Infant girl with progressive hypotonia

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The Case

A 9-month-old girl is brought to the emergency department for evaluation after 3 days of poor feeding and 1 day of decreased activity.  She is normally breastfed and has recently taken pureed solids. Over 3 days she has shown less interest in feeding and has produced no stools and fewer wet diapers. The day prior to presentation, she was no longer crawling or pulling herself to stand. On the morning of evaluation, she is no longer able to lift her head. WHAT'S THE DIAGNOSIS? READ ON TO FIND MORE CLUES.

Physical examination

Physical exam is remarkable for a listless infant who is still able to make eye contact and be reassured by her mother. Her temperature is 98.9°F; heart rate is 174 beats per minute; respiratory rate is 30 breaths per minute; and weight is 20 lb, 4.5 oz, which is above the 95% percentile for age. She is normocephalic and her anterior fontanel is soft and flat. Her lungs, heart, and abdominal exams are unremarkable. She has good peripheral perfusion and her skin has no rashes or lesions.

On neurologic exam, the girl has transient visual attention but she cannot track objects fully. Her pupils are slowly reactive to light. She has mild bilateral ptosis and her expressions demonstrate mild symmetric facial weakness. She has a prominent head lag and is unable to lift her head from the prone position. She is able to sit upright without support but is unable to pull herself to stand. She moves all her extremities and has normal extremity tone and intact reflexes with no clonus.

The infant's white blood cell count is 12.7 x10³/mcL with 47% neutrophils, 43% lymphocytes, and 9% monocytes. Her chemistries are remarkable for a bicarbonate of 17 mEq/L; urea nitrogen, 11 mg/dL; and creatinine, 0.2 mg/dL. Urinalysis reveals 4+ ketones and a specific gravity of 1.025. Cerebral spinal fluid studies including cell count and protein are all normal and cultures are obtained. Head computed tomography (CT) results are unremarkable. The patient is admitted to the hospital for further evaluation and management.

Differential diagnosis

On further examination, this previously well infant shows loss of developmental motor milestones and the presence of cranial nerve (CN) palsies including ophthalmoplegia and facial weakness as well as a significant head lag. The differential diagnosis for hypotonia in infancy is extensive.¹ Acquired rather than congenital hypotonia focuses the differential diagnosis. The presence of CN palsies narrows the differential even further (Table). A systematic approach to hypotonia by determining the level of the neurologic lesion is helpful in directing evaluation toward the final diagnosis.

Altered mental status suggests central pathology including infarction, brainstem encephalitis, and metabolic encephalopathy.¹ Mental status can be challenging to assess in infants but observing their level of awareness can be helpful. The patient is able to make eye contact and demonstrate stranger anxiety while recognizing and being reassured by her parent. Furthermore, there is a lack of upper motor neuron findings such as hyperactive reflexes suggesting a central nervous system cause although this can be variably present, especially early in the clinical presentation. Head CT is reassuring assessing for acute bleed or infarction but magnetic resonance imaging should be considered if there is strong concern for other central etiologies.

Intact mental status suggests peripheral nervous system pathology including lower motor neuron, neuromuscular junction, and muscular disorders. Lower motor neuron disease (Guillain-Barrè syndrome, spinal muscular atrophy [SMA]) often presents with hypoactive or absent reflexes, which are not seen in this patient. Guillain-Barré syndrome classically presents with ascending symmetric weakness, although the Miller-Fisher variant can initially present with ophthalmoplegia and ataxia. Spinal muscular atrophy can present any time during infancy with progressive generalized weakness. The SMA type 1 (Werdnig-Hoffman disease) is the most common and severe form often presenting during early infancy whereas SMA type 2 and 3 each present later during infancy with a less severe clinical course.

Neuromuscular junction disease often presents with normal or hypoactive reflexes and demonstrates fatigability of muscles on repeated stimulation (pupillary response, suck), but it may be difficult to assess. Infant botulism presents initially with constipation and poor feeding with CN palsies and a descending symmetrical weakness.² Congenital myasthenic syndromes are a variety of disorders resulting in failure of nerve transmission through cholinergic synapses and can have a variable clinical presentation including age of onset. Toxicities would be unlikely without suspicion of specific exposures (aminoglycosides, magnesium).

Muscular disorders demonstrate hypoactive or absent reflexes, again not demonstrated in this infant. Congenital muscular myopathies and dystrophies are a heterogeneous group of disorders that often present at birth but that can also have a variable presentation.

Nonneurologic causes, particularly systemic diseases such as sepsis and metabolic disorders, also should be considered in any listless infant. The absence of other acute infectious or systemic signs and the presence of focal neurologic findings point toward an underlying neurologic cause. Initial chemistries and cerebral spinal fluid results are reassuring.

Diagnosis

The patient also presents with associated signs of dehydration. On further history, it is revealed there is construction occurring in the neighborhood. The infant presenting with poor feeding, constipation, and cranial palsies makes infant botulism a primary concern. Serum and stool studies for botulism toxin are sent. The patient deteriorates overnight and is no longer able to sit upright, demonstrating progressive hypotonia involving her trunk and extremities as well as the loss of her gag reflex. As a consequence, she is transferred to the intensive care unit and botulism immune globulin (BabyBIG) is administered intravenously by hospital day 2. Clostridium botulinum toxin B is eventually detected in her stool and the diagnosis of infant botulism confirmed.

