SAMIR S. SHAH
HISTORY OF PRESENT ILLNESS
An 8-day-old girl presented to the emergency room after an episode of irregular, rapid breathing followed by stiffening of her body and shaking of her extremities that lasted several seconds. On arrival, the infant was lethargic, cyanotic, and brady-cardic with minimal spontaneous respirations. She underwent emergent endotracheal intubation and received multiple boluses of normal saline, with improvement in her perfusion and heart rate. She then had a generalized seizure and received intravenous lorazepam. Ampicillin and cefotaxime were administered after a blood culture was obtained. According to the family, she had fed poorly that day and had been sleeping more than usual. The infant had been afebrile and had normal stooling and urine output. There was no vomiting, diarrhea, or rashes. There were no ill contacts.
The infant weighed 3400 g at birth and was the product of a full-term gestation. She was born by spontaneous vaginal delivery after an uncomplicated pregnancy. Maternal serology was negative. The infant’s postnatal course was remarkable only for mild jaundice that did not require phototherapy. The mother denied a history of genital herpes simplex virus (HSV) infection. There was no family history of seizures.
T 39.0°C; RR 20/min; HR 180 bpm; BP 86/45 mmHg; SpO2 100% in room air
Weight 25th percentile; Head Circumference 50th percentile
Examination revealed a mechanically ventilated infant. She was sedated but withdrew to painful stimuli. The fontanelle was bulging. There were no head lacterations or skull depressions. The sclera were anicteric, and the pupils were 1.5 mm and symmetrically reactive. There were no cardiac murmurs, and the femoral pulses were weakly palpable. The lungs were clear to auscultation. The abdomen was soft, and the umbilical stump was well healed without erythema or discharge. There were two pustules in the perineal area.
Laboratory results were as follows: sodium, 132 mEq/L; potassium, 3.3 mEq/L; chloride, 99 mEq/L; bicarbonate, 23 mEq/L; glucose, 73 mg/dL; calcium, 8.9 mg/dL; and magnesium, 2.1 mg/dL. The complete blood count revealed 8000 WBCs/mm3, including 33% band forms, 18% segmented neutrophils, 35% lymphocytes, and 10% monocytes. The hemoglobin and platelet count were normal. On cerebrospinal fluid (CSF) examination, there were 879 WBCs/mm3 (48% segmented neutrophils, 19% lymphocytes, and 33% monocytes) and 1739 RBCs/mm3; no organisms were seen on Gram staining. The CSF glucose was 36 mg/dL, and the protein concentration was 400 mg/dL. CSF was sent for bacterial culture and detection of HSV by polymerase chain reaction (PCR). There were no abnormalities on chest radiograph.
COURSE OF ILLNESS
In the intensive care unit, the patient received ampicillin, gentamicin, and acyclovir. A head computed tomogram (CT) was normal, and the patient’s neurologic examination improved quickly during the next day. She was extubated on the second day of hospitalization but required replacement of the endotracheal tube due to multiple episodes of apnea. Electroencephalogram (EEG) revealed status epilepticus. Sustained seizure control was observed only after the addition of phenobarbital and phenytoin. Because HSV was not detected in the CSF by PCR, acyclovir was discontinued. Growth of an organism from the CSF on the third day of hospitalization guided additional therapy.
