Infantile Botulism Case File

Infantile Botulism Case File

Eugene C. Toy, MD, Ericka Simpson, MD, Pedro Mancias, MD, Erin E. Furr-Stimming, MD

CASE 27

A 4-month-old baby girl is brought to the emergency department by her parents with a history of constipation, poor feeding, and weak cry over the past 72 hours. The mother notes that the baby has been constipated for at least 1 week prior to the onset of decreased oral intake. She has also noticed that the baby is unable to suck from a bottle as well as before, and is unable to hold her head up. The baby girl has been irritable. Over the past 24 hours she has developed weakness in her arms, and this morning she was found to have weakness in her legs. On physical examination, the baby is noted to be hypotensive with a blood pressure of 70/30 mm Hg and profoundly hypotonic. She is unable to track with her eyes, and she has marked pooling of her oral secretions. Deep tendon reflexes (DTRs) are reduced.

▶ What is the most likely diagnosis?

▶ What is the next step to confirm the diagnosis?

▶ What is the next step in therapy?

ANSWERS TO CASE 27:

Infantile Botulism                                                    

Summary: A 4-month-old baby girl presents with a 1-week history of constipation and a 72-hour history of poor feeding and weak cry. She has been noted to have difficulty sucking on a bottle, holding her head up, and moving her arms and legs. Her examination is notable for hypotension, hypotonia, generalized hyporeflexia, and weakness of the extraocular muscles.

• Most likely diagnosis: Infantile botulism.
• Next diagnostic to confirm diagnosis: Obtain stool samples to isolate Clostridium botulinum spores and botulin toxin.
• Next therapeutic step: Admit to the intensive care unit (ICU) since respiratory failure can ensue in more than 70% of affected infants, give aggressive supportive care including nasogastric feeds and ventilatory support, and administer antitoxin human botulism immunoglobulin intravenously.

ANALYSIS

Objectives

1. Describe the common clinical manifestations of infantile botulism and food-borne botulism.
2. Understand the pathophysiology of botulism.
3. Know how to treat infantile botulism.

Considerations

This 4-month-old infant presents with profound generalized weakness of the peripheral nervous system. This is based on the findings of generalized hypotonia, hyporeflexia, and weakness. The history is critical in this case as it describes a descending weakness as opposed to an ascending weakness often seen in Guillain-Barré syndrome (GBS). The presence of autonomic dysfunction with hypotension and constipation is key to diagnosing this infant. Although dysautonomia may be seen in patients with GBS, the pattern of developing weakness is different (ascending in GBS and descending in botulism); additionally, GBS is rare in children younger than 1 year. Hypotonia can also be seen in central nervous system (CNS) diseases such as meningitis and encephalitis; however, the absence of fever favors a diagnosis of botulism or other processes. Other considerations in the differential diagnosis include toxic causes, such as heavy metals, organophosphates, and anticholinergics, and metabolic causes, such as Reye syndrome, hepatic encephalopathy, hypermagnesemia, hypothyroidism, and organic acidurias. Other neuromuscular causes to consider include poliomyelitis, GBS, congenital myasthenia gravis (excluded by neonatal and maternal history), muscular dystrophy, and spinal muscular atrophy. Poliomyelitis is asymmetric and is associated with an elevated white blood cell counts (WBCs) in the cerebrospinal fluid (CSF), whereas spinal muscular atrophy will not affect the autonomic nervous system.

APPROACH TO:

Infantile Botulism                                        

DEFINITIONS

INFANTILE BOTULISM: A subacute neuroparalytic disease caused by intestinal colonization with C. botulinum toxin type A or B that typically occurs when spores are ingested.

ELECTROMYOGRAPHY (EMG) WITH REPETITIVE NERVE STIMULATION STUDIES: An electrophysiologic test that evaluates motor unit action potentials and function at the neuromuscular junction. When performed at different frequencies, it is helpful in differentiating a presynaptic neuromuscular junction transmission disorder such as botulism from a postsynaptic neuromuscular junction transmission disorder such as acquired myasthenia gravis.

DYSAUTONOMIA: Dysfunction of the autonomic nervous system manifested by tachycardia, bradycardia, hypotension, hypertension, hyperthermia, hypothermia, blurred vision, xerostomia, constipation, diarrhea, bladder urgency, bladder hesitancy, erectile dysfunction, hyperhidrosis, or anhydrosis.

CLINICAL APPROACH

Infantile botulism is caused by a neurotoxin produced by C. botulinum, a spore-forming anaerobic gram-positive bacillus found in soil. There are seven distinct types (A-G) described based on different types of toxins produced. Infantile botulism is specifically caused by types A and B. Type E is also associated with disease in humans, whereas types C and D cause disease in birds and fish as well as nonhuman mammals.

