Botulinum toxin (BoNT) is a proteinaceous exotoxin that is produced in the growth and reproduction of anaerobic Clostridium botulinum, a gram-positive and spore-shaped rod bacteria.[1,2] BoNT, as a neurotoxin, is the strongest biotoxin among all known natural and synthetic toxins. Investigations have demonstrated that BoNT could affect the cholinergic motor nerve endings to disturb the release of acetylcholine via the antagonism of calcium ions, thus inhibiting shrink of muscle fibers, causing flaccid paralysis of muscles and developing temporary denervation [3,4] (Fig. 1). Specially, the paralysis of respiratory muscle represents the main cause of deaths among botulism patients.
BoNT was initially used as a biological weapon, because it could destroy nerve systems of organisms, leading to dizziness, dyspnea, muscle weakness, and some other symptoms. Later, it was medically used to treat facial spasm and other muscle movement disorders. On the basis of its function of focal muscle paralysis, BoNT has been successfully applied in clinic for treating various diseases caused by skeletal muscle spasms since 1979, such as strabismus, facial tic, refractory headache, chronic migraine, and hyperhidrosis.[6–8] Moreover, Jean Carruthers, an ophthalmologist in Canada, found that the frown lines of patients disappeared after the injection of BoNT for blepharospasm treatment, and this discovery promoted a novel cosmetic practice that revolutionized aesthetic treatment. Since then, growing studies have indicated that BoNT could be employed as a cosmetic procedure. Furthermore, in 2002, the Food and Drug Administration (FDA) of USA approved the use of BoNT in cosmetology field, and then, BoNT injection has gradually become a major and common aesthetic services all over the world.
Currently, yearning for youthful look is an obsession for most women, so cosmetic injection of BoNT has swept the world for this purpose. However, the majority of people have little knowledge about adverse effects of BoNT on human bodies. It has been reported that frequent application of BoNT in short time or overdose might lead to botulism, which could endanger the physical and mental health of people, even their lives. The main clinical symptoms of botulism include muscle weakness, blepharoptosis, facial palsy, and rising difficulty. Figure 2 has been removed from the article prior to publication. The authors were not able to get patient consent for the use of this image. In the current study, we reported 86 botulism patients caused by cosmetic injection of BoNT who were admitted in our hospital from April 2009 to June 2013.
2 Clinical materials and methods
2.1 Study subjects
All of the subjects enrolled in our report were females, aged between 17 and 63 years (Table 1). They all developed botulism after BoNT injection in upper arm, forehead, gastrocnemius muscle, masseter muscle, or some other sites to achieve “rejuvenation.” Some of them only received BoNT injection in 1 site while some others in several sites. All of 86 patients were directly injected with A-type BoNT with no history of drug or food allergies. Patients presented rising difficulty, blepharoptosis, weak convergence reflex, facial palsy, limb myasthenia, cyanotic lips, and tachypnea. The study was approved by the Ethics Committee of our hospital. Written informed consent was obtained from each participant. The patients agreed to show their images for publication.
2.2 Diagnosis modality
On the basis of chief complaints, the patients’ poisoning statuses and degrees were determined according to the history of cosmetic BoNT injection, clinical symptoms, and signs as well as other auxiliary examinations. The classification standards were as follows: mild botulism: developing dizziness, headache, fatigue, blepharoptosis, and/or blurred vision, not affecting normal life; moderate botulism: apart from the above listed symptoms, dysphagia and/or bucking were observed, and nasal feeding was adopted accordingly; and severe botulism: apart from all of the above-mentioned symptoms, respiratory failure appeared and mechanical ventilation was applied.
2.3 Auxiliary examinations
Auxiliary examinations used for patients’ diagnosis included those on renal and liver functions, blood index detection, chest X-ray, and abdominal ultrasound.
2.4 Differential diagnosis
On the basis of the patients’ chief complaints and their clinical symptoms, the differential diagnosis was conducted to discriminate BoNT botulism from myasthenia gravis, Guillain–Barre syndrome, cerebrovascular diseases, cervical vertebra diseases, and polymyositis.
2.5 Therapeutic methods
All of the patients received comprehensive treatments, including nerve nutrition, systemic support and symptomatic treatment, and the injection of botulinum antitoxin serum. The concrete steps and standards are listed as follows.
2.6 Nerve nutrition: patients took neurotrophic drugs
2.6.1 Systemic support
Dysphagia patients received nasal feeding or intravenous nutrition to maintain the water-electrolyte balance.
2.6.2 Symptomatic treatment
Patients should pay attention to rest and psychological counseling. For those patients with moderate to severe botulism, their signs would be monitored closely. Severe patients would accept tracheal intubation and mechanical ventilation.
