INTRODUCTIONBotulism is an acute neurologic disorder that causes potentially life-threatening neuroparalysis due to a neurotoxin produced by Clostridium botulinum. The toxin binds irreversibly to the presynaptic membranes of peripheral neuromuscular and autonomic nerve junctions. Toxin binding blocks acetylcholine release, resulting in weakness, flaccid paralysis, and, often, respiratory arrest. Cure occurs following sprouting of new nerve terminals.The 3 main clinical presentations of botulism include infant botulism (IB), foodborne botulism (FBB), and wound botulism (WB). Additionally, because of the potency of the toxin, the possibility of botulism as a bioterrorism agent or biological weapon is a great
Infant botulism is caused by ingested C botulinum spores that germinate in the intestine and produce toxin. These spores typically come from bee honey or the environment. Most infants fully recover with supportive treatment; the attributed infant mortality rate is less than 1%. Improperly canned or home-prepared foods are common sources of the toxin that can result in foodborne botulism. Wound botulism results from contamination of a wound with toxin-producing C botulinum. Foodborne botulism and wound botulism occur predominantly in adults and are the focus of this article.C botulinum is an anaerobic gram-positive rod that survives in soil and marine sediment by forming spores. Under anaerobic conditions that permit germination, it synthesizes and releases a potent exotoxin. Microbiologically, the organism stains gram-positive in cultures less than 18 hours old. The organism may stain gram-negative after 18 hours of incubation, potentially complicating attempts at diagnosis. On a molecular weight basis, botulinum toxins are the most potent toxins known.
Eight antigenically distinct C botulinum toxins are known, including A, B, C (alpha), C (beta), D, E, F, and G. Each strain of C botulinum can produce only a single toxin type. Types A, B, E, and, rarely, F cause human disease. Toxins A and B are the most potent, and the consumption of small amounts of food contaminated with these types has resulted in full-blown disease. During the last 20 years, toxin A has been the most common cause of foodborne outbreaks; toxins B and E follow in frequency. In 15% of C botulinum infection outbreaks, the toxin type is not determined. Toxins C and D cause disease in various animals. Type G toxin has been associated with sudden death but not with neuroparalytic illness. It was isolated from autopsy material from 5 patients in Switzerland in 1977.
ETIOLOGY Causes of wound botulism have been associated with traumatic injury involving contamination with soil, chronic abuse of intravenous drugs (e.g, black-tar heroin), and cesarean delivery. Wound botulism illness can occur even after antibiotics are administered to prevent wound infection. Foodborne botulism results from the ingestion of preformed neurotoxins; A, B, and E are the most common. On average, 24 cases of foodborne botulism are reported annually.High-risk foods include home-canned or home-processed low-acid fruits and vegetables; fish and fish products; and condiments, such as relish and chili peppers.Commercially processed foods and improperly handled fresh foods are occasionally associated with botulism outbreaks.Outbreaks of foodborne botulism in restaurants, schools, and private homes have been traced to uncommon sources, such as commercial pot-pies, baked potatoes, beef stew, turkey loaf, sautéed onions, chopped garlic in oil, and cheese sauce.
EPIDEMIOLOGYBetween 1990 and 2000, the Centers for Disease Control reported 263 individualcases from 160 foodborne botulism events in the United States with a case-fatalityrate of 4%. Thirty-nine percent (103 cases and 58 events) occurred in Alaska, all ofwhich were attributable to traditional Alaska aboriginal foods. In the lower 49 states,home-canned food was implicated in 70 (91%) events with canned asparagus beingthe most numerous cause. Two restaurant-associated outbreaks affected 25 persons.The median number of cases per year was 23 (range 17–43), the median number ofevents per year was 14 (range 9–24). The highest incidence rates occurred in Alaska,Idaho, Washington, and Oregon. All other states had an incidence rate of 1 case perten million people or less.The number of cases of food borne and infant botulism has changed little in recentyears, but wound botulism has increased because of the use of black tar heroin,especially in California. Botulism outbreaks and deaths from 1950-1997
PATHOPHYSIOLOGYThe mechanism of action involves toxin-mediated blockade of neuromuscular transmission in cholinergic nerve fibers. This is accomplished by either inhibiting acetylcholine release at the presynaptic clefts of the myoneural junctions or by binding acetylcholine itself. Toxins are absorbed from the stomach and small intestine, where they are not denatured by digestive enzymes. Subsequently, they are hematogenously disseminated and block neuromuscular transmission in cholinergic nerve fibers. The nervous, gastrointestinal, endocrine, and metabolic systems are predominantly affected.Because the motor end plate responds to acetylcholine, botulinum toxin ingestion results in hypotonia that manifests as descending symmetric flaccid paralysis and is usually associated with gastrointestinal symptoms of nausea, vomiting, and diarrhea. Cranial nerves are affected early in the disease course. Later complications include paralytic ileus, severe constipation, and urinary retention
