Annals of B Pod - Infantile Botulism
/HISTORY OF PRESENT ILLNESS
The patient is a five-week old male presenting with poor feeding. The infant was born via spontaneous vaginal delivery at forty weeks to a Group B Streptococcus (GBS) positive mother who did not receive appropriate antibiotic therapy during delivery. The pregnancy was also complicated by oligohydramnios in the third trimester. Postnatal course has been uncomplicated, and the child has received all routine care. Patient is up to date on vaccinations.
The patient’s mother reports that he has been fed breast milk exclusively since birth, however two days ago he began to exhibit difficulties with feeding. He was noted to have poor latching with both the breast and bottle, resulting in decreased number of wet diapers. He has also been more irritable and lethargic, with a constant but weak cry. The patient was taken to the pediatrician’s office and was subsequently referred to the emergency department (ED) with concern for dehydration.
Past medical history: None
Past surgical history: None
Medications: None
Allergies: No known allergies
Physical exam
Vitals: T 36.9 HR 165 BP 95/73 RR 42 SpO2 99% on RA
The patient is a lethargic male infant who is quietly whimpering. His fontanelles are open, soft, and flat. He does not have a dysmorphic appearance. Mucous membranes are dry. Cardiopulmonary examination is unremarkable. Pulses are strong and symmetric in all extremities. Capillary refill is two seconds. There is globally decreased tone with weak suck but good grasp and normal reflexes. He is measured to be in the 50th percentile for height, weight, and head circumference.
Diagnostics
WBC: 5.1 Hgb: 14.3 Hct: 40.9 Plt: 420
Na: 138 K: 4.5 Cl: 106 HCO3: 21 BUN: 15 Cr: 0.24 Glucose: 59
Procalcitonin: <0.10
VBG: 7.36 / 36.7 / 21.2 / -4
UA: Negative
Influenza: Negative
CSF; Clear, RBC 11 / WBC 1 / gram stain negative
ECG: Normal sinus rhythm
CXR: Negative
Hospital Course
The patient’s initial presentation was concerning for a serious bacterial infection (SBI). He was resuscitated with 20 mL/kg of normal saline and 4 mL/kg of dextrose-containing fluid with little improvement in appearance. Blood, urine, and cerebrospinal fluid (CSF) cultures were obtained, and the patient was started on ceftriaxone and ampicillin empirically. He was admitted to the Neonatal Intensive Care Unit (NICU) for further care.
While in the NICU, the patient’s broad-spectrum antibiotics were continued. Respiratory viral panel was negative. Transthoracic echocardiography was obtained to evaluate for a cardiac etiology of the patient’s symptoms and was unremarkable. On hospital day two, the patient’s tone worsened and he was intubated for hypercapnic respiratory failure. Neurology was consulted and raised concern for infantile botulism. They also recommended obtaining an MRI of the brain, which was normal. Botulism stool studies were obtained and sent to the Ohio Department of Health for testing. The patient was started on baby botulism immune globulin (baby BIG). Antibiotics were discontinued after cultures showed no growth after forty-eight hours.
While awaiting results of botulism testing, alternative diagnoses were explored. Laboratory testing for spinal muscular atrophy and enterovirus were negative. Electromyography (EMG) demonstrated a presynaptic neuromuscular junction dysfunction consistent with botulism. The patient’s respiratory status improved after receiving baby BIG and he was extubated on hospital day five. The following day stool studies returned positive for botulinum toxin B. The patient’s tone and feeding gradually improved, and he was discharged on hospital day fourteen with mild residual hypotonia .
Botulism
Epidemiology and Pathophysiology
Botulism is a rare disease caused by exposure to neurotoxins from Clostridium botulinum, a spore-forming, gram-positive rod that is naturally present in soil, dust, and aquatic sediment. Botulism presents in several discrete clinical contexts, all of which cause symmetric flaccid paralysis. [1] Foodborne botulism is caused by the single consumption of food contaminated with pre-formed botulinum toxin (BT). It is a rare condition, with 109 outbreaks occurring in the United States (US) between 1920 and 2014. [2] Wound botulism is caused by the contamination and germination of C. botulinum within a wound. Although exceedingly rare, the number of cases has increased over the past two decades, primarily due to “skin popping” among intravenous drug users. [3]
Infantile botulism, the focus of this article, is by far the most common form of botulism, with 141 cases occurring in 2017. [4] The earliest reports of infantile botulism suggested an association with infant ingestion of honey. Epidemiologic data suggests honey ingestion-associated botulism occurs infrequently, though infants should still not be given honey until one year of age as a precautionary measure. Instead, a disproportionate number of cases occur in areas of recent soil disturbance such as agricultural regions and areas undergoing construction, raising the concern for transmission through repeated exposure to environmental spores. [5] Infantile botulism is caused by the gastrointestinal colonization and subsequent intra-intestinal toxin production of ingested C. botulinum. [6] Infantile botulism typically affects infants under six months of age, when the gastrointestinal flora is least developed. The well-developed gut flora found in adults and older children protects against intestinal colonization of C. botulinum, though cases of adult intestinal botulism have been described in patients with anatomic gastrointestinal tract abnormalities. [7]
All botulism infections are associated with production of BT, a potent neurotoxin that prevents the release of acetylcholine in the neuromuscular junction. Under normal conditions, depolarization at the pre-synaptic axon terminal causes acetylcholine to be released from the pre-synaptic membrane into the synaptic cleft. Acetylcholine release is facilitated by the soluble N-ethyl-maleimide-sensitive factor attachment protein receptor (SNARE) complex. [8] BT cleaves SNARE proteins within the pre-synaptic nerve, thereby preventing acetylcholine’s release into the synaptic cleft. [8]
Clinical Presentation
Image 1: Representative image of infantile hypotonia. Image courtesy of: Peredo DE, Hannibal MC. The Floppy Infant: Evaluation of Hypotonia. Pediatrics in Review. 2009;30(9).
