Clinical Profile of Children with Acute Febrile Encephalopathy in a Tertiary Health Care Center of Nepal

Address for correspondence: Dr. Poonam Sharma Registrar Department of Paediatrics, Shahid Gangalal National Heart Center, Kathmandu, Nepal E-mail: medponam@gmail.com Tel: +9779855056256 1Dr. Poonam Sharma, MBBS, MD, Department of Paediatrics, Shahid Gangalal National Heart Center, Kathmandu, Nepal, 2Dr. BK Sarmah, MBBS. MD, Professor and HoD, Department of Paediatrics, College of Medical Sciences, Bharatpur, Chitwan, Nepal, 3Dr. PawanaKayastha, MBBS. MD, Department of Paediatrics, Kathmandu Medical College, Kathmandu, Nepal, 4Dr. Asim Shrestha, MBBS. MD. Department of Paediatrics, Kathmandu University School of Medical Sciences, Dhulikhel, Nepal, 5Dr. Damodar Tiwari,MBBS. MD.Department of Paediatrics, College of Medical Sciences, Bharatpur, Chitwan, Nepal Abstract


Introduction
E ncephalopathy is a diff use disease of brain that alters its structure and func on 1 .Acute febrile encephalopathy is defi ned as short dura on fever with altered consciousness which is a common problem in pediatric pa ents leading to hospitaliza on 2 .This diff use and nonspecifi c brain insult manifested by a combina on of coma, seizures and decerebra on, is an important cause of morbidity and mortality in young hospitalized children 3 making signifi cant demands of intensive and high dependency care resources 4 .
The profi le of acute febrile encephalopathy varies not only in diff erent geographical regions of world but also in diff erent areas and seasons in the same country 3 .Although central nervous system infec on is the most common cause of fever with altered sensorium in children throughout the world, 4 it can result from a wide variety of primary e ologies, posing a diagnos c challenge to medical staff .Bacterial meningi s, asep c meningi s, encephali s, cerebral malaria, CNS tuberculosis and enteric encephalopathy are some of the common causes. 3The survivors are o en le with disabling neurological problems if not diagnosed in me and aggressively managed 1,5 .Outcome of such illness may range from complete recovery through varying degrees of neurological disability to death from either acute ilness or complica ons.A be er understanding of the causes and outcomes of this heterogeneous group of children will aid the design of protocols for their inves ga on and management 6 .
There is signifi cantly more severe morbidity and higher mortality due to acute febrile encephalopathy in developing countries like Nepal where adequate health facili es may not be readily available or accessible to everyone.There is lack of proper u liza on and aff ordability of health resources among the general popula on due to various adverse cultural and socioeconomic factors 7 .Similarly malnutri on and anemia which are rampant in developing countries have been known to be a signifi cant contribu ng factor to mortality in these pa ents 8 .Proper data on incidence, severity, and outcome are a prerequisite for informed provision of health-care resources for this group 6 .Very limited work has been done to know the actual burden of the diff erent neurological disease in Nepalese children 7 .
This prospec ve observa onal study was conducted for one year to evaluate the profi le of hospitalized children with acute febrile encephalopathy, to recognize the prevalence of local causes and to highlight the preven ve and therapeu c interven on to help in reduc on and improvement in the management of these topical diseases.

Material and Methods
This prospec ve observa onal study was done in children admi ed with acute febrile encephalopathy within a span of one year (April 2011 to March 2012) in the Department of Paediatrics of College of Medical Sciences-Teaching Hospital which is a ter ary care referral hospital in Central Nepal.
Acute febrile encephalopathy was defi ned as fever for less than 2 weeks dura on and altered sensorium (a modifi ed GCS of less than 12 for more than 12 hours).
All hospitalized children of 1 month to 14 years of age with acute febrile encephalopathy admi ed within April 2011 to March 2012 were included in the study.Children having evidence of trauma c coma, febrile convulsions, seizure disorder, hypoglycemia, hypoxia, dyselectrolemia, uremia and similar disorders were excluded from the study.
Detail systemic and neurological examina on was done to iden fy the probable cause and to note the severity of neurological damage.Baseline inves ga ons were done as per the hospital protocol and special inves ga ons were done according to the suspected diagnosis.Lumber puncture was done in all cases unless contraindicated and detail CSF examina on was done.Neuroimaging with CT scan brain was done as and when required or feasible.
Analysis was performed using the sta s cal so ware package SPSS version 20.Sta s cal method included determina on of mean, standard devia on, chi-square test, p-value and co-rela on coeffi cient values.This study was approved by the ethical review board of College of Medical Sciences-Teaching Hospital, Bharatpur, Nepal.

