A Study of Acute Febrile Encephalopathy with Special Reference to Viral Etiology

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1 Original Article A Study of Acute Febrile Encephalopathy with Special Reference 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 viral etiology, 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 the period of 1 st February 2004 to 31st January 2005 based on the following inclusion criteria: (1) Age more than 1 month and less than 18 years and (2) A diagnoses of acute febrile encephalopathy, based on the following criteria: (i) fever (ii) acute depression 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 was the most frequent diagnosis 51(33.8 %) followed by tubercular meningitis 12 (7.9 %), and cerebral malaria 8 (5.2 %) in the patient group of non-viral causes. Fifty-seven cases (37.3%) were suspected as viral encephalitis and mean age of the cases suspected as viral encephalitis was 2.8 ± 2.9 (Range 1 mth- 10 yrs) with male: female ratio of 1.28: 1. Etiological diagnosis was reached or considered probable in 41 (72%) cases out of the suspected patients. The most common etiological agent identified was enterovirus 71 in 20 patients (35.1 %). The other viruses identified were mumps in 6 (10.5%), Japanese encephalitis 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 significant neurological sequels at discharge. Conclusion. The etiology of acute febrile encephalopathy varies from infectious etiologies to noninfectious metabolic disorders. 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 epidemiological background. [Indian J Pediatr 2008; 75 (8) : ] swatikarmarkar@gmail.com Key words : Acute febrile encephalopathy; Viral encephalitis Acute encephalopathy refers to a state of rapid deterioration of brain function, usually presenting as an alteration in state of consciousness, with or without focal neurological signs 1. Several unrelated disorders such as bacterial and viral infections of the CNS, Reye s syndrome, cerebral malaria, and electrolyte imbalance may present as acute febrile encephalopathy in children. Often no definitive cause can be assigned and a provisional diagnosis of viral encephalitis is made. In India, the illness would need to be distinguished from other CNS infections such as bacterial meningitis, Correspondence and Reprint requests : Dr. Swati Arun Karmarkar, MD, Lady Hardinge Medical College, New Delhi, India. [Received October 12, 2007; Accepted April 16, 2008] tubercular meningitis and cerebral malaria. Toxic encephalopathies such as shigella encephalopathy, enteric encephalopathy, Reye s syndrome, and heat stroke also need a special consideration in a tropical country like India. The incidence of encephalitis in India is unknown because of problems in establishing viral diagnosis and the fact that a wide variety of CNS disorders, both infectious 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 paucity of systematic studies for the etiological confirmation of cases of viral encephalitis. There remains a need for systematic round the year studies on the epidemiology and the etiology of acute encephalopathic illnesses seen in children in India. In this study, an effort has been made to identify the Indian Journal of Pediatrics, Volume 75 August,

2 S.A. Karmarkar et al etiology of patients who present with acute febrile encephalopathy and to make a clinico-radiological correlation, focusing chiefly on the viral agents. Aims and objectives (1). To study the etiological profile of patients with acute febrile encephalopathy syndrome, (2) To determine the viral etiology, and (3) To correlate the clinical and the radiological features of patients with viral encephalitis. MATERIAL AND METHODS It was a hospital based prospective study of the patients with acute febrile encephalopathy syndrome admitted in Kalawati Saran Children s Hospital from 1 st February 2004 to 31 st January 2005 in collaboration with the Department of Microbiology, National Institute of Communicable Diseases, New Delhi, and the Department of Radiodiagnosis, Dr Ram Manohar Lohia Hospital, New Delhi. All the consecutive cases admitted to one of the three pediatric units of the hospital on Mondays and Thursdays during this period, have been studied based on the following inclusion criteria: 1) Age more than 1month and less than 18 years and 2) A case diagnosed to have acute febrile encephalopathy, based on the following criteria: (i) fever (ii) acute depression 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. The clinical and the demographic information were recorded based on a pre-structured proforma, together with the results of physical examination at the time of admission. A careful record of the patient s progress in hospital was maintained. An attempt was made to determine the cause of illness from the results of the following investigations: Complete hemogram, kidney function 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, gram stain and culture, sugar and protein). Patients were suspected to have viral encephalitis based on the following criteria: Absence of bacteria on direct microscopy or culture with no other alternative diagnosis identifiable with or without a CSF pleocytosis