiple clinical applications of botulinum toxins. Multiple factors play a role in inducing immunogenicity, such as the manufacturing process, antigenic protein load, presence of accessory proteins, overall toxin dose, frequency of injections, and prior exposure to botulinum toxins (11; 13).
Immunogenicity can be primary when there is a lack of response to botulinum toxins in a toxin-naïve patient or it can occur as a secondary nonresponsiveness in patients who have previously responded, but the development of neutralizing antibodies has caused botulinum toxins to be less effective or ineffective. It seems that antigenic protein load is correlated to the protein content of the core toxin (150 kD).
Clinical studies showed almost the same rate of immunogenicity for both toxins: 1.2% for onaBoNT-A and 1.1% for incoBoNT-A (11; 13). Naumann and colleagues reported a frequency of neutralizing antibody development in cervical dystonia in four of 312 subjects (1.28%) in a metaanalysis of onaBoNT-A clinical trials (30). A meta-analysis of onaBoNT-A in a clinical trial database for 10 therapeutic and aesthetic indications spanning 30 years showed 27 out of 5846 subjects (0.5%) to have positive neutralizing antibodies at any point during the studies and 17 out of 5846 subjects (0.3%) remaining positive at study exit (23).
A more recent study investigated the prevalence of neutralizing antibodies against botulinum toxin-A. This study evaluated neutralizing antibodies in individuals receiving botulinum toxin-A. Only individuals who had received at least four injections over the course of at least 1 year were included. Of 596 patients included, 83 patients developed neutralizing antibodies, which was about 13.9%. This study corroborated previous findings that the probability of developing neutralizing antibodies increases with dose and duration of treatment (01).
A study of 45 patients receiving botulinum toxin-A for cosmetic indications evaluated the latency between injections before and after BNT162b2 mRNA vaccine for Covid-19. The study found that the latency increased from 96 days to 118 days (03). Further research on antibody development in the setting of Covid-19 vaccination is needed.
Currently, the standard of care of injecting patients with a frequency of not less than every 3 months and avoiding high doses of toxin in each single injection controls immunogenicity at significantly low levels when compared with older reports. However, in patients with urologic disorders, secondary unresponsiveness may occur due to the fact that the uroepithelium is more sensitive to antigens (eg, bacterial antigens).
Special considerations
Special considerations for the use of botulinum toxins is relatively limited due to its local effect; however, patients with a history of amyotrophic lateral sclerosis, myasthenia graves, or Lambert-Eaton syndromes may be at increased risk for side effects. Additionally, patients who are pregnant, plan to become pregnant, or are breastfeeding will need to consider the risks and benefits with their provider. Patients with urologic disorders may encounter secondary unresponsiveness due to the fact that the uroepithelium is more sensitive to antigens (eg, bacterial antigens).
Scientific basis
Botulinum toxin is a neuromuscular blocking agent that functions by inhibiting the release of acetylcholine. This is achieved by inhibition of synaptic SNARE proteins (soluble N-ethylmaleimide-sensitive factor-activation protein receptor). The SNARE proteins normally help fuse the synaptic vesicles to the synaptic membrane, and consequently, neurotransmitters are released. Besides the same mechanism of action, each toxin is a distinct biological property with its own characteristic features such as molecular structure, formulation, potency, and pharmacokinetics that is unique to each botulinum toxin. Each toxin exerts its effect at the site of injection and spreads. The diffusion and migration of the botulinum toxin is responsible for its local, distal, and systemic side effects (11; 13).
Nontoxin accessory proteins do not play a role in the mechanism of action of botulinum toxins but the nontoxin accessory proteins (eg, hemagglutinating and nonhemagglutinating proteins) act as adjuvants for the development of neutralizing antibodies.
In theory, reducing the nontoxin accessory protein load may minimize immunoresistance but this remains an unresolved issue among product comparisons.
There are two distinct serotypes of botulinum toxin, types A and B. Both botulinum toxin-A and botulinum toxin-B work to deactivate SNARE proteins. The one difference between the two toxins is how the deactivation occurs.
Botulinum toxin-A is a zinc metalloproteinase, which catalytically cleaves synaptosomal-associated membrane protein 25-kd (SNAP-25). This deactivation prevents acetylcholine release.
Botulinum toxin-B deactivates SNARE by cleaving vesicle-associated membrane protein (VAMP) (11; 13).
In both cases, acetylcholine-containing vesicles in the motor neuron are unable to fuse with the cell membrane.
References
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Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
-
Robert Fekete MD
Dr. Fekete of New York Medical College received consultation fees from Acadia Pharmaceutical, Acorda, Adamas/Supernus Pharmaceuticals, Amneal/Impax, Kyowa Kirin, Lundbeck Inc., Neurocrine Inc., and Teva Pharmaceutical, Inc.
See Profile
Former Authors
- Anthony H Wheeler MD
- Joseph K C Tsui MD
- Charles E Argoff MD
- Howard S Smith MD
- Khashayar Dashtipour MD PhD
- Jessa Koch PharmD
- Joseph Jankovic MD
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