| disease | Japanese Encephalitis |
| alias | Japanese Encephalitis |
The pathogen of epidemic encephalitis B (hereinafter referred to as Japanese encephalitis) was discovered in Japan in 1934, hence the name Japanese encephalitis B. In 1939, the Japanese encephalitis virus was also isolated in China. After liberation, extensive research and investigations were conducted, and the name was changed to epidemic encephalitis B. This disease is primarily distributed in the Far East and Southeast Asia regions of Asia, transmitted by mosquitoes, and commonly occurs in summer and autumn. Clinically, it presents with sudden onset, high fever, impaired consciousness, convulsions, tonic spasms, and meningeal irritation signs. Severe cases often leave sequelae after the illness.
bubble_chart Epidemiology
(1) Source of Pestilence The primary sources are domestic animals and poultry, mainly pigs (nearly 100% of piglets are infected after one epidemic season), followed by horses, cattle, sheep, dogs, chickens, ducks, etc. Among these, young pigs that have not yet experienced summer are the most significant. After infection, animals may experience 3–5 days of viremia, enabling mosquitoes to become infected and transmit the virus. Typically, 2–4 weeks before a human epidemic of Japanese encephalitis, an outbreak occurs among poultry. Patients exhibit brief viremia during the late incubation period and early onset of illness, but due to the low viral load and short duration, its epidemiological significance is minimal.
(2) Transmission Route Mosquitoes are the primary vectors, with certain species of *Culex*, *Aedes*, and *Anopheles* capable of transmitting the disease, among which *Culex tritaeniorhynchus* is the most important. The virus in mosquitoes can be passed transovarially and overwinter, allowing them to serve as long-term reservoirs for the virus.
(3) Susceptibility Humans are generally susceptible, with most adults showing asymptomatic infections. Cases are predominantly seen in children under 10 years old, with the highest incidence among those aged 2–6. In recent years, due to widespread vaccination of children and adolescents against Japanese encephalitis, the proportion of cases among adults and the elderly has increased, along with a higher fatality rate. Males are more affected than females. Neutralizing antibodies typically appear about one week after infection, providing immunity that can persist for 4 years or longer, making reinfection rare.(4) Epidemiological Characteristics The disease exhibits strict seasonality, with 80–90% of cases concentrated in July, August, and September. However, due to variations in geography and climate, the peak period differs by region: June–July in southern China, July–August in northern China, and August–September in northeastern China, all aligning with the peak mosquito density.
The pathogen of this disease belongs to subgroup 1 of the Flavivirus genus in the family Flaviviridae. It is spherical in shape, with a diameter of 20–40 nm, and is a single-stranded RNA virus. It has a lipid envelope and surface hemagglutinin, which can agglutinate chicken red blood cells. The virus replicates in the cytoplasm and is highly sensitive to temperature, ether, and acid. It can be passaged in suckling mouse brain tissue and also grows in chicken embryos, monkey kidney cells, chicken embryo cells, and Hela cells, among others. Its antigenicity is relatively stable.
After being bitten by mosquitoes infected with the Japanese encephalitis virus, the virus first multiplies in local tissue cells, lymph nodes, and vascular endothelial cells, continuously invading the bloodstream and forming viremia. Whether the disease develops depends on the viral load, virulence, and the host's immune function. The vast majority of infected individuals do not develop symptoms, resulting in asymptomatic infections. When the invading viral load is high, the virulence is strong, and the host's immune function is insufficient, the virus continues to replicate and spreads throughout the body via the bloodstream. Due to the virus's neurotropism, it can break through the blood-brain barrier and invade the central nervous system, especially when the blood-brain barrier is compromised or the brain parenchyma already harbors the virus, making it easier to trigger the disease.
It can cause extensive lesions in the brain parenchyma, with the most pronounced changes occurring in the cerebral cortex, brainstem, and basal ganglia, followed by the pons, cerebellum, and medulla oblongata, while spinal cord lesions are the mildest. The basic pathological changes include: ① damage to vascular endothelial cells, manifested by dilation, congestion, hemorrhage, and thrombosis of small blood vessels in the meninges and brain parenchyma, as well as perivascular cuff-like cell infiltration; ② degeneration and necrosis of nerve cells, leading to the formation of variously sized sieve-like softening foci after liquefaction and dissolution; ③ local proliferation of glial cells, forming glial nodules. In some patients, severe cerebral edema may occur, leading to increased intracranial pressure or further progression to brain herniation.
bubble_chart Clinical Manifestations
The incubation period is 10 to 15 days. Most patients experience mild symptoms or asymptomatic latent infections, with only a few developing central nervous system symptoms such as high fever, impaired consciousness, and convulsions. The course of a typical case can be divided into four stages.
