A study of acute febrile encephalopathy with special reference to viral etiology

A study of acute febrile encephalopathy with special reference to viral etiology
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  Indian Journal of Pediatrics, Volume 75—August, 2008801 Original Article Correspondence and Reprint requests :  Dr. Swati Arun Karmarkar,MD, Lady Hardinge Medical College, New Delhi, India. [Received October 12, 2007; Accepted April 16, 2008] Acute encephalopathy refers to a state of rapiddeterioration of brain function, usually presenting as analteration in state of consciousness, with or without focalneurological signs 1 . Several unrelated disorders such as bacterial and viral infections of the CNS, Reye’ssyndrome, cerebral malaria, and electrolyte imbalancemay present as acute febrile encephalopathy in children.Often no definitive cause can be assigned and aprovisional diagnosis of ‘viral encephalitis’ is made. InIndia, the illness would need to be distinguished fromother CNS infections such as bacterial meningitis,tubercular meningitis and cerebral malaria. Toxicencephalopathies such as shigella encephalopathy, entericencephalopathy, Reye’s syndrome, and heat stroke alsoneed a special consideration in a tropical country likeIndia. The incidence of encephalitis in India is unknown because of problems in establishing viral diagnosis andthe fact that a wide variety of CNS disorders, bothinfectious and non-infectious, may mimic the illness.Apart from isolated efforts to investigate etiology of outbreaks in various parts of the country there is a paucityof systematic studies for the etiological confirmation of cases of viral encephalitis. There remains a need forsystematic round the year studies on the epidemiologyand the etiology of acute encephalopathic illnesses seen inchildren in India. In this study, an effort has been made to identify the A Study of Acute Febrile Encephalopathy with SpecialReference to Viral Etiology S.A. Karmarkar, Satinder Aneja, Shashi Khare, Arun Saini, Anju Seth and B.K.Y. Chauhan Lady Hardinge Medical College, New Delhi, India ABSTRACT Objective.  To study the etiological profile of patients with acute febrile encephalopathy syndrome focusing chiefly on the viraletiology, and to correlate clinical and radiological features of patients with viral encephalitis. Methods. A prospective hospital based study conducted on the consecutive patients admitted in a pediatric unit during theperiod of 1 st  February 2004 to 31st January 2005 based on the following inclusion criteria: (1) Age more than 1 month and lessthan 18 years and (2) A diagnoses of acute febrile encephalopathy, based on the following criteria: (i) fever (ii) acutedepression of consciousness or mental deterioration for more than 12 hours with or without motor or sensory deficit and (iii)Total duration of illness at the time of admission 1 week or less. Results.  The final study group comprised of 151 patients with mean age of 3.21 ± 2.9 (range of mth - 13 years) and male:female ratio of 1.71: 1. A diagnosis other than viral encephalitis was reached in 94 patients (62.3 %). Pyogenic meningitis wasthe most frequent diagnosis 51(33.8 %) followed by tubercular meningitis 12 (7.9 %), and cerebral malaria 8 (5.2 %) in thepatient group of non-viral causes. Fifty-seven cases (37.3%) were suspected as viral encephalitis and mean age of the casessuspected as viral encephalitis was 2.8 ± 2.9 (Range 1 mth- 10 yrs) with male: female ratio of 1.28: 1. Etiological diagnosiswas reached or considered probable in 41 (72%) cases out of the suspected patients. The most common etiological agentidentified was enterovirus 71 in 20 patients (35.1 %). The other viruses identified were mumps in 6 (10.5%), Japaneseencephalitis in 5 (8.7%), and measles in 4 (7%) cases. MRI brain was done in 39 patients and was abnormal in 14 patients.Out of 57 cases of suspected viral encephalitis 10 patients expired within 48 hours, 2 > 48 hours and 19 atients had significantneurological sequels at discharge. Conclusion.  