Specialty Conference Moderator DAVID K. HENDERSON, MD Discussants DAVID K. HENDERSON,:..MD DAVID B. TILLMAN, MD ....:.HERBERT H. WE.BB.. M.D. *:PHILLIP J..RAIMONDI, MD S ARUR ARTU..R A......SCHWARTZ,M MD.
Refer to: Henderson DK, Tillman DB, Webb HH, et al: Infectious disease emergencies: The clostridial syndromesTeaching Conference, University of California, Los Angeles, and Harbor General Hospital, Torrance (Specialty Conference). West J Med 129:101-120, Aug 1978
Infectious Disease Emergencies: The Clostridial Syndromes
This Isatranscropt .of one. of the regular teaching0co0nfrences In In-
fecous Diseases held weekly at tarbor Gener.al Hospital, Torrance OA. This transcript has been: edited by.Doctors David K. Henderson, Anthony W. Chow, an:d Luien B. Gwz.
DAVID K. HENDERSON, MD: * This conference deals with a number of disease states caused by various members of the genus Clostridium. While these syndromes constitute a nonhomogeneous group, all of them require emergent recognition, pronmpt initiation of specific therapy and aggressive supportive care. We have chosen to discuss these syndromes as a group to focus on the extreme potency of the toxins elaborated by the clostridia, and to comment on specific and nonspecific measures which should be employed in the therapy of these syndromes. The syndromes to be discussed include botulism, tetanqs and clostridial soft tissue infection. Before beginning our discussion of these clostridial emergency syndromes, perhaps we should first review a little of the bacteriology of these unusual organisms. The clostridia are anaerobic, pleomorphic, spore-forming, usually Gram-positive bacilli. Most strains are strictly anaerobic, while a few are slightly aerotolerant. All clostridia form spores, * Division of Infectious Diseases, Harbor General Hospital, Department of Medicine, VA Wadsworth Hospital Center, Los Angeles; Assistant Professor of Medicine, UCLA School of
Medicine.
From the Departments of Medicine and Surgery, Harbor General Hospital, Torrance. CA; the Division of Pulmonary Medicine, San Pedro and Peninsula Hospital, San Pedro, CA; and the Research and Medical Services, VA Wadsworth Hospital Center, Los Angeles. Reprint requests to: David K. Henderson, MD, Division of Infectious Diseases, Department of Medicine, Harbor General
Hospital, Torrance, CA 90502.
some more readily than others; and most, but not all, are motile. These organisms reside primarily in the soil, and are nearly ubiquitous in distribution. Meyer, in his classic studies on botulism, found Clostridium botulinum in from 1 to 25 percent of all soil samples taken from several continents.1 The organisms upon which we shall focus our attention today share another feature in common -all of therm produce potent exotxins. These toxins are among the most highly lethal poisons known to man and are the major reason why the organisms and the disease states they produce remain some of the most feared in clinical medicine.
Botulism DAVID K. HENDERSON, MD
History ALL OF THE clostridial emergency syndromes have firmly established historical roots. The disease entity which is to be discussed first, botulism, is no exception. A summary of some of the historical highlights will be presented here. Should the reader desire more detailed historical information, several excellent reviews of this topic have been published.1-4 The clinical syndrome we know as botulism obtained its name because of its association with THE WESTERN JOURNAL OF MEDICINE
101
THE CLOSTRIDIAL SYNDROMES
blood sausage in Germany in the late 1700's. Centuries earlier, in about 900 AD, Leo VI, an emperor of Byzantium, recognized blood sausage as being potentially lethal and forbade its consumption by his subjects. For this reason, according to Meyer,5 he acquired the title "Leo the Wise." In 1895 the Belgian microbiologist Van Ermengem first isolated the causative agent from salted, uncooked ham which had caused a neuroparalytic syndrome in 34 musicians.4 The myth that botulism was associated only with spoiled meat products was dispelled by separate outbreaks, both caused by contaminated beans, in Germany and in Stanford, California, in 1904 and 1913, respectively.5 A pronounced rise in the incidence of the disease paralleled the rapid growth of the commercial canning industry in the United States in the early 20th century. By 1919 a California botulism commission had been funded by the commercial canning industry and this resulted in the eventual development of safer canning procedures as well as legislation to guarantee them. Since that time, sporadic outbreaks of botulism have occurred, usually traceable to home-canned, dried or smoked, poorly processed, or poorly prepared foods. The outbreaks caused by commercial foods have usually been traceable to errors in processing or storage of the food.
Bacteriology Eight toxigenic serotypes of C botulinum exist (types A, B, Ca, C,B, D, E, F and G). The organisms are classified by the toxins they produce. Types A, B, E and F have been shown to produce disease in man. The organisms produce. their toxins while in the vegetative state in a environment of pH 4.6 to 5.3.3 These organisms, many of which require some vitamin and amino acid supplementation for propagation on artificial media, all require strict anaerobic conditions for growth. Complete absence of oxygen may not be necessary for toxin production. C botulinum spores are able to withstand surprising amounts of heat, drying, freezing, ionizing radiation and chemical exposure.4 The spores themselves may contain minute amounts of toxin.
