Background: Acute viral encephalitis (AVE) is an unconscious state that either accompanies or follows a short febrile viral illness and is characterized by a diffuse and nonspecific brain insult manifested by the combination of coma, seizures, and decerebration and frequently results in delayed neurological deficit. Aim and Objective: To evaluate the clinical features and the outcomes of patients presenting with AVE. Materials and Methods: The patients presenting with AVE with serologically confirmed viral parameters were consecutively recruited from the department of medicine/neurology from a tertiary care center of Lucknow, Uttar Pradesh, India. These patients were then subjected to detailed clinical examination, laboratory examination, and radiological assessment. The modified Rankin Scale (mRS) was calculated at the time of discharge and after 1 month of follow-up. Results: One hundred and eight patients were diagnosed with AVE over a period of 2 years. The mean age of the patients of AVE was 28.97 ± 16.7 years. The most common complaints were fever (100%), headache (94.4%), and altered mental state (92.5%). Out of the 108 patients, Japanese encephalitis (JE) was the most common etiology followed by herpes simplex virus (HSV) encephalitis. Of the total number of patients, 27 died, 9 were diagnosed with JE, 4 with hematopoietic stem cell (HSC) encephalitis, 5 with miscellaneous group, and 11 with the nonspecific group of viral encephalitis (NSAVE). The mRS at discharge was <3 in 44 patients and >3 in 35 patients with AVE. After 1 month, mRS was <3 in 57 patients and >3 in 22 patients with AVE. Conclusion: In this study, JE meningitis was the leading cause of AVE followed by NSAVE and HSV encephalitis. The outcome in cases with AVE can be fatal or more disabling than other etiologies and prompt diagnosis and supportive care remain the backbone of treatment.
Keywords: Acute viral encephalitis (AVE), Japanese encephalitis (JE), modified Rankin Scale (mRS)
|How to cite this article:
Kumar S, Pandey AK, Gutch M, Razi SM, Gupta A, Jain N, Shakya S, Gupta KK. Acute viral encephalitis clinical features and outcome: Experience from a tertiary center of North India. Ann Trop Med Public Health 2015;8:262-6
|How to cite this URL:
Kumar S, Pandey AK, Gutch M, Razi SM, Gupta A, Jain N, Shakya S, Gupta KK. Acute viral encephalitis clinical features and outcome: Experience from a tertiary center of North India. Ann Trop Med Public Health [serial online] 2015 [cited 2020 Aug 6];8:262-6. Available from: https://www.atmph.org/text.asp?2015/8/6/262/162640
Encephalitis means inflammation of the brain parenchyma and strictly speaking, this is a pathological diagnosis. However, because of the obvious practical limitations of this, surrogate clinical markers of inflammation are used.  An infection by a virus is the most common and important cause of encephalitis, although other organisms may sometimes cause it. It is usually caused by an alteration of the normal immune function in the context of a previous viral infection or following vaccination that is very well-reported [acute disseminated encephalomyelitis (ADEM)]. Infectious encephalitis may also be difficult to distinguish from an encephalopathy that may be associated with numerous metabolic causes. The characteristic presentations of viral encephalitis usually comprise fever, headache, and clouding of consciousness together with seizures and focal neurology in some cases. The common causes are the herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) and the following other herpes viruses: Varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV6), adenoviruses, influenza A, enteroviruses, poliovirus, measles, mumps and rubella viruses, rabies, and arboviruses such as Japanese B encephalitis, St. Louis encephalitis virus, and West Nile encephalitis virus.  In South Asian countries like India and Nepal, Japanese encephalitis virus (JEV) has been the leading reported cause of acute encephalitis in children and adults, accounting for 31% and 45% of the cases, respectively. However, the causes of the disease in the remaining cases were not extensively studied.  Improved insight into the specific viral etiology and pathogen-specific clinical outcome of acute encephalitis in this region are essential for strategies of prevention and clinical management. We conducted a 2-year prospective descriptive study of adults with acute encephalitis who were admitted to the medical ward of a North Indian tertiary center.
