A Fatal Case of Brainstem Encephalitis Caused by Human Parechovirus
There is increasing recognition of human parechovirus (HPeV) as a neurotropic virus, especially type 3, which can cause sepsis and encephalitis in young infants. We present a case of neonatal brainstem encephalitis caused by HPeV and review the fifteen published cases in the literature. This is the first report of HPeV causing brainstem encephalitis. Earlier use of polymerase chain reaction testing for HPeV should be considered in appropriate cases.
Keyword : Brainstem encephalitis; Human parechovirus; Neonate
Human parechovirus (HPeV) is a single-stranded non-enveloped RNA virus belonging to the picornaviridae family. HPeV 1 and 2, previously named echovirus 22 and 23, were discovered in 1961. HPeV type 3 was first reported in Japan in 2004, when it was isolated in the stools of an infant with transient paralysis.1 Subsequently more types of HPeV have been identified. To our knowledge, this is the first case of neonatal brainstem encephalitis caused by HPeV in the literature.
A female baby was born in good condition weighing 2.64 kg to non-consanguineous Somali parents. An emergency Caesarean section was performed for maternal pyrexia at 36 weeks gestation. Maternal high vaginal swab was positive for group B Streptococcus, and the baby was treated for one week with parenteral antibiotics. There was no significant family history of neurological or metabolic diseases. She subsequently presented at three weeks of age with a 24 hour history of poor feeding, irritability, seizures and apnoea. On admission, she was hypothermic (32 degrees Celsius) and hypotensive. She received fluid resuscitation and was intubated, ventilated, and transferred to Neonatal Intensive Care Unit (NICU), Great Ormond Street Hospital for Children, London. ?
She was treated for presumed neonatal sepsis with parenteral antimicrobials and acyclovir, as well as inotropes for cardiovascular instability. She was commenced on maintenance phenobarbitone for seizures, with levels within therapeutic range. The initial workup for infective aetiology did not identify a specific cause. Lumbar puncture was a slight traumatic tap. Cerebrospinal fluid (CSF) examination showed total white cell count of 25 x 106/L, with 100% lymphocytes, and red cell count of 250 x 106/L, CSF protein was raised at 1.7 g/dL. CSF and serum glucose were normal.
It was negative for cytomegalovirus DNA, enterovirus RNA, herpes simplex virus DNA by PCR. Bacterial cultures from CSF, blood, throat swab and stool were negative. Nasopharyngeal aspirate polymerase chain reaction (PCR) for rhinovirus 1 and 2, parainfluenza 1, 2 and 3, influenza A/B, Respiratory Syncytial Virus, human metapneumovirus, adenovirus and enterovirus were negative. Blood for Epstein-Barr virus viral capsid antigen immunoglobulin G was negative. Extensive metabolic screening was negative.
Sedatives were weaned off following cardiovascular stabilisation but she had very little spontaneous movement, no respiratory effort and bilateral pinpoint pupils. There was no improvement after a trial of naloxone. Electroencephalogram (EEG) at that time showed generally low amplitude but no evidence of encephalopathy or epileptic discharges. Magnetic resonance imaging (MRI) of the brain on day 3 of admission showed marked signal abnormality in white matter and swelling in the brainstem and upper cervical cord, with restricted diffusion, compatible with encephalitis (Figure 1). Somatosensory evoked potentials (SSEPs) performed on day 7 of admission obtained a response from cervical cord but no cortical response, indicating a severe disorder of brainstem function.
Blinking, corneal and gag reflexes were absent. Deep tendon reflexes were present. Repeated EEG showed frequent epileptiform discharges, and phenobarbitone was continued. Nerve conduction study and electromyography (EMG) showed normal conduction in legs, but motor and sensory studies were affected in the arms and her tongue was denervated. A second MRI brain scan on day 11 of admission showed resolving oedema with gliotic changes in the brainstem (Figure 1). A course of pulsed methylprednisolone and intravenous immunoglobulin did not result in any improvement. Further virological investigations were carried out, including a test for HPeV PCR in CSF, which was positive. The parechovirus RNA assay was developed in-house at Micropathology Ltd. Its target is the 5' UTR gene of HPeV type 1 to 6. It is a nested RT-PCR assay and the second round is performed on a realtime PCR device (Roche LightCycler) using Sybr Green and melting curve analysis as the detection method. ?
Her neurological state remained unchanged with absent brainstem reflexes and ventilator dependency. A third MRI brain scan on day 23 of admission showed a gliotic scar over the brainstem with resolution of edematous changes (Figure 1). EEG at that time showed decrease in the epileptiform discharges. SSEPs showed no response from the cord and cortical area. EMG showed denervation. Visual evoked potentials and electroretinography were normal. Clinical ethics and multidisciplinary team meeting was arranged to discuss withdrawal of care. Her treatment care was subsequently withdrawn and she passed away afterwards.
HPeV infections most commonly are enteric and respiratory, but sepsis, meningitis, encephalitis and hepatitis have been described.2 More severe diseases in the neonates comprising sepsis and encephalitis are associated with the recently emerged HPeV type 3.3 Almost all reported cases of HPeV encephalitis that were typed were due to type 3.4,5 In 1989, Koskiniemi et al presented a case of severe encephalitis caused by HPeV 1.6 Subsequently, fifteen more cases of HPeV encephalitis have been reported.4,5,7-9 Presenting symptoms are non-specific such as fever, irritability, seizure, apnoea and sepsis-like picture. MRI brain scans show particular patterns affecting white matter in internal capsule, periventricular area, corpus callosum, optic radiation and cerebral peduncles. Punctate lesions are also identified. The findings are derived from infection with different subtypes of human parechoviruses. Diagnosis is mainly by HPeV PCR in CSF. These children have variable prognosis (Table 1).
Its neurotropic property is further supported by Harvala et al who reported a predilection of HPeV type 3 to cause CNS infections in young infants.2 Similar result was found by Benshop et al.10 It had been postulated that the use of different cellular receptors may be the reason explaining the neurotropic property of HPeV type 3.11 The exact reason why neonates are susceptible to HPeV type 3 is not known. Ito et al found that only 56.5-73.9% of adults of child bearing age were seropositive for HPeV type 3, in contrast to 97% seropositivity of HPeV type 1.1 Lack of protective transplacental antibodies may well pose a high risk to neonates. Prospective studies on the prevalence would be very useful in understanding the impact of this virus.
Diagnosis of viral encephalitis in the neonatal period can be challenging as the immune and inflammatory response especially in the CSF might not be present. Herpes simplex virus and cytomegalovirus are readily treated in neonatal CNS infection. Wolthers et al analysed 716 CSF samples in young children previously tested for enterovirus PCR. They found that the addition of a virus-specific PCR led to a 31% increase in detection of a viral cause of neonatal sepsis or central nervous system symptoms in children aged <5 years. They concluded that HPeV could be the second most common cause of viral sepsis and meningitis in young children.3arly and accurate diagnosis can potentially lead to shortening the duration of antimicrobial and antiviral treatment.
Although there is no proven treatment for HPeV infection, accurate diagnosis and characterisation of HPeV infection is an important first step to a clearer understanding of its pathophysiology and eventually more effective treatments. From this case presented we would recommend earlier testing for HPeV by PCR in neonatal encephalitis of unknown origin.
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