Wound botulism results when wounds are contaminated with Cbotulinum spores. Wound botulism has developed following traumatic injurythat involved soil contamination, among injection drug users (particularly thosewho use black-tar heroin), and after cesarean delivery. The wound may appeardeceptively benign. Traumatized and devitalized tissue provides an anaerobicmedium for the spores to germinate into vegetative organisms and to produceneurotoxin, which then disseminates hematogenously. The nervous, endocrine,and metabolic systems are predominantly affected. Symptoms develop after anincubation period of 4-14 days, with a mean of 10 days. The clinical symptoms ofwound botulism are similar to those of foodborne botulism except thatgastrointestinal symptoms (including nausea, vomiting, diarrhea) are
CLINCAL SIGNS AND SYMPTOMS Foodborne botulism Foodborne botulism should be suspected in patients who present with an acute gastrointestinal illness associated with neurologic symptoms. Symptoms usually appear within 12-36 hours following consumption of contaminated food products. The severity of the illness varies from mild to severe, but death can occur within 24 hours. The incubation period is usually 18-36 hours. Depending on toxin dose, the incubation period ranges from 2 hours to 8 days. The onset of symptoms can be abrupt or can evolve over several days.
Wound botulismPatients with wound botulism typically have a history of traumatic injury with wounds that are contaminated with soil.Since 1994, the number of patients with wound botulism who have a history of chronic intravenous drug abuse has increased dramatically. In most cases, black-tar heroin has been the implicated vehicle. A study by Yuan et al followed 17 heroin users who had recurrent botulism after using black-tar heroin. Physicians need to be alert to recognize botulism, especially in patients who use black-tar heroin or in those with a history of injection drug–associated botulism.Rare cases of wound botulism after cesarean delivery have been documented.Aside from a longer incubation period, wound botulism is similar to foodborne botulism. The incubation period of wound botulism ranges from 4-14 days, with a mean of 10 days. Unlike foodborne botulism, wound botulism causes no gastrointestinal symptoms. Patients may be febrile, but this is more likely due to the wound infection rather than the wound botulism. In many cases, the wound appears benign.
Generally, botulism progresses as follows:Preceding or following the onset of paralysis are nonspecific findings such as nausea, vomiting, abdominal pain, malaise, dizziness, dry mouth, dry throat, and, occasionally, sore throat. Except for nerves I and II, the cranial nerves are affected first.Cranial nerve paralysis manifests as blurred vision, diplopia, ptosis, extraocular muscle weakness or paresis, fixed/dilated pupils, dysarthria, dysphagia, and/or suppressed gag reflex. Additional neurologic manifestations include symmetric descending paralysis or weakness of motor and autonomic nerves.Respiratory muscle weakness may be subtle or progressive, advancing rapidly to respiratory failure. Progressive muscle weakness occurs and often involves the muscles of the head and neck, as well as intercostal diaphragmatic muscles and those of the extremities.
The autonomic nervous system is also involved.Manifestations of this include the following:1 Paralytic ileus advancing to severe constipation2 Gastric dilatation3 Bladder distention advancing to urinary retention4 Orthostatic hypotension5 Reduced salivation6 Reduced lacrimation
Other neurologic findings include the following: Changes in deep tendon reflexes, which may be either intact or diminished Incoordination due to muscle weakness Absence of pathologic reflexes and normal findings on sensory and gait examinations Normal results on mental status examination Many patients with foodborne botulism and wound botulism are afebrile.
DIAGNOSISLaboratory Studies Laboratory tests are not helpful in the routine diagnosis of botulism. WBC counts and erythrocyte sedimentation rates are normal. Cerebrospinal fluid is normal, except for occasional mild elevations in protein concentration. A mouse neutralization bioassay confirms botulism by isolating the botulism toxin. Toxin may be identified in serum, stool, vomitus, gastric aspirate, and suspected foods. C botulinum may be grown on selective media from samples of stool or foods. Note that the specimens for toxin analysis should be refrigerated, but culture samples of C botulinum should not be refrigerated. Because intestinal carriage is rare, identifying the organism or its toxin in vomitus, gastric fluid, or stool strongly suggests the diagnosis.Isolation of the organism from food without toxin is insufficient grounds for the diagnosis. Only experienced personnel who have been immunized with botulinum toxoid should handle the specimens. Because the toxin may enter the blood stream through the eye or via small breaks in the skin, precaution is warranted. Wound cultures that grow C botulinum suggest of wound botulism.