The etiology of acute febrile encephalopathy varies from infectious etiologies to noninfectious metabolicdisorders. There are no distinguishing clinical or radiological features to differentiate the various causes of viral encephalitis.The clinical and the radiological findings in encephalitis should be interpreted in the geographical and other epidemiologicalbackground. [Indian J Pediatr 2008; 75 (8) : 801-805] E-mail :  Key words :   Acute febrile encephalopathy; Viral encephalitis   S.A. Karmarkar et al  802Indian Journal of Pediatrics, Volume 75—August, 2008 etiology of patients who present with acute febrileencephalopathy and to make a clinico-radiologicalcorrelation, focusing chiefly on the viral agents. Aims and objectives (1). To study the etiological profile of patients with acutefebrile encephalopathy syndrome, (2) To determine theviral etiology, and (3) To correlate the clinical and theradiological features of patients with viral encephalitis. MATERIAL AND METHODS It was a hospital based prospective study of the patientswith acute febrile encephalopathy syndrome admitted inKalawati Saran Children’s Hospital from 1 st  February 2004to 31 st  January 2005 in collaboration with the Departmentof Microbiology, National Institute of CommunicableDiseases, New Delhi, and the Department of Radiodiagnosis, Dr Ram Manohar Lohia Hospital, NewDelhi. All the consecutive cases admitted to one of thethree pediatric units of the hospital on Mondays andThursdays during this period, have been studied basedon the following inclusion criteria: 1) Age more than1month and less than 18 years and 2) A case diagnosed tohave acute febrile encephalopathy, based on the followingcriteria: (i) fever (ii) acute depression of consciousness ormental deterioration for more than 12 hours with orwithout motor or sensory deficit and iii) total duration of illness at the time of admission 1 week or less.The clinical and the demographic information wererecorded based on a pre-structured proforma, togetherwith the results of physical examination at the time of admission. A careful record of the patient’s progress inhospital was maintained. An attempt was made todetermine the cause of illness from the results of thefollowing investigations: Complete hemogram, kidneyfunction tests, serum electrolytes, random blood glucose,liver function test, peripheral smear for malarial parasites, P. falciparum  antigen test, blood culture and sensitivity,and lumbar puncture for CSF study (cell count, gramstain and culture, sugar and protein).Patients were suspected to have viral encephalitis based on the following criteria: Absence of bacteria ondirect microscopy or culture with no other alternativediagnosis identifiable with or without a CSF pleocytosiswith lymphocytic predominance. All these patients withsuspected viral encephalitis were subjected to viralisolation and serology. CSF and serum samples of thesepatients were analyzed at the National Institute of Communicable diseases, New Delhi. All specimens wereinoculated into the following three cell lines: RD cells,HEp 2 cells, and Vero cell line for viral isolation. IgMELISA was done for the following viruses: 1) Herpessimplex 1 2) Measles 3) Mumps 4) Rubella, 5) Varicellazoster6) Japanese encephalitis virus and, 7) Dengue virus.Microneutralisation test was done to detect antienterovirus 71 antibodies.A viral pathogen was regarded as etiologic if one of thefollowing criteria was met:(i)CSF and/or serum contained virus-specific IgM byELISA, (ii) Virus was isolated in CSF, or (iii) A four-fold rise in serum antibody titers was demonstratedInfection with enterovirus 71 was considered probableif antibodies were detected in the serum by neutralizationtest.Radiological investigations, CT Scan and/ or MRIwere done when indicated and possible. The patientswere treated according to the standard