In adults, normal intestinal flora prevents colonization of C. botulinum in the gut. However, in infants, normal intestinal flora has not developed, and as such intestinal colonization of C. botulism can take place. Colonization typically occurs in the cecum. Toxins are produced and absorbed throughout the intestinal tract after colonization occurs. The toxin irreversibly binds to presynaptic cholinergic receptors at motor nerve terminals and is then internalized. Inside the cell, the toxin acts as a protease, damaging membrane proteins, inhibiting the release of acetylcholine, and disrupting exocytosis. Thus, the inhibition of acetylcholine release results in disruption of neurotransmission between the nerve and end plate on the muscle.

In the United States, 95% of infantile botulism occurs in patients younger than 6 months. Approximately 60 cases of botulism are reported each year, and infantile botulism is the most common form of botulism in the United States with the majority of cases found in Utah, Pennsylvania, and California. The two most commonly recognized sources of botulinum spores are honey and soil contamination. A history of honey consumption is seen in almost 15% of cases reported to the Centers for Disease Control and Prevention (CDC). Thus, honey should not be given to infants younger than 1 year. The typical incubation period is anywhere from 3 to 30 days. A lack of history of ingestion of honey should not deter one from evaluating and treating a patient for botulism if all the signs and symptoms are consistent with this diagnosis.

Food-borne botulism accounts for almost 1000 reported annual cases worldwide. Type B contamination is most commonly seen in Europe, whereas type A is more commonly seen in China. Outbreaks in Alaska, Canada, and Japan have been reported with type E. The majority of cases in the United States occur from home-canned vegetables.

The clinical presentation of infantile botulism includes constipation, feeding difficulties, hypotonia, respiratory difficulties, cranial nerve abnormalities, and hyporeflexia. The most common signs and symptoms at the time of hospital admission include weakness, poor feeding, constipation, lethargy, weak cry, irritability, and respiratory distress. Constipation is often the first symptom and can precede the other symptoms by several weeks. Dysautonomia can occur early in the disease prior to signs of weakness. Ptosis, lack of ocular motility, facial weakness, and mydriasis can also be noted. Weakness occurs in a descending fashion beginning in the head and working its way down the limbs. Respiratory distress is a late sign in the disease but can quickly result in respiratory failure requiring intubation and mechanical ventilation. Poor anal sphincter tone is also described.

The clinical presentation for food-borne botulism includes progressive symmetric descending weakness or paralysis affecting the muscles of the head followed by those of the neck and then the limbs. Sensation and cognitive function are normal. Respiratory distress occurs from diaphragmatic weakness and airway obstruction. Half of affected patients have dilated or unreactive pupils. Other symptoms include dysphagia, dysarthria, diplopia, dry mouth, dysphonia, and diminished gag. Gastrointestinal symptoms such as nausea, vomiting, and diarrhea often precede the neurologic symptoms.

Serum samples for botulinum toxin are frequently negative in infantile botulism; thus, the preferred modality for diagnosis is from infant fecal specimens. Diagnosis is supported by the isolation of C. botulinum spores from stool samples and confirmed by the presence of botulinum toxin in stool. A minimum of 25 to 50 g of feces is required to detect C. botulinum spores and its toxin. Enema fluids may be required in constipated individuals; however, a passed stool sample is preferred. The collected sample should be placed in a sterile container and refrigerated. Laboratory confirmation via mouse bioassay is performed by the CDC or state health departments. It is important to highlight that stool anaerobic cultures can often take 6 days to identify an organism and initial detection of toxin can take between 1 and 4 days to result; therefore, antitoxin therapy should not be delayed in cases of suspected infantile botulism and should be given as soon as possible. Clinical presentation and EMG with repetitive nerve stimulation study aid in early diagnosis of infant botulism while confirmatory stool studies are pending. The EMG findings of decreased amplitude of motor units in two muscle groups, tetanic and posttetanic facilitation (>120% of baseline at stimulation rates >10 Hz), and absence of posttetanic exhaustion are supportive for the diagnosis of infantile botulism.

Treatment

Any infant with clinical findings suspicious for infantile botulism should be hospitalized, closely monitored, and given supportive care including mechanical ventilation, nasogastric tube feedings, etc. Most will require ICU care because 70% of infants experience respiratory depression and may require intubation and mechanical ventilation. Treatment is with antitoxin and should be administered as soon as possible. Treatment should not be delayed while awaiting confirmatory tests. The botulinum immunoglobulin has been shown to shorten hospital stay, reduce severity of illness, and decrease total cost of hospitalization.

Botulinum immunoglobulin is a human-derived antitoxin that is effective against types A and B toxins; however, in cases where human botulinum immunoglobulin is inaccessible due to cost, equine botulinum antitoxin is an effective and safe alternative. Antibiotics are not indicated in infantile botulism because of the concern for increased lysis of bacteria causing increased release and availability of toxin for gastrointestinal absorption. The infant case fatality rate is less than 2%, and on average, infants will spend 44 days in the hospital. Rare cases of relapse have been reported with no known predictors identified. Most relapses occur within 2 weeks of being discharged from the hospital.