Other TestsPatients with botulism may have mild nonspecific abnormalities on electrocardiography.Results from nerve conduction studies are normal, and electromyography (EMG) reveals reduced amplitude of compound muscle action potentials.EMG may be useful in establishing a diagnosis of botulism, but the findings can be nonspecific and nondiagnostic, even in severe cases. Characteristic findings in patients with botulism include brief low-voltage compound motor-units, small M- wave amplitudes, and overly abundant action potentials. An incremental increase in M-wave amplitude with rapid repetitive nerve stimulation may help to localize the disorder to the neuromuscular junction.Single-fiber EMG may be a more useful and sensitive method for the rapid diagnosis of botulism intoxication, particularly in the absence of signs of general muscular weakness.The results of the edrophonium chloride, or Tensilon, test for myasthenia gravis may be falsely positive in patients with botulism. If positive, it is typically much less dramatically positive than in patients with myasthenia gravis.
TREATMENTMedical CareRigorous and supportive care is essential in patients with botulism.Meticulous airway management is paramount, as respiratory failure is the most important threat to survival in patients with botulism.Patients with symptoms of botulism or known exposure should be hospitalized and closely observed.Spirometry, pulse oximetry, vital capacity, and arterial blood gases should be evaluated sequentially.Respiratory failure can occur with unexpected rapidity.Intubation and mechanical ventilation should be strongly considered when the vital capacity is less than 30% of predicted, especially when paralysis is progressing rapidly and hypoxemia with hypercarbia is present.Many patients require intubation and ventilatory support for a few days to months.Tracheostomy may prove necessary to manage secretions.
Patients with bowel sounds are administered catharticsand enemas to remove unabsorbed botulinum toxin fromthe intestine.Magnesium salts, citrate, and sulfate should not beadministered because magnesium can potentiate thetoxin-induced neuromuscular blockade.Stress ulcer prophylaxis is also a standard component ofintensive care management.If an ileus is present, nasogastric suction and intravenoushyperalimentation are very helpful supportive measures.If no ileus is present, tube feeding can be used fornutritional supplementation.A Foley catheter is often used to treat bladderincontinence. This must be monitored conscientiouslyand changed regularly.
Measures to reduce the risk of nosocomial infections includethe following:Close observation for hospital-acquired infections, especiallypneumonia(particularly aspiration pneumonia), is necessary,as is precaution to prevent aspiration. Aggressive pulmonarytoilet with clearance of secretions, ventilatory support, andincentive spirometry are typically used.Close observation for urinary tract infection is essential. Foleycatheters should be changed on a regular basis.Meticulous skin care is required to prevent decubital ulcersand skin breakdown.Careful attention to peripheral and central intravenouscatheters with regular site rotation to reduce the risks ofthrombophlebitis, cellulitis, and line infections should be partof the supportive care.Deep venous thrombosis (DVT) prophylaxis is also a standardcomponent of intensive care management.
Surgical Care Wound botulism requires incision and thorough debridement of the infected wound, antitoxin therapy, and high-dose intravenous penicillin therapy.DietNasogastric suction and intravenous hyperalimentation are important when an ileus is present. If no ileus is present or when the ileus resolves, tube feeding can be used for nutritional supplementation.Oral intake should be reinstituted gradually under the following conditions:Respiratory status is stable without mechanical ventilation.Swallowing safety has been assessed and confirmed with a swallowing study, as appropriate.Ileus has resolved.
ActivityBedrest is initially required.Increase activity as tolerated.