treatmentprotocols followed in the hospital. This includedsupportive care eg: inotropic agents where indicated if thepatient was hemodynamically compromised,decongestive therapy for treatment of raised intracranialtension and intravenous antibiotics. During the recoveryphase, the patients underwent rehabilitation in the PMRdepartment. RESULTS A total of 157 cases with the diagnosis of acute febrileencephalopathy were admitted however, six patients hadto be excluded because of the inability to acquire CSF andserum samples. The final study group comprised of 151patients with mean age of 3.21 ± 2.9 (range of 1mth – 13years) and male: female ratio was 1.71: 1. The age-wisedistribution is depicted in Table 1. The majority of patients were from Delhi but cases from neighboringstates like Haryana, Uttar Pardesh, and Rajasthan werealso admitted in the hospital. Most of the patients were belonged to poor socioeconomic strata. T ABLE  1.   Age and Sex Distribution of the Study GroupAge GroupMaleFemaleTotal (%) 1mth- 1 year351651(33.8 %)1 year – 5 years442569(45.7%)> 5 years161531(20.5%)Total9556151(100.0 %) All these 151 patients were thoroughly investigated forthe etiology of the encephalopathy; a diagnosis other thanviral encephalitis was reached in 94 patients as shown inTable 2. Pyogenic meningitis was the most frequentdiagnosis followed by tubercular meningitis and cerebralmalaria. Apart from these three etiological diagnoses,conditions like hepatic encephalopathy, dyselectro-lytemia, diabetes ketoacidosis, reyes syndrome,septicemia and ADEM were diagnosed as the cause of encephalopathy.  A Study of Acute Febrile Encephalopathy with Special Reference to Viral Etiology Indian Journal of Pediatrics, Volume 75—August, 2008803 DISCUSSION This study was a hospital based prospective study of thepatients with acute febrile encephalopathy syndromeadmitted in Kalawati Saran Children’s Hospital from 1 st February 2004 to 31 st  January 2005. It aimed at studyingthe etiological profile of the patients with acute febrileencephalopathy with special focus on the viral etiologyand to correlate the clinical and the radiological featuresof the patients with viral encephalitis.Neonates were excluded from the study becausefrequently they have conditions like hypoxic-ischemicencephalopathy, metabolic disorders, septicemia in whichencephalopathy is only one aspect not a distinct entity. 2 Only patients with continuing alteration of consciousnessof more than twelve hours were included to exclude mostcases of simple convulsions and aseptic meningitis. Adiagnosis other than viral encephalitis was reached in 94patients (62.2 %) as shown in Table 2. Pyogenic meningitiswas the most common diagnosis made in 51 (33.8 %) casesamong non-viral causes. Viruses are traditionallyconsidered to cause most cases of encephalitis, but bacterial infection is still found in a number of patients asa cause of meningo-encephalitis  per se  or as a cause of condition that mimic encephalitis. Poor socio-economicstatus and lack of routine vaccination against H influenzaand pneumococcus can explain the large number of pyogenic meningitis in the present study. A diagnosis of tubercular meningitis was made in 12 (7.9%) cases.Tubercular meningitis usually has a gradual onset andpatients are generally not admitted to hospital within aweek of onset of illness. However, occasionally patientshave short histories and such cases may be difficult todifferentiate from viral encephalitis. Cerebral malaria wasdiagnosed in eight cases (5.2%). Anemia, hepatomegalyand splenomegaly were present in all cases of cerebralmalaria. Three cases of ADEM, aged 1, 1.5 and 3 yearswere diagnosed in the present study based on clinicalfeatures and characteristic MRI features. However, apreceding history of respiratory infection, exanthem, orvaccination could not be elicited in any of these patients.The diagnosis of Reye’s syndrome was made in three T ABLE  2. Etiology of Acute Febrile