A Severe Case of Enterovirus A71 Acute Flaccid Myelitis With Encephalitis

A 10-month-old, previously healthy female presented to a Tennessee pediatric emergency department in October 2019 with acute onset of unresponsiveness in the setting of 3 days of fever and emesis. In the days leading up to this presentation, she was evaluated in an emergency department and by her primary care pediatrician for fever and received intravenous fluids and antipyretics for an apparent viral illness. On the morning of presentation, she had persistent fever despite antipyretics, with somnolence that prompted her parents to seek emergency care. Upon arrival, she was noted to be tachypneic, tachycardic, and hypotensive with intermittent eye opening, impaired smooth pursuit eye movements, normal tone, preserved to slightly diminished reflexes, and apparent paralysis (no movement observed spontaneously or in response to physical stimulation). She received fluid resuscitation and broad-spectrum antibiotics. After initial resuscitation, she became hypertensive. She was admitted to the pediatric intensive care unit (ICU) and subsequently intubated on hospital day 1 (HD1) due to hypoxemia and apneic episodes. Hypotonia and hyporeflexia (1+) developed on HD2 with continued lack of spontaneous movement in all extremities despite intubation and no sedation or paralytic medications. Head computed tomography without contrast on HD1 was unremarkable. Complete blood count showed leukocytosis of 31 600/µL. Lumbar puncture on HD1 showed cerebrospinal fluid (CSF) pleocytosis (289 cells/mL: 63% lymphocytes, 25% monocytes/macrophages, 11% atypical lymphocytes, 1% neutrophils) with normal glucose and protein, elevated immunoglobulin G index (1.02), and absence of oligoclonal bands. Respiratory viral nucleic acid testing was positive for rhino/enterovirus. Electroencephalogram showed mild generalized nonspecific cerebral dysfunction without seizures. Magnetic resonance imaging (MRI) of the brain and cervical spine with gadolinium contrast on HD2 (Figure 1) showed low diffusivity and T2 prolongation without corresponding enhancement in the region of the anterior commissure, hippocampal tails, and dorsal brainstem. T2 prolongation extended into the cervicomedullary junction and cervical spine central gray matter. A thoracolumbar spine MRI obtained on HD10 showed longitudinally extensive T2 prolongation in the central gray matter of the lower cervical, thoracic, and lumbar spinal cord, along with enhancement of the ventral cauda equina nerve roots. Magnetic resonance imaging of brain/cervical spine (obtained on hospital day 2; A–E) and thoracolumbar spine (obtained on hospital day 10; F) without and with contrast. Axial diffusion-weighted imaging (A–C) showing low diffusivity in the region of the anterior commissure (arrows, A), hippocampal tails (arrowheads, A), dorsal pons (arrows, B), and dorsal medulla (arrows, C). Sagittal T2-weighed images of the brainstem and cervical spine (D) showing T2 prolongation in the dorsal brainstem (black arrow) extending into the cervical spinal cord (white arrow). An axial T2-weighted image of the cervical spinal cord showing T2 prolongation within the central gray matter (arrows, E). A sagittal T1-weighted post-contrast fat-suppressed image of the thoracolumbar spine showing anterior cauda equina nerve root enhancement (F). The patient’s clinical exam upon presentation raised concern for infectious and autoimmune processes. Infectious possibilities included meningoencephalitis (such as bacterial and viral infections including enterovirus-related acute flaccid myelitis [AFM] and arboviruses). The autoimmune inflammatory processes that were considered included neuromyelitis optica spectrum disorder with aquaporin-4 antibodies (NMOSD-AQP4-Ab) or myelin-oligodendrocyte glycoprotein antibody (MOG-Ab) demyelinating syndromes (acute demyelinating encephalomyelitis phenotype) given respiratory failure with severe weakness and initially preserved reflexes in all extremities. Brain MRI with supratentorial and brainstem abnormalities could be consistent with AQP4-Ab or MOG-Ab demyelinating syndromes. However, the viral prodrome, acute onset of paralysis, hypotonia, progressive hyporeflexia, pleocytosis, and longitudinally extensive T2 prolongation restricted to the gray matter of the entire spinal cord without evidence of contrast enhancement raised suspicion for AFM. Since the supratentorial MRI findings and encephalopathy were considered inconsistent with enterovirus D68 (EV-D68)–associated AFM, NMOSD was considered more likely (antibody testing was still pending at the time the treatment decision was made). The patient received high-dose intravenous methylprednisolone (30 mg/kg/day for 10 days followed by a 10-week taper) and plasma exchange (PLEX, 5 treatments over 10 days), followed by intravenous immunoglobulin (IVIG, 2 g/kg over 3 days). On HD7, she exhibited withdrawal to pain in the upper extremities and slight improvement in tone. Spontaneous movements and tone continued to improve with progression to spasticity and hyperreflexia on HD16 and extubation on HD17. She received 16 days of invasive mechanical ventilation (MV) and 7 days of noninvasive MV. After a 26-day ICU stay and a 34-day total hospital stay, she was discharged to an inpatient rehabilitation facility. Further laboratory evaluation showed negative cerebrospinal fluid (CSF) enterovirus polymerase chain reaction (PCR) and negative serum AQP4-Ab and MOG-Ab (obtained prior to PLEX). A stool specimen was cultured for enterovirus and determined to grow rhinovirus based on typical cytopathology, but this was not confirmed by molecular testing. Ultimately, enterovirus A71 (EV-A71) was identified in the stool by reverse transcriptase-PCR and sequencing of the VP1 gene. At her infectious disease outpatient follow-up visit in early December 2019, the patient exhibited new symptoms of myoclonic jerks while sleeping but had improved strength with continued hypertonia and hyperreflexia. By follow-up in neurology clinic mid-December 2019, the patient was able to bear weight independently and was starting to cruise along furniture again. She continued to have myoclonic jerks while sleeping. Follow-up brain and total spine MRI without and