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Infant Botulism
Symposium on Unusual Infections
Infant Botulism Richard A. Polin, M.D.,* and Lawrence W. Brown, M.D. t
Botulism is an acute neuromuscular disease produced by the toxin of Clostridium botulinum. Until recently it was assumed that the disease in children or adults could only be caused by the ingestion of preformed toxin or, more rarely, following elaboration of toxin by organisms in unsterile wounds. Infant botulism is unique as it is caused by the release of toxin from organisms colonizing the gastrointestinal tract. Prior to 1975, the youngest documented case of botulism was reported in a 15 month old child stricken in a food-borne epidemic. However, unexplained cases of infantile hypotonia with cranial nerve impairment which may well have been botulism had been previously reported. 16 In 1976 Pickett et al. described two cases of botulism in infants less than six months of age. 23 Uneventful and spontaneous recovery occurred within one to two weeks of the recognition of the illness. As of January, 1979,98 cases of infant botulism had been identified by the Center for Disease Control; it conservatively estimates the incidence to be at least 250 cases yearly in this country and more throughout the world. 6 The first case reported outside the United States occurred in England. 28
HISTORICAL BACKGROUND Outbreaks of paralytic disease following consumption of contaminated food have been recognized for centuries. The term botulism is derived from the Latin word for sausage, but other pork products, meats, fish, and cheese were common sources of botulism in the nineteenth century. Following an outbreak of botulism in 1894 involving 23 persons which resulted in three deaths, Van Ermengen isolated a spore-forming anaerobe, which he designated Bacillus botulinum, from the spleen of one of the victims and from the contaminated 'Assistant Professor of Pediatrics, The Children's Hospital of Philadelphia and the University of Pennsylvania School of Medicine, Philadelphia, Pa. t Assistant Professor of Pediatrics and Neurology, St. Christopher'S Hospital for Children and Temple University School of Medicine, Philadelphia, Pa.
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ham.30 Further studies led him to describe the microbiologic and pathophysiologic features of the disease: 1. Botulism is an intoxication and not an infectious disease. (Infant botulism is an exception, being a toxi-infection.) 2. The toxin is produced by a specific bacterium and is not destroyed by mild chemical agents or gastric acidity. 3. The toxin is inactivated by heat. In the 75 year period between 1899 and 1973 the Center for Disease Control documented 688 separate outbreaks of food-borne botulism involving almost 1800 persons with a fatality rate of 55 per cent. 5 The number of reported cases peaked in the 1930's, presumably because of increased home canning during the Depression. In the experience of the Center for Disease Control, the major sources of the botulinal toxin in reported cases include: vegetables, 57 per cent; fish products, 15 per cent; preserved fruits, 12 per cent; and condiments including honey, 8 per cent. Eight different serotypes of botulinal organisms have been identified on the basis of antigenic differences in the toxin elaborated, of which only types A, B, E, and F have been associated with human illness. As in older individuals, most cases of infant botulism in the eastern United States are caused by type B Clostridium botulism, whereas in the West, type A is predominant, reflecting the known geographic distribution of type A and B spores in American soil. It should be noted that while the distribution of adult cases in California approximates the ratio of A to B contamination in the soil (12: 1), a marked overrepresentation of type B infant botulism (3:2) exists, suggesting either unusual sensitivity of infants to type B botulism or the presence of other sources of infection. 10
CLINICAL PRESENTATION The Center for Disease Control recently summarized the data derived from the first 58 cases of infant botulism detected between January 1, 1975 and December 31, 1977. 6 Most affected infants were products of full-term uncomplicated pregnancies. In general, they were completely well before the onset of symptoms. Fifty-seven per cent were male infants and ages ranged from three to 26 weeks. During 1977 most cases occurred during the autumn months. Constipation was a common presenting symptom with the onset occurring up to three weeks before the development of other signs. Cranial nerve deficits were common; every patient in Clay'S series had involvement of the seventh, ninth, tenth, and eleventh cranial nerves. 11 Paralysis of gaze and pupillary sluggishness were helpful but inconsistent findings. Virtually all infants manifested generalized weakness and the incidence of diminished head control was striking. Deep tendon reflexes were variable but tended to be decreased or absent. A marked discrepancy existed in the severity of symptoms; some infants showed mild lethargy and weakness whereas others demonstrated more severe cra-
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nial nerve involvement and hypotonia which rapidly progressed to respiratory insufficiency. The only two fatalities were infants who succumbed to respiratory arrest. All survivors recovered completely within three weeks to six months. Two case histories are presented below. Case 1 A two month old female infant was admitted to The Children's Hospital of Philadelphia with a history of progressive weakness of three days' duration. She weighed 3.38 kg at birth. The infant's mother was 33 years old and had a full-term uncomplicated pregnancy. The infant was primarily breast-fed but occasionally was given a supplemental proprietary formula. No other foods were offered. Approximately three weeks prior to admission the parents noted an alteration in the sleep habits of the baby and increased irritability. A decrease in the frequency of stools was also evident. Generalized weakness, difficulty in sucking, and a hoarse cry were noted for three days prior to admission. The child was afebrile. She was admitted to a community hospital where severe hypotonia was noted, and because of progressive weakness, the infant was transferred to Children's Hospital. Growth and development prior to this illness were normal. The family history was negative for neuromuscular disease. On admission, physical examination revealed a floppy, normally developed female infant without evidence of acute distress. Abnormalities were detected only on neurologic examination and included diffuse hypotonia with marked head lag, bilateral ptosis, a weak cry and sucking reflex, an absent gag reflex, and paucity of facial movements. Serum chemistry and hematologic values were normal. The lumbar puncture was traumatic and revealed no white blood cells and 40,000 red blood cells per cm3 • The electromyogram was interpreted as myopathic. An incremental response to rapid stimulation and brief, small amplitude, overabundant action potentials were noted. The child was given a trial dose of neostigmine to which she responded with an improvement in muscle tone; later, however, no response was evident. She required assisted ventilation by the fifth day of acute illness. On the ninth day some minimal improvement in tone was noted, followed by a return of the gag reflex on the eleventh day. The ventilator was discontinued on the twelfth day of illness. Neurologic recovery was considered to be complete three months later. Type B botulinal toxin had been isolated from her stool during the first week of hospitalization.
