Symptom-Based Diagnosis in Pediatrics (CHOP Morning Report) 1st Ed.

CASE 12-3

Three-Month-Old Boy

SAMIR S. SHAH

HISTORY OF PRESENT ILLNESS

A 3-month-old boy was referred from his pediatrician to the emergency department for evaluation. The parents state that 5 days ago they noticed a change in his stooling pattern. Instead of the usual 4 stools per day, he began passing only one stool per day and now he has not stooled in 2 days. He was taken to the pediatrician for evaluation of his constipation. They note that his feeding intake had decreased from vigorous breastfeeding every 3 hours to relatively poor feeding attempts, often requiring to be wakened for feeds. On the day of admission, they commented that he was not holding onto his pacifier well and that he has been drooling more over the past week. He was also not holding his head up as well as he did 2 weeks ago. He has had no fevers and otherwise his review of systems was negative.

MEDICAL HISTORY

There were no complications during the mother’s pregnancy or the infant’s birth. His birth weight was 4100 g. Nasolacrimal duct obstruction that was noted shortly after birth resolved by 2 months of age. His development had been progressing normally.

PHYSICAL EXAMINATION

T 36.5°C; RR 47/min; HR 175 bpm; BP 87/39 mmHg; SpO2 96% on room air; Weight 6.3 kg

The initial examination revealed an infant in no acute distress. He was awake and alert, but not making any vigorous movements. He had a weak cry, moderately weak gag. His heart sounds were normal. Femoral pulses were strong and capillary refill was brisk. His abdomen was soft without organomegaly. He had poor truncal tone. The remainder of the physical examination was normal.

DIAGNOSTIC STUDIES

Electrolytes, blood urea nitrogen, creatinine, and glucose were normal except for a bicarbonate level of 16 mEq/L. Serum aminotransferases and bilirubin were normal. The WBC count was 11 400/mm3 (71% segmented neutrophils, 25% lymphocytes, 3% monocytes); hemoglobin, 9.5 g/dL; and platelets, 425 000/mm3. Examination of the cerebrospinal fluid (CSF) revealed 3 WBCs/mm3 and 10 RBCs/mm3. CSF protein was 24 mg/dL and glucose was 67 mg/dL. There were no organisms on CSF Gram stain. Blood, CSF, and urine cultures were obtained.

COURSE OF ILLNESS

The infant was treated with intravenous cefotaxime for presumed bacterial infection while awaiting culture results. On the third day of hospitalization, his respiratory effort worsened, he had difficulty handling oral secretions, and his gag reflex was diminished requiring endotracheal intubation. What is the most likely diagnosis?

DISCUSSION CASE 12-3

DIFFERENTIAL DIAGNOSIS

Infectious diseases such as meningitis and encephalitis must be considered in any child presenting with lethargy. Dehydration can cause lethargy and altered stooling patterns. Children with viral or bacterial gastroenteritis usually have vomiting or diarrhea though constipation may be present in the severely dehydrated child. Neonatal myasthenia gravis may cause with neurologic abnormalities including lethargy and ptosis but does not usually cause constipation or changes in stooling pattern. Additionally, myasthenia gravis typically presents with a waxing and waning course. Several inborn errors of metabolism may present with lethargy but usually cause other symptoms such as vomiting or irritability. Congenital myopathies (e.g., myotubular myopathy, central core disease, nemaline rod disease) can cause muscular weakness and hypotonia. Focusing on the change in stooling pattern in this patient, hypothyroidism must also be considered as a cause. Tick paralysis is rare in infants but manifests as symmetrical ascending flaccidity; gait abnormalities are the initial manifestation in older children. Guillain-Barré syndrome, though rare in children, should also be considered. Guillain-Barré syndrome manifests as an ascending paralysis resulting from an acute inflammatory polyradiculoneuropathy; a key clinical finding is cytoalbuminemic dissociation (elevated CSF protein without elevation of CSF white blood cells). The Miller-Fisher variant of Guillain-Barré syndrome presents with the triad of ataxia, areflexia, and ophthalmoplegia. Other possible diagnoses include poliomyelitis, anticholinergic poisoning, intracranial hemorrhage from accidental or nonaccidental trauma, cerebrovascular accident, and intussusception. However, the constellation of neurologic changes associated with the change in stooling pattern most strongly suggest infant botulism.

