A Seven-Month-Old Infant With Acute Onset of Neurologic Deterioration

Abstract

A 7-month-old Caucasian male infant presented in December 2006 with generalized weakness and loss of developmental milestones over the course of 3 days. The parents noted that he was no longer able to lift his head, sit, roll, crawl, or pull himself to a standing position. In addition, the child had lost the ability to grasp objects and did not seem to be able to track or focus on his parents’ faces. At times, his eyes appeared to cross or were rolled back. He did not show much facial expression even when crying, and his cry was weak and muffled. He had not been eating well and seemed to be drooling more often. His breathing was irregular at times. He had not had recent fever, vomiting, rash, diarrhea, constipation, or seizure activity. There was no history of a fall or trauma. Two weeks before the onset of his illness, the infant had been evaluated by his pediatrician for a mild cough and runny nose, which subsequently resolved without treatment. Several days before and during the current illness, he had been exposed to several sick children, including a 1-year-old girl who had been recently hospitalized for diarrhea and respiratory distress and a 7-month-old infant diagnosed with pneumonia. The patient’s medical history was unremarkable. He was born full-term by vaginal delivery. He had received his scheduled immunizations at 2 and 4 months of age. His family history was significant for maternal history of childhood seizures and maternal marijuana and methamphetamine use during pregnancy. The infant lived in a rural community of Northern California with his parents, a 2-year-old sibling, and some family friends. He had no known exposure to any animals except dogs. He had no history of recent travel or insect bites. On day 3 of his illness, the infant was taken to a local emergency department, where a computed tomography (CT) scan of the head was reportedly normal. Complete blood count (CBC) showed a white blood cell (WBC) count of 21,800/mm3 with 38% segmented neutrophils, 14% band forms, 43% lymphocytes, 5% monocytes, and 0% eosinophils. Hemoglobin was 12.6 g/dL and platelet count was 629,000/mm3. Serum electrolytes, blood urea nitrogen, creatinine, liver transaminases, total protein, albumin, and urinalysis were normal. A lumbar puncture (LP) revealed clear cerebrospinal fluid (CSF) with 3 WBC/mm3, 7 red blood cells (RBC)/mm3, protein of 56 mg/dL and glucose of 57 mg/dL. The Gram stain of the CSF showed no organisms, and the bacterial culture eventually yielded no growth. He was empirically treated with ceftriaxone and vancomycin, but these were discontinued once the CSF showed no evidence of bacterial meningitis. Because of drooling, gagging, and intermittent apneic episodes with associated oxygen desaturations down to 80%, he was transferred to the pediatric intensive care unit of Children’s Hospital & Research Center, Oakland. At admission, the child had a temperature of 35.8°C, heart rate of 108 beats/min, respiratory rate of 28 breaths/min, and blood pressure of 106/58. His weight was 8.3 kg (50th percentile), height was 69 cm (50th percentile), and head circumference was 46 cm (75th–90th percentile). Physical examination demonstrated an alert child with hoarse cry but normal chest, cardiovascular, abdominal, dermatological, and external genital exams. The neurologic examination was significant for inability to abduct his left eye, weak or absent movement of the lower face particularly on the left side, bilateral ptosis, weak suck, and drooling. His pupils were equally reactive. He was able to move all of his extremities against gravity, but muscle tone was decreased in upper and lower extremities. He could roll from supine to prone and lift his head off the bed, but there was significant head lag when he was pulled to sitting and he slumped forward when he was placed in a sitting position. The child had slight dysmetria of his right upper extremity but no tremor was noted. His patellar reflexes were brisk, and several beats of clonus were present at the right ankle but not at the left. Plantar reflexes appeared to be upgoing bilaterally. A magnetic resonance imaging (MRI) scan of the brain revealed an inhomogeneous, enhancing area of abnormal signal extending from the upper medulla to the dorsal pons. The area appeared to be swollen with expansion into the left cerebellopontine