2.6.3 Botulinum antitoxin serum
Patients with negative skin test were given 10,000 IU antitoxin serum via intramuscular injection, once every 12 hours; patients with positive or weak positive skin test were given 10,000 IU via desensitization injection, once a day. For all the patients, once the conditions were improved or stopped exacerbating, the injection dose could be reduced. The amount of antitoxin serum should be about 30,000∼50,000 IU.
3.1 Clinical information of 86 patients with botulism
In our investigation, the patients were injected with different dosages of BoNT, ranging from 6 to 1000 U (Table 2). The clinical symptoms of botulism occurred within 0∼36 days after injection, mainly between 2nd and 6th day after the operation (Fig. 3). What is more, according to Spearman analysis, the injection dose of BoNT was negatively correlated with botulism onset time. The detailed symptoms of the patients and the numbers of corresponding events were as follows: headache, 18 cases; dizziness, 68 cases; insomnia, 33 cases; fatigue, 74 cases; blurred vision, 72 cases; eye opening difficulty, 62 cases; slurred speech, 37 cases; dysphagia, 61cases; bucking, 35 cases; constipation, 15 cases; anxiety, 36 cases; nasal feeding, 21 cases; and prejudices in normal life, 26 cases (Table 3). Fatigue and blurred vision were the most frequently observed symptoms.
3.2 Auxiliary examinations
To exactly identify the poisoning statuses of patients, several auxiliary examinations were performed. The majority of patients (80 cases) had normal kidney function. The examination on liver function found mild abnormality in 8 cases, with a slight increase in amylase. Ten patients presented raised platelet count and neutrophil number. Five cases developed tachycardia and 9 had lung infection showed in X-ray chest radiograph. All patients got normal abdominal viscera via ultrasound detection.
3.3 Treatment outcomes
After treatments, the patients received comprehensive examinations again. The discharge criteria were as follows: subjective symptoms significantly relieved or disappeared; no respiratory muscle involved; regaining smooth feeding and drinking; recovering the strength of limb muscle and restoring normal sight. Patients were discharged from our hospital within 1∼20 days after receiving combined therapies and botulinum antitoxin serum injection.
BoNT, a zinc-dependent endopeptidase, is a strong, irreversible and fatal neurotoxin, and inappropriate application of BoNT may cause botulism. It has been reported that the toxicity of BoNT is significantly higher than that of potassium cyanide. The lethal dose of BoNT for human beings is only 0.1 μg, and 1 g crystalline toxin could kill over 1 million people.[10,11] According to its antigenic difference, BoNT could be categorized into 7 serotypes: A, B, C, D, E, F, and G, among which the A, B, E, and F types are involved in human botulism, while C and D types are responsible for animals botulism.[12,13] In addition, BoNT/A is clinically applied most prevalently because of its stability, strongest toxicity, easy preparation, and longest time of maintaining function in low temperature. The patients in our report were all BoNT/A-poisoned cases.
The application of BoNT in cosmetic field has been widely reported worldwide.[14,15] Compared with traditional chemical cosmetic methods, such as chemical peeling and face lift, BoNT cosmetology is characterized by little injury, no wound, fast effects, and rapid recovery. Therefore, BoNT injection in cosmetic area has become more and more popular. For cosmetology, the effects of BoNT will occur about 2∼3 days after injection and will be obvious 1 week later. Such effect could last for 12∼24 weeks and need only 1 more injection half a year later to maintain. Moreover, evidence proves that the injection dose of BoNT is closely related to its effects on muscle paralysis and to wrinkle smooth. Injection with a high dose of BoNT can produce strong paralysis effect with long action time. However, excessive injection of BoNT can also cause side effects due to the involvement of near muscles.
With the wild application of BoNT in cosmetic field, people in need can repeatedly receive such operation in a short period, which may cause botulism due to BoNT overdose. What is more, in many individual medical cosmetology institutions, BoNT uses are frequently arbitrary. The majority of the patients in our report had received BoNT injection in irregular beauty salons. Some of them had taken BoNT in several sites, and some received BoNT injection several times at the same site, resulting in toxin accumulation and consequent botulism. Certain symptoms such as headache, dizziness, insomnia, fatigue, and dysphagia appeared in these cases, but were relieved or disappeared after antitoxin serum treatment and symptomatic therapies. Furthermore, the FDA referred in February 2008 that the safety, effectiveness, and proper dosages of BoNT in certain diseases and populations are still not clear. As a result, the dosages of BoNT should be strictly controlled for whatever disease treatment or cosmetology to avoid the occurrence of side effects.