Results
Among total of 1072 pa ents admi ed in the pediatric ward, 59 cases presented with acute onset fever with encephalopathy.However, only 54 children were included in this study as the rest either expired or went against medical advice before establishment of diagnosis.The incidence of acute febrile encephalopathy was 5.50% among whom 19 (35.2%) were female and 35 (64.8%) children were male.There were 24 children (44.4%) within the age group of one to fi ve years.Table 1 shows the distribu on of cases among diff erent age groups.The mean dura on of fever was 4.41 days with fever las ng for less than 48 hours in 15 (27.8%) children, for 2-7 days in 33 (61.1%) children and for more than seven days in six (11.1%) children.Similarly the mean dura on of onset of altered sensorium was 28± 19 hours with 38 (70.4%) children having altered sensorium for less than 24 hours, 15 (27.8%) children for 24 to 72 hours and one child with more than three days.The GCS was less than 7 in two cases, 7-10 in 24 (44.4%)cases, 10-12 in 20 (37%) cases and more than 12 in eightcases.The average GCS at the me of presenta on was 10.5±10.5 with minimum of 6 and maximum of 12. Seizure and vomi ng were the most common presen ng complains seen in 32 (59.3%) and 25 (46.3%)children respec vely.Table No. 2 shows the frequency of various presen ng complains and Table 3 shows the frequency of various clinical features among children with acute febrile encephalopathy.Meningeal irrita on signs were present in 27 (50%) children among which neck s ff ness was present in 25 (46.3%),Kernig's sign in 24 (44.4%) and Brudzinsky sign in 9 (16.7%)children.
Viral encephali s was the most common diagnosis seen in 34 (63%) children followed by bacterial meningi s in 12 (22.2%)children, cerebral malaria, enteric encephalopathy and hepa c encephalopathy in four, three and one case respec vely.Among those with viral encephali s, one case each was diagnosed as HSV and Mumps encephali s.The maximum number of children with viral encephali s were within 5 to 14 years of age seen in 17 (50%) cases and those with bacterial meningi s were within 1 to 5 year of age seen in 8 (66.7%) children.In this study, 21 (61.8%)children with viral encephali s presented with seizures in comparison to 7 (58.3%)children with bacterial meningi s.Similarly 17 (50%) cases of viral encephali s presented with a GCS of 10 to 12 whereas 8 (66.9%) cases of bacterial meningi s presented with a GCS of 7 to 10.In this study meningeal signs were present in 18 (52.9%) of viral encephali s, 8 (66.7%) of bacterial meningi s.CT Scan Brain was found to be abnormal in 7 (13%) cases with three having cerebral edema, two having ventricular enhancement and one each of calcifi ed granuloma and sinus thrombosis.