Symmetric flaccid paralysis develops due to decreased acetylcholine within the synaptic cleft. Paralysis typically occurs in a descending fashion, with cranial nerve palsies oftentimes as the first presenting signs. Diplopia, one of the first presenting symptoms in adults, is difficult to detect in infants. Thus, cranial nerve dysfunction in infants is largely demonstrated by decreased gag and suck resulting in poor feeding. Diminished range of eye movement and ptosis can also be recognized on physical exam. Progressive hypotonia and weakness then follows. Autonomic symptoms such as constipation, decreased tearing, anhidrosis, dry mouth, and hypotension may also present early in the disease course. As the clinical course progresses, loss of deep tendon reflexes may invariably occur, and late stages typically involve paralysis of diaphragmatic muscles leading to respiratory failure. As expected, sensation is preserved given that the effect of BT is isolated to the neuromuscular junction. Clinical suspicion for infantile botulism should remain high in any patient presenting with cranial nerve deficits, hypotonia, constipation, or respiratory failure of unknown etiology. [9]
Diagnosis
Though a thorough history and neurologic examination are usually sufficient to make a preliminary diagnosis, stool bioassay remains the gold standard for diagnosis. [10] Unfortunately, botulism testing is a send out test at almost every institution and can take several days to result. As such, treatment should be initiated prior to confirmatory testing if clinical suspicion is high. Stool samples may also be difficult to obtain given that constipation is frequently seen in infantile botulism. If necessary, sterile water enemas may be used to obtain stool samples. Serum testing is rarely available, poorly sensitive, and of little utility. [10] EMG is of varying utility, thought to depend largely on timing of clinical course and amount of nerve stimulation that is occurring, [11] with patterns resembling a few other neuromuscular disorders, including Lambert-Eaton syndrome. Studies have shown that single fiber EMGs are more sensitive and specific, [12] and given this diagnostic test is usually readily available, it may support the diagnosis while awaiting stool confirmation. [13]
As infantile botulism is a relatively rare diagnosis, it may be missed on initial presentation, and clinical mimics do exist. A 2007 study found that from 1992 to 2005, five percent of patients treated with baby BIG were later found to have alternative diagnoses. [14] The most common final diagnoses were spinal muscular atrophy, metabolic disorders, and infectious diseases such as meningoencephalitis. [14] Viral encephalitis was chief among the missed infectious conditions. Many of the infants ultimately diagnosed with metabolic disorders would likely have been diagnosed at birth with the modern newborn screening implemented today, however the differential should remain broad when encountering an infant with change in muscle tone. [14]
Treatment
Supportive care is still a mainstay of ED and ICU management, and maintaining a broad differential diagnosis with a high suspicion for infantile botulism in the appropriate settings is vital to ensure that this diagnosis is not missed by emergency providers. If clinical suspicion is high, initiating diagnostic testing and therapy in concert with pediatric specialists is crucial as baby BIG remains the only curative therapy available for the treatment of botulism.
Baby BIG irreversibly binds to BT, thus preventing BT from exerting its effects at the neuromuscular junction. [15] In 2006, a landmark randomized-control study randomized 122 patients to receive baby BIG versus supportive care alone. [15] Baby BIG was found to reduce mean hospital length of stay by fifty-four percent, and similar decreases were seen in ICU length of stay, duration of mechanical ventilation, and duration of tube feeding. [15] Subsequent investigations have confirmed the efficacy of baby BIG, however note that the clinical effects are diminished if not administered within the first seven days of hospitalization. Therefore, empiric administration of baby BIG is recommended if clinical suspicion is high while awaiting stool studies. [16]
Baby BIG has a 28-day half-life and can usually be administered as a single dose. The drug is generally well tolerated, with the most common adverse effect being a transient erythematous rash. Serious immune reactions are very rare. Baby BIG is an orphan drug produced exclusively by the California Department of Public Health through their Infantile Botulism Treatment and Prevention Program (IBTPP). The on-call IBTPP physician must be contacted in order to obtain the drug. Many patients will receive antibiotics during initial presentation out of concern for SBI. While it makes intuitive sense to administer antibiotics to patients with infantile botulism given that it is caused by a bacterium, antibiotics are not recommended in confirmed cases of infantile botulism. Gastrointestinal colonization is typically self-limited, and antibiotics theoretically increase the risk of cell death and lysis, resulting in increased toxoid release and worsening paralysis. [15]
Prior to modern intensive care and the invention of baby BIG, mortality from botulism was estimated to be as high as sixty percent. [17] Infantile botulism mortality is difficult to fully characterize as it was only fully recognized as a disease entity in the 1970s, and for many years, had a purported association with sudden infant death syndrome (SIDS), both of which skew much of the data. [17] Thankfully, in the modern era, mortality is as low as two percent, and most patients make a full recovery with complete return of motor function. [18]
Summary
While quite rare, infantile botulism should remain on the differential for any infant presenting with hypotonia. The classic presentation will be symmetric, descending flaccid paralysis. Although stool assays remain the gold standard for diagnosis, recovery time is markedly hastened with early initiation of baby BIG, and treatment should be implemented prior to receiving confirmatory testing. Morbidity and mortality are markedly reduced with current therapies, with full recovery of neurologic function with early treatment.
