Acquired Presynaptic Neuromuscular Junction Disorders: Infant Botulism and Lambert-Eaton Myasthenic Syndrome

Infant Botulism

Botulism is derived from the Latin botulus , for sausage. Van Ermengem in 1897 isolated the spore-forming anaerobe Bacillus botulinum from the spleen of a victim and the contaminated ham involved. This toxigenic form of botulism is the best known, and before the advent of modern food processing, was the most common form of botulism in the developed world. There are three other forms of botulism in addition to food-borne toxin ingestion: wound, infant, “adult onset infant botulism,” and iatrogenic.

It would have been impossible to recognize infant botulism in an earlier era of high infant mortality, and thus it was not recognized until 1976. This form of human botulism is caused by Clostridium botulinum colonization within the flora of the susceptible infant colon and subsequent production of toxin. Infant botulism is now the most common form of human botulism in the developed world.

Clinical Concerns

Typical patients are healthy full-term infants with painless constipation for days to months before onset of weakness. This weakness, poor feeding, a paucity of movement, and seeming lethargy are the most common initial concerns. At presentation, three cardinal features are recognized: symmetrical weakness of bulbar, face, and neck more than appendicular musculature; a nonirritable, awake sensorium; and the absence of fever. Bulbar weakness and poor head support are seen in all patients; ophthalmoparesis and pupillary sluggishness or dilatation are frequent and helpful findings. The face is typically expressionless, drooling is present, and a high-pitched, mewing cry develops that is recognized as characteristic by clinicians in areas of high prevalence. Some infants have a suggestion of fatigability, manifesting as bursts of movement amid a too-immobile restful state. Muscle stretch reflexes are often absent, but their presence does not rule out the diagnosis. Many infants progress rapidly to require assisted ventilation, usually initiated out of concern for a secure airway.

Once infant botulism is recognized and treated, patients with the classic syndrome may need ventilatory assistance or airway support for many months, with a mean of 3 weeks. Patients typically recover in the reverse order of their symptoms’ appearance, with limb movements reappearing before the infant has a competent airway. In exceptional cases, relapse may occur well into the course of recovery.

Epidemiology

The median age of affected infants is 10 weeks, with 95% being younger than 6 months old. The vast majority of patients are between 1 week and 11 months old, but rare adult cases of “infant botulism” can arise in the setting of severe gastrointestinal illness. There are case reports of infant botulism starting with symptoms at 38 hours and 54 hours of life due to different forms of Clostridia such as type F.

Although infant botulism is widespread, having been recognized in all regions of the United States and four continents, clusters of increased incidence in California, Utah, and the suburban Philadelphia region are the best documented. This may be related to soil type and alkalinity. In both Pennsylvania and Utah, many patients were known to have been exposed to nearby construction or agricultural soil conditions, with wind and alkaline soil noted in the Utah group. There is some suggestion of seasonal variation in susceptibility, with the greatest incidence in the summer and fall when there is no snow and conditions favor spore dissemination, but cases do occur year-round in more temperate climates. Whether breast feeding confers a susceptibility risk or protective benefit is controversial. In southeastern Pennsylvania, a case-controlled epidemiologic survey found that breastfeeding was a major factor in relative risk. One report showing cases occurring across all major racial and ethnic groups in California also found that breastfeeding seemed to slow the onset of symptoms, and those who were breastfed had a later age of onset of symptoms (median age of onset 116 days) compared to bottle-fed infants (median age of symptom onset 66 days).

The pathogenic C. botulinum organisms are ubiquitous. C. botulinum is comprised of four phylogenetically distinct species of bacteria that form botulinum neurotoxin, which accounts for the multiple forms of botulinum toxin designated types A through G. Infant botulism is associated almost exclusively with toxin type A or B. The distribution of human disease parallels the regional soil distribution, with type A being common in the Rocky Mountain states and type B infection in the Great Plains states and to the east. Unlike the food-borne toxigenic form of human botulism, epidemic outbreaks of infant botulism are not seen. There are no reported cases of disease by fecal-oral contamination from other affected infants, and the affected infant is typically the only ill member of the family. Taken together, these facts suggest that human exposure to C. botulinum spores is a fairly common event, and colonization causing symptomatic weakness reflects features of individual susceptibility more than an effect of random exposure to the organism. Exposure’s partial role in incidence is suggested, however, by an increased relative risk following dietary exposure to honey (odds ratio 9.8) or corn syrup (odds ratio 5.2), in which spores may be found. In Europe, as many as 59% of infant botulism cases have been linked to honey with ongoing case reports. Nonetheless, before the widely distributed American Academy of Pediatrics cautionary recommendation, exposure to honey explained only 16% to 30% of cases in the USA.

There are hints that risk factors change with the age of the infant. In older infants, a history of long-standing infrequent stooling, breastfeeding, and honey or corn syrup exposure is correlated with disease. In infants younger than 2 months of age, only rural residence with presumed aerosolized soil exposure is a risk factor. The fact that normal intestinal microflora changes with the introduction of formula or solid foods likely plays a role in the ability of C. botulinum to colonize the infant’s colon. This is supported by the fact that in a majority of the Pennsylvania cases, the infants had first been introduced to non-breast milk foods within 4 weeks of the onset of disease. Although breastfeeding is a risk factor for infant botulism, it appears to provide some protection against the most serious, acute presentation of sudden infant death.

