Hypoglycemia and a Weak Cry in a 4-month-old Infant

A 4-month-old term male infant presents to the emergency department with poor feeding in late summer. His mother reports that he has not been breastfeeding well for the past 2 days and is acting more sleepy. His latch feels “gentle” to mom, and he does not feed for more than a few minutes. On the day of presentation, he has 2 very brief feeds but has otherwise been sleeping. He normally stools daily, but his last stool was 3 days ago and was yellow and seedy. He has not voided in the past 24 hours. He has not had any vomiting or fevers. No one in the home is ill or had a recent illness, and the patient does not have cough or rhinorrhea. He was born at 38 weeks at home via spontaneous vaginal delivery for a planned home birth. His birthweight was 3,360 g (50th percentile), and he has continued to grow along the same growth curve. He received a vitamin K injection after delivery and has received his 2- and 4-month vaccines. His state newborn screen is normal. He has been exclusively breastfed, and according to his parents, he has been healthy and developing normally. He lives in a rural area without any pets. His parents deny any recent insect bites or contact with animals.In the emergency department, he is afebrile (temperature, 98.7°F [37.1°C]), with a pulse of 155 beats/min, blood pressure of 86/58 mm Hg, respiratory rate of 28 breaths/min, and oxygen saturation of 100% on room air. His weight is 15.7 lb (7.12 kg) (33rd percentile), length is 26.8 in (68 cm) (70th percentile), and head circumference is 16.9 in (43 cm) (55th percentile). He is sleeping and wakes easily with the examination but quickly falls back asleep. His anterior fontanelle is open, soft, and flat, and there are no external signs of head trauma. He has normal cardiovascular and respiratory examination findings except for a weak cry. His abdomen is soft, without masses palpated. His penis is uncircumcised, with bilateral testes descended. On his neurologic examination, he is a sleepy infant with normal tone but mild head lag. Cranial nerves II-XII are grossly intact, including his pupils are briskly reactive to light, and he has a normal gag reflex. It is difficult to fully assess his strength due to his sleepiness, but he has normal reflexes.A fingerstick blood glucose level is 39 mg/dL (2.2 mmol/L) (reference range, 60–120 mg/dL (3.3–6.7 mmol/L]), and an abdominal radiograph shows prominent loops of bowel without free air or pneumatosis. He is given a dextrose fluid bolus with improvement in his blood glucose level to 75 mg/dL (4.2 mmol/L). He seems briefly more alert and is able to breastfeed for 5 minutes.Further laboratory values (reference ranges in parentheses) are obtained and include white blood cell count, 9,600/μL (9.6 × 109/L) (5,000–13,000/μL [5–13 × 109/L]); hemoglobin, 12.0 g/dL (120 g/L) (9.5–14 g/dL[95–140 g/L]); platelet count, 721 × 103/μL (721 × 109/L) (163–369 × 103/μL [163–369 × 109/L]); sodium, 143 mEq/L (143 mmol/L) (136–145 mEq/L [136–145 mmol/L]); potassium, 4.7 mEq/L (4.7 mmol/L) (4.1–5.3 mEq/L [4.1–5.3 mmol/L]); chloride, 106 mEq/L (106 mmol/L) (98–107 mEq/L (98–107 mmol/L]); carbon dioxide, 18 mEq/L (18 mmol/L) (20–31 mEq/L [20–31 mmol/L]); creatinine, 0.38 mg/dL (33.6 μmol/L) (0.2–0.4 mg/dL [17.7–35.4 μmol/L]); blood urea nitrogen, 19 mg/dL (6.8 mmol/L) (9–23 mg/dL [3.2–8.2 mmol/L]); calcium, 10 mg/dL (2.5 mmol/L) (8.7–10.4 mg/dL [2.2–2.6 mmol/L]), and normal transaminase levels. Urinalysis is notable for moderate ketones but is otherwise normal. C-reactive protein and lactic acid levels are normal. Thyroid test results are appropriate for age. His urine drug screen is negative.Due to his abnormal abdominal radiograph and sleepiness, abdominal ultrasonography is performed and does not show intussusception. A head computed tomographic scan is also ordered and normal. When he returns from radiology, his mother reports that the patient has been sleeping and did not fuss with the ultrasonography or transportation. She also notes a new “gurgling” noise in the back of his throat. Further history and tests confirm his diagnosis.In this patient with hypotonia and a weak cry, the differential diagnosis includes sepsis, drug ingestion, poliomyelitis, acute flaccid myelitis, infantile botulism, seizure disorder, encephalitis/meningitis, myasthenia gravis, Guillain-Barre syndrome (GBS), spinal muscular atrophy (SMA), mitochondrial disorders, and heavy metal poisoning. (1)(2) An infectious etiology is thought to be less likely as he is afebrile with a normal white blood cell count and C-reactive protein level. SMA was moved lower on the differential diagnosis due to the patient’s acute onset of symptoms; SMA presents with a progressive weakness over weeks to months. (1) Poliomyelitis usually has asymmetrical clinical findings and a cerebrospinal fluid pleocytosis, (1) which was not the case in this patient. And GBS presents with an ascending paralysis and is rare in children younger than 1 year. (1)On repeated examination, the patient progressively develops pooling of his saliva, bilateral ptosis, sluggishly reactive pupils, an expressionless face, significant head lag, areflexia in his upper extremities, and generalized weakness, so he is intubated for further evaluation. An electroencephalogram is obtained and is normal. A brain magnetic resonance image is somewhat concerning for leptomeningeal enhancement, but a repeated study 48 hours later is normal. A lumbar puncture is normal, with no evidence of cerebrospinal pleocytosis, cytoalbuminologic dissociation, oligoclonal banding, or microbiologic evidence of viral or bacterial meningitis. The results of the lumbar puncture make meningitis and GBS much less likely. Furthermore, because the magnetic resonance image does not show any gray matter changes to suggest