Infant botulism

Infant botulism is uncommon with only 90 laboratory-confirmed cases per year in the United States between 2006 and 2010.² It typically occurs any time in the first 12 months of life with a median age of 3 to 4 months.³ Infant botulism is caused by C botulinum, a gram-positive spore-forming obligate anaerobic bacilli. Cases occur from ingestion of C botulinum spores that typically originate from the soil, although food sources such as honey and canned foods are also implicated. Most cases occur in a geographic distribution where soil supports the spores, such as California, Utah, and Pennsylvania.⁴

Disruption of the soil where spores exist, such as with construction, places neighboring infants at risk of spore ingestion. Spores germinate in the infant's immature gastrointestinal tract that has yet to be fully populated with competitive normal flora. Furthermore, there is an association with the transition from breast milk and the introduction of formula or solid foods, which are thought to change bowel flora allowing spores to germinate.⁵ The C botulinum spores produce 8 neurotoxin types A to G but only A, B, E, and F are implicated in infant botulism. Types A and B account for the vast majority of infant botulism in the United States. The neurotoxins block acetylcholine release into the neuromuscular junction, preventing muscle contraction and resulting in muscle paresis.

Clinical manifestations are based on neurotoxin activity on cholinergic synapses and their respective terminal effectors. In the gastrointestinal tract, this can manifest as constipation, often the first sign of infant botulism.⁶ Cranial nerve palsies may be demonstrated by eye abnormalities (ophthalmoplegia and abnormal pupillary response); poor suck manifesting as poor feeding; and weak cry and gag. A classic symmetric, descending paralysis starting from the muscles of the head and neck and progressing to the trunk and extremities manifests as weakness and hypotonia. Ultimately, diaphragmatic involvement can result in respiratory failure. Autonomic involvement can result in heart rate and blood pressure lability. Clinical progression can occur quickly over hours to days and persist for weeks to months.

Electrophysiology studies can be helpful but are not diagnostic. Normal nerve conduction studies with an abnormal electromyography suggest pathology at the neuromuscular junction, although this is not specific for infant botulism. Detection of C botulinum neurotoxin confirms the diagnosis. Toxin is detected in the serum of only 1% of cases of infant botulism.²

Stool should be obtained by enema to ensure an adequate sample of at least 10 ml of enema effluent to detect both C botulinum spores and toxin but it may take several days for results. Clinical suspicion should guide treatment even in the absence of laboratory confirmation² and should be directed by the California Department of Public Health (24-hour hotline: 510-231-7600; www.infantbotulism.org/). Supportive care should focus on both respiratory and nutritional support. Respiratory complications are prevented though airway positioning and monitoring for the need for intubation. Nutritional compromise is avoided by early enteral feeding.

Antibiotics should be avoided, particularly aminoglycosides, which can potentiate neuromuscular blockade. Human BabyBIG has demonstrated remarkable efficacy. When compared with placebo, patients with infant botulism types A or B treated with BabyBIG have a decreased hospital length of stay (2.6 vs 5.7 weeks, respectively), intensive care length of stay (1.8 vs 5 weeks), and mechanical ventilation (1.8 vs 4.4 weeks) with significant cost savings per patient despite the expense of BabyBIG.⁷

Patient outcome

The patient in intensive care is closely monitored for airway compromise and early nasogastric feeds are initiated. She regains her gag reflex and avoids intubation, so she is transferred back to the pediatric ward on hospital day 4. She continues to gradually regain her strength and is able to sit upright and fully feed on her own by hospital day 8, when she is discharged. Her remarkably short and uncomplicated hospital course is attributed to early recognition and treatment of infant botulism. On her 1-month outpatient follow-up visit, she has regained her strength and is nearly back to baseline, according to her parents.

Conclusion

Hypotonia in infancy is challenging given the extensive differential diagnosis, so a systematic approach including a detailed history and physical examination should be undertaken to help focus the diagnostic evaluation. Distinguishing congenital versus acquired hypotonia is a useful first step in the evaluation process. In addition, determining the level of the neurologic lesion is helpful to further narrow the differential.

Infant botulism is a rare disease, but given the spectrum of clinical presentation, it may be underdiagnosed and is often unrecognized early. Any infant who presents with constipation and feeding difficulty in association with CN palsies and hypotonia should make one suspicious. Given the rapid and severe clinical progression and the time taken to detect C botulinum toxin, efficacious treatment with BabyBIG should be based on clinical suspicion rather than laboratory confirmation.

REFERENCES

1. Peredo DE, Hannibal MC. The floppy infant: evaluation of hypotonia. Pediatr Rev. 2009;30(9): e66-e76.

2. American Academy of Pediatrics. Botulism and infant botulism (Clostridium botulinum). In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, eds. Red Book: 2012 Report of the Committee on Infectious Diseases. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012.

3. Koepke R, Sobel J, Amon SS. Global occurrence of infant botulism, 1976-2006. Pediatrics. 2008;122(1):e73-e82.

4. Thompson JA, Filloux FM, Van Orman CB, et al. Infant botulism in the age of botulism immune globulin. Neurology. 2005;64(12):2029-2032.

5. Fox CK, Keet CA, Strober JB. Recent advances in infant botulism. Pediatr Neurol. 2005;32(3):149-154.

6. Risko W. Infant botulism. Pediatr Rev. 2006;27(1):36-37.

7. Arnon SS, Schechter R, Maslanka SE, Jewell NP, Hatheway CL. Human botulism immune globulin for the treatment of infant botulism. N Engl J Med. 2006;354(5):462-471.

Dr Cho is associate professor of pediatrics, Division of Academic General Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California. He has nothing to disclose in regard to affiliations with or financial interests in any organizations that may have an interest in any part of this article.