International Journal of Nutrition, Pharmacology, Neurological Diseases

REVIEW ARTICLE
Year
: 2011  |  Volume : 1  |  Issue : 2  |  Page : 126--133

Adverse effects of botulinum neurotoxin A in spasticity management


Tapan N Joshi1, Sonal Joshi2,  
1 VA Central Iowa Health Care System, Des Moines, IA, USA
2 Orthopedic and Neurological Rehabilitation, 1101 S. Capital of Texas Hwy, Austin, TX, USA

Correspondence Address:
Tapan N Joshi
VA Central Iowa Healthcare System, 3600, 30th Street, Des Moines, IA - 50310
USA

Abstract

Over the last few decades, Botulinum neurotoxin has evolved from a well-publicized public health threat of food-borne illness, due to contaminated foods, to a widely used therapeutic measure. Botulinum neurotoxin A is one of the seven distinct neurotoxins produced by Clostridium botulinum. The mechanism of action is to block the transmission of overactive nerve impulses to the targeted muscle by selectively preventing the release of the neurotransmitter acetylcholine at the neuromuscular junction. Its efficacy is evident in the treatment of both adults and children with spasticity of various causes. It is considered a safe therapy with most of the adverse events being self-limited and transient. Serious side effects like unwanted muscle weakness and suboptimal response to therapy mainly due to antibody formation are uncommon, but possible. This article gives an in-depth review of the possible adverse effects of botulinum toxin A and their pathogenesis for spasticity management. Physicians should carefully perform a detailed clinical assessment of every patient individually, for a benefit-risk profile, while making treatment decisions, to prevent such adverse events.



How to cite this article:
Joshi TN, Joshi S. Adverse effects of botulinum neurotoxin A in spasticity management.Int J Nutr Pharmacol Neurol Dis 2011;1:126-133


How to cite this URL:
Joshi TN, Joshi S. Adverse effects of botulinum neurotoxin A in spasticity management. Int J Nutr Pharmacol Neurol Dis [serial online] 2011 [cited 2019 Sep 15 ];1:126-133
Available from: http://www.ijnpnd.com/text.asp?2011/1/2/126/84202


Full Text

 Introduction



Spasticity is a velocity-dependent increase in tonic stretch reflexes, with exaggerated tendon responses. [1] It is a debilitating consequence of upper motor neuron lesions caused by cerebrovascular accident (CVA), traumatic brain injury (TBI), spinal cord injury (SCI), cerebral palsy (CP), multiple sclerosis (MS), and so on. [2] Although the pathophysiology of spasticity is not entirely clear, it is due to an imbalance between the excitatory and inhibitory input and the alpha motor neurons. [3],[4] The resulting symptoms can be divided into 'positive' and 'negative'. 'Negative' symptoms like decreased dexterity and coordination are usually treated by rehabilitation measures like physical and occupational therapies. 'Positive' symptoms like hypertonia, muscle spasm, pain, and discordant activation of muscles are treated with rehabilitation and pharmacological interventions. Depending upon the affected area, spasticity can be classified as generalized, regional or focal. [5] Early intervention is critical, as otherwise, over the period of time, spasticity may lead to contractures leading to postural deformity and impediment of mobility and activities of daily living.

As the clinical effect of spasticity is diverse, its treatment usually involves a multidisciplinary approach. It involves rehabilitation including physical and occupational therapies, pharmacological management with oral antispastic agents, peripheral chemodenervation with botulinum toxin or phenol, intrathecal pump implantation or surgical interventions such as tendon transfer / release, and selective dorsal rhizotomy (SDR). Apart from their other side effects, oral antispastic medications frequently cause central nervous system depression and elevated liver functions, making them intolerable to patients. Besides, they are not an ideal option to treat regional spasticity, that is, treating spasticity in an upper extremity, while not influencing the lower extremity spasticity, as it provides false strength to the lower extremity muscles helping the subject to ambulate. The intrathecal baclofen pump is an invasive procedure and it is more beneficial for generalized spasticity, especially lower extremity spasticity. Surgical interventions like tendon transfer and SDR are not available to every patient, plus their role in neurologically improving patients is debatable due to their irreversible effects.