As BoNT could inhibit acetylcholine release, muscles dominated by cranial nerves and motor nerves will be paralytic among botulism patients, and this phenomenon may be aggravated along with acetylcholine exhaust. Early application of botulinum antitoxin serum and certain symptomatic support treatments, such as active infection prevention, is important for botulism treatment.[16,17] The earlier the treatments are performed, the better the effects are. However, cosmetic botulism is insidious, and often evades from being detected in early examination. Furthermore, as operators and patients frequently possess insufficient or little knowledge about botulism, botulism may occur among people receiving BoNt injection, leading to pulmonary infection and other complications.
In a word, cosmetic botulism is a severe event caused by inappropriate injection of BoNT. The injection dosage of BoNT is positively correlated with botulism severity. Once botulism occurs, timely and appropriate treatments are needed to improve patients’ clinical outcomes.
Conceptualization: Lili Bai, Peng Zhang.
Data curation: Lili Bai, Peng Zhang.
Formal analysis: Lili Bai, Peng Zhang.
Funding acquisition: Zewu Qiu.
Investigation: Zewu Qiu.
Methodology: Zewu Qiu.
Project administration: Zewu Qiu.
Resources: Xiaobo Peng, Xingwang Wang, Peng Zhang, Zewu Qiu.
Software: Xiaobo Peng, Xingwang Wang, Peng Zhang.
Supervision: Xiaobo Peng, Xingwang Wang, Kun Wan.
Validation: Yanqing Liu, Xin Wang, Xingwang Wang, Kun Wan.
Visualization: Yanqing Liu, Yawei Sun, Xin Wang, Xingwang Wang, Guodong Lin, Kun Wan.
Writing – original draft: Yanqing Liu, Yawei Sun, Xin Wang, Guodong Lin, Kun Wan.
Writing – review & editing: Yawei Sun, Xin Wang.
. Oh HM, Chung ME. Botulinum toxin
for neuropathic pain: a review of the literature. Toxins 2015;7:3127–54.
. Shukla HD, Sharma SK. Clostridium botulinum: a bug with beauty and weapon. Crit Rev Microbiol 2005;31:11–8.
. Rossetto O, Megighian A, Scorzeto M, et al. Botulinum neurotoxins. Toxicon 2013;67:31–6.
. Jung HE, Lee JS, Lee TH, et al. Long-term outcomes of balloon dilation versus botulinum toxin
injection in patients with primary achalasia. Korean J Intern Med 2014;29:738–45.
. Pita R, Romero A. Toxins as weapons: a historical review. Forensic Sci Rev 2014;26:85–96.
. Gardner R, Dawson EL, Adams GG, et al. The use of botulinum toxin
to treat strabismus following retinal detachment surgery. Strabismus 2013;21:8–12.
. Paracka L, Kollewe K, Dengler R, et al. Botulinum toxin
therapy for hyperhidrosis: reduction of injection site pain by nitrous oxide/oxygen mixtures. J Neural Transm (Vienna) 2015;122:1279–82.
. Lin KH, Chen SP, Fuh JL, et al. Efficacy, safety, and predictors of response to botulinum toxin
type A in refractory chronic migraine: a retrospective study. J Chin Med Assoc 2014;77:10–5.
. Kopera D. Botulinum toxin
historical aspects: from food poisoning to pharmaceutical. Int J Dermatol 2011;50:976–80.
. Rossow H, Kinnunen PM, Nikkari S. [Botulinum toxin
as a biological weapon]. Duodecim 2012;128:1678–84.
. Yiannakopoulou E. Serious and long-term adverse events associated with the therapeutic and cosmetic
use of botulinum toxin
. Pharmacology 2015;95:65–9.
. Park KY, Hyun MY, Jeong SY, et al. Botulinum toxin
for the treatment of refractory erythema and flushing of rosacea. Dermatology 2015;230:299–301.
. Ting PT, Freiman A. The story of Clostridium botulinum: from food poisoning to Botox. Clin Med (Lond) 2004;4:258–61.
. Steinsapir KD, Groth MJ, Boxrud CA. Persistence of upper blepharoptosis after cosmetic botulinum toxin
type A. Dermatol Surg 2015;41:833–40.
. Steinsapir KD, Rootman D, Wulc A, et al. Cosmetic
microdroplet botulinum toxin
A forehead lift: a new treatment paradigm. Ophthal Plast Reconstr Surg 2015;31:263–8.
. Maslanka SE, Luquez C, Dykes JK, et al. A novel botulinum neurotoxin, previously reported as serotype H, has a hybrid-like structure with regions of similarity to the structures of serotypes A and F and is neutralized with serotype A antitoxin. J Infect Dis 2016;213:379–85.
. Torii Y, Shinmura M, Kohda T, et al. Differences in immunological responses of polyclonal botulinum A1 and A2 antitoxin against A1 and A2 toxin. Toxicon 2013;73:9–16.