Discussion
It is a known fact that acute febrile encephalopathy is an important source of morbidity and mortality among children that make heavy demands in pediatric intensive care unit and neuro-rehabilita on resources.Despite being such an important disease en ty there is paucity in the studies regarding the incidence, clinical features, e ology and prognosis of this disease in the world literature.Especially in Nepal, very few studies regarding this rela vely common neurologic disease have been conducted.This study has been done in order to fulfi ll some of the gap in the available data.
There is lack of suffi cient data regarding the actual incidence of acute febrile encephalopathy in children and almost all of the data are hospital based.Wong et al. has es mated the incidence of nontrauma c coma to be 30/100,000 children in the Northern region of England 6 .The incidence of acute febrile encephalopathy in this hospital was 5.50% which is similar to another study done in eastern Nepal where the incidence was noted to be 6.2%, however a much higher incidence of 10-15% was noted in India 9,10 58 had JE.Ten pa ents had concomitant infec ons, four with malaria and six with bacterial meningi s, and were excluded from analysis.Clinical fi ndings were as follows: boys, 69%; age 4-14 years, 71%; presenta on during summer and autumn, 83%; fever >3 days, 69%; altered sensorium <2 days, 50%; Glasgow coma score 8-12, 63%; seizures, 58%.Four (8.3%.The most common age of children aff ected with acute febrile encephalopathy in this study was within one to fi ve years of age which is similar to the study done in India 10 and to correlate clinical and radiological features of pa ents with viral encephali s.\n\nMETHODS:A prospec ve hospital based study conducted on the consecu ve pa ents admi ed in a pediatric unit during the period of 1(st.However in Malaysia, febrile encephalopathy was found to occur at a much younger age with half of the cases being less than one year of age 11 .
Similarly male were found to be more aff ected than females with a ra o of 1.8:1 which is consistent with that noted by various authors 2,3,10,11,12 pulse, heart rate, blood pressure, coma severity by Glasgow coma scale (GCS.Although no plausible mechanism has been proposed for the male preponderance of acute febrile encephalopathy, it may possibly be because of the gender biasness in seeking medical care especially in this part of the world.As noted by Khinchi et al from Nepal, this study also revealed increased number of cases during the monsoon season of July to August which may be due to the increase transmission of the diseases during the monsoon months 13 .Similarly acute febrile encephalopathy was found to occur more frequently in people of low socioeconomic status in our country, present in 32 (59%) children, which was similar to that noted in India 10 and to correlate clinical and radiological features of pa ents with viral encephali s.\n\nMETHODS:A prospec ve hospital based study conducted on the consecu ve pa ents admi ed in a pediatric unit during the period of 1(st.This could be because increased incidence of overcrowding, poor hygiene, poor nutri onal status and subop mal immunity increases suscep bility to various infec ous diseases, febrile encephalopathy being one of them.One alarming fact noted during the study was only 50% of children of more than one year had received complete vaccina on including the Japanese encephali s vaccine.JE vaccines were not received by 37.5% of children and 12.5% of parents did not know about the vaccina on status of their child.Japanese encephali s vaccine has been introduced in the na onal immuniza on schedule of Nepal since 2009 ini ally in 16 districts extending to 31 endemic districts of the Terai region 14 .
In this study, the mean dura on of fever was 4.4 ± 3.57 days similar to that noted by Rayamajhi et al. 9 58 had JE.Ten pa ents had concomitant infec ons, four with malaria and six with bacterial meningi s, and were excluded from analysis.Clinical fi ndings were as follows: boys, 69%; age 4-14 years, 71%; presenta on during summer and autumn, 83%; fever >3 days, 69%; altered sensorium <2 days, 50%; Glasgow coma score 8-12, 63%; seizures, 58%.Four (8.3%The fever was present for less than 72 hours in 47.8% of children in the current study which is more than that noted by Singh et al 3 from Nepal and less than that noted by Anga et al of Papua New Guinea 2 .In the same study made by Singh et al in a ter ary center of Eastern Nepal, the mean dura on of altered sensorium and of GCS was 27.9 ± 19.1 hours and 9.6 ± 3.2 respec vely with 96.3% of children having the altered sensorium for less than 72 hours which is similar to the observa on made in the current study 3 .Similarly the median GCS of 12 in our study was similar to that made by Anga et al where the median was 13 2 .A nega ve correla on between the GCS at presenta on and the me taken for normaliza on was being observed.This suggests that children who had a higher GCS at presenta on recovered quickly in comparison to those with poorer GCS.Various authors have noted GCS at the me of presenta on and the dura on of altered sensorium to be a signifi cant predictor of normal outcome 2,9 defi ned as fever, seizures and/or altered consciousness, is a common presenta on in children in tropical developing countries.Outcomes range from complete recovery through varying degrees of neurological disability which slowly resolve or remain permanent to death from either the acute illness or complica ons.Whilst bacterial meningi s accounts for a propor on of children aff ected, the ae ology in many remains unclear but includes malaria and probably viral encephali s.AIM: To understand the ae ology, presenta on and outcome of febrile encephalopathy in children in Papua New Guinea.METHODS: Children aged between 1 month and 12 years presen ng to Port Moresby General Hospital with febrile encephalopathy were studied prospec vely.A detailed history and examina on and the following laboratory inves ga ons were undertaken as appropriate: cerebrospinal fl uid (CSF.