Patients with focal or regional spasticity often have impaired activities of daily living depending upon the involved area. Peripheral chemodenervation gives an option to tailor the treatment to the individual need, for example, involved upper extremity muscles can be treated without weakening the muscles necessary for ambulation. In addition, its reversible nature and outpatient treatment option make peripheral chemodenervation increasingly popular with both physicians and patients. Of late, phenol / alcohol have gradually fallen out of favor, as they are difficult to obtain in a sterile form and cause adverse reactions like dysesthesia. They are usually given at the motor nerve endplate using a peripheral electrical nerve stimulator, which is technically difficult, time-consuming, and often painful to patients, especially those with intact sensation. Botulinum toxin is usually injected intramuscularly, which is technically easy, less time-consuming, and at the same time equally efficacious when comparisons are made. [6] Therefore, botulinum toxin is gaining rapid acceptance for spasticity management. [Table 1] documents its various uses other than spasticity management.{Table 1}

 History



Botulinum toxin is produced by a gram-positive, rod-shaped bacteria Clostridium botulinum under anaerobic conditions. In 1820, Justinus Kerner described botulism by describing a cluster of symptoms including dry mouth, mydriasis, and paralysis of skeletal muscles. It was suspected of being associated with a German sausage, so it was named after the Latin word for sausage, 'botulus'. Several nations produced botulinum toxin in World War II as a potential biological weapon, but it was never used in combat. Three decades later, it was used for medical purposes, initially for the treatment of strabismus. [7] Botulinum neurotoxin has been utilized successfully since the late 1980s to treat limb spasticity. [8]

 Mechanism of Action



Its mechanism of action is to block the transmission of overactive nerve impulses to the targeted muscles by selectively preventing the release of neurotransmitter acetylcholine at the neuromuscular junctions. Botulinum neurotoxins are produced by seven distinct serotypes - A, B, C 1 , D, E, F, and G. [9] Commercially, they are available in two serotypes, type A (e.g., Botox® , Dysport® , Xeomin® , Neuronox® ) and type B (e.g., Myobloc® , Neurobloc® ). They differ in their potency and duration of action. [10] Botulinum neurotoxin has a light and a heavy chain linked together, with a disulfide bond for activation. The heavy chain acts as a binding and translocation domain, while the light chain acts as a catalytic domain. Following binding to cholinergic nerve terminals, it is transported into the nerve terminal by endocytosis. Once in the nerve terminal, the toxin inactivates proteins regulating exocytosis of neurotransmitter. The net effect is the inhibition of acetylcholine release. Botulinum neurotoxin type A cleaves SNAP-25 (Synaptosomal-associated protein-25) while type B works on VAMP (Vesicle associated membrane protein). [11] This process takes several days to complete. That is why botulinum neurotoxin takes from 3 to 7 days to show clinical effects. It is worth noting that initially its clinical effect lasts about 12-14 weeks due to neuronal sprouting at the site of chemical neurolysis. Therefore, the injection treatment needs to be repeated every three months. After chronic use, one may notice the summation effects of botulinum toxin, enabling an increase in time interval between the treatment courses.