Given these features of epidemiology, it is hard to conceive how any program of prevention could be successful. Infant botulism is a rare disease, and the evidence suggests that host features are more substantial risk factors than exposure. Although breastfeeding is a known risk factor, the clear benefits of breastfeeding outweigh the tiny risk of contracting infant botulism. The single addressable public health factor has already been dealt with—the recommended exclusion of honey and corn syrup from the diet of infants younger than 1 year. More important is a program of education for primary practitioners who, with enhanced awareness and continued vigilance, are best situated to prevent the complications of infant botulism through early diagnosis.

Pathogenesis

Infant botulism is caused by colonization of the large intestine by toxin-forming C. botulinum or related organisms. C. botulinum is not a normal constituent of gut microflora. Apparently, its absence is due to competition from other microorganisms: adult germ-free mice support large-intestine colonization, but immediately upon exposure to other normal flora, the colonization is cleared. An important exception that may have relevance for human infant botulism is seen during early postnatal development of mice: normal pups of 7 to 13 days can sustain enteric colonization, but older and younger mice cannot. Interestingly, like C. botulinum , other Clostridium species are excluded from the gut of breastfed infants, but the addition of any other food supplement results in the occasional appearance of colonization. This may explain the increased incidence of breastfeeding in older affected infants who, with even a small amount of supplementation from other food sources, may become more susceptible to colonization with C. botulinum .

Clostridia are obligatory anaerobic, Gram-positive, spore-forming rods. In general, they grow best in high pH media, although a combination of temperature, osmolarity, redox potential, the presence of food preservatives, and competing microorganisms affects growth in an interrelated fashion. Each strain produces a single toxin type, although the genes for multiple toxins sometimes exist within a strain, and occasionally a single strain produces two types of toxin. The C. botulinum species is an aggregate of multiple strains, likely the result of convergent evolutionary branches that have in common the production of botulinum toxins. Since this classification of species was developed, other Clostridium species have been found to produce botulinum toxin, thus demonstrating the difficulty of representing the complexity of bacterial phylogeny with a single nomenclature.

Botulinum toxin is the most toxic substance known. The lethal ingested dose is estimated to be less than 1 nanogram/kg body weight. Although abundant toxin is produced in the colon in infant botulism, apparently only a minute amount is absorbed. In the human infant, C. botulinum behaves more like the normal flora than an enteric pathogen; it does not invade the colonic mucosa, and there is no direct cytotoxic effect. The colon must therefore be a good barrier to toxin uptake, but more proximal regions of the gastrointestinal tract are likely not barriers to absorption, given the expression of symptoms with only minute toxin ingestion. The fact that many infants with symptomatic botulism have a history of chronic constipation suggests that diminished intestinal motility is a cause as well as a consequence of infant botulism. These infants may be at higher risk for colonization in the first place, they may be more likely to absorb the toxin once it is made by reflux through the length of the colon and the ileocecal junction, or both possibilities may be true. Breastfeeding is associated with increased colonic motility, which may explain the later onset and less severe expression, though not the increased incidence, of infant botulism in breastfed infants.

The various exquisitely tailored botulinum toxins are likely the consequence of complex pathways of convergent evolution. Seven different serotypes have evolved, designated by the letters A through G. The botulinum toxins are similar in action to tetanus toxin, although the targeted cell differs: tetanus toxin affects Renshaw cells of the spinal cord while botulinum toxin alters the secretive exocytosis of motor neurons of the brain stem and spinal cord. Botulinum toxin is synthesized initially as a large 150-kDa protein that is autocleaved into two fragments bonded by disulfide links. The larger 100-kDa heavy-chain fragment of each of the botulinum toxins is responsible for binding to a variety of specific gangliosides that characterize the axon terminus of cholinergic motor neurons. Once internalized by endosomic uptake, the light chain separates and escapes the endosome into the cytoplasm of the presynaptic terminal. Here, a zinc-dependent protease function of the light chain targets one of three proteins essential to the sequence of synaptic vesicle docking and exocytosis. These targeted proteins are enzymatically cleaved at a site distinct for each toxin type. Types A and E toxin cleave a protein known as SNAP 25. Types B, D, F, and G (as well as the short chain of the tetanus toxin) cleave a critical vesicle-associated membrane protein (VAMP, also known as synaptobrevin). Botulinum toxin type C cleaves the syntaxin molecule. The consequence of inactivation of any one of these crucial docking proteins is an inability to release quanta of acetylcholine from the presynaptic terminal in response to an action potential. The remarkable potency of botulinum toxin stems from this combination of high-affinity uptake at presynaptic terminals, mediated by the 100-kDa fragment, and highly efficient enzymatic protease activity mediated by the 50-kDa fragment.

Recovery from this intoxication requires the spontaneous degradation of the toxin and the synthesis and transport of new SNAP 25, VAMP, or syntaxin protein from the neuronal perikaryon. Morphologically, recovery is associated with new sprouting from the presynaptic terminal in the neuromuscular junction; whether this is a necessary feature of recovery is not known. While the muscle is denervated, there is spread of the acetylcholine receptor from the site of the original junction, but with recovery of synaptic quantal release, the regular arrangement of the synapse is reestablished. Subtle differences in the frequency of spontaneous quantal release of acetylcholine are apparent in the different forms of botulinum toxin. With type B cleavage of VAMP only, the stimulated release of acetylcholine quanta is inhibited. In contrast, with type A cleavage of SNAP 25, both stimulated and spontaneous quantal release of acetylcholine are inhibited. This difference may be associated with more significant denervation responses in muscle affected by type A toxin, with greater alteration of resting membrane potential and frequency of abnormal spontaneous activity. These differences may be reflected in single-fiber electrophysiologic studies.

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