A case of Japanese encephalitis misdiagnosed as tuberculous meningoencephalitis

Backgroud Japanese encephalitis is a kind of central nervous system infectious disease caused by Japanese encephalitis virus transmitted through mosquito1.Most patients with JE are acute onset and critically ill, with high fever, disturbance of consciousness, epilepsy, abnormal mental behavior, cognitive impairment, and positive meningeal irritation. A 15-year-old boy was admitted to the hospital with acute febrile illness,headache,jet vomiting,disorder of consciousness,diagnosed as central nervous system (CNS) infection. According to the characteristics of blood and cerebrospinal fluid (CSF), the patient was initially diagnosed with meningoencephalitis and took antituberculosis treatment.However,subsequent magnetic resonance images(MRI) did not match the performance of typical tuberculous meningoencephalitis.Further laboratory testing for infections was conducted. JE was confirmed by the Disease Control Center of Lanzhou City through the detection of Japanese encephalitis IgM antibodies in both blood and CSF of the patients.After diagnosis of JE, the patient was provided the treatment of Human immunoglobulin and methylprednisolone therapy.After 3 weeks, the patient was transferred to the department of rehabilitation medicine to continue treatment. After 3 months and 6 months of follow-up, the patient recovered and the FIM score were 126, which were completely independent. similar encephalitis.

performance of typical tuberculous meningoencephalitis.Further laboratory testing for infections was conducted. JE was confirmed by the Disease Control Center of Lanzhou City through the detection of Japanese encephalitis IgM antibodies in both blood and CSF of the patients.After diagnosis of JE, the patient was provided the treatment of Human immunoglobulin and methylprednisolone therapy.After 3 weeks, the patient was transferred to the department of rehabilitation medicine to continue treatment. After 3 months and 6 months of follow-up, the patient recovered and the FIM score were 126, which were completely independent.

Conclusion
Given the similar clinical manifestations of Japanese encephalitis and other types of encephalitis, it is essential to enhance the awareness of Japanese encephalitis. Background 3 JEV is a kind of zoonotic flavivirus that spreads between birds and pigs,mainly occurs in summer and autumn,which leads to JE in Southeast Asia.In the case of human infection with JEV,the virus rapidly causes central nervous system infectious diseases,which seriously threaten human health.The course of JE can be divided into three periods [2]:①prodromal period:manifested as fever,headache, nausea and vomiting;② encephalitis period:more than 3 to 5 days after the prodromal period,confusion,meningeal irritation,muscle rigidity,dyskinesia,etc.;③recovery period or sequelae.From the clinical manifestations,JE and other types of intracranial infections are difficult to identify,and the diagnosis of JE relies mainly on serological and pathogenic examinations.

Case Presentation
A14-years-old boy was referred to our hospital with symptoms of fever,headache for 5 days,disorder of consciousness for 1 day on August 7,2017 from Tongwei County of Gansu Province,whose diagnosis considers fever to be investigated and central nervous system infectious diseases.At that time, we considered central nervous system infectious diseases.During physical examination,the patient had fever(38.8°C) and somnolence.The blood pressure,heart rate and respiratory were normal.The neck of patient was stiff,and the Kernig sign was positive.
The initial laboratory investigation at admission displayed white blood cells were7.69×109/L (normal range: 4-10×109/L) and neutrophil ratio wae 0.69 (normal range:0.50-0.70).Liver and kidney function were normal.Erythrocyte sedimentation rate was normal,but C-reactive protein was 8.71mg/L(normal range:0.00-8.20mg/L). Subsequently, a lumbar puncture was conducted and the test of CSF was performed.The CSF appeared colorless and transparent,with an initial pressure of 130cmH2O.The white cells of CSF were On the 2nd day after admission,the brain MRI of patient displayed bilateral thalamus and left frontal lobe showed a low signal on T1-weighted images,a high signal on T2-weighted images,a high signal on fluid-attenuated inversion recovery,a high signal on diffusion weighted imaging,and infectious diseases were considered(as shown in figure 1A to H).The electroencephalogram of patient showed that there were moderate abnormality with diffuse slow wave in the whole brain.Combined with above examination results,tuberculous meningoencephalitis is considered to be non-exclusive.To confirm the source of tuberculosis infection,the patient was applied further chest CT,which prompted multiple nodules in both lungs,bilateral pleural localized hypertrophy,and more consideration of tuberculosis(as shown in figure 3A).Subsequently,the patient was taken the following treatment:Anti-tuberculosis (rifampicin 0.45g oral qd,isoniazid 600mg intravenous drip qd,ethambutol hydrochloride 0.75g oral qd,pyrazinamide 1g oral qd) and nutritional nerve(Cyphocholine sodium 0.75g intravenous drip qd),lowering the skull pressure (mannitol 125ml intravenous drip q12h),sedation (olanzapine 5mg oral qn),anti-epilepsy (levizalacetin 0.5g oral bid),liver protection (reducing glutathione 1.2g intravenous drip 5 qd),cooling and prevention treatment such as complications.
After usage of anti-tuberculosis drugs,the patient had irritability and persistent fever.Combined with the patient's medical history,the onset season and the characteristics of CSF and MRI,the second test of CSF was performed immediately.The CSF appeared colorless and transparent,with an initial pressure of 150cmH2O.The white blood cells of CSF were 34×106/L and mononuclear cell percentage was 96%.Pandy test was positive.Meanwhile,the protein was 0.47g/L(normal Range:0.24-0.44g/L),glucose was 3.9mmol/L,chlorine was 113.1mmol/L in the CSF.The acid resistant dyeing test and ink dyeing test were negative.The Samples of the patient's blood and CSF were sent to the center for disease control and prevention of Lanzhou City for further identification of CNS infection which detected specific IgM antibodies of JEV by using ELISA.After signing informed consent with patients and their families,we adjust the treatment plan for the patient according to the test results,as follows:Human immunoglobulin 0.4g/kg·d intravenous drip qd for 5 days,as well as methylprednisolone 500mg intravenous drip qd for 3 days,and gradually reduced to methylprednisolone until withdrawal (regular monitoring during medication, pay attention to prevent adverse reactions).After 3 weeks of treatment,the patient was conscious,the headache was relieved,the body temperature returned to normal,and there was no spontaneous language.The patient could answer questions with nodding or shaking,and then the patient was transferred to the rehabilitation medicine department of our hospital for further treatment.
Follow-up:after discharge,the patient continued to take anti-tuberculosis drugs and antiepileptic drugs.Three months after discharge from the hospital,the patient review the brain CT:slightly hypodense of the basal ganglia and bilateral frontal lobes, calcification of left frontal lobe and right parietal(as shown in figure 2A to D),and chest CT multiple lung 6 nodules,considering inflammatory lesions,it is recommended to review after treatment(as shown in figure 3B).Six months after discharge,the third test of CSF was performed.The CSF appeared colorless and transparent,with an initial pressure of 140cmH2O.The white blood cells of CSF were 3×106/L.Pandy test was negative.Meanwhile,the protein was 0.29g/L,glucose was 3.8mmol/L,chlorine was 127.7mmol/L in the CSF.The acid resistant dyeing test and ink dyeing test were negative.3 months and 6 months after discharge,the function independent measure (FIM) of the patient were assessed as 126 points which were completely independent.