 Common Side-Effects of Botulinum Toxin A



Botulinum toxin A (BoNTA) is an approved treatment option for focal or segmental spasticity management. Two of the most popular BoNTA drugs are Botox® and Dysport® . Complications and side-effects can be divided into two categories; procedure-related and pharmacological. Procedure-related complications are localized and similar to complications due to any intramuscular injection procedure. They include pain and soreness at the injection site, tenderness, swelling, bruising, bleeding, and injury to surrounding structures. Most of the procedure-related complications can be dealt by pain medications, for example, acetaminophen, ibuprofen, and modalities such as the ice pack. Topical anesthetics are not effective in diminishing pain at the injection site. [12] Hypersensitivity is a serious pharmacological side effect. Persons with egg allergy should not be injected with BoNTA due to the presence of human albumin in its formulation, while milk allergy is a potential contraindication for Dysport® . BoNTA is classified as a category C drug for pregnancy and lactating women. Other most reported pharmacological side-effects include asthenia, headache, flu-like symptoms, blurred vision, dry mouth, upper respiratory infections, urinary tract infections, over-weakness of targeted muscles and fatigue. In addition to its effect at the motor end plate, BoNTA also blocks cholinergic neurotransmission in the autonomic nervous system, that is, pre- and post-ganglionic parasympathetic nerve fibers and non-adrenergic sympathetic fibers to the sweat glands. [13] The severity of the autonomic dysfunction is dose-dependent and usually lasts longer than the paralytic effect. [14] Its anticholinergic adverse effects may include dry mouth, reduced sweating, constipation, [15] postural hypotension [16] or neurogenic bladder and bowel [17],[18] . Turkel et al.[19] conducted a pooled analysis of randomized, double-blind, placebo-controlled trials of BoNTA for the treatment of post stroke spasticity. It showed no statistical difference in the side effects between the study and placebo groups, except nausea, which was higher in the BoNTA group. Meta-analysis performed by Naumann et al.[20] demonstrated no severe adverse reaction secondary to BoNTA treatment and concluded its favorable safety and tolerability profile. [Table 2] depicts a summary of the double-blind, randomized, placebo-controlled trials, [12],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36] evaluating the safety of BoNTA for the treatment of spasticity due to various reasons, including CVA, MS, CP, SCI, and TBI. In some studies, incidences of adverse events are reported to be higher, but overall there is no clinical or statistical difference between the two groups and they are self-limiting. Few studies report the same adverse events profile. No patient has required hospitalization. Due to the increased usage of botulinum toxin, more serious, but uncommon, complications have come to light, which include clinical resistance to BoNTA and generalized / distant muscle weakness.{Table 2}

Suboptimal response to Botulinum toxin A therapy

Clinical resistance or suboptimal response to BoNTA treatment can be due to immunoresistance, secondary to antibodies to botulinum toxin (ABT) or due to technique-related variables like the status of the selected muscle, for example, contracture, fibrosis; total number of muscles selected; total dose of BoNTA administered, and injection technique. [5] Muscle contracture and severe spasticity may appear to be clinically similar. A pre-injection, EMG-evaluation is helpful to differentiate them. If a contracture presents along with spasticity, it will cause a suboptimal response after the BoNTA injection. [37] The physician's experience with BoNTA administration is important in preventing many factors. An inexperienced physician selects high numbers of muscles or lowers the total dose of BoNTA hindering the desired clinical outcome. The injection technique is equally important. BoNTA injections based on the palpatory ('Blind') method provide less effective outcomes than the EMG-guided technique [38] or a technique using an electrical peripheral stimulator. Guidance helps the clinicians to inject the chosen muscles only. Electrical stimulation is more specific than the EMG-guided technique, as it provides direct visual confirmation of the specific muscle contraction although it may cause increased pain in patients with normal sensation or dysesthesia. Of late, an ultrasound-guided injection technique is becoming more popular, as it is accurate, virtually pain-free, and still provides direct visualization. [39]

Antigenicity of Botulinum toxin A

Development of BoNTA antibodies causing immunoresistance is a serious complication. It may be primary or secondary. Primary resistance causes no-response to the initial treatment of BoNTA due to ABT being already present in the system, while secondary resistance causes response decrement over a period of time during the treatment course. Incidences of antibody formation reported by randomized, placebo-controlled, double-blind trials are very low. [22],[40] Antigenicity may depend on the protein load and molecular weight of the toxin, but it is not comparable between Botox® and Dysport® , due to their different formulations and variable protein compositions. Botox® contains a uniform 900 kD complex, 900 μg sodium chloride, and 500 μg serum human albumin. [41] Dysport® contains variable-sized neurotoxin complexes up to 900 kD, 2.5 mg lactose, and 125 μg serum human albumin. [42] Studies reporting the antigenicity of different BoNTAs may also not be equated due to the heterogenicity in the assay methods of antibody detections. Herrmann et al.[43] reported that 31.8% of the subjects developed antibodies after receiving BoNTA preparations. He used Botox® and Dysport® for his study and did not report the incidences separately. Frequency of antibody formation has been reported as being from 5 to 9.5% with Dysport®.[44] Botox® had a high protein load in its old formulation causing a high rate of antibody formation. It was reported to be about 5% in the literature. [44],[45]