|Materials and Methods|
This prospective observational study was conducted in a tertiary care center in North India over a period of 2 years. All the consecutive patients between 14 years and 60 years of age who were admitted to the medicine ward with fever or with altered mentation, either at the onset of fever or following fever that lasted for at least 24 h, were enrolled into the study. Patients in whom the persistent altered mental state could be attributed to one or more deranged metabolic parameters such as hypoglycemia (<50 mg/dL), hypoxia (PaO 2 < 60 mmHg), hypercarbia (PaCO 2 > 50 mmHg), hyponatremia (<120 mg/dL), hypernatremia (>150 mg/dL), azotemia (serum creatinine >3 mg/dL), intracranial space-occupying lesion (ICSOL), or endocrinopathies were excluded. Patients having cerebrovascular diseases followed by fever were also excluded as structural lesion in the brain could be a reason for the altered mental state.
All the patients who presented with fever with an altered mental state were subjected to detailed history and clinical examinations after exclusion of other causes of altered sensorium. Hemogram, metabolic profile, chest radiography, and electrocardiogram were done. Peripheral smear for malarial parasite was examined in all the patients. A histidine-rich protein-based immunochromatographic card test for Plasmodium falciparum malaria was carried out on patients with negative peripheral smears where clinical suspicion for complicated malaria was high. At admission, blood cultures and urine cultures were done and the clinically obvious sites of sepsis were investigated. At admission, cerebrospinal fluid (CSF) was analyzed for cytology, protein levels, glucose-to-blood glucose ratio, Gram stain, culture sensitivity for microbes, and adenosine deaminase levels. All the patients underwent noncontrast- and contrast-enhanced computed tomography (CECT) of the brain. This was followed by a magnetic resonance imaging (MRI) scan of the brain using contrast, if required. Tests for detecting immunoglobulin M (IgM) antibodies against JE (anti-JEV IgM antibody kit, Panbio JE-Dengue IgM combo, Inverness Medical Innovations, Brisbane, Queensland, Australia) and HSV (Abcam’s anti-Herpes simplex virus Type 1 and 2 (HSV1+2) IgM Human in vitro ELISA (Enzyme-Linked Immunosorbent Assay), kit – DSI, SRL, Italy, anti-HSV1/2 fast ELISA) and for other viral etiologies in CSF were carried out in the suspected cases of viral encephalitis. The modified Rankin Scale (mRS) was applied for outcome assessment at the time of discharge and after 1 month of follow-up.
During the study period of 2 years, the diagnosis of acute viral encephalitis (AVE) was established in a total of 108 patients aged between 14 years and 60 years with a mean age of 28.97 ± 16.7 years after applying the exclusion criteria. There were 69 (63.9%) males and 39 (36.1%) females. The most common complaints were fever (100%), headache (94.4%), and altered mental state (92.5%) followed by seizures (49.0%). The Glasgow Coma Scale (GCS) score at the time of presentation was ≤7 in 23 (42.5%) JE patients followed by 4 (33.3%) HSV encephalitis patients and 24 (80%) patients in the nonspecific group of viral encephalitis (NSAVE). Of the 108 patients, JE (n0 = 54, 50%) was the most common etiology followed by NSAVE (n = 30, 27.7%), HSV encephalitis (n0 = 12, 11.1%), and miscellaneous group encephalitis (n = 12, 11.1%) [Table 1].
|Table 1: Characteristics of patients with AVE
Click here to view
Among the AVE patients, the definite diagnosis of JE in 54 patients was established by finding CSF antibodies against JE virus while the diagnosis of HSV and miscellaneous group encephalitis in 12 patients each were based on the MRI and CSF serology reports. In the remaining 30 patients, a definite diagnosis could not be done despite carrying out all possible investigations available at our institute; presumptive diagnosis of AVE was considered on the basis of clinical features and routine CSF studies [Table 2]. Seasonal variations in the cases of viral encephalitis was observed in our study too [Figure 1].
|Figure 1: Seasonal trend in AVE
Click here to view
|Table 2: Characteristic CSF findings in AVE
Click here to view
All the AVE patients were subjected to baseline imaging with CT scan of the brain but only 58 patients showed abnormalities on imaging. MRI of the brain was carried out in only 49 patients with AVE. The bilateral T2 thalamic hyperintensities, in particular hemorrhage, was the most common finding in patients with JE in whom MRI of the brain was carried out. The MRI of the brain of patients with JE encephalitis showed hyperintense signal in bilateral thalami with focal hemorrhage in left thalamus in a patient with Japanese encephalitis in: Axial FLAIR image [Figure 2] and the MRI of the brain of patients with HSV encephalitis showed characteristic T2-weighted hyperintensity corresponding to edematous changes in the temporal lobes [Figure 3]. Nonspecific CT findings of meningeal enhancement with Ill defined hypodensities were seen [Figure 4].