The common clinical features that a child with febrile encephalopathy presents with are seizures, vomi ng and headache which could be due to the direct cerebral insult or it could also suggest increased intracranial pressure.In our study seizure was the most common symptom which was present in 59.3% which was followed by vomi ng and headache.Analysis of the symptoms were done by various authors were Rayamajhi et al. and Singh et al. no ced seizures to be present in 58% and 50% of children respec vely 3,9 blood and CSF cultures, peripheral smear and serology for malarial parasite, and serology for Japanese encephali s (JE.The various clinical signs and symptoms as described in Table 2 is consistent with that noted by diff erent na onal and interna onal authors 2,3,9 58 had JE.Ten pa ents had concomitant infec ons, four with malaria and six with bacterial meningi s, and were excluded from analysis.Clinical fi ndings were as follows: boys, 69%; age 4-14 years, 71%; presenta on during summer and autumn, 83%; fever >3 days, 69%; altered sensorium <2 days, 50%; Glasgow coma score 8-12, 63%; seizures, 58%.Four (8.3%.
In the current study signs of meningeal irrita on were evaluated in 46 children who were of more than two years of age among whom posi ve results were seen in 50% of children similar to that observed by Karmakar et al. 10 and to correlate clinical and radiological features of pa ents with viral encephali s.\n\nMETHODS:A prospec ve hospital based study conducted on the consecu ve pa ents admi ed in a pediatric unit during the period of 1(st In our study, neck s ff ness was present in 46.3% of children.Various authors have reported diff erent frequencies of neck s ff ness ranging from 30% to 50% of children with febrile encephalopathy 2,12 .Similar to our observa on, authors have reported a higher incidence of Kernig's sign present in 44 to 50% while Brudzinski sign was the least common sign of meningeal irrita on 2,3,15 defi ned as fever, seizures and/ or altered consciousness, is a common presenta on in children in tropical developing countries.Outcomes range from complete recovery through varying degrees of neurological disability which slowly resolve or remain permanent to death from either the acute illness or complica ons.Whilst bacterial meningi s accounts for a propor on of children aff ected, the ae ology in many remains unclear but includes malaria and probably viral encephali s.AIM: To understand the ae ology, presenta on and outcome of febrile encephalopathy in children in Papua New Guinea.METHODS: Children aged between 1 month and 12 years presen ng to Port Moresby General Hospital with febrile encephalopathy were studied prospec vely.A detailed history and examina on and the following laboratory inves ga ons were undertaken as appropriate: cerebrospinal fl uid (CSF.
Viral encephali s was the most common cause of febrile encephalopathy seen in 63% of cases followed by bacterial meningi s, cerebral malaria and enteric encephalopathy seen in 22.2%, 7.4% and 5.6 % of cases respec vely.Similar e ology was noted in Central India where acute febrile encephalopathy was most common due to viral encephali s followed by pyogenic meningi s, cerebral malaria and tuberculosis meningi s 16 prospec ve study, carried out in a ter ary care hospital of central India.Dura on of the study was two years (2010 to 2012.Singh et al. reported viral encephali s to be the most common illness presen ng with fever and altered sensorium which was present in 45.8% of cases 3 .Similarly bacterial meningi s was second most common diagnosis which was present in 42% of the cases and the cerebral malaria in 7.5% of cases.However Kumar et al. showed bacterial meningi s to be one of the predominant cause of febrile encephalopathy which was present in 44 % of cases and viral encephali s in 36.4% of cases 17 and any organisms were cultured.Blood examina on included white cell count and es ma ons of haemoglobin, urea, glucose, and electrolyte concentra ons and serum alanine aminotransferase and aspartate aminotransferase.A fi rm diagnosis was established in 278 pa ents (38%.
In the current study, among 39 cases who underwent CT scan of brain, abnormal fi ndings were noted in 13% of the children.Among the abnormal fi ndings, cerebral edema was the most common fi nding which was present in 5.5% of children followed by ventricular enhancement, calcifi ed granuloma and sinus thrombosis in three, one and one case each.Nadel et al. reported abnormal CT scan fi nding present in 36% of the children with acute febrile encephalopathy however 5% of the cases had accidental fi nding 18 .The most common fi nding was cerebral edema followed by ventricular dilata on.As the fi nding of the CT scan are no specifi c and do not help in the management or in the diagnosis, emergency CT scan head in a child with acute febrile encephalopathy does not have much signifi cance 18 .Its usefulness is limited to assess for signs of intracranial mass eff ect prior to lumbar puncture and to monitor complica ons like hydrocephalus 19 .
While comparing among viral encephali s and bacterial meningi s, the current study noted that children with bacterial meningi s were slightly younger than those with viral encephali s.Similarly seizure was more common in viral encephali s whereas low GCS at presenta on was common in bacterial meningi s.Similarly 52.9% of children with viral encephali s had signs of meningeal irrita on in comparison to 66.7% of cases with bacterial meningi s.This observa on could have been made as bacterial meningi s has a prolonged course of illness and causes more focal and local irrita on of brain and meninges in comparison to a more global involvement of the brain in viral infec on.However because of small sample size this data was not sta s cally signifi cant

Conclusion
Acute onset of fever with altered sensorium is a common problem encountered by a pediatrician especially those prac cing in or nearby tropical countries.Found to be more common in monsoon months, inadequate nutri on and poor hygiene increased the risk while early health care seeking behavior reduced the morbidity and the possible mortality of this dreadful condi on.Emergency CT scan in children with acute febrile encephalopathy has limited role for monitoring complica on, hence emergency management and stabiliza on of the child has the prior importance.

Limitations of this study
Being a hospital based study done in a ter ary care center; the incidence observed in this study may not refl ect the actual incidence of acute febrile encephalopathy of the en re popula on.Also because of the small sample size correla on between the individual diagnosis with diff erent clinical features and prognos c factors could not be made.Due to the limita ons in the laboratory inves ga ons facility, iden fi ca on of the causa ve organism could not be made in most of the case.

Table 1 :
Distribu on of cases according to the age group

Table 2 :
Distribu on of presen ng complains among children

Table 3 :
Distribu on of cases according to the frequency of the clinical signs