Toxin The toxins elaborated by C botulinum are extremely potent. Jensen notes that the lethal dose of type A toxin for white mice may be as little as
102
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10-'3 grams per kg of body weight, or about 950 molecules of toxin per mouse.' The toxins are proteins and, with the exception of the type C strains, are serologically distinct. Antitoxin to type Ca neutralizes the toxins of both the Ca strains as well as the CfB toxin; while antitoxin to the toxin produced by the C8 strain neutralizes only Cft toxin. The toxin is not destroyed by the process of gastrointestinal digestion, and, in fact, may be potentiated in the process of digestion and absorption-presumably due to the action of nonspecific proteases in the stomach cleaving the toxin to a more active form.7-9 The toxins are heat labile and are inactivated by boiling for six to ten minutes, but are otherwise reasonably stable, withstanding wide variations of pH, chemicals and ionizing radiation.3 The toxins are rapidly absorbed from the gastrointestinal tract and rapidly become bound to neural tissue, probably by transport via the bloodstream or the lymphatics.10 The toxins act at the level of the neuromyal junction. Release of acetylcholine is inhibited from the terminal axons producing a neuroparalytic syndrome similar to that induced by hypermagnesemia, hypocalcemia, aminoglycoside toxicity and the Eaton-Lambert syndrome." Several investigators have studied nerve conduction and stimulation and have found that repetitive stimuli (25 to 50 stimuli per second) resulted in facilitation of the action potential of the affected muscles (posttetanic facilitation). This situation is not unique in clinical medicine and roughly parallels the electrical findings in the Eaton-Lambert syndrome.'2 The amplitude of the facilitated action potential, however, has been found to be less than normal, unlike the Eaton-Lambert syndrome.1' Kao and co-workers have further documented the blockade of acetylcholine release and suggested that the block may be at the level of exocytosis of acetylcholine granules from the terminal axons.'3 The various toxins differ widely in their affinity for neural tissue. Type A toxin is the most tightly bound, type E next and type B the least well bound. The variations in binding relate inversely to the facility with which the toxin may be recovered from the serum (that is, those toxins that are poorly bound remain in the serum longer). The toxins which continue to circulate are, therefore, more readily available for neutralization by antitoxin.
THE CLOSTRIDIAL SYNDROMES
TABLE 1.-Frequency of Botulism Cases in the United States, 1899-1973, by Serotype* Cases with Identifiable
All Cases
Type
(Percent)
Type A .............. 23.1 Type B .............. 6.3 .3.2 Type E 0.1 Type F ............ Types A and B .0.3 Untypeable ...... ...... 66.7
Serotype
(Percent)
69.4 20.0 9.4 0.4 0.8
*Modified from data accumulated by the Center for Disease Control.'4
Epidemiology According to the Center for Disease Control (CDC) in Atlanta, 688 outbreaks of botulism (1,784 cases) have occurred in the United States from 1899 to 1973.'4 Both the incidence and the fatality rate climbed steadily until the 1940's. From the early 1940's until 1970 the incidence fell from nearly 40 cases per year to fewer than 20. In the 1940's, mortality occurred in more than 60 percent of all cases. By the 1960's, the incidence and the fatality rate had dropped to nearly 25 percent.14 Since the 1960's the incidence and the fatality rate have remained fairly constant.
Vegetables have become the most commonly implicated source in food-borne botulism. Vegetables accounted for 17.4 percent of all outbreaks reported, while meats, including fish and poultry, accounted for only 6.1 percent.'4 Of the 688 outbreaks reported from 1899 to 1973, nearly 67 percent could not be traced to any contaminated food source. If the cases in which no identifiable source can be documented are eliminated, vegetables account for more than 50 percent of the remaining cases.
Nearly two thirds of the cases summarized by the CDC were untypeable. The frequency of botulism cases by serotypes is presented in Table 1. Type A remains the most common serotype seen in clinical disease. Also of interest is the fact that there is a geographic variation in both the frequency of cases seen and in the serotype found. Type A, for instance, is most commonly found in the western United States. Approximately 90 percent of all cases of type A botulism occurring in the United States are found west of the Mississippi River.'4 Of the cases of type B botulism, 67 percent are found east of the Mississippi.'4 More than a third of all cases occurred in California.
The reason for the high incidence of botulism in California is unclear. Werner and Chin have postulated that a heightened awareness of the disease or possibly a higher concentration of the spores of C botulinum in the soil of California might account for this increased incidence.'5 Type E botulism has been most closely associated with fish and marine products. Most cases of type E botulism in the United States have occurred in Alaska and in states surrounding the Great Lakes.14 Type F botulism is extremely rare. Only two outbreaks in humans have been reported,'167 and one of these outbreaks occurred in Califomnia. Additionally, one outbreak each of types Ca and type D botulism in humans was reported by Dolman.4
Diagnosis Symptomatology Symptoms of botulism are relatively specific and usually suggest the diagnosis early in the course of the disease. Unfortunately the diagnosis is frequently missed early in the development of the disease since it is relatively uncommon and most physicians have a low index of suspicion. The onset of the disease usually occurs between 12 and 48 hours after the ingestion of contaminated food. Rapid onset of the disease (that is, development of symptomatology in less than 24 hours after ingestion) is a poor prognostic sign and predicts a more severe illness with a more protracted course and a higher fatality rate.'s Cranial nerve symptoms, most commonly relating to the extraocular muscles (diplopia, ptosis and blurred vision), pharynx (dysphagia, pharyngeal pain), or larynx (dysphonia) are among the most common specific presenting symptoms. These presenting complaints are commonly followed by the development of a symmetrical descending paralysis which affects all muscle groups but spares the sensorium. In addition to the above symptoms, other common presenting manifestations of botulism include nausea, vomiting, abdominal pain, abdominal cramping, early diarrhea, late constipation, dizziness and occasionally symptoms of urinary retention.