Case 2 A four and one half month old male infant was admitted to a local hospital with a three day history of constipation, poor feeding, and generalized weakness. The infant's birth weight was 3.78 kg. The infant's mother had a fullterm uncomplicated pregnancy, and normal labor and delivery. He was breastfed exclusively until two weeks prior to admission when he began to eat cereals. Acetaminophen and Ambusol were given the week prior to admission for fever and teething. He received a second diphtheria, pertussis, and tetanus immunization three days prior to the onset of symptoms. Examination revealed a floppy, poorly responsive infant with normal cranial nerve function and intact deep tendon reflexes. He was transferred to The Children's Hospital of Philadelphia on the following day because of increasing respiratory distress. On admission he was lethargic and demonstrated minimal spontaneous movements. Cranial nerve examination revealed bilateral ptosis, sluggishly reactive pupils, facial diplegia, a poor gag reflex with pooling of thick secretions, and it poor sucking reflex. Deep tendon reflexes were diminished. Initial laboratory results revealed normal complete blood count, blood urea nitrogen, calcium, magnesium, and liver function. The lumbar puncture demonstrated one white blood cell, four red blood cells, protein levels of 27 mg per dl, and a glucose level of 104 mg per dl. During the lumbar puncture the pa-
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tient suffered a cardiopulmonary arrest but was easily resuscitated with intubation and placement on continuous end expiratory pressure. Neither edrophonium nor neostigmine tests produced any noticeable improvement. On the third hospital day an electromyogram revealed a myopathic pattern. Repetitive nerve stimulation studies showed a 200 per cent increment in voltage at a frequency of 50 HZ. Nerve conduction velocities were normal. The hospital course was one of gradual improvement. Following the demonstration of the "staircase phenomenon" consistent with botulism (see below), treatment with oral penicillin, 125 mg every six hours for 10 days, was initiated. He was obstipated until the fourth day of hospitalization, when normal stools began to form following administration of a Dulcolax suppository. During the ensuing week his motor function and spontaneous ventilation improved. He was extubated on the eleventh day of hospitalization. On the twenty-second day, when he was transferred to a convalescent unit, the patient demonstrated improving cranial nerve function, mildly decreased deep tendon reflexes, and persistent marked hypotonia. During the following month, he regained normal muscle strength and tone, and deep tendon reflexes. The results of physical examination at eight months of age were completely normal. Stool specimens obtained on the :first day of his hospitalization demonstrated type B botulinal toxin and organisms. Simultaneous serum samples taken two and three weeks later were negative as were samples of foods, vitamins, and household items. Stool samples from both parents and a sibling were negative for botulinal toxin and organisms.
LABORATORY DIAGNOSIS If a high degree of suspicion exists, it is possible to make a tentative diagnosis of infant botulism and perform confirmative tests on the first day of hospitalization. By history, these infants are generally healthy, and are products of full-term uncomplicated pregnancies. Constipation is a frequent early sign, occurring up to 10 days prior to progressive muscle weakness, poor feeding, and apparent lethargy. Usually there is no recent intercurrent infection but a history of recent immunization is common (a function of the age of the patient population). Often the infant has been breast-fed and only rarely is there a history of ingestion of home canned fruits or vegetables. There is no history of tick bites. On examination, the infant will have a paucity of spontaneous movements, generalized weakness, diminished or absent deep tendon reflexes, and variable cranial nerve dysfunction (facial diplegia, ptosis, extraocular palsies, and poor gag and suck reflexes). Routine laboratory examinations include complete blood count, blood urea nitrogen, electrolytes, calcium, magnesium, lumbar puncture, and chest radiograph. They are generally normal unless pneumonitis or dehydration has supervened. Special laboratory studies performed on infants in the early stages of disease may include edrophonium or neostigmine testing for myasthenia gravis, toxicology studies for heavy metals and organophosphates, and electrodiagnostic procedures. Routine electromyography frequently demonstrates brief, small amplitude, overly abundant motor unit potentials. This nonspecific finding usually represents myopathy but can also be seen in partial denervation. The most helpful study is augmentation of the amplitude of the evoked muscle action potential
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at nerve stimulation frequencies greater than 10 HZ. A positive incremental response ("the staircase phenomenon") at these rapid rates is seen in most cases. 2 • 13 The normal response to slower rates of stimulation (between two and five cycles per second) helps to distinguish botulism from myasthenia gravis in which there is an abnormal decremental response. Other disorders that may produce a similar "staircase phenomenon" and electromyographic pattern include antibiotic toxicity, snakebite, and the Eaton-Lambert syndrome. Final diagnosis can be made only by isolation of the organism in the stool or demonstration of toxin in the stool. Unlike other botulism syndromes in older children and adults, serum is uniformly negative for toxin. Constipation may make stool collection exceedingly difficult; a saline enema may facilitate collection of a stool sample. The toxin and organism may be present throughout the recovery phase of the disease.