angle on T2-weighted images. Distortion of the fourth ventricle and mild enlargement of the third and lateral ventricles were also noted. An MRI of the spine was normal. The patient was given intravenous dexamethasone at 1 mg/kg/d divided every 6 hours to decrease the mass effect on his brainstem. His clinical response was dramatic. Within 4 days, his oral intake improved, and he began making eye contact and pushing himself up on his hands and knees. His tone remained decreased on his right side compared with his left, but his extraocular movements and facial weakness returned to normal. A repeat brain MRI at this point showed about a 75% decrease in the size of the abnormal area. A second LP performed on the seventh day of illness revealed 3 WBC/mm3, 0 RBC/mm3, protein of 24 mg/dL, and glucose of 65 mg/dL. The Gram stain of the CSF showed no organisms, and the bacterial culture again yielded no growth. A comprehensive evaluation for infectious etiologies was performed, and a test performed on this CSF sample revealed his diagnosis. For denouement see p. 1078. Denouement Continued from p. 1072. Specimens, including acute and convalescent sera, cerebrospinal fluid (CSF) (from the second lumbar puncture), and nasopharyngeal and throat swabs, were sent to the Viral and Rickettsial Disease Laboratory of the California Department of Health Services. Testing for Western Equine Encephalitis, West Nile Virus, herpes simplex virus, varicella zoster virus, Epstein-Barr virus, measles virus, Mycoplasma, Chlamydia, influenza virus, adenovirus, human metapneumovirus, respiratory syncytial virus, and parvovirus were negative. However, the patient’s CSF, as well as his nasopharyngeal and throat swabs, all tested positive for enterovirus by real-time polymerase chain reaction (PCR). Further subtyping of the enterovirus was unsuccessful. Based on these results and the pattern of his magnetic resonance imaging (MRI) abnormalities, the patient was diagnosed with brainstem encephalitis, or rhomboencephalitis caused by enterovirus. Enteroviruses cause a broad range of diseases, including nonspecific febrile and exanthematous illnesses, myocarditis, pericarditis, aseptic meningitis, and meningoencephalitis.1 Brainstem encephalitis or rhombencephalitis, although a less common manifestation, has been associated with epidemics of hand, foot, and mouth disease caused by enterovirus 71. These outbreaks have generally peaked during the summer and fall, but some have been reported during the winter. Other neurologic syndromes that have been described with enterovirus 71 include aseptic meningitis, encephalitis, cerebellar ataxia, cranial nerve palsies, Guillain-Barré syndrome, and acute flaccid paralysis.2–11 During a 1998 epidemic of hand-foot-and-mouth disease caused by enterovirus 71 in Taiwan, at least 130,000 persons were affected resulting in at least 405 hospitalizations for central nervous system (CNS) disease and 78 deaths, mostly from acute neurogenic pulmonary edema.12 The chief neurologic complication was rhombencephalitis.11 Neurologic symptoms began 2 to 5 days after the onset of fever or skin or mucosal lesions. Clinical manifestations included generalized myoclonic jerks with tremor, ataxia, ocular disturbances (nystagmus, strabismus, or gaze paresis), bulbar palsy (dysphagia, dysarthria, dysphonia, or facial weakness), hyporeflexia or areflexia, transient urinary retention, transient visual hallucinations, acute cardiopulmonary failure, and hyperventilation or Cheyne-Stokes respirations. The CSF in enteroviral meningitis or encephalitis usually is characterized by a mild pleocytosis with minimally elevated protein and normal glucose concentrations, although normal white blood cell counts can occur. In the 1998 epidemic in Taiwan, the mean CSF white blood cell count was 33/mm3 among patients with aseptic meningitis, 151/mm3 among those with acute flaccid paralysis, and 194/mm3 among those with rhomboencephalitis. There was no significant difference in the CSF glucose, protein, or lactate among these 3 groups.11 Enteroviral genome detection in the CSF by PCR remains the diagnostic test of choice. Although there have been no published studies on the sensitivity and specificity of PCR in patients with enteroviral encephalitis, in diagnosing enteroviral meningitis, PCR has been demonstrated to have a sensitivity and specificity of 86–100% and 92–100%, respectively.1 Descriptions of the