The new formulation contains 80% less complex protein load than the older product (5 vs. 25 ng / 100 unit) causing a decrease in antibody formation, by six times. [46] Yablon et al.[47] reported a very low incidence of antibody formation (0.5%) when treated with the newer Botox® preparation. On the other hand, botulinum toxin A - Xeomin® is free of accessory proteins binding the active substance. The molecular weight of botulinum toxin for Xeomin® is 140 kD only. So theoretically, antibody formation should be much less, as the protein load is minimal. Yet, the antigenicity reported in its prescribing information is comparable to other BoNTA drugs. [48] Other risk factors for antibody formation can be the dosing frequency, the total cumulative dose, [43],[49],[50] and a higher weight-adjusted maximum dose per treatment. [43],[47],[51] However, Zuber et al.[52] and Tsui et al.[53] found that a high cumulative dose of BoNTA was not sufficient to cause the production of ABT. Some investigators [54] have also suggested that prolonged exposure (> 14 injection series) does not in itself increase the risk of antibody-induced therapy failure. However, it is not advisable to inject BoNTA before the completion of 12 weeks to prevent antibody formation, as a short time period between injections causes increased antibody formation. [52] Age has not been found to be a significant factor in antibody formation. [43],[47] BoNTA is a biological product and like every other biological product its antigenicity is not always consistent. Cases are published showing patients with ABT continuing to respond to BoNTA. [48],[52] Reports are also available describing patients with secondary resistance due to ABT formation after receiving low dose of BoNTA at optimum interval periods. [55],[56]

If clinically encountered, antibodies can be confirmed by patient-based clinical tests such as the frontalis test, sternocleidomastoid test, extensor digitorum bravis (EDB) test or laboratory tests, for example, mouse-protection assay (MPA), indirect enzyme-linked immunosorbent assay (ELISA), and western blot immunoassay. It is important to note that clinical tests are not a direct measurement of antibodies, but rather demonstrate a patients' potential for a positive clinical response to future treatment. To perform a clinical test, BoNTA is injected into the respective muscle in a small quantity and strength is measured after three to seven days. If muscle weakness is not encountered, it will be concluded that the patient has developed ABT. ELISA and western blot immunoassay have low sensitivity and specificity, with a low antibody titer. MPA is a gold standard test as it has high specificity. [57] It is a qualitative test, but not quantitative.

If the physician continues to encounter suboptimal response, the dose and / or site should be changed followed by EDB or frontalis test, to measure the response. Upon receipt of an unfavorable response, preferably MPA should be ordered to confirm antibodies. Patients with secondary resistance with BoNTA can be treated with botulinum toxin type B. [58] It has been shown that repeated use of plasma exchange and immunoadsorption in order to decrease antibody load can resensitize patients with secondary resistance to BoNTA. [59]

Unwanted regional or distant muscle weakness after Botulinum toxin A treatment

Another undesirable effect associated with BoNTA is unwanted muscle weakness. Occasionally, an inexperienced clinician injects aggressively with a higher dose causing over-weakness of the targeted muscles. Therefore, it is advisable to start with a lower dose and increase it according to the patient's response. One of the main advantages of botulinum toxin treatment is its focal effect. However, in some cases the toxin has been shown to spread and cause regional / distant or generalized muscle weakness. Regional weakness manifests in an adjacent anatomical area like dysphagia / dysphonia, after injections in the neck muscle for cervical dystonia [60] or diplopia / facial palsy, after BoNTA treatment for blepharospasm. [61] Regional weakness can be due to a local spread of the toxin from the intended sites of action causing unwanted inhibition of transmission at the nerve endings. An incorrect injection technique and higher dilution [62] may potentiate the spread of the toxin. Distant muscle weakness occurs in anatomically separate and distant sites. Individuals with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis or neuromuscular junction disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) should be monitored closely, if treated with BoNTA, as there may be an increased risk of generalized or distant muscle weakness. [63] It is possible that the decreased function of an alpha motor neuron makes these patients more susceptible to BoNTA. Patients treated concomitantly with agents interfering with neuromuscular transmission (for example, aminoglycosides, curare-like agents) should also be observed closely for the same reason. [64] Most of the cases described in the literature reporting distant/regional or generalized muscle weakness, after BoNTA administration, did not have the clinical conditions reported earlier nor did they receive agents causing neuromuscular blockade. Underlying comorbidities could also make subjects receiving BoNTA predisposed to systemic involvement. Naidu et al.[65] conducted a retrospective safety analysis of BoNTA in 1147 pediatric CP patients (1980 injection episodes). The authors suggested that systemic adverse events occurred in 1 - 2% of children and the risk of serious respiratory events was related to the child's GMFCS (Gross motor function classification system) level and the pre-existing medical morbidities, including impairment of bulbar function and history of respiratory disease. In adult patients with reduced lung function, treated for upper limb spasticity, upper respiratory tract infections were reported more frequently when treated with Botox®.[40]

