In late March 2023, the World Health Organization (WHO) issued a disease outbreak
notification regarding an iatrogenic outbreak of botulism in 87 patients who underwent
bariatric (weight-loss) procedures at two Turkish hospitals in Istanbul and Izmir
[1,2]. However, authorities believe there may be more victims to come, with those
affected estimating that more than 250 may have been affected by the current outbreak.
The patients reportedly underwent the procedures between February 3 and March 1, 2023.
Since then, the authorities have suspended activities at these centres and launched
an internal investigation. It has been determined that all affected patients received
intragastric botulinum neurotoxin (BoNT), an off-label use for a well-known product
in cosmetic dermatology [2].
The European Centres for Disease Prevention and Control (ECDC) has noted that the
iatrogenic botulism cases linked to the current outbreak have been reported in Germany,
Austria, France, Switzerland, and Turkiye [2]. All affected patients are reported
to be adults with the majority being middle-aged women. Multiple patients have been
admitted to the intensive care unit due to worsening condition. The reported symptoms
of these patients have been summarized in Fig. 1.
Fig. 1
A schematic demonstrating the chain of events during the current outbreak. Patients
from multiple European countries visited Turkiye for intragastric botulinum neurotoxin
injections (for weight loss). The patients travel back to their home countries where
they developed the depicted early (within first three days) and late (fourth day onwards)
complications. This triggered a public health response in the European countries including
Germany, France, Switzerland, and Austria. Brackets depict the number of confirmed
cases in each country. Note – the authors remain neutral in regards with territorial
disputes. The images were adapted from the Noun Project.
Fig. 1
1
What is botulinum Neurotoxin?
As one of the most poisonous toxins, Botulinum neurotoxins are metallo-endoproteases
produced by gram positive, anaerobic Clostridium spp. Due to the toxin's ability to
inhibit the release of neurotransmitter (acetylcholine) at the striated neuro-muscular
junction, it is widely used for disorders characterized by muscular dystonia or hypertonia
[3]. However, its use in cosmetology for aesthetic purposes is perhaps the best known
with nearly three million injections used annually [4]. The toxin is cleaved into
a two-chain molecule (light and heavy chain) connected by a disulphide bridge. The
heavy chain binds to the presynaptic receptors and is responsible for translocation
of the light chain into the neuronal cytoplasm. The light chain possesses the proteolytic
activity and act as a zinc endopeptidase [5].
There are seven known serotypes (A to G) with more than 40 subtypes described based
on variations in amino acid sequences [6]. Recently, an eighth serotype (X) has been
described [7]. Serotypes C and D are associated with botulism in animals and birds
while serotypes A, B, E, and F (rarely) are linked to food-borne botulism in humans
[8]. Among these serotypes, the most potent is Botulinum toxin A (BTA) which is also
used for medical purposes. In Turkiye, there are three BTA products that are approved
(Table 1).
Table 1
List of Botulism Toxin products licensed by the Turkish Medicines and Medical Device
Agency.
Table 1
Producta
BOTOX®
Dysport®
NABOTA®
Manufacturer
Allergan Pharmaceuticals
Gen Pharmaceuticals and Health Products
Seltek Ilac Marketing and Foreign Trade
Active Ingredient
Onabotulinumtoxin A
Clostridium botulinum Type A hemagglutinin complex
Botulism Toxin type A
Excipients
•
Human Albumin
•
Human Albumin
•
Human Albumin
•
Sodium Chloride
•
Lactose (cattle)
•
Sodium Chloride
Units per vial
50/100/200 units
500 units
100 units
Preparation
Lyophilized Powder for Solution for Injection
Powder for solution for injection
Lyophilized powder for solution for injection
Usage Form
By injections intramuscularly, into the wall of the urinary bladder or into the skin
By injections intramuscularly, intradermally, or subcutaneously
By injections subcutaneously
Storage
Refrigerator (2 °C–8 °C) or freezer (−5 °C or below)
Refrigerator (2 °C–8 °C). Do not freeze.
Refrigerator (2 °C–8 °C). Do not freeze.