Physical Findings The CDC lists five cardinal features of botulism.'4 They are as follows: (1) fever is absent, (2) mental status is normal, (3) the pulse rate THE WESTERN JOURNAL OF MEDICINE
103
THE CLOSTRIDIAL SYNDROMES TABLE 2.-Wound Botulism* No epidemiologic evidence for food contamination. There is an apparent wound source of the organism. Gastrointestinal symptoms are uncommon. Fever may be present (secondary to wound infection). The incubation period is slightly longer (4-14 days). Toxin may be identified in both the serum and the wound. Wound cultures may be positive for Clostridium botulinum. *After Merson and Dowell.24
is normal or slow, (4) sensory deficits are absent and (5) neurological manifestations are symmetrical. A few of these cardinal features may be masked by concurrent problems. Fever, as well as tachycardia, may be present if a patient has developed a complicating infection, such as aspiration pneumonia or urinary tract infection. Mild alteration in the mental status may be noted. The patient may be agitated, combative or drowsy; but most patients are arousable and oriented. Nearly three fourths of the patients reviewed by the CDc had respiratory embarassment, almost half had specific muscle paresis and nearly half had involvement of the eye muscles.14 Less common findings from this series included pupillary findings, dry mucous membranes, cerebellar findings and postural hypotension.'4
Laboratory Diagnosis General laboratory evaluation in botulism is of little value. Most of the routine screening procedures are not affected by the disease. The blood count, urine analysis, cerebrospinal fluid evaluation and serum electrolytes are all normal. Radiographic findings are not generally helpful as well, with the possible exception that an early ileus due to botulism may be present on an abdominal film.'9 The electrocardiogram (ECG) is frequently abnormal, but is usually nonspecific. Abnormalities one may see on the ECG include nonspecific ST segment changes and T-wave inversion. Occasionally botulism may cause a pattern on the ECG that is indistinguishable from inferior infarction. An extremely helpful laboratory aid in the diagnosis of botulism is the electromyogram (EMG). Several investigators have stressed the importance of showing posttetanic facilitation of the muscle action potential. At least one group of investigators has suggested that this facilitation, while similar to the electrical findings in the 104
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*
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*
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Eaton-Lambert syndrome, is specific enough to assist in confirming the diagnosis of botulism.1" Cherington has also noted the phenomenon of posttetanic facilitation in patients with botulism.20 Additionally, he notes that less frequent stimuli (that is, a rate of two stimuli per second) resulted in a decrement in the recorded action potential. In this paper the author also notes that the onset of the electrical abnormality may lag behind the early symptomatology of botulism, and that the degree of posttetanic facilitation which occurs relates directly to the severity of the disease.20 By far the best way to confirm the diagnosis of botulism in the laboratory is by demonstrating the presence of toxin in the affected patient. Classically, clinicians have examiied serum and incriminated foods for the presence of the toxin by using the mouse neutralization test.21 Mice are protected with type-specific antisera and then injected intraperitoneally with samples from chemically suspect material. Recent attention has focused on stool specimens as a fairly reliable source of toxin in patients with clinical botulism.22 Therefore, when the diagnosis of botulism is suspected,' samples of serum, gastric contents, stool and epidemiologically incriminated foods should be sent immedi.ately to the nearest reference laboratory for confirmation. In addition, physicians should notify local, state and federal public health officials.23
Wound Botulism Two other clinically distinct syndromes caused by C botulinum deserve our attention. The first, wound botulism, was reviewed in some detail by Merson and Dowell in 1973.24 These authors reviewed nine cases of botulism resulting from wounds contaminated with C botulinum and outlined the difference in clinical presentation of wound botulism from classical, food-borne botulism. The salient features of wound botulism are outlined in Table 2. The absence of gastrointestinal symptoms, the clinical signs of wound infection (for example, fever and induration), and the frequent finding of the organism or the toxin in the wound are obvious differences in the clinical syndromes. All of the cases reported by Merson and Dowell were either untyped or type A. This alone could account for the paucity of gastrointestinal symptoms. After the acquisition of the toxin, however, patients develop the characteristic clinical syndrome with the classical electrical findings of botulism.24
THE CLOSTRIDIAL SYNDROMES
TABLE 3.-Therapy of Botulism
Administration of antitoxin. Elimination of persistent organisms. Supportive care. Pharmacologic manipulation.