DISCUSSION CASE 19-1
Seizures are a feature of almost all brain disorders in the newborn. The time of onset of the first seizure is helpful in determining the cause. The cause of neonatal seizures occurring after the first 72 hours of life includes intracranial infection, intracranial hemorrhage, metabolic abnormalities, developmental defects, and drug withdrawal. Intracranial infections occur in 5%-10% of neonatal seizures. Common bacterial causes in the age group include group B Streptococcus (GBS) and Escherichia coli; Listeria monocytogenes is less common. E. coli may cause ventriculitis or brain abscesses (Figure 19-1). Early-onset GBS infection typically includes bacteremia, pneumonia, and meningitis. Late-onset GBS infection (infection beyond the first week of life) may include meningitis with other foci of infection, such as osteomyelitis (Figure 19-2), arthritis, and cellulitis-adenitis syndrome. Seizures with HSV typically occur during the second week of life and 30% of infected infants present with a vesicular rash. Congenital infections, particularly cytomegalovirus and Toxoplasma gondii, may present with seizures in the context of intracranial calcifications. The calcifications tend to be periventricular for cytomegalovirus and diffuse for toxoplasmosis (Figure 19-3). Intracranial hemorrhages are frequently associated with hypoxic-ischemic or traumatic birth injury. Intraventricular hemorrhages principally occur in the premature infant, and subarachnoid and subdural hemorrhages usually occur in the term infant. Metabolic abnormalities include disturbances of glucose, calcium, magnesium, and sodium. Hypocalcemia is associated with low birth weight, asphyxia, maternal diabetes, transient neonatal hypoparathyroidism, and micro-deletions of chromosome 22q11. Other metabolic abnormalities include inborn errors of metabolism, especially aminoacidurias, because protein and glucose feedings have been initiated. Aberrations of brain development are usually related to a disturbance of neuronal migration such as lissencephaly, pachygyria, and polymicrogyria. Passive addiction of the newborn and drug withdrawal may involve narcotic-analgesics (methadone), sedative-hypnotics (shorter-acting barbiturates), cocaine, alcohol, and tricyclic antidepressants. In the case described, the results of CSF analysis suggested an intracranial infection, but interpretation of the Gram stain was misleading.
FIGURE 19-1. Brain MRI of an infant with meningitis caused by Escherichia coli. The MRI shows a large multiseptated cystic lesion within the right cerebral hemisphere with irregular peripheral enhancement. There is inflammation of the adjacent lateral ventricle and choroid with mass effect.
FIGURE 19-2. Lower leg radiograph of an infant with late onset group B Streptococcal osteomyelitis. The radiograph demonstrates an area of focal bony erosion (arrow) at the medial metaphyseal region of the proximal right tibia associated with faint periosteal reaction.
FIGURE 19-3. Computed tomography of the head in an infant with congenital toxoplasmosis. There are scattered intracranial calcifications, predominantly involving the cortex and subcortical white matter.
The diagnosis is meningitis due to L. monocytogenes, a Gram-positive rod. On the fourth day of hospitalization, the organism was noted to have only intermediate susceptibility to ampicillin. The patient was switched to intravenous vancomycin, and gentamicin was continued. CSF from the lumbar puncture, repeated on the sixth day of hospitalization, was sterile. Head CT was repeated on the eighth day of hospitalization and revealed bilateral frontal, parietal, and temporal lobe infarcts but no ventriculomegaly. Mechanical ventilation was required until the ninth day of hospitalization. The infant was discharged after 21 days of antibiotic therapy.
INCIDENCE AND EPIDEMIOLOGY
Listeria monocytogenes, a motile Gram-positive rod, was first isolated in 1926 during an investigation of epidemic perinatal infection among a colony of rabbits. It is a common veterinary pathogen that causes meningoencephalitis in sheep and cattle. It is widespread in the environment and is found commonly in soil and decaying vegetation. Many foods are contaminated with this organism; it has been recovered from raw vegetables, fish, poultry, beef, prepared meats, unpasteurized milk, and certain types of cheese. The organism has been isolated from the stools of 5% of healthy adults, and higher rates of recovery have been reported for household contacts of patients with clinical infection. Infection in humans is uncommon but occurs most frequently in neonates, pregnant women, and elderly or immunosup-pressed patients. Human infection occurs most commonly following ingestion of contaminated food, but it can also occur through direct animal contact, as has been documented in veterinaries and farmers, and through vertical transmission from mother to neonate, either transplacentally or through an infected birth canal. Approximately 30% of all L. monocytogenes infections occur in neonates.
Neonatal L. monocytogenes infection, like group B streptococcal infection, manifests in both an early-and late-onset form. Clinical manifestations of L. monocytogenes infection are similar to those of other neonatal bacterial infections. Signs of infections include temperature instability, respiratory distress, irritability, lethargy, and poor feeding.
