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

Mok, Q

Prabhakar, P

Yau, MM

UCL Discovery

HK J Paediatr (new series) 2011;16:xx-xxA Fatal Case of Brainstem Encephalitis Causedby Human ParechovirusMM YAU, Q MOK, P PRABHAKARAbstract 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 brainstemencephalitis caused by HPeV and review the fifteen published cases in the literature. This is the firstreport of HPeV causing brainstem encephalitis. Earlier use of polymerase chain reaction testing for HPeVshould be considered in appropriate cases.Key words Brainstem encephalitis;  Human parechovirus;  NeonateDepartment of Paediatric and Adolescent Medicine, TseungKwan O Hospital, 2 Po Ning Lane, Hang Hau, Tseung KwanO, N.T., Hong Kong, China; Department of Neurology, GreatOrmond Street Hospital NHS Trust, London, United KingdomMM YAU xxxGreat Ormond Street Hospital NHS Trust, London, UnitedKingdomQ MOK xxxP PRABHAKAR xxxCorrespondence to: Dr MM YAUReceived November 8, 2010IntroductionHuman parechovirus (HPeV) is a single-stranded non-enveloped RNA virus belonging to the picornaviridaefamily. HPeV 1 and 2, previously named echovirus 22 and23, were discovered in 1961. HPeV type 3 was first reportedin Japan in 2004, when it was isolated in the stools of aninfant with transient paralysis.1. Subsequently more typesof HPeV have been identified. To our knowledge, this isthe first case of neonatal brainstem encephalitis caused byHPeV in the literature.Case StudyA female baby was born in good condition weighing2.64 kg to non-consanguineous Somali parents. Anemergency Caesarean section was performed for maternalpyrexia at 36 weeks gestation. Maternal high vaginal swabwas positive for group B Streptococcus, and the baby wastreated for one week with parenteral antibiotics. There wasno significant family history of neurological or metabolicdiseases. She subsequently presented at three weeks of agewith a 24 hour history of poor feeding, irritability, seizuresand apnoea. On admission, she was hypothermic (32degrees Celsius) and hypotensive. She received fluidresuscitation and was intubated, ventilated, and transferredto Neonatal Intensive Care Unit (NICU), Great OrmondStreet Hospital for Children, London.  She was treated for presumed neonatal sepsis withparenteral antimicrobials and acyclovir, as well as inotropesfor cardiovascular instability. She was commenced onmaintenance phenobarbitone for seizures, with levels withintherapeutic range. The initial workup for infective aetiologydid not identify a specific cause. Lumbar puncture was aslight traumatic tap. Cerebrospinal fluid (CSF) examinationshowed total white cell count of 25 x 106/L, with 100%lymphocytes, and red cell count of 250 x 106/L, CSF proteinwas raised at 1.7 g/dL. CSF and serum glucose were normal.12xxx2 3It was negative for cytomegalovirus DNA, enterovirus RNA,herpes simplex virus DNA by PCR. Bacterial cultures fromCSF, blood, throat swab and stool were negative.Nasopharyngeal aspirate polymerase chain reaction (PCR)for rhinovirus 1 and 2, parainfluenza 1, 2 and 3, influenzaA/B, Respiratory Syncytial Virus, human metapneumovirus,adenovirus and enterovirus were negative. Blood forEpstein-Barr virus viral capsid antigen immunoglobulin Gwas negative. Extensive metabolic screening was negative.Sedatives were weaned off following cardiovascularstabilisation 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 generallylow amplitude but no evidence of encephalopathy orepileptic discharges. Magnetic resonance imaging (MRI)of the brain on day 3 of admission showed marked signalabnormality in white matter and swelling in the brainstemand upper cervical cord, with restricted diffusion,compatible with encephalitis (Figure 1). Somatosensoryevoked potentials (SSEPs) performed on day 7 of admissionobtained a response from cervical cord but no corticalresponse, indicating a severe disorder of