DIFFERENTIAL DIAGNOSIS A wide spectrum of infectious, toxic, and metabolic diseases can produce a profound depression of neuromuscular activity, hyporeflexia, cranial nerve dysfunction, and altered levels of consciousness in the young infant. Sepsis with or without meningitis may cause neuromuscular depression, and must be the first consideration in the acutely ill, floppy infant. Although any bacterial or viral organism may be associated, poliomyelitis, Epstein-Barr virus infections, and diphtheria mimic botulism most closely. Distinctive features of poliomyelitis include a preparalytic phase of fever, headache, and gastrointestinal complaints followed by aseptic meningitis. When paralysis ensues it is usually asymmetric, and bulbar involvement is less frequent than is involvement of the extremities. Like botulism, poliomyelitis is a pure motor neuropathy without a sensory component. Infection with Epstein-Barr virus may produce a syndrome of encephalitis with or without peripheral or cranial nerve weakness. Diphtheritic polyneuropathy can be excluded since the primary infection always precedes it by one to two weeks. The onset of this disorder is usually characterized by ocular and palatal weakness, it may be accompanied by myocarditis, and it involves sensory as well as motor nerves. Postinfectious polyneuropathy (Guillain-Barre syndrome) is rare in patients under six mOnths of age. The diagnosis is difficult since hypotonia and hyporeflexia are nonspecific, and a systematic sensory motor examination is virtually impossible in the sick infant. Elevation of cerebrospinal fluid protein, delayed nerve conduction velocity, and neuropathic electromyography may confirm the diagnosis in the absence of other possible causes for polyneuropathy such as heavy metal poisoning. A progressively ascending, flaccid sensory motor neuropathy can be caused by tick bite. However, prompt recovery usually occurs following removal of the offending insect.
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Congenital myasthenia gravis can be mild and may present at any time during infancy. Generally, muscle weakness is not severe and ophthalmoplegia is unusual. Facial weakness, a feeble cry, a weak sucking reflex, ptosis, and a swallowing dysfunction are common presenting signs. Edrophonium or neostigmine testing is positive and slow repetitive nerve stimulation demonstrates a decremental response (Jolly test). Metabolic and toxic abnormalities may cause nonspecific weakness and hypotonia. Hyperkalemia or hypokalemia, hyponatremia, hypermagnesemia, and hypercalcemia or hypocalcemia may produce a similar picture in the infant. Toxic encephalopathies secondary to renal or hepatic failure may present in early infancy. Organophosphate poisoning has been reported as early as eight weeks of age but usually presents with signs of cholinergic excess in addition. Reyes syndrome has been reported in infancy also, but seizures, hepatomegaly, hypoglycemia, and a history of a preceding infection help to distinguish this syndrome from botulism. Subacute necrotizing encephalomyelopathy (Leigh's disease) may be confused with botulism since both are characterized by weakness, hypotonia, and ophthalmoplegia. However, Leigh's disease occurs later in infancy, is more chronic, is associated with blindness and hearing loss, and is frequently accompanied by seizures.
TREATMENT The treatment of infant botulism is controversial but generally includes supportive respiratory and nutritional care as well as the administration of specific antitoxin, antibiotics, or drugs that affect neuromuscular function. Every child in whom infant botulism is suspected should be transferred to a center in which intensive respiratory care is available. Not only the infant with impending respiratory failure should be transferred, but also those infants in whom cranial nerve dysfunction or marked hypotonia is evident. The only fatalities in infant botulism have been caused by potentially avoidable respiratory complications. The efficacy of botulinal antitoxin has not been firmly established and seems to differ considerably from one toxin type to another. In adults who have type E botulism, the administration of E antitoxin has hastened recovery and lowered mortality almost IO-fold. lB • 25 Results with types A and B botulism have been less satisfactory, suggesting that both A and B botulinal toxins may irreversibly bind to the nerve endings and thus are not amenable to neutralization. Serum sickness and other allergic reactions have occasionally been reported following the use of equine antisera which has discouraged most physicians from administering antitoxin in proven cases of infant botulism. Human antitoxin might become an acceptable alternative, but supplies are currently unavailable. Only one case of an infant being given equine trivalent antitoxin has been reported. It was administered on the suspicion of food-borne botulism, and no dramatic improvement was noted.
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It is unknown whether antibiotics are indicated, though some infants with botulism have been initially treated with antibiotics for sepsis. Treatment with oral or parenteral penicillin can be justified because of the active enteric infection with Clostridia. However, it is the experience of most observers that there is no difference in the clinical course of antibiotic-treated versus untreated patients. Furthermore, there may be prolonged excretion of both toxin and culture positive stools for many n":tonths regardless of therapy.2 A theoretical objection to the use of antibiotics is that the death of botulinal organisms might lead to release of toxin on autolysis. Drugs that affect the neuromuscular function have been tried in syndromes of adult botulism. Guanidine and germine facilitate the release of acetylcholine from the nerve terminals and have produced clinical improvement in uncontrolled series. 8 , 9 However, neither drug has proved to be as effective as initially expected.14 Although cholinesterase inhibitors such as edrophonium and neostigmine may produce transient improvement in the early stages of disease, all treated infants become rapidly refractory to these agents. Enemas or cathartics have been suggested occasionally for adult botulism so that preformed toxin can be evacuated prior to absorption. A similar rationale might be applicable to infant botulism and, indeed, clinical improvement has been seen on occasion following purgation. In one anecdotal report, administration of a laxative increased excretion of botulinal toxin eight-fold. 22 The first stool was estimated to contain 366,000 mouse lethal doses of toxin.
PATHOPHYSIOLOGY Source of Toxin Preformed botulinal toxin has not been identified in the foods or drugs administered to any infant, nor has there been a common food source. Both breast-fed and formula-fed babies are represented in case reports and most children have been fed a variety of solid foods. Arnon et al. tested 21 food and drug items used by five of the patients in their series and found only one container of honey that was positive for C. botulinum organism." The Center for Disease Control, however, has reported C. botulinum organisms in three additional containers of honey fed to affected infants and in 13 per cent of all honey samples tested. 7 Soil and household dust samples have rarely contained botulinal organisms. Excluding a preformed source of toxin, infant botulism is now believed to be caused by the ingestion of spores or vegetative cells of C. botulinum (toxi-infection theory). Toxin is produced by Clostridia growing in the gastrointestinal tract, resulting in disease symptoms upon gut absorption. Experimentally, botulism may be produced in animals that are fed spores or in which the spores have been implanted intraperitoneally in semipermeable membranes. 2o. 26 These studies have been criticized because the heat used to inactivate residual toxin may have activated the formation of vegetative cells from spores. Re-
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cently, an intriguing new animal model has been reported in which there is age dependence in gastrointestinal colonization by botulinal spores administered intragastrically.27 However, despite the existence of the organism and toxin production, these animals show no signs of neuromuscular weakness or constipation. Evidence against the toxiinfection theory is that C. botulinum has never been isolated from the stools of asymptomatic individuals who have ingested spores. I2 A similar investigation in infants less than six months old has not been carried out nor has there been an adequate explanation for the predilection of disease for this age group.