with lymphocytic predominance. All these patients with suspected viral encephalitis were subjected to viral isolation and serology. CSF and serum samples of these patients were analyzed at the National Institute of Communicable diseases, New Delhi. All specimens were inoculated into the following three cell lines: RD cells, HEp 2 cells, and Vero cell line for viral isolation. IgM ELISA was done for the following viruses: 1) Herpes simplex 1 2) Measles 3) Mumps 4) Rubella, 5) Varicella zoster6) Japanese encephalitis virus and, 7) Dengue virus. Microneutralisation test was done to detect anti enterovirus 71 antibodies. A viral pathogen was regarded as etiologic if one of the following criteria was met: (i) CSF and/or serum contained virus-specific IgM by ELISA, (ii) Virus was isolated in CSF, or (iii) A fourfold rise in serum antibody titers was demonstrated Infection with enterovirus 71 was considered probable if antibodies were detected in the serum by neutralization test. Radiological investigations, CT Scan and/ or MRI were done when indicated and possible. The patients were treated according to the standard treatment protocols followed in the hospital. This included supportive care eg: inotropic agents where indicated if the patient was hemodynamically compromised, decongestive therapy for treatment of raised intracranial tension and intravenous antibiotics. During the recovery phase, the patients underwent rehabilitation in the PMR department. RESULTS A total of 157 cases with the diagnosis of acute febrile encephalopathy were admitted however, six patients had to be excluded because of the inability to acquire CSF and serum samples. The final study group comprised of 151 patients with mean age of 3.21 ± 2.9 (range of 1mth 13 years) and male: female ratio was 1.71: 1. The age-wise distribution is depicted in Table 1. The majority of patients were from Delhi but cases from neighboring states like Haryana, Uttar Pardesh, and Rajasthan were also admitted in the hospital. Most of the patients were belonged to poor socioeconomic strata. TABLE 1. Age and Sex Distribution of the Study Group Age Group Male Female Total (%) 1mth- 1 year (33.8 %) 1 year 5 years (45.7%) > 5 years (20.5%) Total (100.0 %) All these 151 patients were thoroughly investigated for the etiology of the encephalopathy; a diagnosis other than viral encephalitis was reached in 94 patients as shown in Table 2. Pyogenic meningitis was the most frequent diagnosis followed by tubercular meningitis and cerebral malaria. Apart from these three etiological diagnoses, conditions like hepatic encephalopathy, dyselectrolytemia, diabetes ketoacidosis, reyes syndrome, septicemia and ADEM were diagnosed as the cause of encephalopathy. 802 Indian Journal of Pediatrics, Volume 75 August, 2008

3 A Study of Acute Febrile Encephalopathy with Special Reference to Viral Etiology TABLE 2. Etiology of Acute Febrile Encephalopathy Diagnosis No. of cases (%) Suspected viral etiology 57 (37.3) Pyogenic meningitis 51 (33.8) Tubercular meningitis 12 (7.9) Cerebral malaria 08 (5.2) Dyselectrolytemia 06 (4) Hepatic encephalopathy 03 (2) DKA 03 (2) ADEM 02 (1.3) Septicemia 02 (1.3) Reyes syndrome 03 (2) Shigellosis 01 (.67) Enteric fever 01 (.67) Prolonged coma after seizure 01 (.67) IC bleed due to Aplastic anemia 01 (.67) TOTAL 151 (100) Fifty-seven cases were suspected as viral encephalitis out of total 151 cases. Mean age of cases suspected as viral encephalitis was 2.8 ± 2.9 (Range 1mth- 10 yrs) with male: female ratio 1.28: 1. Etiological diagnosis was reached or considered probable in 41(72%) cases out of the 57 suspected cases of viral encephalitis as shown in Table 3. In 8 patients of these, virus showing characteristic cytopathic effects of enterovirus could be isolated in CSF. The mean CSF cell count in the patients was 27.40± (range: 0-520), median 10 cells. The mean CSF protein concentration was 32.23± (range: 10-89), median 26 mg/dl. The mean CSF sugar level was 76.46± (range: ), median 75 mg/dl. A normal CSF picture was seen in 15 patients (26%). The CSF protein levels were raised in only 15 patients (26%). Table 4 shows the clinical features of patients with viral encephalitis. TABLE 3. Diagnosis of the Cases Suspected as Viral Encephalitis Etiology No. of cases (%) EV71 20 (35.1) Mumps 6 (10.5) Japanese Encephalitis 5 (8.7) Measles 4 (7) Herpes 1 (1.8) Varicella zoster 1 (1.8) Rubella 1 (1.8) Dengue 1 (1.8) Mixed 2 (3.5) Etiology Unknown 16 (28) Total 57 (100) MRI brain was done in 39 patients. In 18 patients MRI could not be done either due to early death or poor general condition of the patient. Of the 39 patients, MRI was abnormal in 14 patients. Table 5 shows the clinical features and the MRI findings of these patients. Out of 57 cases of suspected viral encephalitis 10 patients expired within 48 hours, 2 > 48 hours and 19 patients had significant neurological sequels at discharge. TABLE 4. Clinical Profile of the Cases Suspected as Viral Encephalitis Clinical features No of cases (%) Convulsions (generalized) Convulsions (focal) 40 (70.17) 3 (5.26) Meningeal signs 34 (59.64) Raised ICT 12 (21.05) Skin lesions 8 (14) Abnormal involuntary movts. 