Infant Botulism A third and more recently identified syndrome of botulism is infant botulism. This syndrome, unlike the classical food-borne illness, probably results from the ingestion of spores of C botulinum. The spores germinate in the gut of the infant and subsequently produce their toxin in vivo. The clinical presentation is that of neuromuscular paralysis. Constipation is a frequent presenting complaint with subsequent development of weakness, lethargy and hypotonia. Death has been attributed to respiratory insufficiency. Infants under six months of age are most commonly affected, and the diagnosis can be established on the basis of clinical presentation, the characteristic electromyogram, and showing the presence of the toxin in serum, and particularly in stool specimens.25 The causative agent may also be cultured from the stool or gastric aspiration. The incidence of this newly recognized syndrome is not certain, although one preliminary estimate from the California Department of Health suggests 100 cases a year may occur in California.26
Differential Diagnosis While the clinical syndrome of food-borne botulism is fairly specific, several different disease states are frequently confused with botulism. Of the 438 suspected outbreaks of botulism reported to the CDC in a recent ten year period, 75 (17.1 percent) were subsequently confirmed as outbreaks of botulism.14 Other than botulism, the most common final diagnoses in these cases include Guillain-Barre syndrome, chemical intoxication and food poisoning. The presence of fever and abnormal cerebrospinal fluid findings should help exclude botulism and suggest one of the viral encephalitides. The presence of focal neurologic symptoms or findings should suggest a mass lesion or midbrain stroke syndrome. Paresthesias suggest the Guillain-Barre syndrome (along with its characteristic ascending paresis), tick paralysis, and shellfish poisoning. Rapid onset (that is, the development of symptoms within minutes or hours after ingestiotn)
should suggest chemical intoxication, shellfish or mushroom poisoning. Chemicals likely to be implicated in poisonings of this sort include carbon monoxide, barium carbonate, organic phosphates, methanol and atropine. Myasthenia gravis can be distinguished on the basis of muscular fatiguability, a positive response to intravenous injection of endrophonium chloride and nerve conduction studies that show decreasing amplitude of the action potential with repetitive stimuli. Diarrhea without subsequent cranial nerve involvement is most likely to be due to Staphylococcus, Shigella, Salmonella, toxigenic Escherichia coli, Clostridium perfringens, or other bacterial pathogens. In addition, several antibiotics have been noted to cause a neuroparalytic syndrome after administration, especially following the induction of general anesthesia.- Nearly all of the aminoglycosides, polymyxins and bacitracin have been implicated in this syndrome.27
Therapy The principles for managing patients with clinical botulism are outlined in Table 3. All patients with clinical botulism should be admitted to an intensive care area of the hospital, evaluated and treated promptly. Samples of serum, gastric contents, stool and incriminated foodstuffs should be obtained and sent to a reference laboratory. Patients should be skin tested for horse serum sensitivity, and if it is present, desensitized as quickly as possible. If the toxin type is unknown, trivalent antitoxin, containing antitoxin to types A, B and E should be administered. The trivalent antitoxin is manufactured by Connaught Laboratories of Toronto, Ontario, Canada. This preparation is available either from the California State Health Department or from the CDC. The contents of one vial should be administered intravenously every four hours for a total of four or five doses.15 Since some toxins have been shown present in the serum as late as several weeks after ingestion, continued monitoring of the serum (especially in tvpe B botulism) for the presence of toxin is advisable. If subsequent. toxin is detected in the serum, more antitoxin should be administered. If the outbreak is known to be caused by organisms of type A or B, a bivalent preparation is commercially available from Lederle Laboratories, Los Angeles. Monovalent Type E antiTHE WESTERN JOURNAL OF MEDICINE
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THE CLOSTRIDIAL SYNDROMES
toxin is also available from the CDC in the event of a known type E outbreak. In the unlikely event that the clinical botulism is found to be caused by types C, D, F, or G organisms, polyvalent antitoxin manufactured by the Serum Institute of Denmark is available from the CDC. 14 The patient's condition should be monitored closely. The gastrointestinal tract should be emptied. This can be accomplished by inducing emesis, lavage, cathartics and high enemas in appropriate patients. Incipient paralysis is a clear contraindication to the use of emetics, and the presence of bowel atony or ileus should mandate against the use of cathartics. Some investigators have advocated the use of antibiotics, usually penicillin.28 The efficacy of antibiotics in food-borne botulism has not been established. Careful pulmonary management of patients with neuroparalytic syndromes has probably been one of the major contributing factors to the lowered mortality due to these diseases since the 1940's. Other adjunctive therapies should include attention to the patient's bowel habits, cardiac status, muscle tone, integumentary system and nutritional status. Prophylactic low dose heparin may be of value in preventing the complications of thrombophlebitis and subsequent pulmonary embolism. Cardiac monitoring is essential because of the propensity for this disease to terminate in sudden death-probably due to cardiac arrhythmias. Decubitus ulceration may be a cause of sepsis and death in chronically bedridden patients,29 and careful attention to positioning and physical therapy can help prevent ulceration as well as other musculoskeletal complications such as contractions. Parenteral hyperalimentation may be advisable in some patients to increase their caloric intake. Several drugs have been tnred in an attempt to reverse the blockade of acetylcholine release. Of those tried, guanidine hydrochloride has received the most attention. Several case reports have appeared suggesting some beneficial effect of the drug in clinical botulism,30'3' and several failures have been reported as well.3233 Its use remains controversial and attempts to use the drug should be accompanied by careful monitoring of objective clinical measures of the disease. Side effects of guanidine include nausea, vomiting, paresthesias, fasciculations and rare idiosyn-
106
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*
129
*
2
cratic reactions including bone marrow toxicity. In cases in which wound botulism is suspected, all of the above modalities should be employed. After the administration of the antitoxin, aggressive debridement and drainage of the wound should be carried out.24 Penicillin should also be administered, though again its efficacy has not been proved. Proper management of infant botulism has not been completely delineated. Patients should be given antitoxin, although its efficacy in this new clinical syndrome has yet to be established. Gastrointestinal evacuation should be carried out unless ileus is present, and patients should be given supportive care. The possibility that antibiotics, administered either by the oral or parenteral route, may be of value is still theoretical. The management of asymptomatic patients with possible exposure to botulism is less certain. If the patient is known to have consumed contaminated food and presents within one week of the ingestion, he should be admitted, evaluated and treated with antitoxin. The diagnostic studies outlined above should be carried out and adjunctive therapy administered as the clinical course dictates. If it is not certain whether the patient has consumed contaminated food, and he remains asymptomatic, the patient should be admitted to the hospital for observation; The gastrointestinal tract should be emptied and serum, stool and gastric contents sent for diagnostic studies. The decision whether to administer antitoxin is a difficult one, and the possible complications of the antitoxin (for example, anaphylaxis or serum sickness) should be weighed carefully. At the first sign or symptom suggestive of botulism, it is advisable to administer the antitoxin. Finally, I should emphasize that the care of a patient with botulism is dependent on careful planning and attention to detail. All the people involved in the care of the patient-nurses; primary physicians; consultants in pulmonary medicine, infectious diseases and otolaryngology, and physical therapists-should plan the patient's therapy and each should be fully aware of the
continuing therapeutic plan. The second clostridial syndrome to be discussed is tetanus. As indicated by the following description, tetanus has firmly established historical roots as well.
