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 »  Abstract
 » Introduction
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ORIGINAL ARTICLE
Year : 2012  |  Volume : 60  |  Issue : 2  |  Page : 168-173

The etiological diagnosis and outcome in patients of acute febrile encephalopathy: A prospective observational study at tertiary care center


1 Department of Medicine, CSMMU, Lucknow, India
2 Department of Neurology, CSMMU, Lucknow, India

Date of Submission28-Dec-2011
Date of Decision20-Jan-2012
Date of Acceptance04-Mar-2012
Date of Web Publication19-May-2012

Correspondence Address:
Aniyang Modi
Department of Medicine, CSMMU, Lucknow - 226003
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.96394

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 » Abstract 

Background: Acute febrile encephalopathy (AFE) is a clinical term used to an altered mental state that either accompanies or follows a short febrile illness and is characterized by a diffuse and nonspecific brain insult manifested by a combination of coma, seizures, and decerebration. Objective: To identify the etiological diagnosis and outcome in adult patients with AFE. Settings and Design: A prospective observational study was done in patients aged 14 years or above who were admitted with AFE at a tertiary care center in northwest India. Materials and Methods: The non-infectious causes of unconsciousness were excluded and then only a diagnosis of AFE was considered. Cerebrospinal fluid (CSF) analysis and imaging of brain was done to determine the possible etiology. Outcome was assessed at 1 month of follow-up after discharge by using modified Rankin Scale (mRS). Data were analyzed and presented as mean, median, and percentages. A P value of <0.05 was considered significant. Results: Of the total 120 patients studied, pyogenic meningitis was the most common cause accounting for 36.7%, followed by acute viral encephalitis (AVE) in 28.33% of the patients (Japanese B encephalitis in 12.5%, herpes simplex virus encephalitis in 3.33%, and other undetermined viral etiology in 12.5%). Cerebral malaria, sepsis associated encephalopathy (SAE), and tuberculous meningitis were diagnosed in 21.7%, 9.17%, and 4.2% of cases, respectively. Of the total, 16 patients died, 6 with AVE, 3 with pyogenic meningitis, 3 with cerebral malaria, and 4 with SAE. mRS at discharge was >3 in 14 patients with AVE (P < 0.001), and in the remaining it was <3. After 1 month, mRS was >3 in six patients with AVE and in the rest it was ≤1 (P < 0.001). Conclusions: In this study, pyogenic meningitis was the leading cause of AFE, followed by AVE and cerebral malaria. The outcome in cases with AVE can be fatal or more disabling than other etiologies.


Keywords: Acute febrile encephalopathy, acute viral encephalitis, cerebral malaria, pyogenic meningitis, sepsis associated encephalopathy


How to cite this article:
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

How to cite this URL:
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 [serial online] 2012 [cited 2019 Oct 22];60:168-73. Available from: http://www.neurologyindia.com/text.asp?2012/60/2/168/96394



 » Introduction Top


Acute febrile encephalopathy (AFE) is a clinical term used to describe patients presenting with short febrile illnesses with altered mental state. It is a very common clinical entity encountered by every physician in emergency departments. Although AFE is one of the major causes of hospital admissions of children and adults in India, only a few studies have been done so far. [1] Central nervous system (CNS) infections are the most common causes of altered mental status in patients with nontraumatic coma. The various etiologies are virus, bacterium, or a parasite. In febrile illnesses, encephalopathy may result from pathogenic mechanism directly affecting the nervous system or it may be due to systemic complications like hypoglycemia, hyperpyrexia, hypotension, hypoxia, or electrolyte imbalance. [2] The profile of febrile encephalopathy varies across different geographic areas and in different seasons. Fever with altered mental state commonly results from bacterial meningitis, Japanese B encephalitis (JE), cerebral malaria (CM), and typhoid encephalopathy. [3] In tropical countries like India, CM, JE, and bacterial meningitis are the common causes of AFE, while tuberculous meningitis (TBM) can present with subacute or chronic history. [3] Most acutely ill febrile patients with encephalopathy can make complete neurological recovery once the underlying cause is identified and treated promptly and appropriately, but considerable skill and knowledge is required to distinguish the various groups. This study was carried out to evaluate the patients presenting with AFE in a tertiary care center in northern India to understand the etiology, prevalence, any seasonal variation, and their outcomes, over a period of 1 year.