Action of Toxins The isolation of botulinal toxin in the 1940's allowed Guyton and MacDonald to localize the effect in the myoneural junction. 15 These investigators demonstrated that muscle poisoned by the toxin does not respond to neostigmine but will contract when exposed to acetylcholine. Thus, botulinal toxin appears to inhibit acetylcholine release at the motor end plate. Acetylcholine is stored in synaptic vesicles in packets called quanta and when an electrical impulse travels down the axoplasm, it is released in a burst of 100 to 200 quanta. Contraction is produced when the acetylcholine combines with a receptor site on the muscle end plate. Excessive acetylcholine is inactivated by acetylcholine esterase. In botulism, release of acetylcholine is impaired, although the mechanism is not entirely clear. Brooks theorized that the toxin attaches at the presynaptic terminal, thus preventing conduction of the nerve impulses. 3 • 4 Different receptor sites might be involved in external binding of the toxin and intraneuronal blockade of acetylcholine release. 24 More recent physiologic and electron microscopic evidence has further confirmed that botulinal toxin interferes with acetylcholine release in its final step of exocytosis.u
BOTULISM AND SUDDEN INFANT DEATH SYNDROME The question of a possible relationship between infant botulism and the sudden infant death syndrome was raised on the basis of age distribution. 2 Recently, Arnon et al. reviewed 211 cases of the sudden infant death syndrome in California and isolated botulinal toxin or organisms in 4.3 per cent of the unexplained deaths in infants under six months of age. I Necropsy findings were completely nonspecific as to whether botulism was identified. Contrary retrospective evidence was advanced in a Scottish study of the sudden infant death syndrome in which stool homogenates from 116 necropsies were injected into mice and no paralysis or unusual mortality was noted. 29 The currently accepted concept of infant botulism is based on hospitalized patients, most of whom have survived with appropriate ventilator management. However, even in a hospital environment, apparently normal children may progress to respiratory arrest in hours. Further investigation is necessary to understand the extent of infant morbidity and mortality produced by botulism.
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SUMMARY Infant botulism is a unique neuromuscular disease affecting infants less than six months old. It is the result of intraintestinal toxin production by C. botulinum (toxi-infection). Characteristic symptoms include constipation, lethargy, and decreased feeding. Physical examination often reveals generalized hypotonia with cranial nerve impairment. Recovery is dependent on supportive care in an intensive care setting. The relationship of this disease to the sudden infant death syndrome requires further study. ACKNOWLEDGMENT
The authors wish to thank Barbara Erwins for her editorial assistance.
REFERENCES 1. Arnon, S. S., Damus, K., Midura, T. F., et al.: Intestinal infection and toxin production by Clostridium botulinum as one cause of sudden infant death syndrome. Lancet, 1 :1273,1978. 2. Amon, S. S., Midura, T. F., Clay, A. S., et al.: Infant botulism: Epidemiological, clinical and laboratory aspects. J.A.M.A., 237:1946,1977. 3. Brooks, V. B.: An intracellular study of the action of repetitive nerve volleys and of botulinum toxin on miniature end-plate potentials. J. Physiol., 134:264, 1956. 4. Brooks, V. G.: The action of botulinum toxin on motor nerve filaments. J. Physiol., 123:501, 1954. 5. Center for Disease Control. Botulism in the U.S., 1899-1973. Center for Disease Control, Atlanta, Georgia, 1974. 6. Center for Disease Control. Followup on infant botulism - United States. Morbidity and Mortality Weekly Report, 27:17-23, 1978. 7. Center for Disease Control. Honey and infant botulism. Morbidity and Mortality Weekly Report, 27 :249-255, 1978. 8. Cherrington, M., and Greenburg, H.: Botulism and germine. Neurology, 21 :966, 1971. 9. Cherrington, M., and Ryan, D. W.: Treatment of botulism with guanidine. New Engl. J. Med., 282: 195, 1970. 10. Chin, J.: Personal communication, 1978. 11. Clay, S. A., Ramseyer, J. C., Fishman, L. S., et al.: Acute infantile motor unit disorder. Infant botulism? Arch. Neurol., 34:236, 1977. 12. Easton, E. J., and Meyer, K. F.: Occurrence of Bacillus botulinus in human and animal excreta. J. Infect. Dis., 35:207, 1924. 13. Engel, W. K.: Brief, small abundant motor unit action potentials: A further critique of electromyographic interpretation. Neurology, 25:173, 1975. 14. Faich, G. A., Graver, R. W., and Sato, S.: Failure of guanidine therapy in botulism A. New Engl. J. Med., 285:773,1971. 15. Guyton, A. C., and MacDonald, M. A.: Physiology of botulinum toxin. A.M.A. Arch. Neurol. Psychiatry, 57:578, 1947. 16. Grover, W. D., Peckham, G. J., and Berman, P. H.: Recovery following cranial nerve dysfunction and muscle weakness in infancy. Dev. Med. Child. Neurol., 16:163, 1974. 17. Kao, I., Drachman, D. B., and Price, D. L.: Botulinum toxin: mechanism of presynaptic blockade. Science, 193:1256, 1976. 18. Koenig, M. G., Spickard, A., Cardella, M. A., et al.: Clinical and laboratory observations on type E botulism in man. Medicine, 43:517, 1964. 19. Midura, T. F., and Arnon, S. S.: Infant botulism: Identification of Clostridium botulinum and its toxin in faeces. Lancet, 2:934, 1976. 20. Minervin, S. M.: On the parenteral-enteral method of administering serum in cases of botulism. In Ingram, M., and Roberts, T. A. (eds.): Botulism. London, Chapman and Hall, 1966, p. 336-343. 21. Orr, P. E.: The pathogenicity of Bacillus botulinus. J. Infect. Dis., 30:118,1922. 22. Peterson, D. R.: Personal communication, 1978. 23. Pickett, J., Berg, B., Chaplin, E., et al.: Syndrome of botulism in infancy: Clinical and electrophysiologic study. New Engl. J. Med., 295:770,1976.