AUTHORED BY DAVID HABIB, MD
Editing BY the Annals of B Pod Editors
References
Sobel, J. (2005). Botulism, Clinical Infectious Diseases, 41(8), 1167–1173
Fleck-Derderian, S., Shankar, M., Rao, A.K., Chatham-Stephens, K., Adjei, S., Sobel, J., Meltzer, M.I., Meaney-Delman, D., Pillai, S.K. (2017). The Epidemiology of Foodborne Botulism Outbreaks: A Systematic Review. Clinical Infectious Diseases, 66(1), 73-81
Peak, C.M., Rosen, H., Kamali, A., Poe, A., Shahkarami, M., Kimura, A.C., Jain, S., McDonald, E. (2019) Wound Botulism Outbreak Among Persons Who Use Black Tar Heroin – San Diego County, California, 2017-2018. Morbidity and Mortality Weekly Report, 67(5152), 1415-1418
Centers for Disease Control and Prevention (CDC). Botulism Annual Summary, 2017. Atlanta, Georgia: U.S. Department of Health and Human Services, CDC, 2019
Long, S.S. (2007). Infant Botulism and Treatment with BIG-IV (BabyBIG). Pediatric Infectious Disease Journal, 26(3), 261-262
Rosow, L.K., Strober, J.B. (2015). Infant botulism: Review and Clinical Update. Pediatric Neurology, 52(5), 487-492
Guru, P.K., Becker, T.L., Stephens, A., Cannistraro R.J., Eidelman, B.H., Hata, D.J., Brumble, L. (2018). Adult Intestinal Botulism: A Rare Presentation in an Immunocompromised Patient with Short Bowel Syndrome. Mayo Clinic Proceedings: Innovations, Quality & Outcomes, 2(3), 291-296
Dressler, D., Adib S.F. (2005). Botulinum Toxin: Mechanisms of Action. European Neurology, 53(1), 3-9
Cagan E, Peker E, Dogan M, Caksen H. Infant Botulism. The Eurasian Journal of Medicine. 2010;42(2):92-94
Fox, C.K. (2005). Recent Advances in Infant Botulism. Pediatric Neurology, 32(3), 149-154
Brook, I. Infant botulism. J Perinatol 27, 175–180 (2007)
Padua L, Aprile I, Monaco ML, et al. Neurophysiological assessment in the diagnosis of botulism: Usefulness of single-fiber EMG. Muscle & Nerve. 1999;22(10):1388-1392.
Cherian, A., Baheti, N.N., Iype, T. (2013). Electrophysiological Study in Neuromuscular Junction Disorders. Annals of Indian Academy of Neurology, 16(1), 34-41
Francisco, A.M.O., Arnon, S.S. (2007). Clinical Mimics of Infant Botulism. Pediatrics, 119(4), 826-828
Arnon, S.S., Schechter, R., Maslanka, S.E., Jewell, N.P., Hatheway, C.L. (2006). Human Botulism Immune Globulin for the Treatment of Infant Botulism. The New England Journal of Medicine, 25(12), 462-471
Payne, J.R., Khouri, J.M., Jewell, N.P., Arnon, S.S. (2018). Efficacy of Human Botulism Immune Globulin for the Treatment of Infant Botulism: The First 12 years Post Licensure. The Journal of Pediatrics, 193(2), 172-177
Dembek, Z.F., Smith, L.A., Rusnak, J.M. (2007). Botulism: Cause, Effects, Diagnosis, Clinical and Laboratory Identification, and Treatment Modalities. Disaster Medicine and Public Health Preparedness, 1(2), 122-134
Jackson, K.A., Mahon, B.E., Copeland, J., Fagan, R.P. (2015) Botulism Mortality in the USA, 1975-2009. The Botulinum Journal, 3(1), 6-17
Arnon, S.S., Midura, T.F., Clay, S.A., Wood, R.M., Chin, J. (1977). Infant Botulism: Epidemological, Clinical and Laboratory Aspects. The Journal of the American Medical Association, 237(18), 1946-1951
Peck, M.W. (2006). Clostridium botulinum and the safety of minimally heated, chilled foods: an emerging issue? Journal of Applied Microbiology, 101(3), 556-570