EncephalopathyDiagnosisNo. of cases(%) Suspected viral etiology57(37.3)Pyogenic meningitis51(33.8)Tubercular meningitis12(7.9)Cerebral malaria08(5.2)Dyselectrolytemia06(4)Hepatic encephalopathy03(2)DKA03(2)ADEM02(1.3)Septicemia02(1.3)Reyes syndrome03(2)Shigellosis01(.67)Enteric fever01(.67)Prolonged coma after seizure01(.67)IC bleed due to Aplastic anemia01(.67)TOTAL151(100) Fifty-seven cases were suspected as viral encephalitisout of total 151 cases. Mean age of cases suspected as viralencephalitis was 2.8 ± 2.9 (Range 1mth- 10 yrs) with male:female ratio 1.28: 1. Etiological diagnosis was reached orconsidered probable in 41(72%) cases out of the 57suspected cases of viral encephalitis as shown in Table 3.In 8 patients of these, virus showing characteristiccytopathic effects of enterovirus could be isolated in CSF.The mean CSF cell count in the patients was 27.40±70.885(range: 0-520), median 10 cells. The mean CSF proteinconcentration was 32.23±20.105 (range: 10-89), median 26mg/dL. The mean CSF sugar level was 76.46±28.987(range: 18-148), median 75 mg/dL. A normal CSF picturewas seen in 15 patients (26%). The CSF protein levels wereraised in only 15 patients (26%). Table 4 shows the clinicalfeatures of patients with viral encephalitis. T ABLE  3.   Diagnosis of the Cases Suspected as Viral EncephalitisEtiologyNo. of cases (%) EV7120(35.1)Mumps6(10.5) Japanese Encephalitis5(8.7)Measles4(7)Herpes1(1.8)Varicella zoster1(1.8)Rubella1(1.8)Dengue1(1.8)Mixed2(3.5)Etiology Unknown16(28)Total57(100) MRI brain was done in 39 patients. In 18 patients MRIcould not be done either due to early death or poorgeneral condition of the patient. Of the 39 patients, MRIwas abnormal in 14 patients. Table 5 shows the clinicalfeatures and the MRI findings of these patients. Out of 57cases of suspected viral encephalitis 10 patients expiredwithin 48 hours, 2 > 48 hours and 19 patients hadsignificant neurological sequels at discharge. T ABLE  4.Clinical Profile of the Cases Suspected as ViralEncephalitisClinical featuresNo of cases(%) Convulsions (generalized)Convulsions (focal)40(70.17)3(5.26)Meningeal signs34(59.64)Raised ICT12(21.05)Skin lesions8(14)Abnormal involuntary movts.6(11)Ataxia2(3.5)Focal deficit6(11)Cranial nerve palsy5(8.77)  S.A. Karmarkar et al  804Indian Journal of Pediatrics, Volume 75—August, 2008 patients aged 3, 5 and 6 years on the basis of clinicalfeatures, more than three times elevated liver enzymesand CT scan head showing diffuse cerebral edema in all.Serum bilirubin was within normal limits in all threepatients, which is consistent with the fact that Reye’ssyndrome mostly causes anicteric hepatitis. 3 Dyselectrolytemia as the cause of encephalopathy wasconsidered in 6(6.3%) patients after excluding otherpossible causes. Three patients had hyponatremia andthree had hypernatremia. All of them had varing degreeof dehydration due to diarrhea with or without vomiting.Other causes of febrile encephalopathy included diabeticketoacidosis, hepatic encephalopathy, shigellaencephalopthy, enteric encephalopathy, prolonged comaafter seizures, septicemia, and intracranial hemorrhagesecondary to aplastic anemia.Out of the 57 suspected cases of viral encephalitis inthe present study, the etiological diagnosis was reached orconsidered probable in 41(72%) cases. Other similarstudies have identified a viral agent in 26-65% of suspected cases. 4, 5, 6, 7, 8, 9 The most common etiological agent identified in thepresent study was enterovirus 71 in 20 patients (35.1%).The other viruses identified were mumps in six (10.5%), Japanese encephalitis in five (8.7%), and measles in four(7%) cases. Herpes virus, varicella zoster, rubella anddengue virus were identified in 1 case each, as shown intable 3. In encephalitis cases, virus is seldom found in theCSF. 