Indications
•
Paediatric cerebral palsy
•
Blepharospasm
•
Frowning
•
Blepharospasm
•
Hemifacial spasm
•
Correction of facial lines
•
Cervical dystonia
•
Spasmodic torticollis
•
Focal spasticity after stroke
•
Axillary hyperhidrosis
•
Chronic migraine
•
Focal spasticity after stroke
•
Correction of facial lines
•
Paediatric cerebral palsy
•
Correction of facial lines
Absolute Contraindications
•
Allergic to components
•
Allergic to components
•
Allergic to components
•
Injection site infection
•
Injection site infection
•
Urinary tract infections
•
Neuromuscular junction disorders
•
Cervical dystonia
•
Urinary tract infections
•
Shouldn't be used in patients younger than 20 years old
Pregnancy/Breastfeeding
Contraindicated
Contraindicated
Must use birth control methods. Contraindicated for breastfeeding.
Very Common Side Effects (1 in 10 patients)
•
Viral infections
•
Droopy upper eyelid
•
Droopy upper eyelid
•
Ear infections
•
Muscle weakness
•
Dizziness
•
Urinary tract infections
•
Difficulty swallowing
•
Drooping eyelids
•
Dry mouth
•
Pain
•
Injection site reactions
•
Muscle Weakness
•
Headache
•
Difficulty swallowing
•
Urinary retention
ATC Code
M03AX01
M03AX01
M03AX01
Licensed since
December 2022 (50 units)
July 2002
April 2021
October 2010 (100 units)
December 2022 (200 units)
Barcode
8699490550618 (50 units)
8699783790110
8680869372016
8699490579015 (100 units)
8699490550625 (200 units)
Product Catalogue (in Turkish)
http://www.ilacabak.com/pdf/9d3dfeea956936a.pdf
http://www.ilacabak.com/pdf/be7ade73e982b69.pdf
http://www.ilacabak.com/pdf/2b832667775c866.pdf
a
Data source - List of Licensed Medicinal Products for Human Use 28th April 2023 (available
from https://www.titck.gov.tr/dinamikmodul/85; accessed 05th May 2023).
Apart from food-borne botulism (caused due to improper processing, storage, and transportation),
there are other forms of botulism including infant botulism, wound-borne botulism,
and the less common iatrogenic botulism. Iatrogenic botulism typically occurs due
to accidental overdose or use of contaminated (sub-standard) products [8]. In the
current outbreak, the Turkish authorities have suspected both the use of high dose
injections that led to incessant vomiting causing subsequent electrolyte disbalances,
and the use of illegal generics with non-standardized dosages and recommendations
guidelines as the root cause of the crisis.
The effects of the toxin usually occur 24–72 hours post injection, peaking within
the first two weeks, followed by gradual diminishing of its effects over the next
three to four months [9]. Based on extrapolations from mouse models, it has been suggested
that a dose of 33 units/Kg can cause systemic toxicity while a dose of 38–42 units/Kg
is lethal for humans [10]. Identification of patients suffering from botulism is based
on the clinical presentation and documented medical history of use of unlicensed injections
or undergoing off-label procedures [11]. Laboratory and radiologic investigations
may not be warranted in all cases. Respiratory failure is the primary cause of death
and patients should be monitored closely [11]. Management of the affected patients
require administration of botulinum antitoxin in suspected and confirmed cases of
iatrogenic botulism as soon as possible.
2
Are botulinum injections effective in weight loss?
The literature is sparse on the clear benefits of intragastric botulinum injections
and weight loss. From our literature search, we found that 13% of the total output
on this topic comes from Turkish researchers and clinicians.2 In a recent prospective
study from Turkiye, 56 obese patients received 8–10 1ml injections of BTA (25 units
per injection) into the gastric antrum during upper gastrointestinal endoscopy after
6–12 hours of fasting [12]. Within the first two to three months after the procedure,
the authors noted a mean weight loss of 9 kg. It is pertinent to note that the patients
were advised to follow a specific diet after the procedure. Interestingly, most patients
felt a decrease in appetite and early satiety, with half of the patients being satisfied
with the results [12]. There were no reports of serious side effects in the study.
Another retrospective study reported significant reduction in weight loss when injecting
BTA in combination with liraglutide (a glucagon-like peptide-1 agonist used to treat
diabetes and chronic obesity) than BTA alone [13]. Multiple other studies have reported
on the benefits of combining BTA intragastric injections with low-calorie diet [[14],
[15], [16]]. In a study from Jordon, the authors noted that although BTA injections
are associated with lesser weight loss in comparison with gastric balloons, shorter
procedure duration and fewer postoperative complications may make BTA injections a
favourable treatment modality [17].