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24. Simpson, L. L., deB Verster, F., and Trapp, J. T.: Electrophysiological manifestation of experimental botulinal intoxication: Depression of cortical EEG. Exp. Neurol., 19:199, 1967. 25. Smith, L. D. S.: Botulism: The Organism, Its Toxins, The Disease. Springfield, Ill., Charles C Thomas, 1977. 26. Starin, W. A., and Dack, G. M.: Pathogenicity of Clostridium botulinum. J. Infect. Dis., 36:383, 1928. 27. Sugigama, H., and Mills, D. C.: Intraintestinal toxin in infant mice challenged intragastrically with C. botulinum spores. Infect. Immun., 21 :59, 1978. 28. Turner, H. D., Brett, E. M., Gilbert, R. J., et al.: Infant botulism in England. Lancet, 1 :1277,1978. 29. Urquhart, G. E. D., and Grist, N. R.: Botulism and sudden infant death. Lancet, 2:1411,1976. 30. Van Ennengen, E: Ueber einen neuen anaeroben Bacillus und seine Beziehungen zum Botulismus. Ztschr. Hyg. Infekt., 26:1,1897. Division of Neonatology The Children's Hospital of Philadelphia 34th Street and Civic Center Boulevard Philadelphia, Pennsylvania 19104
Infant Botulism Richard A. Polin, M.D.,* and Lawrence W. Brown, M.D. t
Botulism is an acute neuromuscular disease produced by the toxin of Clostridium botulinum. Until recently it was assumed that the disease in children or adults could only be caused by the ingestion of preformed toxin or, more rarely, following elaboration of toxin by organisms in unsterile wounds. Infant botulism is unique as it is caused by the release of toxin from organisms colonizing the gastrointestinal tract. Prior to 1975, the youngest documented case of botulism was reported in a 15 month old child stricken in a food-borne epidemic. However, unexplained cases of infantile hypotonia with cranial nerve impairment which may well have been botulism had been previously reported. 16 In 1976 Pickett et al. described two cases of botulism in infants less than six months of age. 23 Uneventful and spontaneous recovery occurred within one to two weeks of the recognition of the illness. As of January, 1979,98 cases of infant botulism had been identified by the Center for Disease Control; it conservatively estimates the incidence to be at least 250 cases yearly in this country and more throughout the world. 6 The first case reported outside the United States occurred in England. 28
HISTORICAL BACKGROUND Outbreaks of paralytic disease following consumption of contaminated food have been recognized for centuries. The term botulism is derived from the Latin word for sausage, but other pork products, meats, fish, and cheese were common sources of botulism in the nineteenth century. Following an outbreak of botulism in 1894 involving 23 persons which resulted in three deaths, Van Ermengen isolated a spore-forming anaerobe, which he designated Bacillus botulinum, from the spleen of one of the victims and from the contaminated 'Assistant Professor of Pediatrics, The Children's Hospital of Philadelphia and the University of Pennsylvania School of Medicine, Philadelphia, Pa. t Assistant Professor of Pediatrics and Neurology, St. Christopher'S Hospital for Children and Temple University School of Medicine, Philadelphia, Pa.
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ham.30 Further studies led him to describe the microbiologic and pathophysiologic features of the disease: 1. Botulism is an intoxication and not an infectious disease. (Infant botulism is an exception, being a toxi-infection.) 2. The toxin is produced by a specific bacterium and is not destroyed by mild chemical agents or gastric acidity. 3. The toxin is inactivated by heat. In the 75 year period between 1899 and 1973 the Center for Disease Control documented 688 separate outbreaks of food-borne botulism involving almost 1800 persons with a fatality rate of 55 per cent. 5 The number of reported cases peaked in the 1930's, presumably because of increased home canning during the Depression. In the experience of the Center for Disease Control, the major sources of the botulinal toxin in reported cases include: vegetables, 57 per cent; fish products, 15 per cent; preserved fruits, 12 per cent; and condiments including honey, 8 per cent. Eight different serotypes of botulinal organisms have been identified on the basis of antigenic differences in the toxin elaborated, of which only types A, B, E, and F have been associated with human illness. As in older individuals, most cases of infant botulism in the eastern United States are caused by type B Clostridium botulism, whereas in the West, type A is predominant, reflecting the known geographic distribution of type A and B spores in American soil. It should be noted that while the distribution of adult cases in California approximates the ratio of A to B contamination in the soil (12: 1), a marked overrepresentation of type B infant botulism (3:2) exists, suggesting either unusual sensitivity of infants to type B botulism or the presence of other sources of infection. 10
CLINICAL PRESENTATION The Center for Disease Control recently summarized the data derived from the first 58 cases of infant botulism detected between January 1, 1975 and December 31, 1977. 6 Most affected infants were products of full-term uncomplicated pregnancies. In general, they were completely well before the onset of symptoms. Fifty-seven per cent were male infants and ages ranged from three to 26 weeks. During 1977 most cases occurred during the autumn months. Constipation was a common presenting symptom with the onset occurring up to three weeks before the development of other signs. Cranial nerve deficits were common; every patient in Clay'S series had involvement of the seventh, ninth, tenth, and eleventh cranial nerves. 11 Paralysis of gaze and pupillary sluggishness were helpful but inconsistent findings. Virtually all infants manifested generalized weakness and the incidence of diminished head control was striking. Deep tendon reflexes were variable but tended to be decreased or absent. A marked discrepancy existed in the severity of symptoms; some infants showed mild lethargy and weakness whereas others demonstrated more severe cra-
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nial nerve involvement and hypotonia which rapidly progressed to respiratory insufficiency. The only two fatalities were infants who succumbed to respiratory arrest. All survivors recovered completely within three weeks to six months. Two case histories are presented below. Case 1 A two month old female infant was admitted to The Children's Hospital of Philadelphia with a history of progressive weakness of three days' duration. She weighed 3.38 kg at birth. The infant's mother was 33 years old and had a full-term uncomplicated pregnancy. The infant was primarily breast-fed but occasionally was given a supplemental proprietary formula. No other foods were offered. Approximately three weeks prior to admission the parents noted an alteration in the sleep habits of the baby and increased irritability. A decrease in the frequency of stools was also evident. Generalized weakness, difficulty in sucking, and a hoarse cry were noted for three days prior to admission. The child was afebrile. She was admitted to a community hospital where severe hypotonia was noted, and because of progressive weakness, the infant