Discussion
JE is an acute infectious disease caused by JEV infection,mainly involving the brain parenchyma.JE is transmitted by vector mosquito bites,and the onset time is obviously seasonal. The peak period is mainly distributed from July to September. Gansu Province is located in the northwestern part of China,with traditional rural areas as the main.The epidemic situation is prevalent and the epidemic may be related to the high temperature and rainfall in Gansu Province from July to September in 2017 [1].The patient lives in the countryside for a long time.The high temperature and heavy rain weather are suitable for the breeding of mosquitoes and the mosquito density is high.The above factors increases the risk of disease.In recent years,due to the widespread use of Japanese encephalitis vaccine,the incidence of Japanese encephalitis in children and adolescents has significantly reduced the encephalitis and adulthood of Japanese encephalitis [3].Patients with JE and tuberculosis co-infection, underlying disease and low immune levels are two risk factors for adult cases [4]. Making a detailed inquiry of the patient's medical history, the patient has no clear history of JE vaccination.Therefore, vaccination against JE is of great significance to prevent the spread of the disease.

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The patient has acute onset,with headache, fever, and disturbance of consciousness as the main clinical manifestations.It is difficult to distinguish from other types of encephalitis and is often neglected and misdiagnosed.After admission,a central systemic infectious disease was pointed by the results of patient's CSF examination and brain MRI.Combined with the chest CT results of the patient,we once diagnosed tuberculous meningoencephalitis(TBM).We found that the characteristics of Cerebrospinal fluid are different between JE and tuberculous meningitis through reviewing the literature.Typical Cerebrospinal fluid examination results of JE include moderate increase of cell number(10-100mm3), mild increase of protein(50-200mg/dl) and normal glucose levels [5].However,the number of cerebrospinal fluid cells in TBM patients is mostly(100-1000)×106/L,mainly lymphocytes [6].Typically,the CSF shows a high CSF white cell count,which is predominantly lymphocytic,with a high protein and low CSF to blood glucose ratio [7].
In addition,with the wide application of MRI,the MRI examination of head can clearly show the lesion and pathological features,which is great significance for the auxiliary diagnosis of JE.JE is metamorphic inflammation,and the lesion is mainly located in gray matter,which is mainly affected by thalamic involvement.Pathological features of JE:in the acute phase,the pia mater and brain parenchyma are hyperemia and edema,the nerve cells are degenerated and necrotic,the Nissl body disappears, some thrombosis occurs and a small amount of bleeding occurs;in the subacute phase, nerve cells damage and diffuse glial cells hyperplasia;in the chronic phase,nerve tissue occurs focal liquefaction and form a softening lesion,part of the cerebral cortex, basal ganglia occur calcification.Therefore, the MRI of JE has some characteristic changes.A research showed that the typical severe JE, the lesions involved mainly in the bilateral thalamus,cerebral and medial temporal lobe,and may have the involvement of temporal lobe,frontal lobe and basal ganglia [8].The lesion of JE usually 8 shows a low signal on T1, a high signal on T2, and a high signal on FLAIR;after a few months of tracking,the lesion range is reduced,and T1 and T2 are low signals [5].  [9].Intracranial tuberculosis is a chronic granuloma formed by Mycobacterium tuberculosis infecting brain parenchyma.Early tuberculoma showed equal T1 or slightly longer T1 and long T2 signals, and showed small nodular enhancement. Late tuberculoma could form a complete capsule with equal or slightly longer T1 and slightly longer T2 signals [10]. 9 At present,JE is still based on prevention.Gamma globulin can induce inflammatory cell apoptosis;methylprednisolone inhibits inflammatory response,inhibits inflammatory factor release and synthesis, and reduces brain edema.In combination with the condition of this patient, human immunoglobulin and methylprednisolone were used for treatment,while the adverse effects of hormones were closely observed, and complications were actively prevented. Ethics approval and consent to participate Not applicable.

Consent for publication
We obtained a confirmation statement of consent for publication from the patient's parents.

Competing interests
The authors declare that they have no competing interests. 13