However, the results from these studies need cautious interpretations. Firstly, the
studies have variations in the site of injections (antrum vs fundus vs body of the
stomach), dosage of injections, diet control methods, follow-up time points, and small
number of participants included in the study (mostly <100 patients). A recent meta-analysis
of randomized controlled trials reported that the procedure might be successful only
if ≥ 200 units of BTA are administered at multiple sites in the gastric wall along
with diet control [18]. Yet again, the authors cautioned interpretation due to low
sample size, need for subgroup analysis (leading to higher chances of Type I errors),
and limited power of the included studies. Such an effect is clearly seen when one
considers pooled data from studies whereby there is no mean difference for absolute
weight loss and BMI reduction when comparing BTA injections with saline injections
and/or control subjects [18,19]. Furthermore, long term follow-ups (>6 months) are
scarcely reported that limit our understanding of the possible side effects [20].
Apart from its obvious benefits of shorter durations, less costly, fewer complications,
a study reported that patients post-BTA injections felt less anxiousness, positive
personality, less hostility than before the procedure [21]. However, the patients
reported higher levels of depression post-injections, which was found to be statistically
non-significant. According to the Food and Drug Authority (U.S. FDA), such intragastric
use of BTA would classify the procedure as Level 1 risk which requires the procedure
to result in at least 5% total body weight loss which is statistically superior to
diet and exercise control [22]. However, these criteria are yet to be demonstrated
in literature with only one study partially fulfilling these criteria [19]. Given
these findings, the effectiveness of BTA for weight loss remains to be elucidated
clinically.
3
Public health response
Clearly, there is need for public education regarding the possible side-effects of
getting intragastric BTA injections and for stricter and more vigilant monitoring
of such procedures in medical centres. For its part, the Turkish Guidelines on Clinical
Protocols for Obesity and Metabolic Surgery are clear that there is controversial
and inconsistent evidence in the literature regarding the use of BTA injections for
weight loss procedures. The guidelines also state the procedure has not been approved
yet.3 Additionally, The Turkish Association of Bariatric and Metabolic Surgery also
state that the patient should be notified about the current literature and efficacy
of this procedure. Strongly, the association stresses that intragastric BTA injections
should be administered only as part of clinical trials or scientific investigations
that have been cleared by relevant research ethics committees. Deviations from these
guidelines could open the medical professionals to malpractice suits.4
Nevertheless, the Turkish Ministry of Health has noted that the use of botulinum toxin
as an approach to bariatric surgery is still practiced in many private practices throughout
the country. As a response to the issue, the Turkish Association of Clinical Microbiology
and Infectious Diseases has underlined the importance of increasing the stocks of
botulinum antitoxin in Turkish hospitals to reserve the national capacity in approaching
and treating patients suffering from botulism poisoning [23]. The British authorities
have also advised their citizens to generally avoid undergoing such procedures. In
cases where patients do wish to proceed with such procedures, it has been recommended
that patients should be cautious and ensure that the clinic is reputable and that
the products being used have CE mark (
C
∈
) and approval for use in the home countries [24]. The Robert Koch Institute (RKI)
in Germany, on the other hand, has reminded the clinicians of the obligation to report
all cases of botulism to relevant authorities, even in cases of suspicion [25].
4
Conclusions
Though a rare event, iatrogenic botulism is a serious condition that requires constant
patient monitoring and rapid administration of antitoxins. There is a need for stricter
enforcement of guidelines that prohibit the off-label use of botulinum toxin for weight
loss procedures. Furthermore, there is need for public education against opting for
such procedures. Stricter controls and oversight of international medical tourism
are needed for this and other potentially dangerous procedures.
Ethical approval
Not applicable. All data presented in the paper has been collected from open-source
platforms with proper citation and/or from media sources.
Funding
The present paper didn't receive any external funding and was self-supported by the
authors.
Author contributions
NJ and EL conceptualized the paper whilst all authors were involved in data collection,
writing, correction, and finalizing of the final draft. Visualization was done by
NJ. All authors have read and agreed to the final version for publication.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.