Botulism in 4 Adults Following Cosmetic Injections With an Unlicensed, Highly Concentrated Botulinum Preparation FREE

Botulism is a rare paralytic illness caused by the toxins of Clostridium botulinum and toxin-producing strains of Clostridium baratii and Clostridium butyricum. Botulism, left untreated, may result in respiratory failure and death. Two botulinum toxin preparations are licensed in the United States by the US Food and Drug Administration for clinical use. BOTOX (crystalline toxin type A, molecular weight [MW] 900 kD, Allergan Inc, Irvine, Calif) is licensed to treat blepharospasm, strabismus, cervical dystonia, glabellar lines, and primary axillary hyperhydrosis. A typical clinical application varies from 4 to 20 units for cosmetic purposes to up to 300 units for therapeutic purposes.¹ Myobloc/Neurobloc (toxin type B, Solstic Neurosciences, Malvern, Pa) is licensed to treat cervical dystonia. Expanding on- and off-label applications of botulinum toxins have led to widespread use.

Although the precise human lethal dose of crystalline botulinum toxin A is not known, extrapolation from primate studies suggests an approximate intravenous or intramuscular human lethal dose of 40 U/kg,^{2 - 3} each unit being the estimated median lethal dose (LD₅₀) for mice.⁴ Literature review and Centers for Disease Control and Prevention (CDC) surveillance data indicate that no human deaths or reported, laboratory-confirmed cases of botulism have resulted from cosmetic or therapeutic botulinum toxin injections. However, dysphagia and other symptoms of neuromuscular impairment have been reported following therapeutic injection with botulinum toxin A,^{5 - 6} and 2 cases of limited paresis have been reported following therapeutic injection with botulinum toxin B (J.S., CDC, unpublished data, 2001 and 2003). On November 27, the on-call CDC botulism clinical consultant learned of 4 suspected botulism case-patients related to cosmetic injections of botulinum toxin type A.

Clinical summaries of 4 suspected botulism case-patients were initially reported by telephone. Case-patients were later interviewed and examined by medical epidemiologists. Three interviews were limited, as the case-patients were receiving mechanical ventilation. Case-patient family members and staff of the clinic where injections took place were also interviewed. All medical records and financial records from the implicated clinic were reviewed. Clinic patients who had received injections with any botulinum toxin product were contacted by telephone and administered a standardized questionnaire on toxin exposure and symptoms. Additional cases of botulism were sought through nationally broadcast requests, standard reportable disease surveillance, and through review of syndromic surveillance data provided by the American Association of Poison Control Centers.

Serum samples from 3 of 4 suspected case-patients after exposure but prior to administration of therapeutic antitoxin, as well as a posttreatment serum sample from each of the 4 case-patients, were collected. Stool samples were collected from 2 case-patients. Case-patient samples and a vial of toxin taken from the same manufacturer's lot as the toxin implicated in the 4 case-patients' illness were tested by mouse bioassay neutralization test.

On November 23 a clinic received shipment of a 100-μg vial of pure botulinum A neurotoxin (MW 150 kd). The toxin, ordered and shipped from a legitimate manufacturer, was intended for laboratory research, was labeled accordingly, and was not licensed or intended for human use. Clinic staff diluted the 100-μg vial of pure neurotoxin with 10 mL of diluent and drew up the resulting solution into 1-mL syringes for clinical use. Despite having a suspended medical license, a physician working at the clinic administered approximately 2 mL of this toxin solution to case-patient 1 and to himself (case-patient 2). Subsequently, during a scheduled visit, the physician administered a similar amount of the same solution to a third and a fourth patient (case-patients 3 and 4). Each of the 4 case-patients received approximately 4 to 6 intramuscular injections in the facial areas of bilateral crow's feet, nasal bridge, and forehead for cosmetic purposes.

On November 25, case-patient 1 and case-patient 2 traveled together. On November 26, case-patient 1, and on November 27, case-patient 2, presented to a hospital each with complaints of progressive weakness and cranial neuropathies (Table 1). Laboratory, electrocardiogram, and chest x-ray findings were normal. Electromyelogram findings of both were consistent with botulism. Case-patients 3 and 4 presented to a different hospital on November 26 each with progressive weakness, cranial neuropathies, and shortness of breath (Table 1). Laboratory, electrocardiogram, and chest x-ray findings were unremarkable. Later workup indicated normal cerebrospinal fluid analysis. The electromyelogram results revealed motor amplitudes at the lower range or just below normal, normal nerve conduction velocities, and normal sensory amplitudes. Repetitive nerve stimulation was technically limited in case-patient 3 and was not performed in case-patient 4.