 » Materials and Methods Top


All patients between 14 and 60 years of age, admitted to the Department of Medicine, CSM Medical University, with fever of less than 2 weeks duration with altered mentation, either at onset or following fever, and lasting at least 24 h were enrolled into the study after applying the exclusion criteria, as we were trying to look at the profile of the patients presenting with short febrile illness and altered mental state. An effort was made to enrol all consecutive patients, and there were no controls selected. Exclusion criteria included patients in whom persistent altered mental state could be attributed to one or more deranged metabolic parameters such as hypoglycemia (<50 mg/dL), hypoxia (PaO 2 < 60 mm Hg), hypercarbia (PaCO 2 > 50 mm Hg), hyponatremia (<120 mg/dL), hypernatremia (>150 mg/dL), azotemia (serum creatinine >3 mg/dL), space-occupying lesion (ICSOL), or endocrinopathies. 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.

Study design

Detailed history was recorded and detailed clinical examination was done in all the patients who presented with fever with altered mental state of short duration. Investigations done included: hemogram, metabolic profile, chest radiography, and electrocardiogram. Peripheral smear for malarial parasite was examined in all the patients. A histidine-rich protein-based immunochromatographic card test for falciparum malaria was performed in patients with negative peripheral smears where clinical suspicion for complicated malaria was high. Samples for blood cultures and urine cultures were collected and any clinically obvious site of sepsis was investigated. Lumbar puncture was carried out in all the patients at admission, and cerebrospinal fluid (CSF) was analyzed for cytology, protein levels, glucose to blood glucose ratio, gram stain, culture sensitivity for microbes, and adenosine diaminase levels. All patients underwent non-contrast- and contrast-enhanced computed tomography (CT) of the brain. This was followed by a magnetic resonance imaging (MRI) scan of the brain using contrast, if required. Tests for detecting IgM antibodies against JE (anti-Japanese encephalitis virus IgM antibody kit, Panbio JE-Dengue IgM combo, Inverness Medical Innovations, Brisbane, Australia and herpes simplex virus (HSV) (anti-HSV antibody, kit- DSI, SRL, Italy, anti HSV1/2 fast ELISA) in CSF were done in suspected cases of viral encephalitis. Serological tests for other viral etiologies were not available in our institute at the time of this study. Patients were classified into broad groups of pyogenic meningitis (PM), viral encephalitis (meningoencephalitis), and other clinical syndromes on the basis of predesigned diagnostic criteria [1] [Table 1]. Modified Rankin Scale (mRS) [Table 2] at the time of discharge and after 1 month follow-up was used to assess the outcome.
Table 1: Diagnostic criteria used for different etiologies of acute febrile encephalopathy

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Table 2: Modified Rankin Score

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 » Results Top


During the study period, diagnosis of AFE was established in a total of 120 patients after applying the exclusion criteria. The age of patients ranged from 13 to 70 years with a mean of 31.89 ± 14.24 years. There were 76 (63.3%) males and 44 (36.7%) females. The most common complaints were fever (100%), headache (100%), and altered mental state (100%). The Glasgow Coma Scale (GCS) score at the time of presentation was ≤7 in 21 (17.5%) patients, while 99 (82.5%) patients had a GCS of >7 [Table 3]. Of the 120 patients, PM (n = 44; 36.7%) was the most common etiology, followed by acute viral encephalitis (AVE) (n = 34, 28.33%). AVE included 4 patients with HSV encephalitis, 15 patients of JE, and in the remaining 15 patients, the etiology was not identified [Figure 1]. There were 26 (21.7%) patients with CM, 11 (9.17%) patients with sepsis associated encephalopathy (SAE) including 1 patient of enteric encephalopathy, and the remaining 5 (4.2%) patients had TBM.
Table 3: Depicting the characteristics of patients of acute febrile encephalopathy in different etiological diagnosis

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Figure 1: A total of 120 patients of acute febrile encephalopathy were categorized to different etiological diagnosis

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Among patients of AVE, the definite diagnosis of JE in 15 patients was established by demonstrating CSF antibodies against JE virus; the diagnosis of HSV encephalitis in 4 patients was based on MRI and CSF serology report. In the remaining 15 patients, definite diagnosis could not be made despite doing all possible investigations available in our institute and presumptive diagnosis of AVE was considered on the basis of clinical features and routine CSF studies. Among the cases of PM, CSF culture was positive in only four patients. As most of our cases were referred from primary or secondary care centers and they might have been given antibiotics, it could largely be the reason for negative CSF culture. Seasonal variation of prevalence in cases of viral encephalitis and CM was observed in our study too [Figure 2].
Figure 2: The surge of cases of cerebral malaria (CM) and acute viral encephalitis (AVE) in post-monsoon period was seen in the study