For suspected infant botulism occurring in any state, the California Department of Health Services, Infant Botulism Treatment and Prevention Program should be contacted at www.infantbotulism.org or 510-231-7600.

COMPREHENSION QUESTIONS

27.1 A newborn infant has a history of poor suck, poor oral intake, diffusely decreased muscle tone and strength. He responds to noxious stimuli with a weak cry. He is also noted to have external ophthalmoplegia, reactive pupils, facial weakness, and absent DTR’s. What is the likely diagnosis?

A. Infantile botulism

B. Neonatal myasthenia gravis

C. GBS

D. Meningitis

27.2 A 5-month-old baby girl just admitted to the ICU presents with a history of constipation, poor feeding, decreased spontaneous movement, and reduced DTRs. Which of the following diagnostic tests is useful in evaluating this patient with suspected infantile botulism?

A. Serum test for botulinum toxin

B. CSF studies for botulinum toxin

C. EMG with repetitive nerve stimulation studies

D. Pharyngeal culture for botulinum toxin

27.3 A 73-year-old man presents to the emergency room complaining of diplopia, blurred vision, dysphagia, and xerostomia. His examination reveals ptosis, impaired ocular motility, dilated pupils, symmetrical weakness in the arms and legs, and normal cognitive function. Which of the following would be most consistent with his presentation?

A. Antecedent gastrointestinal disease with nausea, vomiting, and diarrhea

B. Loss of sensation in a glove and stocking distribution

C. A history of eating honey from California

D. Normal EMG with repetitive nerve stimulation studies

ANSWERS

27.1 B. This is likely a case of transient neonatal myasthenia gravis. This is due to transplacental IgG antibodies against ACh receptors. Mothers typically have a history of myasthenia gravis however, may be asymptomatic themselves. The vast majority of the patients with transient myasthenia gravis are symptomatic at the time of birth. Detection of ACh receptor blocking, binding, or modulating antibodies can be helpful. Treatment is typically supportive but may need intramuscular neostigmine to help with strength and feeding for a few days/weeks. Prognosis is excellent barring any complications of the transient blocking of the ACh receptors. The presence of reactive pupils and normal DTRs points away from infantile botulism. Likewise, the presence of normal DTRs is unlikely in GBS. The absence of fever makes it unlikely that this is meningitis.

27.2 C. Fecal cultures and not pharyngeal cultures are the best way to diagnose infantile botulism. EMG with repetitive nerve stimulation studies are key in making the diagnosis of infantile botulism.

27.3 A. This case is illustrative of food-borne botulism, which is known to have normal sensation and normal cognitive function. Nausea, vomiting and diarrhea are common antecedent complaints. EMG with repetitive nerve stimulation studies will be abnormal. Botulism from spores in honey occurs primarily in infants. Glove and stocking sensory loss (B) is more likely with diabetes, whereas botulism-related symptoms usually progress from the head and eyes downward. Eating honey from California (C) is not a risk factor for botulism in adults.

    CLINICAL PEARLS    

▶ Infantile botulism is the most common cause of botulism in the United States. ▶ Infantile botulism is proven to be acquired from spores in soil or in honey in only 15% of cases. ▶ Classic presentation for infantile botulism includes antecedent constipation with descending paralysis, ptosis, dilated or unreactive pupils, and weakness in the arms and legs. ▶ The best way to test for infantile botulism is through stool samples via a mouse bioassay. ▶ More than 70% of infants with botulism will eventually require mechanical ventilation.

REFERENCES

Arnon SS, Schecter R, Maslanka SE, et al. Human botulism immune globulin for the treatment of infant botulism. N Engl J Med. 2006;354(5):462-471. 

Chalk CH, Benstead TJ, Keezer M. Medical treatment for botulism. Cochrane Database Syst Rev. 2014;(2):CD008123. 

Cherington M. Clinical spectrum of botulism. Muscle Nerve. 1998;21:701-710. 

Hodowanec A, Bleck TP. Botulism (Clostridium botulinum). In: Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennetts Principles and Practice of Infectious Diseases. 8th ed. Philadelphia, PA: Elsevier Saunders; 2015:2763. 

Thompson JA, Filloux FM, Van Orman CB, et al. Infant botulism in the age of botulism immune globulin. Neurology. 2005;64:2029-2032. 

Vanella de Cuetos EE, Fernandez RA, Bianco MI, et al. Equine botulinum antitoxin for the treatment of infant botulism. Clin Vaccine Immunol. 2011;18(11):1845-1849. 

Wigginton JM, Thill P. Infant botulism. A review of the literature. Clin Pediatr (Phila). 1993;32: 669-674.

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