|Figure 2: Axial FLAIR image shows hyperintense signal in bilateral thalami with focal hemorrhage in left thalamus in a patient with Japanese encephalitis
Click here to view
|Figure 3: Axial FLAIR image shows hyperintense signal in bilateral temporal lobes in a patient with herpes encephalitis
Click here to view
|Figure 4: Ill defined hypodensities in left temporoparietal and right frontotemporal region in plain CT image (Figure-a,b), leptomeningeal enhancement in left temporoparietal sulci is seen in post contrast CT image (Figure-c)
Click here to view
In this study, 29 patients died during the hospital stay out of whom 9 nine had JE, 4 four had HSV, 5 five had miscellaneous group encephalitis, and 11 with NSAVE. The outcome of the remaining 79 patients was assessed at the time of discharge and at 1-month follow-up using the mRS. The mRS scale was most favorable in cases of JE while it fared worst in NSAVE because of residual neurological deficit.
Fever with alteration of consciousness is a common problem leading to hospital admissions of both adults and children in South Asian countries, also termed as acute febrile encephalopathy.  Bhalla et al. have shown in their study that CNS infections constituted of the underlying cause for 75% of patients presenting with fever and altered mentation.  In another study carried out on children, viral encephalitis was the leading cause for nontraumatic coma in India.  In our study, JE was the leading cause for AVE followed by the HSV encephalitis and others. Similar results were obtained in a study conducted in North India by Jain et al. where JEV was the leading cause for the acute encephalitis syndrome (AES) in 16.2% of cases. 
In our study, a male predominance was seen. This male predominance in cases of AVE might have been due to the fact that the exposed skin amenable to mosquito bites was lesser in women as compared to men in India. A similar trend of male predominance was observed in AES surveillance conducted by Kakkar et al. in the North Indian city Kushinagar, Uttar Pradesh between January 2011 and June 2012.  However, none of the CNS infections are known to have a male predominance and this apparent paradox is well-explained by the social factors, rather than medical factors, that play a major role in preference among males for medical care.
Alteration in consciousness in a patient with CNS infection may be due to parenchymal involvement.  This might be true for patients with involvement of both meninges and parenchyma, as in meningoencephalitis, because of the spillage of inflammatory cells to the adjacent brain parenchyma. Further, raised intracranial pressure may be precipitating the event that leads to altered mentation.
The maximum incidence of seizures was recorded with HSV encephalitis patients followed by JEV patients in our study, which is in accordance with the seizure incidence reported in 2008 by Misra et al.  In the present study, the best GCS and mRS scores at the time of discharge and at 1 month after discharge were noted in the patients with measles, mumps, CMV, and the EBV group.
HSV is the most common cause of nonepidemic encephalitis worldwide.  Postmonsoon JE has been reported from many parts of India. The less common varicella encephalitis tends to be fatal in immunocompromised patients. Among the other identifiable viruses, enterovirus, JE virus, and mumps are the important agents.  In our study, the most commonly identifiable cause of encephalitis was JE followed by HSV.
Baseline CT scan was carried out in all the patients of AVE to rule out contraindications for lumbar puncture. Meningeal enhancement can occur in CECT of AVE patients but it remains nonspecific and can occur in proteus etiologies such as carcinomatous meningitis, reactive meningitis, and inflammatory vascular diseases of CNS. Our results also showed normal CT imaging in most of the patients of AVE. MRI of the brain offers a better resolution and was carried out when the findings of CT scan and CSF were inconclusive and the patients did not fit into the criteria of the other etiologies. MRI of the brain in patients with HSV encephalitis and JE may have characteristic findings, as seen in our patients with JE and HSV encephalitis. Bilateral T2 thalamic hyperintensities, in particular hemorrhage, were the most common findings seen in patients with JE out of the seven patients in whom MRI of the brain was carried out. MRI of the brain in patients with HSV encephalitis showed characteristic T2-weighted hyperintensities in the temporal lobes. 