acute flaccid myelitis, no further viral testing is performed, including for enterovirus D68. On further questioning of the parents, they report that the infant ate a few French fries dipped in sweet and sour sauce before admission, but the ingredient list does not include honey. He also rode on a tractor with his father on several occasions. Due to concern for ingestion of botulism spores (possibly while riding on the tractor), the Infant Botulism Treatment and Prevention Program is contacted, and they recommend treating with human botulism immune globulin intravenous (BIG-IV).Lactulose and an enema are given to help the infant stool, and the stool is sent to the state laboratory for botulism testing. He is extubated to high flow nasal canula 24 hours later. He continues to have a weak cry and areflexia, so he is additionally treated with intravenous immunoglobulin. During the next week, his strength begins to recover, and he is breastfeeding well, so he is discharged home. Shortly after discharge, his stool returns positive for botulinum toxin type B, confirming the diagnosis of infant botulism.Infant botulism occurs in infants 12 months of age or younger and is caused by ingestion of Clostridium botulinum spores. Most cases (>90%) have been in infants 6 months and younger. (2) And nearly all cases in the United States are caused by C botulinum toxin type A or type B. (2) Honey is a known source of C botulinum spores, so it is not recommended for infants younger than 12 months even if pasteurized. As infants age, the intestinal flora changes and prevents colonization by C botulinum spores. (2) But in most cases, there is no clear source of the spores, and it is likely acquired by swallowing spores in dust. (2)The spores colonize the infant’s large intestine and produce a neurotoxin that is absorbed into the bloodstream. The toxin binds irreversibly to the neuromuscular junction (NMJ) and leads to a symmetrical, descending paralysis. (2) The first symptom is generally constipation although it is often missed initially; poor feeding is usually the first symptom identified by parents and leads to presentation. (2) Other symptoms include ptosis, sluggish pupils, flat or expressionless facies, loss of suck and gag reflexes, weak cry, hypotonia, and generalized weakness. (2)Pupillary fatigue (shining a light in the pupil to maximal constriction and then letting the pupil dilate and repeating for 1–3 minutes until the pupillary constriction becomes sluggish) is often seen with infant botulism. (2)(3) Also, the initial movement of the infant trying to move away from the bright light will decrease because repeated muscle activity leads to fatigability. (2)(3)The diagnosis requires stool, but due to constipation, “an enema with sterile, nonbacteriostatic water” is usually needed to obtain stool. (2) The stool specimen is tested for C botulinum toxin, often at the state laboratory.Treatment of infant botulism is with BIG-IV, which is a human-derived botulinum antitoxin, and it must be obtained from the California Department of Public Health by contacting the Infant Botulism Treatment and Prevention Program. (3) The antitoxin binds the open NMJ receptors but does not displace the toxin, so treatment stops the progression of symptoms but does not reverse the current symptoms. Because BIG-IV has a half-life of 28 days, when the NMJ receptors are regenerated, the antitoxin can block additional toxin from binding. (2)(4)Complete recovery can take weeks, with constipation being the last symptom to improve. (2) It is important to treat with BIG-IV when infant botulism is suspected and not to wait for the diagnostic testing. Treatment with BIG-IV within 1 week of being admitted to the hospital decreases the mean hospital stay to just 2.5 weeks (compared with 5.5 weeks without treatment). (4) Live virus vaccine administration should be delayed until 6 months after BIG-IV is given. (3)Supportive care is critical in treating infant botulism; nearly 75% of infants require admission to the ICU. (4) All patients with suspected infant botulism should have cardiac, respiratory, and transcutaneous carbon dioxide monitoring. The latter is the most sensitive index of clinical deterioration in these patients. (2)(3) An endotracheal tube is needed to protect the airway in approximately half of all patients. (4) Nasogastric tube feedings with expressed breast milk promote gut motility. (2) In severe disease, patients may have bladder atony and subsequent urinary tract infection, so urine output should be monitored closely. (3) If a patient does have urinary retention, catheters should be avoided due to the risk of infection. The Credé method of gentle manual pressure on the bladder will usually allow it to empty. (3)Antibiotics should be avoided unless there is a secondary infection because they cause lysis of C botulinum, which increases neurotoxin absorption and worsens symptoms. (2) Specifically, aminoglycosides potentiate the action of the toxin at the NMJ and should not be used. (3) Because the toxin does not cross the blood-brain barrier, the motor symptoms resolve with time. (2) Similarly, sensation remains intact, so tactile and auditory stimulation should be provided to these infants while admitted to the hospital. (2)(3)Clinicians should include infant botulism on their differential diagnosis when an infant presents with poor feeding, weak cry, and sluggishly reactive pupils.Contact the Infant Botulism Treatment and Prevention Program (infantbotulism.org) if you have clinical concerns for infant botulism.Do not delay treatment with human botulism immune globulin intravenous for infants with suspected botulism while awaiting stool testing.Human botulism immune globulin intravenous decreases length of stay significantly when given within 1 week of being admitted to the hospital.