Refer to: Henderson DK, Tillman DB, Webb HH, et al: Infectious disease emergencies: The clostridial syndromesTeaching Conference, University of California, Los Angeles, and Harbor General Hospital, Torrance (Specialty Conference). West J Med 129:101-120, Aug 1978
Infectious Disease Emergencies: The Clostridial Syndromes
This Isatranscropt .of one. of the regular teaching0co0nfrences In In-
fecous Diseases held weekly at tarbor Gener.al Hospital, Torrance OA. This transcript has been: edited by.Doctors David K. Henderson, Anthony W. Chow, an:d Luien B. Gwz.
DAVID K. HENDERSON, MD: * This conference deals with a number of disease states caused by various members of the genus Clostridium. While these syndromes constitute a nonhomogeneous group, all of them require emergent recognition, pronmpt initiation of specific therapy and aggressive supportive care. We have chosen to discuss these syndromes as a group to focus on the extreme potency of the toxins elaborated by the clostridia, and to comment on specific and nonspecific measures which should be employed in the therapy of these syndromes. The syndromes to be discussed include botulism, tetanqs and clostridial soft tissue infection. Before beginning our discussion of these clostridial emergency syndromes, perhaps we should first review a little of the bacteriology of these unusual organisms. The clostridia are anaerobic, pleomorphic, spore-forming, usually Gram-positive bacilli. Most strains are strictly anaerobic, while a few are slightly aerotolerant. All clostridia form spores, * Division of Infectious Diseases, Harbor General Hospital, Department of Medicine, VA Wadsworth Hospital Center, Los Angeles; Assistant Professor of Medicine, UCLA School of
Medicine.
From the Departments of Medicine and Surgery, Harbor General Hospital, Torrance. CA; the Division of Pulmonary Medicine, San Pedro and Peninsula Hospital, San Pedro, CA; and the Research and Medical Services, VA Wadsworth Hospital Center, Los Angeles. Reprint requests to: David K. Henderson, MD, Division of Infectious Diseases, Department of Medicine, Harbor General
Hospital, Torrance, CA 90502.
some more readily than others; and most, but not all, are motile. These organisms reside primarily in the soil, and are nearly ubiquitous in distribution. Meyer, in his classic studies on botulism, found Clostridium botulinum in from 1 to 25 percent of all soil samples taken from several continents.1 The organisms upon which we shall focus our attention today share another feature in common -all of therm produce potent exotxins. These toxins are among the most highly lethal poisons known to man and are the major reason why the organisms and the disease states they produce remain some of the most feared in clinical medicine.
Botulism DAVID K. HENDERSON, MD
History ALL OF THE clostridial emergency syndromes have firmly established historical roots. The disease entity which is to be discussed first, botulism, is no exception. A summary of some of the historical highlights will be presented here. Should the reader desire more detailed historical information, several excellent reviews of this topic have been published.1-4 The clinical syndrome we know as botulism obtained its name because of its association with THE WESTERN JOURNAL OF MEDICINE
101
THE CLOSTRIDIAL SYNDROMES
blood sausage in Germany in the late 1700's. Centuries earlier, in about 900 AD, Leo VI, an emperor of Byzantium, recognized blood sausage as being potentially lethal and forbade its consumption by his subjects. For this reason, according to Meyer,5 he acquired the title "Leo the Wise." In 1895 the Belgian microbiologist Van Ermengem first isolated the causative agent from salted, uncooked ham which had caused a neuroparalytic syndrome in 34 musicians.4 The myth that botulism was associated only with spoiled meat products was dispelled by separate outbreaks, both caused by contaminated beans, in Germany and in Stanford, California, in 1904 and 1913, respectively.5 A pronounced rise in the incidence of the disease paralleled the rapid growth of the commercial canning industry in the United States in the early 20th century. By 1919 a California botulism commission had been funded by the commercial canning industry and this resulted in the eventual development of safer canning procedures as well as legislation to guarantee them. Since that time, sporadic outbreaks of botulism have occurred, usually traceable to home-canned, dried or smoked, poorly processed, or poorly prepared foods. The outbreaks caused by commercial foods have usually been traceable to errors in processing or storage of the food.
Bacteriology Eight toxigenic serotypes of C botulinum exist (types A, B, Ca, C,B, D, E, F and G). The organisms are classified by the toxins they produce. Types A, B, E and F have been shown to produce disease in man. The organisms produce. their toxins while in the vegetative state in a environment of pH 4.6 to 5.3.3 These organisms, many of which require some vitamin and amino acid supplementation for propagation on artificial media, all require strict anaerobic conditions for growth. Complete absence of oxygen may not be necessary for toxin production. C botulinum spores are able to withstand surprising amounts of heat, drying, freezing, ionizing radiation and chemical exposure.4 The spores themselves may contain minute amounts of toxin.