brainstem function.Blinking, corneal and gag reflexes were absent. Deeptendon reflexes were present. Repeated EEG showedfrequent epileptiform discharges, and phenobarbitone wascontinued. Nerve conduction study and electromyography(EMG) showed normal conduction in legs, but motor andsensory studies were affected in the arms and her tonguewas denervated. A second MRI brain scan on day 11of admission showed resolving oedema with glioticchanges in the brainstem (Figure 1). A course of pulsedmethylprednisolone and intravenous immunoglobulindid not result in any improvement. Further virologicalinvestigations were carried out, including a test for HPeVPCR in CSF, which was positive. The parechovirus RNAassay was developed in-house at Micropathology Ltd. Itstarget is the 5' UTR gene of HPeV type 1 to 6. It is a nestedRT-PCR assay and the second round is performed on arealtime PCR device (Roche LightCycler) using Sybr Greenand melting curve analysis as the detection method.   Her neurological state remained unchanged with absentbrainstem reflexes and ventilator dependency. A third MRIbrain scan on day 23 of admission showed a gliotic scarover the brainstem with resolution of edematous changes(Figure 1). EEG at that time showed decrease in theepileptiform discharges. SSEPs showed no response fromthe cord and cortical area. EMG showed denervation. Visualevoked potentials and electroretinography were normal.Clinical ethics and multidisciplinary team meeting wasarranged to discuss withdrawal of care. Her treatment carewas subsequently withdrawn and she passed awayafterwards.Discussion HPeV infections most commonly are enteric andrespiratory, but sepsis, meningitis, encephalitis and hepatitishave been described.2 More severe diseases in the neonatescomprising sepsis and encephalitis are associated with therecently emerged HPeV type 3.3 Almost all reported casesof HPeV encephalitis that were typed were due to type 3.4,5In 1989, Koskiniemi et al presented a case of severeencephalitis caused by HPeV 1.6 Subsequently, fifteen morecases of HPeV encephalitis have been reported.4,5,7-9Presenting symptoms are non-specific such as fever,irritability, seizure, apnoea and sepsis-like picture. MRIbrain scans show particular patterns affecting white matterin internal capsule, periventricular area, corpus callosum,optic radiation and cerebral peduncles. Punctate lesions arealso identified. The findings are derived from infection withdifferent subtypes of human parechoviruses. Diagnosis ismainly by HPeV PCR in CSF. These children have variableprognoses (Table 1).Its neurotropic property is further supported by Harvalaet al who reported a predilection of HPeV type 3 to causeCNS infections in young infants.2 Similar result was foundby Benshop et al. It had been postulated that the use ofdifferent cellular receptors may be the reason explainingthe neurotropic property of HPeV type 3.11 The exact reasonwhy neonates are susceptible to HPeV type 3 is not known.Ito et al found that only 56.5-73.9% of adults of childbearing age were seropositive for HPeV type 3, in contrastto 97% seropositivity of HPeV type 1.1 Lack of protectivetransplacental antibodies may well pose a high risk toneonates. Prospective studies on the prevalence would bevery useful in understanding the impact of this virus.Diagnosis of viral encephalitis in the neonatal periodcan be challenging as the immune and inflammatoryresponse especially in the CSF might not be present. Herpessimplex virus and cytomegalovirus are readily treated inneonatal CNS infection. Wolthers et al analysed 716 CSFsamples in young children previously tested for enterovirusPCR. They found that the addition of a virus-specific PCRled to a 31% increase in detection of a viral cause of neonatalsepsis or central nervous system symptoms in children aged<5 years. They concluded that HPeV could be the second4Yau et al 3Table 