was transferred to Children's Hospital. Growth and development prior to this illness were normal. The family history was negative for neuromuscular disease. On admission, physical examination revealed a floppy, normally developed female infant without evidence of acute distress. Abnormalities were detected only on neurologic examination and included diffuse hypotonia with marked head lag, bilateral ptosis, a weak cry and sucking reflex, an absent gag reflex, and paucity of facial movements. Serum chemistry and hematologic values were normal. The lumbar puncture was traumatic and revealed no white blood cells and 40,000 red blood cells per cm3 • The electromyogram was interpreted as myopathic. An incremental response to rapid stimulation and brief, small amplitude, overabundant action potentials were noted. The child was given a trial dose of neostigmine to which she responded with an improvement in muscle tone; later, however, no response was evident. She required assisted ventilation by the fifth day of acute illness. On the ninth day some minimal improvement in tone was noted, followed by a return of the gag reflex on the eleventh day. The ventilator was discontinued on the twelfth day of illness. Neurologic recovery was considered to be complete three months later. Type B botulinal toxin had been isolated from her stool during the first week of hospitalization.
Case 2 A four and one half month old male infant was admitted to a local hospital with a three day history of constipation, poor feeding, and generalized weakness. The infant's birth weight was 3.78 kg. The infant's mother had a fullterm uncomplicated pregnancy, and normal labor and delivery. He was breastfed exclusively until two weeks prior to admission when he began to eat cereals. Acetaminophen and Ambusol were given the week prior to admission for fever and teething. He received a second diphtheria, pertussis, and tetanus immunization three days prior to the onset of symptoms. Examination revealed a floppy, poorly responsive infant with normal cranial nerve function and intact deep tendon reflexes. He was transferred to The Children's Hospital of Philadelphia on the following day because of increasing respiratory distress. On admission he was lethargic and demonstrated minimal spontaneous movements. Cranial nerve examination revealed bilateral ptosis, sluggishly reactive pupils, facial diplegia, a poor gag reflex with pooling of thick secretions, and it poor sucking reflex. Deep tendon reflexes were diminished. Initial laboratory results revealed normal complete blood count, blood urea nitrogen, calcium, magnesium, and liver function. The lumbar puncture demonstrated one white blood cell, four red blood cells, protein levels of 27 mg per dl, and a glucose level of 104 mg per dl. During the lumbar puncture the pa-
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tient suffered a cardiopulmonary arrest but was easily resuscitated with intubation and placement on continuous end expiratory pressure. Neither edrophonium nor neostigmine tests produced any noticeable improvement. On the third hospital day an electromyogram revealed a myopathic pattern. Repetitive nerve stimulation studies showed a 200 per cent increment in voltage at a frequency of 50 HZ. Nerve conduction velocities were normal. The hospital course was one of gradual improvement. Following the demonstration of the "staircase phenomenon" consistent with botulism (see below), treatment with oral penicillin, 125 mg every six hours for 10 days, was initiated. He was obstipated until the fourth day of hospitalization, when normal stools began to form following administration of a Dulcolax suppository. During the ensuing week his motor function and spontaneous ventilation improved. He was extubated on the eleventh day of hospitalization. On the twenty-second day, when he was transferred to a convalescent unit, the patient demonstrated improving cranial nerve function, mildly decreased deep tendon reflexes, and persistent marked hypotonia. During the following month, he regained normal muscle strength and tone, and deep tendon reflexes. The results of physical examination at eight months of age were completely normal. Stool specimens obtained on the :first day of his hospitalization demonstrated type B botulinal toxin and organisms. Simultaneous serum samples taken two and three weeks later were negative as were samples of foods, vitamins, and household items. Stool samples from both parents and a sibling were negative for botulinal toxin and organisms.
LABORATORY DIAGNOSIS If a high degree of suspicion exists, it is possible to make a tentative diagnosis of infant botulism and perform confirmative tests on the first day of hospitalization. By history, these infants are generally healthy, and are products of full-term uncomplicated pregnancies. Constipation is a frequent early sign, occurring up to 10 days prior to progressive muscle weakness, poor feeding, and apparent lethargy. Usually there is no recent intercurrent infection but a history of recent immunization is common (a function of the age of the patient population). Often the infant has been breast-fed and only rarely is there a history of ingestion of home canned fruits or vegetables. There is no history of tick bites. On examination, the infant will have a paucity of spontaneous movements, generalized weakness, diminished or absent deep tendon reflexes, and variable cranial nerve dysfunction (facial diplegia, ptosis, extraocular palsies, and poor gag and suck reflexes). Routine laboratory examinations include complete blood count, blood urea nitrogen, electrolytes, calcium, magnesium, lumbar puncture, and chest radiograph. They are generally normal unless pneumonitis or dehydration has supervened. Special laboratory studies performed on infants in the early stages of disease may include edrophonium or neostigmine testing for myasthenia gravis, toxicology studies for heavy metals and organophosphates, and electrodiagnostic procedures. Routine electromyography frequently demonstrates brief, small amplitude, overly abundant motor unit potentials. This nonspecific finding usually represents myopathy but can also be seen in partial denervation. The most helpful study is augmentation of the amplitude of the evoked muscle action potential
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at nerve stimulation frequencies greater than 10 HZ. A positive incremental response ("the staircase phenomenon") at these rapid rates is seen in most cases. 2 • 13 The normal response to slower rates of stimulation (between two and five cycles per second) helps to distinguish botulism from myasthenia gravis in which there is an abnormal decremental response. Other disorders that may produce a similar "staircase phenomenon" and electromyographic pattern include antibiotic toxicity, snakebite, and the Eaton-Lambert syndrome. Final diagnosis can be made only by isolation of the organism in the stool or demonstration of toxin in the stool. Unlike other botulism syndromes in older children and adults, serum is uniformly negative for toxin. Constipation may make stool collection exceedingly difficult; a saline enema may facilitate collection of a stool sample. The toxin and organism may be present throughout the recovery phase of the disease.