Toxin The toxins elaborated by C botulinum are extremely potent. Jensen notes that the lethal dose of type A toxin for white mice may be as little as
102
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129
*
2
10-'3 grams per kg of body weight, or about 950 molecules of toxin per mouse.' The toxins are proteins and, with the exception of the type C strains, are serologically distinct. Antitoxin to type Ca neutralizes the toxins of both the Ca strains as well as the CfB toxin; while antitoxin to the toxin produced by the C8 strain neutralizes only Cft toxin. The toxin is not destroyed by the process of gastrointestinal digestion, and, in fact, may be potentiated in the process of digestion and absorption-presumably due to the action of nonspecific proteases in the stomach cleaving the toxin to a more active form.7-9 The toxins are heat labile and are inactivated by boiling for six to ten minutes, but are otherwise reasonably stable, withstanding wide variations of pH, chemicals and ionizing radiation.3 The toxins are rapidly absorbed from the gastrointestinal tract and rapidly become bound to neural tissue, probably by transport via the bloodstream or the lymphatics.10 The toxins act at the level of the neuromyal junction. Release of acetylcholine is inhibited from the terminal axons producing a neuroparalytic syndrome similar to that induced by hypermagnesemia, hypocalcemia, aminoglycoside toxicity and the Eaton-Lambert syndrome." Several investigators have studied nerve conduction and stimulation and have found that repetitive stimuli (25 to 50 stimuli per second) resulted in facilitation of the action potential of the affected muscles (posttetanic facilitation). This situation is not unique in clinical medicine and roughly parallels the electrical findings in the Eaton-Lambert syndrome.'2 The amplitude of the facilitated action potential, however, has been found to be less than normal, unlike the Eaton-Lambert syndrome.1' Kao and co-workers have further documented the blockade of acetylcholine release and suggested that the block may be at the level of exocytosis of acetylcholine granules from the terminal axons.'3 The various toxins differ widely in their affinity for neural tissue. Type A toxin is the most tightly bound, type E next and type B the least well bound. The variations in binding relate inversely to the facility with which the toxin may be recovered from the serum (that is, those toxins that are poorly bound remain in the serum longer). The toxins which continue to circulate are, therefore, more readily available for neutralization by antitoxin.
THE CLOSTRIDIAL SYNDROMES
TABLE 1.-Frequency of Botulism Cases in the United States, 1899-1973, by Serotype* Cases with Identifiable
All Cases
Type
(Percent)
Type A .............. 23.1 Type B .............. 6.3 .3.2 Type E 0.1 Type F ............ Types A and B .0.3 Untypeable ...... ...... 66.7
Serotype
(Percent)
69.4 20.0 9.4 0.4 0.8
*Modified from data accumulated by the Center for Disease Control.'4
Epidemiology According to the Center for Disease Control (CDC) in Atlanta, 688 outbreaks of botulism (1,784 cases) have occurred in the United States from 1899 to 1973.'4 Both the incidence and the fatality rate climbed steadily until the 1940's. From the early 1940's until 1970 the incidence fell from nearly 40 cases per year to fewer than 20. In the 1940's, mortality occurred in more than 60 percent of all cases. By the 1960's, the incidence and the fatality rate had dropped to nearly 25 percent.14 Since the 1960's the incidence and the fatality rate have remained fairly constant.
Vegetables have become the most commonly implicated source in food-borne botulism. Vegetables accounted for 17.4 percent of all outbreaks reported, while meats, including fish and poultry, accounted for only 6.1 percent.'4 Of the 688 outbreaks reported from 1899 to 1973, nearly 67 percent could not be traced to any contaminated food source. If the cases in which no identifiable source can be documented are eliminated, vegetables account for more than 50 percent of the remaining cases.
Nearly two thirds of the cases summarized by the CDC were untypeable. The frequency of botulism cases by serotypes is presented in Table 1. Type A remains the most common serotype seen in clinical disease. Also of interest is the fact that there is a geographic variation in both the frequency of cases seen and in the serotype found. Type A, for instance, is most commonly found in the western United States. Approximately 90 percent of all cases of type A botulism occurring in the United States are found west of the Mississippi River.'4 Of the cases of type B botulism, 67 percent are found east of the Mississippi.'4 More than a third of all cases occurred in California.
The reason for the high incidence of botulism in California is unclear. Werner and Chin have postulated that a heightened awareness of the disease or possibly a higher concentration of the spores of C botulinum in the soil of California might account for this increased incidence.'5 Type E botulism has been most closely associated with fish and marine products. Most cases of type E botulism in the United States have occurred in Alaska and in states surrounding the Great Lakes.14 Type F botulism is extremely rare. Only two outbreaks in humans have been reported,'167 and one of these outbreaks occurred in Califomnia. Additionally, one outbreak each of types Ca and type D botulism in humans was reported by Dolman.4
Diagnosis Symptomatology Symptoms of botulism are relatively specific and usually suggest the diagnosis early in the course of the disease. Unfortunately the diagnosis is frequently missed early in the development of the disease since it is relatively uncommon and most physicians have a low index of suspicion. The onset of the disease usually occurs between 12 and 48 hours after the ingestion of contaminated food. Rapid onset of the disease (that is, development of symptomatology in less than 24 hours after ingestion) is a poor prognostic sign and predicts a more severe illness with a more protracted course and a higher fatality rate.'s Cranial nerve symptoms, most commonly relating to the extraocular muscles (diplopia, ptosis and blurred vision), pharynx (dysphagia, pharyngeal pain), or larynx (dysphonia) are among the most common specific presenting symptoms. These presenting complaints are commonly followed by the development of a symmetrical descending paralysis which affects all muscle groups but spares the sensorium. In addition to the above symptoms, other common presenting manifestations of botulism include nausea, vomiting, abdominal pain, abdominal cramping, early diarrhea, late constipation, dizziness and occasionally symptoms of urinary retention.