with contrast in late January 2020 demonstrated resolution of previously seen restricted diffusion. Minimal residual increased T2 prolongation was noted, along with improvement in signal abnormality in the spinal cord. EV-A71 is a non-polio enterovirus that typically causes mucocutaneous syndromes such as herpangina and hand-foot-and-mouth disease (HFMD). EV-A71 also has been associated with severe neurologic manifestations such as meningitis; rhombencephalitis characterized by myoclonus, ataxia, and upper motor neuron signs; and AFM. In contrast, EV-D68, which is more frequently identified than EV-A71 in the setting of AFM in the United States, typically causes respiratory tract infections with rare neurologic manifestations of paralysis and areflexia without supratentorial disease. Patients with EV-A71–associated AFM have been described to have better functional recovery than patients with EV-D68–associated AFM, demonstrated in a recent outbreak to have a higher prevalence of residual motor deficits [1]. Reports of EV-D68 to the Centers for Disease Control and Prevention (CDC) have risen rapidly in recent years, both actively detected in respiratory specimens and corresponding with outbreaks of AFM [2]. However, EV-A71 represented less than 1% of enteroviruses reported to the CDC from 2014 to 2016 [3]. Cyclical outbreaks of EV-A71 neurologic disease have been reported in Asia for decades, but reports in the United States have only been published as isolated cases until the Colorado outbreak in 2018. Despite the presence of neurologic disease in the Colorado patients, the virus was infrequently detected in CSF (20% of specimens tested) but typically identified at nonsterile sites such as the nasopharynx (56%), oropharynx (79%), and rectum (94%) [1]. Infrequent detection of EV-A71 in CSF was also seen in other case series outside of the United States [4]. This may be due, in part, to the more rapid clearance of virus from the CSF than from mucosal tissues and highlights the importance of obtaining viral PCR testing on multiple biologic specimens. Interestingly, our patient presented during the same season as the biennial EV-D68 and EV-A71 outbreaks (in October), but not in an even-numbered year, which is when outbreaks have occurred in the United States and can be expected to surge again this fall [2]. This makes it crucial to consider this diagnosis even in nonoutbreak years. Upon review of the literature, our patient’s presentation was consistent with EV-A71 AFM due to the constellation of viral prodrome, acute onset of paralysis, hyporeflexia, pleocytosis, spinal cord gray matter hyperintensity, and negative AQP4-Ab and MOG-Ab tests. However, the presentation differed in several ways from existing published cases [1]. EV-A71 neurologic disease typically presents with meningitis and/or rhombencephalitis. AFM occurs in less than one-quarter of cases, with a mean of 3 limbs involved. Our patient exhibited all 3 of these neurologic manifestations, with AFM affecting all 4 limbs. Autonomic instability typically manifests as hypertension, whereas our patient experienced both profound hypotension and hypertension. Few published studies have described MRI findings in EV-A71 infection. In our patient, MRI showed low diffusivity within the dorsal brainstem. Similar findings have been previously described in a small subset (8 of 38, 21%) of patients with imaging in a cohort of pediatric patients with EV-A71 neurologic disease [5]. These patients had pulmonary edema and adverse outcomes that were attributed to severe inflammation of the dorsal brainstem, as corroborated by histopathology. Supratentorial findings, as seen in our patient, were even more unusual (1 of 38, 3%) but are reportedly more common in EV-A71 infection compared with EV-D68 infection. Our patient also demonstrated a more severe course with extended intubation and ICU/hospital length of stay of weeks, which appears more typical of EV-D68 AFM than EV-A71 AFM [1]. Interestingly, a small case series reported an association between the degree of leukocytosis and severity of EV-A71 disease [4]. Therefore, the significant leukocytosis might represent a severe inflammatory response related to the patient’s extensive spinal cord abnormalities and quadriparesis requiring extended MV. Despite her severe presentation and improvement only after initiation of IVIG weeks into her illness course, she demonstrated near complete recovery, which is in line with other reported EV-A71 AFM cases. Little research is available on the associations between treatment modality or timing of therapy and neurologic outcome. Reported treatments have included IVIG, steroids, and PLEX, with no controlled studies to compare efficacy or the impact of time from onset to treatment. Treatment of HFMD with glucocorticoids in China, which was due to EV-A71 in more than 65% of cases, has been associated with increased odds of severe outcomes such as weakness, paralysis, encephalopathy, respiratory failure, and death [6]. Based on such observations, the World Health Organization has recommended against using steroids for the treatment of EV-A71–associated neuroinvasive disease. While we were unaware that this patient’s disease was associated with EV-A71 until after hospitalization, it is worth noting her favorable long-term recovery even after steroid treatment. While EV-A71 neurologic disease is rare, the clinical presentation can mimic autoimmune inflammatory conditions such as NMOSD or MOG-Ab demyelinating syndromes. Therefore, EV-A71 disease should be considered early in the clinical evaluation to avoid unnecessary long-term immunotherapy. The unusual features of this case also raise the possibility of either variation in or evolution of EV-A71 neurologic disease. Early testing of multiple biologic specimens in cases of suspected AFM is critical to identifying associated infections such as EV-D68 or EV-A71, which aids in larger scale observational studies of epidemiology, disease manifestations, treatment approaches, and prognosis. Financial support. This work was supported by the Pediatric Infectious Diseases Society-St. Jude Children’s Research Hospital Fellowship Program in Basic Research to M. R. V. Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.