DIFFERENTIAL DIAGNOSIS A wide spectrum of infectious, toxic, and metabolic diseases can produce a profound depression of neuromuscular activity, hyporeflexia, cranial nerve dysfunction, and altered levels of consciousness in the young infant. Sepsis with or without meningitis may cause neuromuscular depression, and must be the first consideration in the acutely ill, floppy infant. Although any bacterial or viral organism may be associated, poliomyelitis, Epstein-Barr virus infections, and diphtheria mimic botulism most closely. Distinctive features of poliomyelitis include a preparalytic phase of fever, headache, and gastrointestinal complaints followed by aseptic meningitis. When paralysis ensues it is usually asymmetric, and bulbar involvement is less frequent than is involvement of the extremities. Like botulism, poliomyelitis is a pure motor neuropathy without a sensory component. Infection with Epstein-Barr virus may produce a syndrome of encephalitis with or without peripheral or cranial nerve weakness. Diphtheritic polyneuropathy can be excluded since the primary infection always precedes it by one to two weeks. The onset of this disorder is usually characterized by ocular and palatal weakness, it may be accompanied by myocarditis, and it involves sensory as well as motor nerves. Postinfectious polyneuropathy (Guillain-Barre syndrome) is rare in patients under six mOnths of age. The diagnosis is difficult since hypotonia and hyporeflexia are nonspecific, and a systematic sensory motor examination is virtually impossible in the sick infant. Elevation of cerebrospinal fluid protein, delayed nerve conduction velocity, and neuropathic electromyography may confirm the diagnosis in the absence of other possible causes for polyneuropathy such as heavy metal poisoning. A progressively ascending, flaccid sensory motor neuropathy can be caused by tick bite. However, prompt recovery usually occurs following removal of the offending insect.
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Congenital myasthenia gravis can be mild and may present at any time during infancy. Generally, muscle weakness is not severe and ophthalmoplegia is unusual. Facial weakness, a feeble cry, a weak sucking reflex, ptosis, and a swallowing dysfunction are common presenting signs. Edrophonium or neostigmine testing is positive and slow repetitive nerve stimulation demonstrates a decremental response (Jolly test). Metabolic and toxic abnormalities may cause nonspecific weakness and hypotonia. Hyperkalemia or hypokalemia, hyponatremia, hypermagnesemia, and hypercalcemia or hypocalcemia may produce a similar picture in the infant. Toxic encephalopathies secondary to renal or hepatic failure may present in early infancy. Organophosphate poisoning has been reported as early as eight weeks of age but usually presents with signs of cholinergic excess in addition. Reyes syndrome has been reported in infancy also, but seizures, hepatomegaly, hypoglycemia, and a history of a preceding infection help to distinguish this syndrome from botulism. Subacute necrotizing encephalomyelopathy (Leigh's disease) may be confused with botulism since both are characterized by weakness, hypotonia, and ophthalmoplegia. However, Leigh's disease occurs later in infancy, is more chronic, is associated with blindness and hearing loss, and is frequently accompanied by seizures.
TREATMENT The treatment of infant botulism is controversial but generally includes supportive respiratory and nutritional care as well as the administration of specific antitoxin, antibiotics, or drugs that affect neuromuscular function. Every child in whom infant botulism is suspected should be transferred to a center in which intensive respiratory care is available. Not only the infant with impending respiratory failure should be transferred, but also those infants in whom cranial nerve dysfunction or marked hypotonia is evident. The only fatalities in infant botulism have been caused by potentially avoidable respiratory complications. The efficacy of botulinal antitoxin has not been firmly established and seems to differ considerably from one toxin type to another. In adults who have type E botulism, the administration of E antitoxin has hastened recovery and lowered mortality almost IO-fold. lB • 25 Results with types A and B botulism have been less satisfactory, suggesting that both A and B botulinal toxins may irreversibly bind to the nerve endings and thus are not amenable to neutralization. Serum sickness and other allergic reactions have occasionally been reported following the use of equine antisera which has discouraged most physicians from administering antitoxin in proven cases of infant botulism. Human antitoxin might become an acceptable alternative, but supplies are currently unavailable. Only one case of an infant being given equine trivalent antitoxin has been reported. It was administered on the suspicion of food-borne botulism, and no dramatic improvement was noted.
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It is unknown whether antibiotics are indicated, though some infants with botulism have been initially treated with antibiotics for sepsis. Treatment with oral or parenteral penicillin can be justified because of the active enteric infection with Clostridia. However, it is the experience of most observers that there is no difference in the clinical course of antibiotic-treated versus untreated patients. Furthermore, there may be prolonged excretion of both toxin and culture positive stools for many n":tonths regardless of therapy.2 A theoretical objection to the use of antibiotics is that the death of botulinal organisms might lead to release of toxin on autolysis. Drugs that affect the neuromuscular function have been tried in syndromes of adult botulism. Guanidine and germine facilitate the release of acetylcholine from the nerve terminals and have produced clinical improvement in uncontrolled series. 8 , 9 However, neither drug has proved to be as effective as initially expected.14 Although cholinesterase inhibitors such as edrophonium and neostigmine may produce transient improvement in the early stages of disease, all treated infants become rapidly refractory to these agents. Enemas or cathartics have been suggested occasionally for adult botulism so that preformed toxin can be evacuated prior to absorption. A similar rationale might be applicable to infant botulism and, indeed, clinical improvement has been seen on occasion following purgation. In one anecdotal report, administration of a laxative increased excretion of botulinal toxin eight-fold. 22 The first stool was estimated to contain 366,000 mouse lethal doses of toxin.