1Demography, clinical and radiological features, diagnostic method and outcomes of the 15 cases reported in literatureGestation andPresenting featuresMRI findingsEEG findingDiagnosisOutcomeage of onsetmethodLegay 20028Not mentioned,Fever, vomiting,Not availableNot availablePCR in CSFGood without10 monthsgeneralised hypotonia,further detailshyporeflexiaVerboon-28/40, 55 daysFever, hypertonia,Extensive cystic leukomalacia; lack ofDiscontinuous normalPCR in CSFCerebral palsy,Maciolekseizures, apnoea, rashmyelination of the posterior limb ofvoltage on aEEGepilepsy, cortical20089internal capsule on inversion recovery(Amplitude-integratedvisual impairmentEEG)at 6 years of age40/40, 6 daysFever, irritability,Diffuse high signal intensity inContinuous normalPCR in stoolHearing disabilityseizures, apnoea, rashperiventricular white matter on T2SE;voltage on aEEGat 7 years of agelactate present in the white matter in MRS;DWI (Diffusion weighted image) showedhigh signal intensity in periventricularwhite matter and corpus callosum39/40, 14 daysFever, irritability,Diffuse high signal intensity in whiteContinuous normalPCR in CSFNormal at 4 yearsseizures, apnoea, rashmatter, multiple punctate white mattervoltage on aEEGof agelesions on T2, lactate present in the whitematter in MRS. DWI showed high signalintensity in the periventricular white matterand corpus callosum; small infarction inleft cerebral peduncle41/40, 6 daysFever, irritability,Mild increase in signal intensity in theContinuous normalPCR in CSFNormal at 2 yearsseizures, apnoea,white matter, punctate white mattervoltage in aEEGof agerashlesions on T2, DWI showed mild increasein signal intensity in the periventricularwhite matter; the corpus callosum andoptic radiation25/40, 90 daysSeizuresMild increase in signal intensity in theContinuous normalPCR in BloodNormal cognition atwhite matter T2; DWI showed highvoltage in aEEG3 years of age,signal intensity in the periventricularepilepsywhite matter and the corpus callosum32/40, 53 daysFever, irritability,Not availableContinuous normalPCR in CSFNormal at 18seizures, rashvoltage in aEEGmonths of age37/40, 7 daysIrritability, seizures,Diffuse high signal intensity in theDiscontinuous normalPCR in CSFSuspectapnoea, diarrhoeaperiventricular white matter withvoltage in aEEGand blooddevelopmentalmultiple punctate lesions on T2, delay indelay at 18 monthsmyelinization; DWI showed high signalof age, mild distalintensity in the periventricular white matter,hypertoniathe corpus callosum, optic radiation, internalcapsule, and cerebral peduncle(continued on page xx)xxx4 3Table 1Demography, clinical and radiological features, diagnostic method and outcomes of the 15 cases reported in literature (cont’d)Gestation andPresenting featuresMRI findingsEEG findingDiagnosisOutcomeage of onsetmethod39/40, 7 daysFever, irritability,High signal intensity in the periventricularContinuous normalPCR in bloodNormal at 18seizures, apnoeawhite matter on T2; DWI showed highvoltage in aEEGmonths of agesignal intensity in the periventricular whitematter, the corpus callosum and internalcapsule, especially on the right side39/40, 9 daysLethargy, seizures,Multiple punctate areas of T1Continuous normalPCR in CSFNormal at 15apnoeahyperintensity and T2 hypointensity involtage in aEEGmonths of agedeep white matter; DWI showed restricteddiffusion in periventricular white matter,deep white matter, corpus callosum, internalcapsule, posterior  thalami, optic radiationsand cerebral peduncles39/40, 8 daysFever, irritability, rashDiffuse high signal intensity in the whiteNot availablePCR in CSFNormal at 9 monthsmatter; multiplepunctate white matter lesionsof ageon T2SE; DWI showed high signal intensityin the periventricular white matter and thecorpus callosumvan Zwol38/40, 21 daysFever, seizure, rash,Restricted diffusion in frontal and temporalMultiple epilepticPCR in CSFDeath on day 