6 (11) Ataxia 2 (3.5) Focal deficit 6 (11) Cranial nerve palsy 5 (8.77) DISCUSSION This study was a hospital based prospective study of the patients with acute febrile encephalopathy syndrome admitted in Kalawati Saran Children s Hospital from 1 st February 2004 to 31 st January It aimed at studying the etiological profile of the patients with acute febrile encephalopathy with special focus on the viral etiology and to correlate the clinical and the radiological features of the patients with viral encephalitis. Neonates were excluded from the study because frequently they have conditions like hypoxic-ischemic encephalopathy, metabolic disorders, septicemia in which encephalopathy is only one aspect not a distinct entity. 2 Only patients with continuing alteration of consciousness of more than twelve hours were included to exclude most cases of simple convulsions and aseptic meningitis. A diagnosis other than viral encephalitis was reached in 94 patients (62.2 %) as shown in Table 2. Pyogenic meningitis was the most common diagnosis made in 51 (33.8 %) cases among non-viral causes. Viruses are traditionally considered to cause most cases of encephalitis, but bacterial infection is still found in a number of patients as a cause of meningo-encephalitis per se or as a cause of condition that mimic encephalitis. Poor socio-economic status and lack of routine vaccination against H influenza and 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 and patients are generally not admitted to hospital within a week of onset of illness. However, occasionally patients have short histories and such cases may be difficult to differentiate from viral encephalitis. Cerebral malaria was diagnosed in eight cases (5.2%). Anemia, hepatomegaly and splenomegaly were present in all cases of cerebral malaria. Three cases of ADEM, aged 1, 1.5 and 3 years were diagnosed in the present study based on clinical features and characteristic MRI features. However, a preceding history of respiratory infection, exanthem, or vaccination could not be elicited in any of these patients. The diagnosis of Reye s syndrome was made in three Indian Journal of Pediatrics, Volume 75 August,

4 S.A. Karmarkar et al TABLE 5. Clinical Correlation of the MRI Findings Etiology Clinical Features Site of Lesion on MRI Enterovirus 71 Ataxia, tremors Midbrain, pons, cerebellum Enterovirus 71 Convulsions,hemiparesis, VIInerve palsy, Midbrain, pons, thalamus myoclonus, tremors Enterovirus 71 Convulsions,raised intracranial tension, Parieto occipital, frontal, temporal, pons, midbrain, Enterovirus 71 blindness Tremors Pons thalamus Enterovirus 71 Convulsions, dystonia Thalamus, cerebellum Enterovirus 71 Convulsions Caudate and lentiform nucleus, substantia nigra Enterovirus 71 Convulsions, hemiparesis Infarct in the MCA territory Japanese encephalitis Hemiparesis,tremors,IIInerve palsy Pons,midbrain, cerebellum Japanese encephalitis No abnormal movements Thalamus Japanese encephalitis Convulsions, blindness Gray and white matter parietal,occipital,temporal, frontal Herpes simplex 1 Convulsions Fronto temporal Measles Hemiparesis, aphasia Infarct in the cerebral hemisphere Mumps Convulsions, stereotypic movements Temporal patients aged 3, 5 and 6 years on the basis of clinical features, more than three times elevated liver enzymes and CT scan head showing diffuse cerebral edema in all. Serum bilirubin was within normal limits in all three patients, which is consistent with the fact that Reye s syndrome mostly causes anicteric hepatitis. 3 Dyselectrolytemia as the cause of encephalopathy was considered in 6(6.3%) patients after excluding other possible causes. Three patients had hyponatremia and three had hypernatremia. All of them had varing degree of dehydration due to diarrhea with or without vomiting. Other causes of febrile encephalopathy included diabetic ketoacidosis, hepatic encephalopathy, shigella encephalopthy, enteric encephalopathy, prolonged coma after seizures, septicemia, and intracranial hemorrhage secondary to aplastic anemia. Out of the 57 suspected cases of viral encephalitis in the present study, the etiological diagnosis was reached or considered probable in 41(72%) cases. Other similar studies have identified a viral agent in 26-65% of 4, 5, 6, 7, 8, 9 suspected cases. The most common etiological agent identified in the present 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 and dengue virus were identified in 1 case each, as shown in table 3. In encephalitis cases, virus is seldom found in the CSF. 5, 9 Virus could be isolated in only 8 (14%) cases in the present study. In India, various epidemics of suspected viral encephalitis have been reported over the years and viruses like Japanese encephalitis, Herpes simplex and Measles etc have been implicated as causative agents. The largest study carried out was in Lucknow in 1990 with 740 children. Japanese Encephalitis was the most common virus identified in 23% while others were adenovirus, parainfluenza, polio, coxsackie and echovirus. 