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CT scan brain as baseline imaging was done in all the patients of AFE. Only 34 patients had shown abnormalities on imaging, CT or MRI. Meningeal enhancement was seen in 41% patients with PM. MRI brain was performed in only 15 patients with AVE. The bilateral T2 thalamic hyperintensities, in particular hemorrhage, was the most common finding seen in five patients of JE out of seven patients in whom MRI brain was done. MRI brain in two patients out of four patients of HSV encephalitis showed characteristic T2-weighted hyperintensity corresponding to edematous changes in the temporal lobes. In six patients, nonspecific MRI findings of meningeal enhancement with cerebritis and cerebral infarction were seen.

In this study, 16 patients died during the hospital stay, 6 with AVE, 3 each with PM and CM, and 4 with SAE. The outcome of the remaining 104 patients was assessed at discharge and at 1 month follow-up using modified Rankin Scale (mRS). At discharge, 14 (P < 0.001) patients with AVE had >3 mRS while all other groups had mRS <3, and at 1 month follow-up, 6 (P < 0.001) patients with AVE had mRS >3 while all other groups had mRS ≤1.


 » Discussion Top


Fever with altered mental state is a common symptom complex leading to hospital admissions in both adults and children in our country and is also known as AFE. Various studies in children with non-traumatic coma have shown that CNS infections are the commonest cause of non-traumatic coma. A study of non-traumatic coma in children has indicated that TBM, PM, and encephalitis together constitute more than 90% of the cases. [4] In another study of 151 children, viral encephalitis was the most common etiology seen in 57 patients. A diagnosis other than viral encephalitis was reached in 94 (62.3%) patients. PM was the most frequent diagnosis (33.8%), followed by TBM (7.9%) and CM (5.2%) in the patient group of non-viral etiology. [5] In our study, results were a bit different. In this study, the lower prevalence of TBM in the setting of AFE might have been because TBM presents in adults in a more subacute/chronic form rather than the acute presentation which is more common in children.

In our study, male predominance was seen. This male predominance in cases of CM might be due to the fact that skin amenable to mosquito bites is lesser in women as compared to men in India. In a study, Panagaria et al. have shown a similar trend of male predominance in HSV encephalitis. [6] Although none of the CNS infections are known to have a male predominance, this apparent male predominance can be attributed to the male dominated social system where a sick male gets preferential medical attention.

It is postulated that alteration in sensorium in a patient with CNS infection indicates an element of parenchymal involvement. [5],[7] This can explain the altered mental state in patients with meningoencephalitis. In CM and leptospirosis, primary parenchymal involvement may be responsible for encephalopathy, but altered mentation in primary meningeal involvement is difficult to explain. Raised intracranial pressure may contribute to altered mentation to some extent. The reason for altered sensorium in meningitis is postulated to be the spillage of inflammatory cells to the adjacent brain parenchyma and the resultant parenchymal involvement. [7] In SAE, metabolic alterations and inflammatory cytokines may play an important role in the pathogenesis of encephalopathy, rather than direct parenchymal involvement.

HSV is a common cause of sporadic encephalitis around the world. [8] Post-monsoon 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. [5] In our study, the most commonly identifiable cause of encephalitis was JE followed by HSV. The surge of cases of viral encephalitis and CM was observed in our study too.

CM, the potentially fatal complication of falciparum malaria is an important cause of unarousable coma in febrile patients in endemic areas. In the endemic areas, CM remains an important differential diagnosis in patients presenting with acute fever and altered mental state. [3] Post-monsoon surge in malarial cases coincides with that of viral encephalitis and the common symptomatology may be confusing to the treating physician. We have encountered a large number of CM cases in our study group with a post-monsoon surge, which suggests that northwest India is also endemic for malaria, in contrast to the previous studies. [1]

Dengue hemorrhagic fever presents as a short febrile illness and thrombocytopenia, but may rarely present with alteration in sensorium. In a study, 62 of 265 patients with AFE from central India tested positive for dengue serology and only 39 met the criterion for definite dengue virus infection. [9] Although we do see epidemics of dengue virus infection every year, in the present study, we did not categorize patients into a separate dengue encephalopathy group, though many patients showed positive serology for dengue in serum.