It has been repeatedly demonstrated by single-fiber EMG (with increased jitter and blocking) that BoNTA affects neuromuscular transmission distant to the injected site. [66],[67] These electromyographic changes are not clinically specific, as they are not always associated with overt or apparent physical weakness. [66],[67],[68],[69] The minimal amount of its diffusion causing subclinical distant neuromuscular blockade can be a possible explanation. The factors affecting BoNTA diffusion causing systemic / distant muscle weakness are still unknown. In rat models, diffusion margins are similar for Botox® and Dysport®.[70] There are several hypothesis regarding mode and factors for diffusion: retrograde axonal spread, systemic vascular spread, role of injection guidance, hypersensitivity to the toxin, dilution volume, and total cumulative dose. There are contradictory evidences in literature regarding the retrograde axonal spread of BoNTA. Using radioactive botulinum toxin A, Wiegand et al.[71] showed a retrograde spread to the corresponding spinal cord segments. On the contrary, Koman et al.[12] showed 20% reduction in M-response, with no change in the H-reflex in pre- and post-BoNTA injections in the gastrocnemius muscle. The H-reflex is a well-standardized measure of central synaptic activity. Thus, it was concluded that BoNTA had no significant 'central' effect. The systemic spread of BoNTA is also possible by entry into the vascular system through the capillary field or the venous system. Nonetheless, it should be a standard practice to aspirate before injecting BoNTA into the muscles, to prevent systemic venous spread. Capillary uptake may be possible. It can be greater with a larger volume (greater dilution), but it is not proven. Lack of injection guidance may lead to an indirect increase in the required dose of BoNTA, in order to achieve a satisfactory clinical response.

Higher weight-adjusted doses can also increase the possibility for a systemic spread of BoNTA, causing distant / generalized weakness. Mall et al.[72] showed significant distant weakness with a BoNTA dose of 1500 units (30 units / kg), but details regarding the needle-guiding technique were deficient. In another double-blind, randomized trial, [73] one out of twenty-five children (4%) developed generalized weakness in the high-dose (24units / kg) BoNTA group. None of the low-dose group (8 units / kg) developed generalized or distant weakness. Crowner et al.[74] demonstrated no relationship between high dose (21 units / kg) of BoNTA and distant muscle weakness. Yet, there are anecdotal evidences available, showing distant muscle weakness after BoNTA treatment with a lower dose. [75] The European consensus group [76] has also suggested a safe upper limit of 30 units / kg of BoNTA for spasticity management of cerebral palsy. Another possible reason could be the total cumulative dose of BoNTA injected. [41] Goldstein [77] has concluded that total doses of 800 - 1200 units of Botox® are safe for spasticity management in young adults, who have more than 45 kg of body weight. As per this author's personal experience, many subjects with spasticity were treated safely and successfully with a higher dose for BoNTA, without having distant muscle weakness. Therefore, the dose should be titrated based on the practitioner's experience and individual patient's response. In chronic SCI, there is a decrease in lean muscle mass secondary to muscle atrophy and its replacement with fatty tissue. [78] Therefore, the requirement of BoNTA can be actually less than the calculated dosage causing indirect overdose, but its effect is not seen universally in all patients. In recent times, the European consensus group has also suggested further studies to clarify the side-effects of high doses in adults. [5]

 Conclusions



As per level I evidence, BoNTA treatment is a safe treatment option for spasticity management with mostly minor and transient adverse events. The clinician's experience is vital for optimum response and to minimize side effects. Serious side effects like generalized / distant muscle weakness and antibody formation are uncommon, but possible. They should be discussed before the administration. Physicians should carefully perform a clinical assessment of every patient individually for the benefit-risk profile, while making treatment decisions. Additional double-blind, placebo-controlled studies evaluating the adverse-effects of high dose of BoNTA treatment for spasticity management are recommended.

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