Vol

DEPARTMENT OF PATHOLOGY
The Johns Hopkins Medical Institutions

Vol. 20, No. 35
THE JOHNS HOPKINS MICROBIOLOGY NEWSLETTER
Tuesday, August 28, 2001

A. Provided by Leslie Edwards Reger, Division of Outbreak Investigation, Maryland Department of Health and Mental Hygiene.

No information available.

B. The Johns Hopkins Hospital. Information provided by Robert W. Allan, M.D., Department of Pathology and Laboratory Medicine.

Case Report: The patient was a 10 week old previously healthy male infant who 1 week prior to admission was noted to be fussy. A day later the mother noticed that his cry had become weaker and two days later she noticed that he had become very floppy "like a noodle" with weaker cry and poor sucking. He had also had no bowel movements since the onset of his symptoms. He was the product of a full-term delivery with no perinatal complications. He was exclusively breast fed. One week prior to admission he received his first immunization shots. He continued to be lethargic, hypotonic and was feeding poorly when he was evaluated at an outside hospital. A head computed tomography study and lumbar puncture were performed which were within normal limits. He was transferred to the Johns Hopkins Hospital for further evaluation and management. On physical examination, his temperature was 36.7 C, heart rate 136/min, respiratory rate 46/min and blood pressure was 92/59 mm Hg. He appeared listless and weak. The abdomen was non-distended and he had bowel sounds. His face appeared symmetric and pupils were equal, round and reactive to light. Gag reflex was intact. He appeared to track toys in all visual fields. He had moderate symmetrical hypotonia in upper and lower extremities. Deep tendon reflexes were 1-2+ in all extremities. The remainder of the physical examination was unremarkable. Laboratory studies on admission revealed a normal complete blood count and basic metabolic panel. EMG performed on the upper extremities was normal. The was no pleocytosis in the cerebrospinal fluid. Blood and CSF cultures were negative. Stool cultures were positive at three days for Clostridium botulinum with background normal fecal flora. He began to improve without any intervention and was discharged. Clostridium botulinum (Infantile Botulism) Organism: Clostridium botulinum are a group of anaerobic, gram positive, straight to slightly curved motile bacilli that produce a characteristic neurotoxin. Seven serologically distinct neurotoxins are recognized, conveniently designated A through G. Human infections are caused by type A, B, E and least frequent F. Type C and D neurotoxins are causes of botulism in birds and non-human mammals, while rare reports of type G infections in humans have been reported. The natural reservoir for Clostridium botulinum is soil and aquatic sediments. Soil surveys in the United States have shown that type A producing strains are found predominantly west of the Mississippi river while type B occurs principally in the East. Type F has been isolated from marine sediment on the west coast of the United States and in our beloved Chesapeake Bay crabs. In the United States, most cases of infant botulism occur in California followed by southeastern Pennsylvania and Utah. The distribution corresponds to regions with high concentrations of C. botulinum in the soil.

Pathogenesis of Neurotoxin: The botulinum neurotoxin acts at peripheral cholinergic synapses. Toxin irreversibly binds to receptors on a nerve ending where it is internalized. Inside the nerve cell the toxin interferes with the release of acetylcholine by specifically degrading the secretory vesicle involved in the exocytosis of acetylcholine. The neuromuscular junction is the most clinically important peripheral cholinergic synapse and the toxin’s action results in the flaccid paralysis and hypotonia. Preganglionic cholinergic synapses in the autonomic nervous system may also be affected.

Clinical Manifestations: The clinical presentation of infantile botulism has a wide range of severity. In the typical case the first sign of illness is constipation, defined as three or more days without defecation in a previously regular infant. This is often overlooked. Listlessness, lethargy, poor suckling, weak cry, pooled oral secretions, hypotonia, loss of head control and general "floppiness" are other common signs. Additional neurological findings include ptosis, ophthalmoplegia, sluggish pupillary reaction to light, diminished gag reflex and poor anal sphincter tone. There is a symmetric descending paralysis with the first signs of involvement being cranial nerve deficits and bulbar palsies (expressionless face, weak cry, ptosis). The typical hospital course is characterized by increasing general weakness and hypotonia which progress until generalized. The deficits are greatest one to two weeks after admission and may remain at that level for 1 to 3 weeks before showing any improvement. Once strength starts to return to normal, the improvement continues steadily over a period of weeks. However, as mentioned, the severity varies widely and rare cases can result in death from respiratory arrest.

For most cases of infantile botulism, the source of C.botulinum is not identified. Honey is the only food item that has been reliably implicated as a source of C. botulinum spores for ill infants. Corn syrup was implicated in previous studies but this has been refuted. In cases of infantile botulism caused by honey, the same type of toxin invariably has been isolated from the honey and the infant. There have been no reports of finding pre-formed toxin in honey; illness results from ingestion of spores followed by colonization of the naive intestinal tract. The number of cases of infant botulism attributed to honey is now low due in large measure to educational campaigns against the practice of feeding infants honey. The source for most cases is the natural environment. The organism responsible for infant botulism is usually the same type as that found in the soil in the region that the infant lives. C. botulinum has been isolated from soils in yards and in vacuum cleaner dust.

All cases of infant botulism have been reported in children less than one year of age; some 95% occurring within the first six months of life. Infants are susceptible because their enteric microflora is less diverse than adults allowing for colonization of the intestines with C. botulinum following ingestion and germination of spores. The possible role of breast feeding and formula feeding as predisposing factors is undetermined. Studies have shown an association between being breast fed and being hospitalized for infant botulism which has been interpreted both to mean that breast feeding predisposes to illness and that breast feeding slows the onset of disease to allow hospitalization to take place. Interestingly, formula fed infants have a mean age of hospitalization of 7.6 weeks compared to 13.8 weeks for breast fed infants. All reports of fulminant onset botulism patients with respiratory arrest were formula fed. The difference in presentation is likely due to a variety of factors including niches in the intestinal flora, immune factors in milk (secretory IgA) and other environmental factors.

Diagnosis: The diagnosis of infant botulism is established by identification of C. botulinum in the feces of an infant with clinical signs and symptoms consistent with botulism. C. botulinum is not part of the normal flora of infants or adults. Enemas with small volume nonbacteriostatic water (not saline) is often needed due to the constipation induced by the toxin. Botulinum toxin is detectable in the stool and serum, though the later is rarely detected in cases of infant botulism. The mouse neutralization test is the most sensitive and specific assay for determining the type of botulinum toxin (A-G) and is available from public health laboratories. In most states, botulism is a reportable illness.

References:

Koneman et. al. Color Atlas and Textbook of Diagnostic Microbiology, 5^th Edition, Lippincott-Raven, Philadelphia, 1997.
Midura, T. Update: Infant Botulilsm. Clinical Microbiology Reviews, Vol. 9 (2): 119-125, 1996.
Arnon, Stephen S. Infant Botulism. Textbook of Pediatric Infectious Disease, fourth edition, Feigin and Cherry, eds. 1998.