DIAGNOSIS

On examination, the infant had marked hypotonia. Due to the rather rapid progression of symptoms, infant botulism was suspected. EMG revealed a modest decremental response, consistent with infant botulism. A stool sample was positive for Clostridium botulinum toxin, confirming the diagnosis of infant botulism. He received botulism immune globulin on the fourth day of hospitalization. He was extubated on the tenth day of hospitalization and required nasogastric feeds for a total of 3 weeks.

INCIDENCE AND EPIDEMIOLOGY

Botulism results from exposure to Clostridium botulinum spores (e.g., infant botulism, wound botulism) or toxin (i.e., foodborne botulism, following injection of botulinum toxin for treatment of hyperhidrosis, muscle spasticity, cervical dystonia, and blepharospasm). Infant botulism occurs due to an intestinal infection by C. botulinum, an anaerobic, Gram-positive, spore-forming bacillus. Clostridium botulinum spores are ubiquitous in the environment and can be cultured from soil and many agricultural products. Honey is one dietary source linked to infant botulism by laboratory testing and epidemiologic studies. Corn syrup does not appear to be a risk factor for infant botulism. In the 1980s, a Food and Drug Administration study found botulism spores in commercially prepared corn syrup. Following changes in corn syrup production, spores have not been identified in corn syrup.

Clostridium botulinum spores from various sources are ingested by infants. These spores colonize the colon and release the organism. The organism produces a toxin that causes the disease. In contrast, the adult form occurs after ingestion of the preformed toxin. Botulism toxin is divided into types A-G, with types A, B, E, and F producing human disease. Cases occur in infants less than 1 year old, with 95% occurring during the first 6 months of life. The age-related vulnerability may be due to the lack of competitive flora and possibly to pH and motility. Affected infants are most commonly breastfed, Caucasian, and reside in rural or suburban areas. The intestinal microflora of breast fed infants as compared with bottle fed infants may make them more susceptible to colonization with C. botulinum. The organism produces a neurotoxin that is taken up by nerve endings and irreversibly blocks acetylcholine release in peripheral cholinergic synapses. Cranial nerves are usually affected first, leading to difficulty swallowing and loss of protective airway reflexes. The recovery phase begins when terminal motor neurons regenerate and new motor endplates develop.

CLINICAL MANIFESTATIONS AND COMPLICATIONS

Clinical signs and symptoms usually develop between 2 weeks and 6 months of age. Patients are afebrile. The typical evolution is a symmetric descending paralysis, progressing from muscles innervated by the cranial nerves to the upper and lower extremities proximally and then to the trunk and distal extremities.

Constipation is the classic initial complaint. Additional presenting complaints include poor feeding, weak suck, weak cry, and hypotonia. Although often described as lethargic, the infant is typically alert but unable to move or smile. Within a week of the initial presentation, additional neurologic symptoms are seen including ptosis, facial diplegia, dysconjugate gaze, weak suck, impaired swallowing or gag reflex, and worsening hypotonia. Paralysis develops in a descending manner; all cranial nerves are eventually involved. A normal initial response of the pupillary light reflex will fatigue with repeated stimulation over 1-2 minutes. This can be helpful in distinguishing infant botulism from congenital myasthenia syndromes. Deep tendon reflexes are initially normal despite profound hypotonia; hyporeflexia develops later in the course. Autonomic dysfunction is common. Decreased tearing and salivation gradually develop. Blood pressure and heart rate may fluctuate dramatically.