3720095hypertoniawhite matter, cerebellar cortex, posteriordischargesof lifelimb of the internal capsule and genucorporis callosi, and anterior and mediodorsalthalamic subnuclei with the anterior thalamicradiation in the anterior limb of the internalcapsule34/40, 35 daysRash, seizure,High signal on DWI symmetrical inMultiple epilepticPCR in CSFDeath on day 53respiratory distresshippocampus and fornix, unilateral in rightdischarges(type 3)of lifeand hypotoniacaudate head and in a limited area of rightfrontal white matter; autopsy showeddiffuse gliotic edema of white matterLevorsonNot mentioned,SepsisWhite matter lesions in bilateralNot availablePCR in CSFGood2009413 daysfrontal region(type 3)Gupta 2010736/40, 7 daysFever, poor feeding,Extensive cystic white matter changesEncephalopathic withPCR in CSFSuspectseizures, apnoeawith volume loss, DWI not availableintermittentdevelopmentalfrontotemporal dischargesdelay at 6 monthsold, normal hearingYau et al 5Figure 1 (a) Diffusion-weighted image of MRI on day 3 showing restricted diffusion over the brainstem. (b) Coronal image of MRI onday 3 showing oedematous change in brainstem and upper cervical cord. (c) Coronal image of MRI on day 23 showing gliotic changes inprevious oedematous areas.(a) (b) (c)most common cause of viral sepsis and meningitis in youngchildren.3 Early and accurate diagnosis can potentially leadto shortening the duration of antimicrobial and antiviraltreatment.Although there is no proven treatment for HPeVinfection, accurate diagnosis and characterisation of HPeVinfection is an important first step to a clearer understandingof its pathophysiology and eventually more effectivetreatments. From this case presented we would recommendearlier testing for HPeV by PCR in neonatal encephalitisof unknown origin.References1. Ito M, Yamashita T, Tsuzuki H, Takeda N, Sakae K. Isolationand identification of a novel human parechovirus. J Gen Virol2004;85(Pt 2):391-8.2. Harvala H, Wolthers KC, Simmonds P. Parechoviruses inchildren: understanding a new infection. Curr Opin Infect Dis2010;23:224-30.3. Wolthers KC, Benschop KS, Schinkel J. Human parechovirusesas an important viral cause of sepsislike illness and meningitisin young children. Clin Infect Dis 2008;47(3):358-63.4. Levorson RE, Jantausch BA, Wiedermann BL, Spiegel HM,Campos JM. Human parechovirus-3 infection: emergingpathogen in neonatal sepsis. Pediatr Infect Dis J 2009;28:545-7.5. Van Zwol AL, Lequin M, Aarts-Tesselaar C, et al. Fatal neonatalparechovirus encephalitis. BMJ Case Reports 2009;doi:10.1136/bcr.05.2009.1883.6. Koskiniemi M, Paetau R, Linnavuori K. Severe encephalitisassociated with disseminated echovirus 22 infection. Scand JInfect Dis 1989;21:463-6.7. Gupta S, Fernandez D, Siddiqui A, Tong WC, Pohl K, JungbluthH. Extensive white matter abnormalities associated withneonatal Parechovirus (HPeV) infection. Eur J Paediatr Neurol2010;14:531-4.8. Legay V, Chomel JJ, Fernandez E, Lina B, Aymard M, KhalfanS. Encephalomyelitis due to human parechovirus type 1. J ClinVirol 2002;25:193-5.9. Verboon-Maciolek MA, Groenendaal F, Hahn CD, et al. Humanparechovirus causes encephalitis with white matter injury inneonates. Ann Neurol 2008;64:266-73.10. Benschop KS, Schinkel J, Minnaar RP, et al. Humanparechovirus infections in Dutch children and the associationbetween serotype and disease severity. Clin Infect Dis 2006;42:204-10.11. Harvala H, Robertson I, Chieochansin T, McWilliam LeitchEC, Templeton K, Simmonds P. Specific association of humanparechovirus type 3 with sepsis and fever in young infants, asidentified by direct typing of cerebrospinal fluid samples.J Infect Dis 2009;199:1753-60.4

A Fatal Case of Brainstem Encephalitis Caused by Human Parechovirus

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A Fatal Case of Brainstem Encephalitis Caused by Human Parechovirus

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