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Consensus Statement |

Botulinum Toxin as a Biological Weapon Medical and Public Health Management

Stephen S. Arnon, MD; Robert Schechter, MD; Thomas V. Inglesby, MD; Donald A. Henderson, MD, MPH; John G. Bartlett, MD; Michael S. Ascher, MD; Edward Eitzen, MD, MPH; Anne D. Fine, MD; Jerome Hauer, MPH; Marcelle Layton, MD; Scott Lillibridge, MD; Michael T. Osterholm, PhD, MPH; Tara O'Toole, MD, MPH; Gerald Parker, PhD, DVM; Trish M. Perl, MD, MSc; Philip K. Russell, MD; David L. Swerdlow, MD; Kevin Tonat, PhD, MPH; for the Working Group on Civilian Biodefense
JAMA. 2001;285(8):1059-1070. doi:10.1001/jama.285.8.1059.
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Objective The Working Group on Civilian Biodefense has developed consensus-based recommendations for measures to be taken by medical and public health professionals if botulinum toxin is used as a biological weapon against a civilian population.

Participants The working group included 23 representatives from academic, government, and private institutions with expertise in public health, emergency management, and clinical medicine.

Evidence The primary authors (S.S.A. and R.S.) searched OLDMEDLINE and MEDLINE (1960–March 1999) and their professional collections for literature concerning use of botulinum toxin as a bioweapon. The literature was reviewed, and opinions were sought from the working group and other experts on diagnosis and management of botulism. Additional MEDLINE searches were conducted through April 2000 during the review and revisions of the consensus statement.

Consensus Process The first draft of the working group's consensus statement was a synthesis of information obtained in the formal evidence-gathering process. The working group convened to review the first draft in May 1999. Working group members reviewed subsequent drafts and suggested additional revisions. The final statement incorporates all relevant evidence obtained in the literature search in conjunction with final consensus recommendations supported by all working group members.

Conclusions An aerosolized or foodborne botulinum toxin weapon would cause acute symmetric, descending flaccid paralysis with prominent bulbar palsies such as diplopia, dysarthria, dysphonia, and dysphagia that would typically present 12 to 72 hours after exposure. Effective response to a deliberate release of botulinum toxin will depend on timely clinical diagnosis, case reporting, and epidemiological investigation. Persons potentially exposed to botulinum toxin should be closely observed, and those with signs of botulism require prompt treatment with antitoxin and supportive care that may include assisted ventilation for weeks or months. Treatment with antitoxin should not be delayed for microbiological testing.

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Figure 1. Mechanism of Action of Botulinum Toxin
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A, Release of acetylcholine at the neuromuscular junction is mediated by the assembly of a synaptic fusion complex that allows the membrane of the synaptic vesicle containing acetylcholine to fuse with the neuronal cell membrane. The synaptic fusion complex is a set of SNARE proteins, which include synaptobrevin, SNAP-25, and syntaxin. After membrane fusion, acetylcholine is released into the synaptic cleft and then bound by receptors on the muscle cell. B, Botulinum toxin binds to the neuronal cell membrane at the nerve terminus and enters the neuron by endocytosis. The light chain of botulinum toxin cleaves specific sites on the SNARE proteins, preventing complete assembly of the synaptic fusion complex and thereby blocking acetylcholine release. Botulinum toxins types B, D, F, and G cleave synaptobrevin; types A, C, and E cleave SNAP-25; and type C cleaves syntaxin. Without acetylcholine release, the muscle is unable to contract. SNARE indicates soluble NSF-attachment protein receptor; NSF, N-ethylmaleimide-sensitive fusion protein; and SNAP-25, synaptosomal-associated protein of 25 kd.
Figure 2. Seventeen-Year-Old Patient With Mild Botulism
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A, Patient at rest. Note bilateral mild ptosis, dilated pupils, disconjugate gaze, and symmetric facial muscles. B, Patient was requested to perform his maximum smile. Note absent periorbital smile creases, ptosis, disconjugate gaze, dilated pupils, and minimally asymmetric smile. As an indication of the extreme potency of botulinum toxin, the patient had 40 × 10−12g/mL of type A botulinum toxin in his serum (ie, 1.25 mouse units/mL) when these photographs were taken.
Figure 3. Fifty-Nine Cases of Botulism, by Interval Between Eating at a Restaurant and Onset of First Neurologic Symptom— Michigan, 1977
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Reproduced from Terranova et al57 with permission of Oxford University Press.
Figure 4. Preferred Positioning of Nonventilated Botulism Patients
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Note flat, rigid mattress tilted at 20°, tightly rolled cloth to support cervical vertebrae, and bumpers to prevent downward sliding. Use of this position may postpone or avoid the need for mechanical ventilation in mildly affected patients because of improved respiratory mechanics and airway protection.



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