In early-onset disease, transplacental transmission after maternal bacteremia or ascending spread from vaginal colonization leads to intrauterine infection with L. monocytogenes. The neonate can also acquire the infection during passage through an infected birth canal. Pregnancy complications, including preterm labor, spontaneous abortion, and stillbirth, are common among infants with early-onset L. monocytogenes infections; length of gestation is less than 35 weeks in approximately 70% of cases. There is often evidence of an acute febrile maternal illness, with symptoms of fatigue, arthralgias, and myalgias preceding delivery by 2-14 days. Blood cultures are positive for L. monocytogenes in 35% of mothers of infants with early-onset listeriosis.
Early-onset infection classically develops within the first or second day of life. Bacteremia (75%) and pneumonia (50%) are usually seen with early-onset infection. Meningitis is seen in 25% of early-onset cases. In severe infection, a granulomatous rash is associated with disseminated disease (granulomatosis infantiseptica). The mortality rate, including stillbirths, is 20%-40% in early-onset infections.
In late-onset infection, the mode of transmission is poorly understood but mechanisms unrelated to maternal carriage may be involved. Late-onset infection develops during the second to eighth week of life, often in full-term infants following uncomplicated delivery. The most common form of L. monocytogenes infection during this period is meningitis, which is present in approximately 95% of cases. Bacteremia (20%) and pneumonia (10%) are less common. Mortality of late-onset infection is generally low (15%) if the infection is diagnosed early and treated appropriately. The presentation of late-onset infection can be subtle, and may be characterized by temperature instability, irritability, poor feeding, and lethargy.
A nosocomial outbreak occurred when nine newborn infants were bathed in mineral oil contaminated with L. monocytogenes. The affected infants developed bacteremia (two cases), meningitis (two cases), or both (five cases); one infant died. Signs of infection developed within 1 week after exposure to the mineral oil.
Lumbar puncture. Isolation of the organism from culture of CSF is the only reliable means of diagnosing meningitis due to L. monocytogenes. The finding of short, sometimes coccoid, Gram-positive rods on microscopic examination of the CSF strongly supports the diagnosis of L. monocytogenes meningitis. However, because of the low concentrations of organisms, most (60%) Gram-stained smears of CSF from infants with L. monocytogenesmeningitisdo not reveal bacteria, as occurred with the infant in this case.
Furthermore, L. monocytogenes sometimes does not stain clearly as Gram positive. In such cases, variable decoloration on Gram staining may cause the organism to appear as a Gram-negative rod and be confused with H. influenzae, especially with longstanding disease or when the patient has received prior antibiotics. In other instances, Listeria has been mistaken for Streptococcus pneumoniae or Corynebacterium spp. CSF glucose is normal in more than 60% of cases of L. monocytogenes meningitis. CSF is often purulent with mononuclear cells predominance in one-third of cases. CSF protein is often elevated, with increasing levels correlated with a poor prognosis.
Additional studies. PCR probes and antibodies to listeriolysin O, the major virulence factor of the organism, have not proved useful for acute diagnosis of invasive disease.
Ampicillin is the preferred agent in the treatment of L. monocytogenes infections. Based on synergy studies in vitro and in animal models, most authorities suggest adding gentamicin to ampicillin for the treatment of meningitis due to L. monocytogenes. There appears to be partial synergy with combinations of ampicillin or vancomycin with rifampin. Vancomycin alone has been used successfully in a few penicillin-allergic adult patients, but others have developed listerial meningitis while receiving the drug. Trimethoprim-sulfamethoxazole is effective in penicillin-allergic patients, but should not be used in neonates because of the concern for bilirubin toxicity. Cephalosporins are not active against L. monocytogenes. Once susceptibility studies become available, changes in therapy may be necessary. The recommended duration of therapy for L. monocytogenes meningitis is 14-21 days.
Corticosteroids should be avoided, if possible, because impairment of cellular immunity due to corticosteroid therapy is a major risk factor for the development of listeriosis. A maternal history of a previous infant with perinatal listeriosis is not an indication for intrapartum antibiotics.
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