There are several complications that lead to the morbidity and mortality associated with infant botulism. Most infants have progressive weakness over a 1-2 week period culminating in respiratory failure. Inability to swallow or protect the airway from oral secretions leads to nasogastric tube feeding and endotracheal intubation. The symptoms remain at a nadir for 1-2 weeks before improving. Most infants require hospitalization for 4-5 weeks. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) occurs due to venous pooling, diminished left atrial filling, and subsequent stimulus for antidiuretic hormone production. SIADH complicates approximately 17% of cases. Secondary infections such as urinary tract infection and aspiration pneumonia also occur.

DIAGNOSIS

The clinical presentation usually suggests infant botulism but the definitive diagnosis is made by testing stool samples.

Detection of organism. A small enema with nonbacteriostatic water (not saline) may be used judiciously to obtain stool for diagnostic testing. The most reliable confirmatory test is detection of C. botulinumtoxin in the infant’s stool using the mouse inoculation toxin neutralization assay. Specimens for toxin assay are transported at 4°C to either the state health department or the Centers for Disease Control and Prevention laboratories for testing. C. botulinum can be cultured from stool after anaerobic incubation on selective egg yolk agar; however, this is rarely required given the reliability of the toxin assay. Serum testing reveals the diagnosis in fewer than 10% of cases.

Electromyography (EMG). EMG, though not typically necessary, will reveal the following: (1) motor unit action potentials of brief duration, small amplitude, and abundant motor-unit potentials (BSAP); (2) incremental response in the muscle action potential produced by high frequency stimulation; (3) normal nerve conduction velocity; and (4) no significant response to injection of edrophonium chloride or neostigmine (to distinguish this condition from myasthenia gravis).

Other studies. Lumbar puncture, often performed because of concern for meningitis, reveals normal CSF cell count, protein, and glucose. Once the diagnosis is made, serum electrolytes should be checked periodically to detect SIADH.

TREATMENT

Keys to successful management include early recognition, prompt treatment with Botulinum immune globulin, and attention to supportive care strategies to minimize disease-associated and iatrogenic complications (Table 12-4). Attention should be directed at protecting the airway, providing adequate ventilation and nutrition, and preventing complications.

TABLE 12-4. Important preventable complications of infant botulism.

Aspiration pneumonia

Urinary tract infection

Bacteremia/sepsis

Syndrome of inappropriate antidiuretic hormone

secretion

Seizures (hyponatremia)

Anemia

Fractures

Clostridium difficile-associated colitis

Endotracheal intubation, required by approximately 70% of children with infant botulism, should be performed when impairment of the infant’s ability to cough, gag, or swallow occurs. In the past, tracheostomies were performed in up to 50% of patients in anticipation of prolonged requirement for mechanical ventilation. Prior to the use of antitoxin, the mean duration of mechanical ventilation was 21 days. Currently, the duration of mechanical ventilation is shorter (median, 6 days; interquartile range, 2-11 days) and late sequelae of airway trauma induced by prolonged endotracheal intubation (e.g., subglottic stenosis) are rare. Prophylactic tracheostomy is not routinely required.

Nasogastric tube feedings are usually required during the course of illness to prevent aspiration of formula. Small volumes of continuous enteral feeding stimulates gut motility and obviates the need for central venous catheterization. Oral feeding can be resumed when the gag, swallow, and suck reflexes have returned. Intake, output, weight, and serum electrolytes must be carefully monitored during this period due to the risk of SIADH.

Antibiotic therapy is often started empirically while the meningoencephalitis and sepsis are excluded. Specific antibiotic therapy is not required for treatment of infant botulism but may be required to treat hospital-acquired infections. Aminoglycoside antibiotics may precipitate rapid deterioration of infants with infant botulism. They contribute to neuromuscular blockade and should be avoided in children in whom the diagnosis of infant botulism is suspected.