PATHOPHYSIOLOGY Source of Toxin Preformed botulinal toxin has not been identified in the foods or drugs administered to any infant, nor has there been a common food source. Both breast-fed and formula-fed babies are represented in case reports and most children have been fed a variety of solid foods. Arnon et al. tested 21 food and drug items used by five of the patients in their series and found only one container of honey that was positive for C. botulinum organism." The Center for Disease Control, however, has reported C. botulinum organisms in three additional containers of honey fed to affected infants and in 13 per cent of all honey samples tested. 7 Soil and household dust samples have rarely contained botulinal organisms. Excluding a preformed source of toxin, infant botulism is now believed to be caused by the ingestion of spores or vegetative cells of C. botulinum (toxi-infection theory). Toxin is produced by Clostridia growing in the gastrointestinal tract, resulting in disease symptoms upon gut absorption. Experimentally, botulism may be produced in animals that are fed spores or in which the spores have been implanted intraperitoneally in semipermeable membranes. 2o. 26 These studies have been criticized because the heat used to inactivate residual toxin may have activated the formation of vegetative cells from spores. Re-
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cently, an intriguing new animal model has been reported in which there is age dependence in gastrointestinal colonization by botulinal spores administered intragastrically.27 However, despite the existence of the organism and toxin production, these animals show no signs of neuromuscular weakness or constipation. Evidence against the toxiinfection theory is that C. botulinum has never been isolated from the stools of asymptomatic individuals who have ingested spores. I2 A similar investigation in infants less than six months old has not been carried out nor has there been an adequate explanation for the predilection of disease for this age group.
Action of Toxins The isolation of botulinal toxin in the 1940's allowed Guyton and MacDonald to localize the effect in the myoneural junction. 15 These investigators demonstrated that muscle poisoned by the toxin does not respond to neostigmine but will contract when exposed to acetylcholine. Thus, botulinal toxin appears to inhibit acetylcholine release at the motor end plate. Acetylcholine is stored in synaptic vesicles in packets called quanta and when an electrical impulse travels down the axoplasm, it is released in a burst of 100 to 200 quanta. Contraction is produced when the acetylcholine combines with a receptor site on the muscle end plate. Excessive acetylcholine is inactivated by acetylcholine esterase. In botulism, release of acetylcholine is impaired, although the mechanism is not entirely clear. Brooks theorized that the toxin attaches at the presynaptic terminal, thus preventing conduction of the nerve impulses. 3 • 4 Different receptor sites might be involved in external binding of the toxin and intraneuronal blockade of acetylcholine release. 24 More recent physiologic and electron microscopic evidence has further confirmed that botulinal toxin interferes with acetylcholine release in its final step of exocytosis.u
BOTULISM AND SUDDEN INFANT DEATH SYNDROME The question of a possible relationship between infant botulism and the sudden infant death syndrome was raised on the basis of age distribution. 2 Recently, Arnon et al. reviewed 211 cases of the sudden infant death syndrome in California and isolated botulinal toxin or organisms in 4.3 per cent of the unexplained deaths in infants under six months of age. I Necropsy findings were completely nonspecific as to whether botulism was identified. Contrary retrospective evidence was advanced in a Scottish study of the sudden infant death syndrome in which stool homogenates from 116 necropsies were injected into mice and no paralysis or unusual mortality was noted. 29 The currently accepted concept of infant botulism is based on hospitalized patients, most of whom have survived with appropriate ventilator management. However, even in a hospital environment, apparently normal children may progress to respiratory arrest in hours. Further investigation is necessary to understand the extent of infant morbidity and mortality produced by botulism.
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SUMMARY Infant botulism is a unique neuromuscular disease affecting infants less than six months old. It is the result of intraintestinal toxin production by C. botulinum (toxi-infection). Characteristic symptoms include constipation, lethargy, and decreased feeding. Physical examination often reveals generalized hypotonia with cranial nerve impairment. Recovery is dependent on supportive care in an intensive care setting. The relationship of this disease to the sudden infant death syndrome requires further study. ACKNOWLEDGMENT
The authors wish to thank Barbara Erwins for her editorial assistance.
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24. Simpson, L. L., deB Verster, F., and Trapp, J. T.: Electrophysiological manifestation of experimental botulinal intoxication: Depression of cortical EEG. Exp. Neurol., 19:199, 1967. 25. Smith, L. D. S.: Botulism: The Organism, Its Toxins, The Disease. Springfield, Ill., Charles C Thomas, 1977. 26. Starin, W. A., and Dack, G. M.: Pathogenicity of Clostridium botulinum. J. Infect. Dis., 36:383, 1928. 27. Sugigama, H., and Mills, D. C.: Intraintestinal toxin in infant mice challenged intragastrically with C. botulinum spores. Infect. Immun., 21 :59, 1978. 28. Turner, H. D., Brett, E. M., Gilbert, R. J., et al.: Infant botulism in England. Lancet, 1 :1277,1978. 29. Urquhart, G. E. D., and Grist, N. R.: Botulism and sudden infant death. Lancet, 2:1411,1976. 30. Van Ennengen, E: Ueber einen neuen anaeroben Bacillus und seine Beziehungen zum Botulismus. Ztschr. Hyg. Infekt., 26:1,1897. Division of Neonatology The Children's Hospital of Philadelphia 34th Street and Civic Center Boulevard Philadelphia, Pennsylvania 19104