Critical Care Medicine
Neuromuscular Weakness in Children: Botulism
Clostridium botulinum toxico-infection
1. Description of the problem
What every clinician needs to know
Intoxication with botulinum toxin occurs through two routes: (1) ingestion of the pre-formed toxin in food botulism; and (2) toxico-infection of the host as in wound botulism. In infant and food botulism, botulinum spores are ingested, germinate in and colonize the gastrointestinal tract of the infant slowly elaborating toxin which is absorbed from the intestinal mucosa).
Clinical symptoms may be similar among the three types of intoxication but evolve over a more gradual pace in toxico-infections reflecting the rate of secretion of the toxin by the organism. Infant botulism is the most common of the botulism syndromes in childhood and will be discussed in detail.
Toxico-infection of the infant GI tract is an age-dependent phenomenon with the vast majority of disease occurring between 2 and 6 months. Infant botulism is rare before 4 weeks or after 9 months.
2. Emergency Management
Stabilizing the patient
Management of infant botulism is, first and foremost, anticipatory and supportive. Neuromuscular transmission in the diaphragm is more resistant to pharmacologic or immunologic blockade than skeletal muscle and respiratory effort may be relatively spared at a time when intubation becomes necessary to protect the airway due to pharyngeal weakness.
Many infants have endured some degree of protein calorie deprivation prior to coming to medical attention due to feeding difficulties, so caloric repletion via feeding tube is almost always necessary.
Once the infant has been stabilized and the presumptive diagnosis of infant botulism is relatively secure, treatment should be initiated with human botulinum immune globulin (BIG). This product is derived from pooled plasma samples from volunteers immunized with pentavalent (types A,B,C,D and E) botulinum toxoid.
In the single controlled trial which garnered FDA approval for the drug, BIG reduced the duration of hospitalization, mechanical ventilation and the need for enteral nutrition compared to placebo. No serious adverse events were attributed to BIG-IV. The product, dubbed Baby BIG, can be obtained through the California Department of Human Services Botulism Treatment and Prevention Program (http://infantbotulism.org) and is administered as a single intravenous dose.
There is no benefit to treating the clostridial colonization. Other intercurrent infections should be managed appropriately while avoiding antibiotics that have a deleterious effect on neuromuscular transmission, such as gentamycin.
As with any paralytic illness, rehabilitative interventions should be introduced prospectively to avoid complications of prolonged immobilization.
Establishing the diagnosis
Because the critical steps of toxin binding and inactivation of ACh release sites are temperature and activity dependent, it comes as no surprise that the warmest and most active neuromuscular junctions are preferentially affected. Hence, neuromuscular transmission failure occurs in a centripedal fashion from the core outward.
In retrospect, the earliest symptom is often decreased bowel movements. This is typically followed by feeding difficulties due to bulbar weakness, diminished facial movement with masking of expression and photophobia caused by paralysis of pupillo-constrictor muscles.
On examination one finds ptosis and masked facies, sluggish dilated pupils and external ophthalmoplegia and pharyngeal weakness with a diminished gag reflex. Hypotonia with proximal weakness is present, along with diminished or absent deep tendon reflexes. Autonomic involvement is common and may cause diminished tearing and salivation with flushing of the skin. The appearance of affected infants is highly stereotypical and lends itself to pattern recognition. In relatively endemic regions, the diagnosis is frequently made by the intern in the emergency room.
The diagnosis is generally clinical and is confirmed by isolation of the toxin from a stool sample. Obtaining a stool sample for laboratory studies may require an enema because of colonic stasis. Electrodiagnostic testing in the hands of an experienced practitioner can often provide pathognomic evidence for a presynaptic defect in neuromuscular transmission typical of infant botulism.
Botulinum toxin is produced by the gram positive anaerobic bacillus clostridium botulinum. It comes in at least seven different serotypes A through G, although, for practical purposes, infant botulism involves almost exclusively types A and B. The toxin is elaborated in the gut and is absorbed into the serum, whereby it gains access to cholinergic nerve terminals not protected by the blood:brain barrier.
Botulinum toxin rapidly binds to sites on the exterior surface of the pre-synaptic nerve terminal, from where it slowly traverses the axolemmal membrane via temperature and synaptic activity dependent processes to bind on the internal membrane surface, where it permanently inactivates acetylcholine release portals in the presynaptic axolemmal membrane of the neuromuscular junction.
As increasing numbers of ACh release sites are blocked, the safety margin for neuromuscular transmission is progressively compromised until a threshold of approximately 70% of release terminals are inactivated and synaptic transmission fails. While the toxin is circulating in serum or on the surface of the presynaptic axon, it is accessible to binding by antibody directed toward the toxin.
The internalized toxin, however, is sequestered and ACh release is permanently blocked with subsequent degeneration of the neuromuscular junction. Recovery is dependent on regeneration of the terminal motor axon and formation of a new neuromuscular junction.
Toxico-infection of the infant GI tract is an age-dependent phenomenon, with the vast majority of disease occurring between 2 and 6 months of age. Infant botulism is rare before 4 weeks or after 9 months. This window of vulnerability appears to be governed in large measure by the developmental biology of the infant's GI tract.
These organisms require a habitable environment to germinate and proliferate. In experimental animals the infant gut cannot be colonized despite ingestion of large numbers of botulinum spores for the first few days or after about 2 weeks. Raising the animals in a germ-free environment or pre-treating with antibiotics, which alters the intestinal bacterial environment, expands the vulnerable window, permitting colonization at earlier and later ages.
Botulinum spores are virtually ubiquitous in the natural environment and are present in virtually any soil sample sent for analysis. The geographical distribution of infant botulism is predominantly in suburban and rural environments and appears to correlate with disruption of topsoil related to farming or construction.
Aerosolized spores probably cling to clothing and are brought into the environment or may be borne on objects or simply windborne in locales contiguous to areas of soil disruption. Although honey has been implicated as a source of infant exposure to botulinum spores, for the most part, it plays little role as a vector in the disease.
The most common serotypes of botulism are types A and B, although other serotypes are rarely reported. Botulinum species are naturally segregated by the Rocky Mountains and central plains, with type A predominating in the west and type B on the east coast.
There are also geographical hot spots for the disease, with disproportionately greater incidences of infant botulism in eastern Pennsylvania in the east, and within the Salt Lake - Provo corridor in Utah and throughout California in the west. Reasons for the geographical inhomogeniety in disease incidence are unclear.
Despite the gravity of the illness and duration of recovery, the outcome is usually excellent. In properly equipped pediatric intensive care units, the mortality rate is virtually zero. The pace of recovery is often protracted due to the tempo of regrowth of new neuromuscular junctions, which is the mechanism through which neuromuscular transmission is reestablished. In general, functional recovery occurs in an inverse sequence of the pattern of loss. Consequently, expect the need for tube feeding to be among the last vestiges of the infant's hospitalization for botulism.
Special considerations for nursing and allied health professionals.
What's the evidence?
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