Physical Findings The CDC lists five cardinal features of botulism.'4 They are as follows: (1) fever is absent, (2) mental status is normal, (3) the pulse rate THE WESTERN JOURNAL OF MEDICINE
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THE CLOSTRIDIAL SYNDROMES TABLE 2.-Wound Botulism* No epidemiologic evidence for food contamination. There is an apparent wound source of the organism. Gastrointestinal symptoms are uncommon. Fever may be present (secondary to wound infection). The incubation period is slightly longer (4-14 days). Toxin may be identified in both the serum and the wound. Wound cultures may be positive for Clostridium botulinum. *After Merson and Dowell.24
is normal or slow, (4) sensory deficits are absent and (5) neurological manifestations are symmetrical. A few of these cardinal features may be masked by concurrent problems. Fever, as well as tachycardia, may be present if a patient has developed a complicating infection, such as aspiration pneumonia or urinary tract infection. Mild alteration in the mental status may be noted. The patient may be agitated, combative or drowsy; but most patients are arousable and oriented. Nearly three fourths of the patients reviewed by the CDc had respiratory embarassment, almost half had specific muscle paresis and nearly half had involvement of the eye muscles.14 Less common findings from this series included pupillary findings, dry mucous membranes, cerebellar findings and postural hypotension.'4
Laboratory Diagnosis General laboratory evaluation in botulism is of little value. Most of the routine screening procedures are not affected by the disease. The blood count, urine analysis, cerebrospinal fluid evaluation and serum electrolytes are all normal. Radiographic findings are not generally helpful as well, with the possible exception that an early ileus due to botulism may be present on an abdominal film.'9 The electrocardiogram (ECG) is frequently abnormal, but is usually nonspecific. Abnormalities one may see on the ECG include nonspecific ST segment changes and T-wave inversion. Occasionally botulism may cause a pattern on the ECG that is indistinguishable from inferior infarction. An extremely helpful laboratory aid in the diagnosis of botulism is the electromyogram (EMG). Several investigators have stressed the importance of showing posttetanic facilitation of the muscle action potential. At least one group of investigators has suggested that this facilitation, while similar to the electrical findings in the 104
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Eaton-Lambert syndrome, is specific enough to assist in confirming the diagnosis of botulism.1" Cherington has also noted the phenomenon of posttetanic facilitation in patients with botulism.20 Additionally, he notes that less frequent stimuli (that is, a rate of two stimuli per second) resulted in a decrement in the recorded action potential. In this paper the author also notes that the onset of the electrical abnormality may lag behind the early symptomatology of botulism, and that the degree of posttetanic facilitation which occurs relates directly to the severity of the disease.20 By far the best way to confirm the diagnosis of botulism in the laboratory is by demonstrating the presence of toxin in the affected patient. Classically, clinicians have examiied serum and incriminated foods for the presence of the toxin by using the mouse neutralization test.21 Mice are protected with type-specific antisera and then injected intraperitoneally with samples from chemically suspect material. Recent attention has focused on stool specimens as a fairly reliable source of toxin in patients with clinical botulism.22 Therefore, when the diagnosis of botulism is suspected,' samples of serum, gastric contents, stool and epidemiologically incriminated foods should be sent immedi.ately to the nearest reference laboratory for confirmation. In addition, physicians should notify local, state and federal public health officials.23
Wound Botulism Two other clinically distinct syndromes caused by C botulinum deserve our attention. The first, wound botulism, was reviewed in some detail by Merson and Dowell in 1973.24 These authors reviewed nine cases of botulism resulting from wounds contaminated with C botulinum and outlined the difference in clinical presentation of wound botulism from classical, food-borne botulism. The salient features of wound botulism are outlined in Table 2. The absence of gastrointestinal symptoms, the clinical signs of wound infection (for example, fever and induration), and the frequent finding of the organism or the toxin in the wound are obvious differences in the clinical syndromes. All of the cases reported by Merson and Dowell were either untyped or type A. This alone could account for the paucity of gastrointestinal symptoms. After the acquisition of the toxin, however, patients develop the characteristic clinical syndrome with the classical electrical findings of botulism.24
THE CLOSTRIDIAL SYNDROMES
TABLE 3.-Therapy of Botulism
Administration of antitoxin. Elimination of persistent organisms. Supportive care. Pharmacologic manipulation.
Infant Botulism A third and more recently identified syndrome of botulism is infant botulism. This syndrome, unlike the classical food-borne illness, probably results from the ingestion of spores of C botulinum. The spores germinate in the gut of the infant and subsequently produce their toxin in vivo. The clinical presentation is that of neuromuscular paralysis. Constipation is a frequent presenting complaint with subsequent development of weakness, lethargy and hypotonia. Death has been attributed to respiratory insufficiency. Infants under six months of age are most commonly affected, and the diagnosis can be established on the basis of clinical presentation, the characteristic electromyogram, and showing the presence of the toxin in serum, and particularly in stool specimens.25 The causative agent may also be cultured from the stool or gastric aspiration. The incidence of this newly recognized syndrome is not certain, although one preliminary estimate from the California Department of Health suggests 100 cases a year may occur in California.26
Differential Diagnosis While the clinical syndrome of food-borne botulism is fairly specific, several different disease states are frequently confused with botulism. Of the 438 suspected outbreaks of botulism reported to the CDC in a recent ten year period, 75 (17.1 percent) were subsequently confirmed as outbreaks of botulism.14 Other than botulism, the most common final diagnoses in these cases include Guillain-Barre syndrome, chemical intoxication and food poisoning. The presence of fever and abnormal cerebrospinal fluid findings should help exclude botulism and suggest one of the viral encephalitides. The presence of focal neurologic symptoms or findings should suggest a mass lesion or midbrain stroke syndrome. Paresthesias suggest the Guillain-Barre syndrome (along with its characteristic ascending paresis), tick paralysis, and shellfish poisoning. Rapid onset (that is, the development of symptoms within minutes or hours after ingestiotn)