Botulism immune globulin intravenous (BIG-IV) has improved outcomes of patients with infant botulism. BIG-IV, derived from pooled plasma of adult volunteers, neutralizes free toxin. BIG-IV was licensed by the U.S. Food and Drug Administration in 2003 for sale by the California Department of Health Services as BabyBIG®. It has a half-life of approximately 28 days in vivo and a large capacity to neutralize botulinum toxin. A single infusion will neutralize for at least 6 months all botulinum toxin that may be absorbed from the colon of an infant. Treatment should not be delayed for confirmatory testing. While the cost per dose is approximately $50 000, treatment is the most cost-effective strategy.

In a double-blind, placebo-controlled randomized trial of 122 infants, BIG-IV or placebo was administered to infants with infant botulism within 3 days of their initial hospital admission. BIG-IV decreased the mean duration of hospitalization from 5.7 to 2.6 weeks, the duration of mechanical ventilation from 4.4 to 1.8 weeks, the duration of intensive care unit stay from 5.0 to 1.8 weeks, and the duration of nasogastric or intravenous feeding from 10.0 to 3.6 weeks. BabyBIG® is available only through the California Deparxtment of Health Services Infant Botulism Treatment and Prevention Program (www.infantbotulism.org or 510-231-7600). It is express-shipped to be given as a single dose. While administration within 3 days of hospitalization is most effective, administration within 4-7 days of hospitalization remains far more effective than no treatment. An open-label study of infants who received BIG-IV found that the mean length of stay was 2.0 weeks for the 287 infants treated within 3 days of hospital admission and 2.9 weeks for the 79 infants treated between 4 and 7 days of hospital admission. The illness usually lasts from 1 to 2 months and the prognosis is excellent. Case fatality rates are less than 1%.

Patients with infant botulism excrete C. botulinum toxin and organisms in their stools. These organisms may be excreted in stool for up to 3 months and, rarely, longer. Therefore, infected infants should not have close contact with other infants (e.g., sharing cribs, toys).

Most live virus vaccines (e.g., measles, mumps, rubella, varicella) should be delayed until 5 months after BabyBIG treatment as the antibodies in BabyBIG may interfere with the effectiveness of live vaccines. Most infants will not require delayed vaccine administration because most affected infants are younger than 6 months of age and the live virus vaccines are typically administered after 12 months of age.

SUGGESTED READINGS

1. Long SS. Infant botulism and treatment with BIG-IV (BabyBIG). Pediatr Infect Dis J. 2007;26:261-262.

2. Graf WD, Hays RM, Astley SJ, et al. Electrodiagnosis reliability in diagnosis of infant botulism. J Pediatr. 1992;120:747-749.

3. Hatheway CL, McCroskey LM. Examination of feces and serum for diagnosis of infant botulism in 336 patients. J Clin Microbiol. 1987;25:2334-2338.

4. Long SS. Clostridium botulinum (botulism). In: Long SS, Pickering LK, Prober CG, eds. Principles and Practice of Pediatric Infectious Diseases. 4th ed. New York: Elsevier Saunders; 2012:970-977.

5. Long SS. Epidemiologic study of infant botulism in Pennsylvania: report of the infant botulism study group. Pediatrics. 1985;75:928-934.

6. Olsen SJ, Swerdlow DL. Risk of infant botulism from corn syrup. Pediatr Infect Dis J. 2000;19:584-585.

7. Schreiner MS, Field E, Ruddy R. Infant botulism: a review of 12 years’ experience at The Children’s Hospital of Philadelphia. Pediatrics. 1991;87:159-165.

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

9. Underwood K, Rubin S, Deakers T, Newth C. Infant botulism: a 30-year experience spanning the introduction of botulism immune globulin intravenous in the intensive care unit at Children’s Hospital Los Angeles. Pediatrics. 207;120:e1380-e1385.

10. Arnon SS, Schechter R, Maslanka SE, Jewell MP, Hatheway CL. Human botulism immune globulin for the treatment of infant botulism. N Engl J Med. 2006;354:462-471.