5, 9 Virus could be isolated in only 8 (14%) cases in thepresent study.In India, various epidemics of suspected viralencephalitis have been reported over the years andviruses like Japanese encephalitis, Herpes simplex andMeasles etc  have been implicated as causative agents. Thelargest study carried out was in Lucknow in 1990 with 740children. Japanese Encephalitis was the most commonvirus identified in 23% while others were adenovirus,parainfluenza, polio, coxsackie and echovirus. 4  Otherstudies have reported cases of Japanese encephalitis invarious parts of the country, but the significance of otherviruses in causing encephalitis is largely unknown. 10, 11 Most of the reported studies from India were based onoutbreak investigation, which makes it difficult to drawany conclusion regarding the frequency of particularvirus as the causative agent in the community. Similarly,the limitation of our study is that it is a hospital basedevaluation of a small number of cases from limitedgeographical area, which were admitted with acute febrileencephalopathy. We need a community based round theyear study to draw any conclusion regarding frequency of any particular virus as a causative agent of encephalitis.We reviewed date regarding viral encephalitis fromthe studies conducted in other countries. In a studyconducted in Beijing,   the most frequently identifiedpathogens were enteroviruses, followed by mumps,rubella, Japanese encephalitis, human herpes virus, andEpstein-Barr virus. 6  A prospective study of Thai   childrenidentified dengue virus in maximum number of cases,followed by Japanese encephalitis, herpes simplex,human herpes virus 6, mumps, enterovirus, varicellazoster virus and rabies. 7  The most common etiologicagents identified in a population-based study in Finlandwere varicella (25%), followed by mumps, herpes simplexand measles. 5 A study conducted in Slovenia theidentified etiological viruses included Central Europeantick- borne encephalitis (28.8 %), varicella- zoster virus(17%), herpes simplex (10%), rubella (2.9 %), mumps(2.3%), measles virus, Chlamydia psittaci  (1.1%) andothers. 12 There is a wide variation in the viral etiological agentsacross the globe and even in the same continent. Severalfactors such as age, geographic location, climate and hostimmune competence affect the epidemiology of viral T ABLE  5. Clinical Correlation of the MRI FindingsEtiologyClinical FeaturesSite of Lesion on MRI Enterovirus 71Ataxia, tremorsMidbrain, pons, cerebellumEnterovirus 71Convulsions,hemiparesis, VIInerve palsy,Midbrain, pons, thalamusmyoclonus, tremorsEnterovirus 71Convulsions,raised intracranial tension,Parieto occipital, frontal, temporal, pons, midbrain, blindnessthalamusEnterovirus 71TremorsPonsEnterovirus 71Convulsions, dystoniaThalamus, cerebellumEnterovirus 71ConvulsionsCaudate and lentiform nucleus, substantia nigraEnterovirus 71Convulsions, hemiparesisInfarct in the MCA territory Japanese encephalitisHemiparesis,tremors,IIInerve palsyPons,midbrain, cerebellum Japanese encephalitisNo abnormal movementsThalamus Japanese encephalitisConvulsions, blindnessGray and white matter parietal,occipital,temporal,frontalHerpes simplex 1ConvulsionsFronto temporalMeaslesHemiparesis, aphasiaInfarct in the cerebral hemisphereMumpsConvulsions, stereotypic movementsTemporal  A Study of Acute Febrile Encephalopathy with Special Reference to Viral Etiology Indian Journal of Pediatrics, Volume 75—August, 2008805 encephalitis. Mumps, measles and rubella encephalitishave been eradicated from developed countries due toeffective vaccination program implementation. 