MRI findings in enteroviral rhombencephalitis have been limited given the relatively recent availability of MRI technology and the infrequency of the disease. A report of MRI findings of patients with clinical signs of brainstem involvement during the 1998 enterovirus 71 epidemic in Taiwan described hyperintensity in the pons, the posterior portions of the medulla oblongata, and the most central part of the midbrain. Occasionally, hyperintense lesions were also noted in the bilateral dentate nuclei of the cerebellum, putamen, thalami, and ventral horns of the cervical spinal cord. Five patients who underwent MRI imaging between 2 weeks to 2 months after full recovery no longer had detectable abnormalities. Two patients who did not fully recover and continued to have neurologic deficits had persistent abnormalities on their MRI likely secondary to tissue destruction.13 Deaths caused by enterovirus 71 occur most often in children less than 3 years of age and are secondary to pulmonary edema and hemorrhage or brainstem encephalitis.2–11 Brainstem encephalitis because of enterovirus 71 has a case-fatality rate of about 14%.11 Of those children who survive, a significant proportion are left with residual neurologic deficits. In one study, 14% had cognitive, cerebellar, and/or cranial nerve dysfunction more than 2 years after initial hospitalization.14 In another recent study, children with enterovirus 71 infection and CNS involvement were followed for a median of 2.9 years.15 Of those with severe CNS involvement but without cardiopulmonary failure, 21% had neurologic sequelae, including 19% with focal limb weakness and atrophy and 2% with facial nerve palsy. In contrast, 75% of those with cardiopulmonary failure after CNS involvement had neurologic sequelae, including 64% with focal limb weakness and atrophy, 61% with dysphagia requiring tube feeding, 57% with central hypoventilation requiring ventilator support, 25% with facial nerve palsy, 18% with psychomotor retardation, and 14% with seizure activity. Cardiopulmonary failure after CNS involvement was also associated with delayed neurodevelopment and reduced cognitive functioning. Although our patient’s clinical improvement was temporally associated with dexamethasone therapy, the role of steroids in the treatment of enteroviral rhombencephalitis remains unclear. In one report describing a group of infants who had survived brainstem encephalitis caused by enterovirus 71, those treated with intravenous corticosteroids appeared to have less severe long-term neurologic disability than those not treated with steroids.16 In contrast, outcomes did not seem to be influenced by treatment with pleconaril or intravenous immunoglobulin (IVIG). Definitive conclusions about efficacy cannot be drawn because of the observational nature of this study and the small number of patients described. Our patient was discharged home on a prolonged tapering steroid course. Three months later, he was seen for follow-up by a neurologist whose examination was significant for mild right ptosis, brisk patellar reflexes, and mild unsteadiness. A repeat MRI of the brain at that time showed interval decrease in swelling involving the medulla and the pons. The patient was subsequently lost to follow-up. Although subtyping of the enterovirus in our patient was not successful, his MRI findings were consistent with those described among patients with rhomboencephalitis because of enterovirus 71. However, our case was a diagnostic challenge because the patient presented solely with neurologic findings localized to the brainstem but without the antecedent symptoms typically seen with enteroviral infection such as fever, rash, vomiting, diarrhea, or mucosal changes. In addition, his CSF lacked the degree of pleocytosis that is typical of enteroviral rhomboencephalitis. Because of the absence of these clues, the MRI of his brain was initially thought to be more concerning for a focal mass lesion rather than inflammation caused by a viral infection. It is, therefore, important for clinicians to consider enteroviral rhombencephalitis in the differential diagnosis of brainstem lesions. This entity can have significant mortality and morbidity. Further studies are needed to determine whether antiviral agents or immune modulators such as IVIG or corticosteroids have a role in treatment. ACKNOWLEDGMENTS Special thanks to Dr. Carol Glaser for her invaluable assistance.