On November 27, a telephone report of the 4 case-patients was provided to the on-call CDC botulism consultant. Based on clinical descriptions, bivalent anti-AB equine antitoxin was dispatched from CDC quarantine stations in Miami and New York and delivered to the bedside within hours. Antitoxin was administered to case-patients 2, 3, and 4 on November 27. Administration of antitoxin to case-patient 1 was delayed based on atypical symptoms of muscle twitching and increased muscle tone noted by a consulting physician. Subsequent epidemiological and laboratory data led to antitoxin administration to case-patient 1. Following protracted hospital courses, prolonged mechanical ventilation, and physical rehabilitation, all case-patients survived (Table 2).

Use of this highly potent pure botulinum A toxin product was isolated to the 4 case-patients. However, a second botulinum toxin A product, also not licensed or intended for human use, had been purchased by the clinic from another distributor. This toxin, which was labeled “For research purposes only. Not for human use,” was sold in vials containing 5.0 ng of purified botulinum toxin type A. It is unclear to what extent this toxin product was used clinically. Medical chart review did uncover 7 additional patients from the clinic who had received botulinum toxin A injections, but the toxin product used in each case could not reliably be discerned from medical records. A telephone survey of these 7 patients indicated that none had botulism. In addition, no further cases of iatrogenic botulism were reported to local, state, or federal health officials. Surveillance data from the Association of Poison Control Centers also revealed no further cases.

Type A toxin was identified in serum samples collected from 3 of the 4 case-patients before administration of antitoxin (Table 2). No toxin activity was identified in serum samples from the 4 case-patients after antitoxin was administered. Botulinum toxin was not detected nor was C botulinum cultured from stool samples for 2 case-patients in which it was tested. Serial dilutions of serum samples indicated toxin levels of 12 to 24 mouse LD₅₀ (mLD₅₀) of toxin per milliliter at the time the serum was drawn (Table 2). Assuming a 5000-mL total blood volume for the average adult, this was equivalent to 21 to 43 times the estimated human lethal dose by injection. A 100-μg vial of toxin taken from the same manufacturer's lot of toxin administered to the patients contained an estimated 4 × 10⁷ mLD₅₀ of toxin, enough to result in 14 286 human adult deaths by injection if disseminated evenly.

We describe the first, to our knowledge, laboratory-confirmed cases of iatrogenic botulism. The 4 case-patients in this cluster may have each been exposed to up to 8 million mLD₅₀, which is 2857 times the estimated human lethal dose by injection, of unlicensed botulinum toxin A due to a dilution error. This toxin was never intended or approved for use in humans. The physician who administered injections to himself and the 3 other case-patients pleaded guilty to a federal criminal charge of misbranding a drug and was sentenced to 3 years in prison. The company that sold the 100-μg vial of pure neurotoxin to the clinic faces no criminal charges, as it was found to be in compliance with toxin shipping regulations and marketing practices. Two individuals associated with the company that shipped the 5-ng vials of toxin pleaded guilty to federal charges, including conspiracy to defraud the United States, and were sentenced to prison terms as well as ordered to pay restitution.

Botulism is a potentially fatal disease, which invariably presents with acute bilateral cranial neuropathies, regardless of exposure mechanism. Early recognition of botulism, treatment in an intensive care setting, provision of mechanical ventilation when indicated, and rapid administration of antitoxin (optimally within 12 hours of presentation) have been associated with improved clinical outcome.^{7 - 9} Suspected cases of botulism should be reported immediately to local health authorities to facilitate rapid epidemiological investigation, provision of antitoxin when indicated, and prevention of further cases. The CDC is available 24 hours a day to consult with state health authorities on suspected botulism cases and facilitate provision of antitoxin when indicated ( Article ).

State health officials requesting equine antitoxin release or consultation on suspected adult botulism cases should contact CDC through its Emergency Operations Center (telephone: 770-488-7100). Similarly, state health officials requesting human antitoxin release or consultation on suspected infant botulism cases should contact the California Infant Botulism Treatment and Prevention Program (telephone: 510-231-7600).

Federal rules governing the possession, transfer, and use of botulinum toxin are described in the Code of Federal Regulations (42 CFR Part 73). The regulations allow a facility to transfer, possess, and use up to 500 μg of toxin without registration or notification of the Select Agent Program.¹⁰ The object of the regulation is to balance the need to prevent intentional harm with the need to allow legitimate, critically needed research to continue. The 100-μg vial of toxin used on the 4 case-patients in this report fell below the regulated toxin amount.

Physicians and patients must be aware of the hazards associated with illegitimate use of unlicensed botulinum toxin products. Only licensed products should be used clinically. Entities inappropriately marketing, selling, or using unlicensed botulinum toxin products should be sought and subjected to full criminal and civil penalties. The Code of Federal Regulations (42 CFR Part 73) should be modified to reduce the weight threshold of individual shipments subject to regulation and should require researchers to provide legal documentation of credentials and adequate laboratory facilities prior to shipment of toxin.