4 Other studies have reported cases of Japanese encephalitis in various parts of the country, but the significance of other 10, 11 viruses in causing encephalitis is largely unknown. Most of the reported studies from India were based on outbreak investigation, which makes it difficult to draw any conclusion regarding the frequency of particular virus as the causative agent in the community. Similarly, the limitation of our study is that it is a hospital based evaluation of a small number of cases from limited geographical area, which were admitted with acute febrile encephalopathy. We need a community based round the year study to draw any conclusion regarding frequency of any particular virus as a causative agent of encephalitis. We reviewed date regarding viral encephalitis from the studies conducted in other countries. In a study conducted in Beijing, the most frequently identified pathogens were enteroviruses, followed by mumps, rubella, Japanese encephalitis, human herpes virus, and Epstein-Barr virus. 6 A prospective study of Thai children identified dengue virus in maximum number of cases, followed by Japanese encephalitis, herpes simplex, human herpes virus 6, mumps, enterovirus, varicella zoster virus and rabies. 7 The most common etiologic agents identified in a population-based study in Finland were varicella (25%), followed by mumps, herpes simplex and measles. 5 A study conducted in Slovenia the identified etiological viruses included Central European tick- borne encephalitis (28.8 %), varicella- zoster virus (17%), herpes simplex (10%), rubella (2.9 %), mumps (2.3%), measles virus, Chlamydia psittaci (1.1%) and others. 12 There is a wide variation in the viral etiological agents across the globe and even in the same continent. Several factors such as age, geographic location, climate and host immune competence affect the epidemiology of viral 804 Indian Journal of Pediatrics, Volume 75 August, 2008

5 A Study of Acute Febrile Encephalopathy with Special Reference to Viral Etiology encephalitis. Mumps, measles and rubella encephalitis have been eradicated from developed countries due to effective vaccination program implementation. 13 Similarly, differences in patients investigated, inclusion criteria for suspicion of viral encephalitis, samples collected, and methods used for diagnosis also affect the etiological pattern. The two most common clinical features in the patients with suspected viral encephalitis were generalized convulsions (70.17%) and meningeal signs (59.64%). Features of raised intracranial tension were seen in 12 patients (21.05%). Skin rashes were present in 7 patients, which included 2 patients with measles and one each with varicella zoster, enterovirus 71 and Japanese encephalitis infection. Two patients of unknown etiology also had a rash. The patient with rubella encephalitis did not present with 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 patients with acute encephalopathy without rash. 15 Parotid swelling was present in none of the patients of mumps encephalitis. A similar observation was made in the study in Beijing, in which only one of the seven patients of mumps encephalitis had parotid swelling. 6 The patients with EV 71 infection presented with tremors, ataxia, dystonia, myoclonus and hemiparesis. In a study in Taiwan, the most common EV 71 associated clinical features were myoclonus, ataxia, intention tremor, nystagmus. Ishimaru and co-workers addressed the finding that encephalitis caused by EV 71 was localized mainly in the cerebellum and partly in the brain stem and the basal ganglia. 16 MRI was abnormal in 7 patients (35%) with EV 71 encephalitis. The MRI done in our patients revealed altered signals in cerebellum, midbrain, pons, thalamus, and cortex. Similarly, in the study from Taiwan, MRI showed involvement of the pons, midbrain, and medulla. 17 The patients with Japanese encephalitis presented 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 the etiology of acute febrile encephalopathy varies from infectious etiologies like meningitis to non-infectious metabolic disorders like diabetic ketoacidosis. Although, viruses have been traditionally thought to cause most cases of encephalitis, pyogenic meningitis and even tubercular meningitis form a sizeable number of cases, especially in our country. Cerebral malaria needs special consideration, and a high index of suspicion, especially in the post-monsoon period. There are no distinguishing clinical or radiological features to differentiate the various causes of viral encephalitis and the clinical and radiological findings in encephalitis should be interpreted in the geographical and other epidemiological background. A sizable number of viral encephalitis cases can be prevented by providing universal coverage of MMR vaccine and limiting mosquitoes breeding. REFERENCES 1. Ginsberg L, Compston DAS. Acute encephalopathy: diagnosis and outcome in patients at a regional neurological unit. Q J Med 1994; 87 : Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress: a clinical and electroencephalographic study. Arch Neurol 1976; 33 : Corey L, Rubin RJ, Bregman D, Gregg MD. Diagnostic criteria for influenza B-associated Reye s syndrome:clinical vs pathological criteria. Pediatrics 1977; 60 : Kumar R, Mathur A, Kumar A, Sethi G, Sharma S, Chaturvedi UC. Virological investigation of acute encephalopathy in India. 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