13 Similarly,differences in patients investigated, inclusion criteria forsuspicion of viral encephalitis, samples collected, andmethods used for diagnosis also affect the etiologicalpattern.The two most common clinical features in the patientswith suspected viral encephalitis were generalizedconvulsions (70.17%) and meningeal signs (59.64%).Features of raised intracranial tension were seen in 12patients (21.05%). Skin rashes were present in 7 patients,which included 2 patients with measles and one each withvaricella zoster, enterovirus 71 and Japanese encephalitisinfection. Two patients of unknown etiology also had arash. The patient with rubella encephalitis did not presentwith a rash, which is known to occur without a rash. 14 Two patients had rash-less measles infection. Wairangkar et al  had isolated measles virus from the CSF of patientswith acute encephalopathy without rash. 15  Parotidswelling was present in none of the patients of mumpsencephalitis. A similar observation was made in the studyin Beijing, in which only one of the seven patients of mumps encephalitis had parotid swelling. 6 The patientswith EV 71 infection presented with tremors, ataxia,dystonia, myoclonus and hemiparesis. In a study inTaiwan, the most common EV 71 associated clinicalfeatures were myoclonus, ataxia, intention tremor,nystagmus. Ishimaru and co-workers addressed thefinding that encephalitis caused by EV 71 was localizedmainly in the cerebellum and partly in the brain stem andthe basal ganglia. 16  MRI was abnormal in 7 patients (35%)with EV 71 encephalitis. The MRI done in our patientsrevealed altered signals in cerebellum, midbrain, pons,thalamus, and cortex. Similarly, in the study from Taiwan,MRI showed involvement of the pons, midbrain, andmedulla. 17 The patients with Japanese encephalitispresented with tremors and hemiparesis. Three patients of  JE had an abnormal MRI in the present study. The sites of lesion were pons, midbrain, cerebellum and thalamus.It can be made out from the present study that theetiology of acute febrile encephalopathy varies frominfectious etiologies like meningitis to non-infectiousmetabolic disorders like diabetic ketoacidosis. Although,viruses have been traditionally thought to cause mostcases of encephalitis, pyogenic meningitis and eventubercular meningitis form a sizeable number of cases,especially in our country. Cerebral malaria needs specialconsideration, and a high index of suspicion, especially inthe post-monsoon period. There are no distinguishingclinical or radiological features to differentiate the variouscauses of viral encephalitis and the clinical andradiological findings in encephalitis should be interpretedin the geographical and other epidemiological background. A sizable number of viral encephalitis casescan be prevented by providing universal coverage of MMR vaccine and limiting mosquitoes breeding. REFERENCES 1.Ginsberg L, Compston DAS. Acute encephalopathy: diagnosisand outcome in patients at a regional neurological unit. Q J  Med  1994; 87 : 169-180.2.Sarnat HB, Sarnat MS. Neonatal encephalopathy followingfetal distress: a clinical and electroencephalographic study.  Arch Neurol  1976; 33 : 696-705.3.Corey L, Rubin RJ, Bregman D, Gregg MD. Diagnostic criteriafor influenza B-associated Reye’s syndrome:clinical vs pathological criteria. Pediatrics  1977; 60 : 702-13.4.Kumar R, Mathur A, Kumar A, Sethi G, Sharma S, ChaturvediUC. Virological investigation of acute encephalopathy inIndia.  Arch Dis Child  1990; 65 : 1227-1230.5.Rantala H, Uhari M. Occurrence of childhood encephalitis: apopulation-based study. Pediatr Infect Dis J   1989; 8 : 426-430.6.Xu U, Zhaori G, Sirkka V et al.  Viral etiology of acutechildhood encephalitis in Beijing diagnosed by analysis of single samples. Pediatr Infect Dis J   1996; 15 : 1018-1024.7.Chokephaibulkit K, Kankirawatana P, Apintanapong S,Pongthapisit V, Yoksan S. Viral etiologies of encephalitis inThai children. Pediatr Infect Dis J   2001; 20 : 216-218.8.Lee T-C, Tsai C-P, Yuan C-L et al.  Encephalitis in Taiwan: Aprospective hospital-based study. Clin J Infect Dis  2003; 56 :193-199.9.Wong V, Yeung CY. Acute viral encephalitis in children.  AustPediatr J   1987; 23 : 339-342.10.Misra UK, Kalita J, Goel D, Mathur A. Clinical, radiologicaland neurophysiological spectrum of JEV encephalitis andother non-specific encephalitis during post-monsoon period inIndia. 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