MEDICATIONSAntibiotics are useful in wound botulism, but they have no role in foodborne botulism.1. Antibiotics:- Penicillin G (Pfizerpen): Preferred drug of choice for wound botulism. Interferes with synthesis of cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms. (Adjunctive to antitoxin: 20 million units/day IV divided q4-6hr)
- Chloramphenicol (Chloromycetin): Alternate to penicillin. Binds to 50S bacterial-ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. Effective against gram-negative and gram-positive bacteria. (50 mg/kg/day IV divided q6hr; in exceptional cases, patients with moderately resistant organisms or severe infections may require increased dosage up to 100 mg/kg/day; decrease these high doses as soon as possible)- Clindamycin (Cleocin): Alternative to penicillin. Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. (150-450 mg PO q6-8hr; not to exceed 1.8 g/day 1.2-2.7 g/day IV/IM divided q6-12hr; not to exceed 4.8 g/day)
2. Antitoxins: -Botulinum antitoxin, heptavalent (HBAT): Investigational antitoxin indicated for naturally occurring noninfant botulism. Equine- derived antitoxin that elicits passive antibody (ie, immediate immunity) against Clostridium botulinum toxins A, B, C, D, E, F, and G. Each 20-mL vial contains equine-derived antibody to the 7 known botulinum toxin types (A through G) with the following nominal potency values: 7500 U anti-A, 5500 U anti-B, 5000 U anti-C, 1000 U anti-D, 8500 U anti-E, 5000 U anti-F, and 1000 U anti-G. Investigational antitoxin indicated for naturally occurring noninfant botulism 20 mL (1 vial) IV infusion; dilute further with 0.9% NaCl to 1:10 ratio before administering Administer slowly by IV infusion via volumetric infusion pump; minimize allergic reactions by starting at 0.5 mL/min for initial 30 minutes If no infusion-related reaction, may increase to 1 mL/min IV for next 30 minutes, then if no reaction evident, may increase to 2 mL/min for remainder of infusion
COMPLICATIONS1. Nosocomial infectionsHospital-acquired pneumonia, especially aspiration pneumonia, can occur.Atelectasis and poor secretion clearance also increase the risk of hospital-acquired pneumonia.Urinary tract infection can occur from in-dwelling Foley catheters.Skin breakdown and decubitus formation can occur.Thrombophlebitis, cellulitis, and line infections can occur. These patients often have peripheral and central intravenous catheters for prolonged periods.Fungal infections can occur; the predisposing factors include prolonged hospitalization, parenteral nutrition, and central venous catheters. DVT prophylaxis is essential to reduce the risk of these potential complications. DVT and pulmonary embolism (PE) are potential complications because patients can be bedridden for weeks to months.Stress ulcers can occur and are common in the intensive care unit setting. Stress ulcer prophylaxis is essential to reduce the risk of this potential complication.2. Hypoxic tissue damage can lead to permanent neurologic deficits.3. Death
PROGNOSISBotulism due to type A toxin is generally more severe than that caused by type B or E.Mortality rates vary based on the age of the patient and the type of botulism. Foodborne botulism carries an overall mortality rate of 5-10%. Botulism carries a higher mortality rate in patients older than 60 years than in younger patients. Wound botulism carries a mortality rate that ranges from 15- 17%. The risk of death due to infant botulism is usually less than 1%.The recovery period ranges from 30-100 days. Artificial respiratory support may be required for months in severe cases. Full neurologic recovery usually occurs. Hypoxic insults, although infrequent, can result in permanent deficits. Some patients experience residual weakness and autonomic dysfunction for as long as a year after disease onset.Mortality is due to the following:Delayed diagnosis and respiratory failureHospital complications such as nosocomial infections (usually pneumonia)
PREVENTIONPrompt notification of public health authorities regarding a suspected case of botulism may prevent further consumption of a contaminated home-canned or commercial food product.Foodborne botulism is best prevented by strict adherence to recommended home-canning techniques. High-temperature pressure cooking is essential to ensure spore elimination from low- acid fruits and vegetables. Although boiling for 10 minutes kills bacteria and destroys the heat labile botulism toxin, the spores are resistant to heat and can survive boiling for 3-5 hours. Food contaminated by botulism toxins usually has a putrefactive odor; however, contaminated food may also look and taste normal. Hence, terminal heating of toxin-containing food can prevent illness and is an important preventive measure.Wound botulism due to intravenous drug abuse can be prevented by cessation of drug use.Wound botulism is best prevented by prompt thorough debridement of contaminated wounds. Prophylactic use of antibiotics after trauma cannot be relied on to prevent wound botulism.
When preserving food at home, kill C botulinum spores by pressure cooking at 250°F (120°C) for 30 minutes.The toxin can be destroyed by boiling for 10 minutes or cooking at 175°F (80°C) for 30 minutes.Do not eat or taste food from bulging cans. Discard food that smells bad.Cessation of intravenous drug use prevents wound botulism due to this vehicle.