SAE is a poorly understood CNS condition that is associated with a wide range of manifestations from lethargy to overt delirium in sepsis patients. Of note, patients with SAE have higher mortality at 6 months, therefore it has serious prognostic implications, particularly who admitted to intensive care unit. [10] Since a large number of patients present to emergency in a tertiary care hospital with sepsis, it becomes an important differential diagnosis of AFE in adults. In our study population, we encountered SAE as an important cause of AFE in adults.

CT scan brain was performed as baseline imaging in all the patients with AFE firstly to rule out contraindications for lumbar puncture. Enhancement of the meninges was seen on contrast-enhanced CT scan in cases of bacterial meningitis. However, meningeal enhancement is a nonspecific sign and may also be caused by other different etiologies like carcinomatous meningitis, reactive meningitis, and inflammatory vascular diseases of CNS. Imaging studies performed in patients with acute meningitis may provide normal findings. Our results also showed normal CT imaging in most of the patients of PM. Therefore, the results of an imaging study do not exclude or prove the presence of acute meningitis. MR imaging of brain offers better resolution, it was performed when the findings of CT scan and CSF were inconclusive and patients were not fitting into the criteria of either CM or SAE. MRI brain in patients with HSV encephalitis and JE may have characteristic findings as demonstrated in our patients with JE [11] and HSV encephalitis. [12] Bilateral T2 thalamic hyperintensities, in particular hemorrhage, were the most common finding seen in patients with JE, out of seven patients in whom MRI brain was done. MRI brain in patients with HSV encephalitis showed characteristic T2-weighted hyperintensities in the temporal lobes.

Many acutely ill febrile patients with encephalopathy can make complete recovery once the underlying cause is treated, but considerable skill is required to correctly diagnose the underlying etiology. 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 with meningoencephalitis. [3],[13] The fact that maximum mortality was seen in patients with AVE and SAE signifies that diffuse cerebral involvement, unavailability of specific drug for most of the viral infections, and multi-organ dysfunction in SAE might have contributed to a large extent in these patients. Raised intracranial pressure may also have contributed to mortality in patients with meningoencephalitis. Mortality was also high in patients in whom a definitive diagnosis could not be made.

Our study is limited by the facts that firstly, polymerase chain reaction (PCR) was not done for diagnosis of viral encephalitis and serology may not always be positive in the initial days. Secondly, 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. Brain MRI was also not done in all patients, which could have contributed in reaching the etiological diagnosis of AFE. To conclude, PM is the most common etiology identified, followed by acute meningoencephalitis and CM in patients with AFE. 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.


 » Acknowledgment Top


We owe thanks to all patients and their attendants for their cooperation and for keeping faith in us. We are also grateful to our head of department for the constant support and encouragement.

 
 » References Top

1.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.  Back to cited text no. 1
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4.Bansal A, Singhi S, Singhi P, Khandelwal N, Ramesh S. Non Traumatic coma in children. Indian J Pediatr 2005;72:467-73.  Back to cited text no. 4
    
5.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.  Back to cited text no. 5
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6.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.  Back to cited text no. 6
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7.Durand M, Calderwood S, Weber D, Miller S, Southwick FS, Caviness VS, et al. Bacterial meningitis in adults: A review of 493 cases. N Engl J Med 1993;328:21-8.  Back to cited text no. 7
    
8.Kennedy PG, Chaudhary A. Herpes simplex encephalitis. J Neurol Neurosurg Psychiatry 2002;73:237-8.  Back to cited text no. 8
    
9.Kumar R, Tripathi S, Tambe JJ, Arora V, Srivastava A, Nag VL. Dengue encephalopathy in children in Northern India: Clinical features and comparison with non dengue. J Neurol Sci 2008;269:41-8.  Back to cited text no. 9
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10.Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell FE, et al. Delirium as a predictor of mortality in mechanically ventilated patients in intensive care unit. JAMA 2004;292:753-62.  Back to cited text no. 10
    
11.Siu JC, Chan YC, Wong CY, Yuen KM. Magnetic resonance imaging findings of Japanese encephalitis. J HK Coll Radiol 2004;7:76-80.  Back to cited text no. 11
    
12.Demaerel P, Wilms G, Robberecht W, Johannik K, Van Hecke P, Carton H, et al. MRI of herpes simplex encephalitis. Neuroradiology 1992;34:490-3.   Back to cited text no. 12
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]

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