should suggest chemical intoxication, shellfish or mushroom poisoning. Chemicals likely to be implicated in poisonings of this sort include carbon monoxide, barium carbonate, organic phosphates, methanol and atropine. Myasthenia gravis can be distinguished on the basis of muscular fatiguability, a positive response to intravenous injection of endrophonium chloride and nerve conduction studies that show decreasing amplitude of the action potential with repetitive stimuli. Diarrhea without subsequent cranial nerve involvement is most likely to be due to Staphylococcus, Shigella, Salmonella, toxigenic Escherichia coli, Clostridium perfringens, or other bacterial pathogens. In addition, several antibiotics have been noted to cause a neuroparalytic syndrome after administration, especially following the induction of general anesthesia.- Nearly all of the aminoglycosides, polymyxins and bacitracin have been implicated in this syndrome.27
Therapy The principles for managing patients with clinical botulism are outlined in Table 3. All patients with clinical botulism should be admitted to an intensive care area of the hospital, evaluated and treated promptly. Samples of serum, gastric contents, stool and incriminated foodstuffs should be obtained and sent to a reference laboratory. Patients should be skin tested for horse serum sensitivity, and if it is present, desensitized as quickly as possible. If the toxin type is unknown, trivalent antitoxin, containing antitoxin to types A, B and E should be administered. The trivalent antitoxin is manufactured by Connaught Laboratories of Toronto, Ontario, Canada. This preparation is available either from the California State Health Department or from the CDC. The contents of one vial should be administered intravenously every four hours for a total of four or five doses.15 Since some toxins have been shown present in the serum as late as several weeks after ingestion, continued monitoring of the serum (especially in tvpe B botulism) for the presence of toxin is advisable. If subsequent. toxin is detected in the serum, more antitoxin should be administered. If the outbreak is known to be caused by organisms of type A or B, a bivalent preparation is commercially available from Lederle Laboratories, Los Angeles. Monovalent Type E antiTHE WESTERN JOURNAL OF MEDICINE
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THE CLOSTRIDIAL SYNDROMES
toxin is also available from the CDC in the event of a known type E outbreak. In the unlikely event that the clinical botulism is found to be caused by types C, D, F, or G organisms, polyvalent antitoxin manufactured by the Serum Institute of Denmark is available from the CDC. 14 The patient's condition should be monitored closely. The gastrointestinal tract should be emptied. This can be accomplished by inducing emesis, lavage, cathartics and high enemas in appropriate patients. Incipient paralysis is a clear contraindication to the use of emetics, and the presence of bowel atony or ileus should mandate against the use of cathartics. Some investigators have advocated the use of antibiotics, usually penicillin.28 The efficacy of antibiotics in food-borne botulism has not been established. Careful pulmonary management of patients with neuroparalytic syndromes has probably been one of the major contributing factors to the lowered mortality due to these diseases since the 1940's. Other adjunctive therapies should include attention to the patient's bowel habits, cardiac status, muscle tone, integumentary system and nutritional status. Prophylactic low dose heparin may be of value in preventing the complications of thrombophlebitis and subsequent pulmonary embolism. Cardiac monitoring is essential because of the propensity for this disease to terminate in sudden death-probably due to cardiac arrhythmias. Decubitus ulceration may be a cause of sepsis and death in chronically bedridden patients,29 and careful attention to positioning and physical therapy can help prevent ulceration as well as other musculoskeletal complications such as contractions. Parenteral hyperalimentation may be advisable in some patients to increase their caloric intake. Several drugs have been tnred in an attempt to reverse the blockade of acetylcholine release. Of those tried, guanidine hydrochloride has received the most attention. Several case reports have appeared suggesting some beneficial effect of the drug in clinical botulism,30'3' and several failures have been reported as well.3233 Its use remains controversial and attempts to use the drug should be accompanied by careful monitoring of objective clinical measures of the disease. Side effects of guanidine include nausea, vomiting, paresthesias, fasciculations and rare idiosyn-
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cratic reactions including bone marrow toxicity. In cases in which wound botulism is suspected, all of the above modalities should be employed. After the administration of the antitoxin, aggressive debridement and drainage of the wound should be carried out.24 Penicillin should also be administered, though again its efficacy has not been proved. Proper management of infant botulism has not been completely delineated. Patients should be given antitoxin, although its efficacy in this new clinical syndrome has yet to be established. Gastrointestinal evacuation should be carried out unless ileus is present, and patients should be given supportive care. The possibility that antibiotics, administered either by the oral or parenteral route, may be of value is still theoretical. The management of asymptomatic patients with possible exposure to botulism is less certain. If the patient is known to have consumed contaminated food and presents within one week of the ingestion, he should be admitted, evaluated and treated with antitoxin. The diagnostic studies outlined above should be carried out and adjunctive therapy administered as the clinical course dictates. If it is not certain whether the patient has consumed contaminated food, and he remains asymptomatic, the patient should be admitted to the hospital for observation; The gastrointestinal tract should be emptied and serum, stool and gastric contents sent for diagnostic studies. The decision whether to administer antitoxin is a difficult one, and the possible complications of the antitoxin (for example, anaphylaxis or serum sickness) should be weighed carefully. At the first sign or symptom suggestive of botulism, it is advisable to administer the antitoxin. Finally, I should emphasize that the care of a patient with botulism is dependent on careful planning and attention to detail. All the people involved in the care of the patient-nurses; primary physicians; consultants in pulmonary medicine, infectious diseases and otolaryngology, and physical therapists-should plan the patient's therapy and each should be fully aware of the
continuing therapeutic plan. The second clostridial syndrome to be discussed is tetanus. As indicated by the following description, tetanus has firmly established historical roots as well.