Most patients with AVE make remarkable recovery once a correct and timely diagnosis is done and the underlying etiology is treated but these require considerable effort. The majority of our patients made a complete recovery; however, a significant number of patients died and a small number of patients were also left with neurologic sequelae. Delayed neurologic recovery and sequelae are well-described in patients with meningoencephalitis.  Mortality remains high if the correct diagnosis is not made in time. The fact that the maximum mortality was seen in patients with NSAVE and JE signifies diffuse cerebral involvement and the unavailability of a specific drug for most of the viral infections. Raised intra-cranial tension (ICT) also contributes to mortality and delayed neurological sequelae in patients with meningoencephalitis.
Waterlogging in paddy fields and saucer-shaped landscape (Terai), floods, poor health resources in the border areas, along with poverty and illiteracy, creates a favorable environment for mosquito breeding and a rapid spread of vector borne diseases in eastern Uttar Pradesh and adjoining Nepal and Bihar. Though the source of infection in the present study is unclear, the data warrant active surveillance of encephalitis cases.
Our study is limited by the fact that first, polymerase chain reaction (PCR) was not done for the diagnosis of viral encephalitis; also, serology may not always be positive in the initial days. Second, the complete serological screening for viral etiologies was not available to us and hence, we could not identify the culprit virus in a substantial number of our patients. MRI of the brain was also not done in all patients, which could have contributed toward making the etiological diagnosis of AVE.
To conclude, JE is the most common etiology identified followed by HSV encephalitis. The outcome in cases with AVE can be fatal or more disabling than other etiologies. Higher prevalence of JE is related to geographic and seasonal variations.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest
Solomon T, Michael BD, Smith PE, Sanderson F, Davies NW, Hart IJ, et al.; National Encephalitis Guidelines Development and Stakeholder Groups. Management of suspected viral encephalitis in adults-Association of British Neurologists and British infection Association national guidelines. J Infect 2012;64:347-73.
Rantalaiho T, Färkkilä M, Vaheri A, Koskiniemi M. Acute encephalitis from 1967 to 1991. J Neurol Sci 2001;184:169-77.
Chaudhary A, Kennedy PG. Diagnosis and treatment of viral encephalitis. Postgrad Med J 2002;78:575-83.
Modi A, Atam V, Jain N, Gutch M, Verma R. The etiological diagnosis and outcome in patients of acute febrile encephalopathy: A prospective observational study at tertiary care center. Neurol India 2012;60:168-73.
Bhalla A, Suri V, Varma S, Sharma N, Mahi S, Singh P, et al. Acute febrile encephalopathy in adults from Northwest India. J Emerg Trauma Shock 2010;3:220-4.
Panagariya A, Jain RS, Gupta S, Garg A, Surekha RK, Mathur V. Herpes simplex encephalitis in North West India. Neurol India 2001;49:360-5.
Jain P, Jain A, Kumar A, Prakash S, Khan DN, Singh KP, et al Epidemiology and etiology of acute encephalitis syndrome in North India. Jpn J Infect Dis 2014;67:197-203.
Kakkar M, Rogawski ET, Abbas SS, Chaturvedi S, Dhole TN, Hossain SS, et al . Acute encephalitis syndrome surveillance, Kushinagar district, Uttar Pradesh, India, 2011-2012. Emerg Infect Dis 2013;19:1361-7.
Karmarkar SA, Aneja S, Khare S, Saini A, Seth A, Chauhan BK. A study of acute febrile encephalopathy with special reference to viral etiology. Indian J Pediatr 2008;75:801-5.
Misra UK, Tan CT, Kalita J. Viral encephalitis and epilepsy. Epilepsia 2008;49 (Suppl 6):13-8.
Banatvala JE. Herpes simplex encephalitis. Lancet Infect Dis 2011;11:80-1.
Potharaju NR. Incidence rate of acute encephalitis syndrome without specific treatment in India and Nepal. Indian J Community Med 2012;37:240-51.
Steiner I, Budka H, Chaudhuri A, Koskiniemi M, Sainio K, Salonen O, et al. Viral encephalitis: A review of diagnostic methods and guidelines for management. Eur J Neurol 2005;12:331-43.
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]