(1) Initial stage [first stage]: The onset is sudden, with body temperature rapidly rising to 39–40°C, accompanied by headache, nausea, and vomiting. Some patients experience drowsiness or mental fatigue, along with grade I neck stiffness. The duration is 1–3 days.
(2) Critical stage: Body temperature continues to rise, possibly exceeding 40°C. Symptoms from the initial stage gradually worsen, with marked impairment of consciousness, progressing from drowsiness to stupor and even unconsciousness. The deeper and longer the unconsciousness, the more severe the condition. Confusion may occur as early as days 1–2 of the illness but is more common on days 3–8. Severe cases may exhibit generalized spasms, tonic convulsions, or tonic paralysis, while a few may show flaccid paralysis. In critical cases, central respiratory failure may occur due to brain parenchymal lesions (especially brainstem involvement), hypoxia, cerebral edema, brain herniation, intracranial hypertension, or hyponatremic encephalopathy. This manifests as irregular breathing patterns, double inhalation, sighing respiration, apnea, Cheyne-Stokes respiration, or mandibular breathing, eventually leading to respiratory arrest. Physical examination may reveal meningeal irritation signs, sluggish or absent pupillary light reflexes, dilated pupils, loss of abdominal and cremasteric reflexes, hyperactive deep reflexes, and positive pathological pyramidal signs such as Babinski's sign.
(4) Sequelae: If neurological symptoms persist beyond six months despite active treatment, they are termed sequelae. About 5–20% of patients develop sequelae, all of whom had severe symptoms such as high fever, unconsciousness, and spasms. The most common sequelae include aphasia, paralysis, and mental disorders. Aphasia often resolves, and limb paralysis may also improve, though death can occur due to complications like pneumonia or bedsores. Mental disorders are more common in adult patients but may gradually recover.
Based on severity, Japanese encephalitis can be classified into four types.
1. Mild type: Patients remain conscious but may exhibit varying degrees of drowsiness, with no spasms (except for occasional febrile convulsions in children). Body temperature ranges between 38–39°C, and most recover within a week. Diagnosis often relies on cerebrospinal fluid and serological tests.
2. Moderate type: Patients exhibit impaired consciousness, such as stupor or light unconsciousness, loss of abdominal and cremasteric reflexes, and possibly short-term spasms. Body temperature typically reaches around 40°C, with a course lasting about 10 days and no sequelae.
3. Severe type: Body temperature remains above 40°C, with unconsciousness and recurrent or persistent spasms. Superficial reflexes are absent, deep reflexes initially disappear then become hyperactive, and pathological reflexes are present. Localizing signs and symptoms may appear, including central respiratory failure. The illness often lasts over two weeks, with convalescence frequently marked by varying degrees of mental abnormalities and paralysis. Some patients develop sequelae.
Based on lesion location and brainstem involvement, combined with symptoms, signs, and the presence of respiratory failure, brain lesion localization can be categorized as follows:
(1) Upper brainstem: Lesions affect the cerebrum and diencephalon without involving the brainstem. Clinically, this manifests as light unconsciousness, pseudo-automatic movements upon orbital pressure, or decorticate rigidity (flexed upper limbs, extended lower limbs). Eye movements remain intact, with initially small or normal pupils that dilate upon neck skin stimulation. Breathing remains stable throughout.
⑵ Upper brainstem level: The lesion is at the midbrain level, manifested as deep unconsciousness and increased muscle tone. Decerebrate rigidity occurs upon supraorbital pressure (extension of upper and lower limbs with pronation of the upper limbs), poor or fixed eye movements, moderately dilated pupils with sluggish or absent light reflex. Central hyperventilation is present (marked nasal tone, rhonchi, elevated blood pH, leading to respiratory alkalosis). The pupils can still dilate upon nuchal skin stimulation, but the response is sluggish.
(3) Lower brainstem lesion: The lesion is at the level of the pons and medulla oblongata, manifested as deep unconsciousness, no response to supraorbital pressure, and flaccid limbs. The corneal reflex disappears, the pupils initially constrict and then dilate, the light reflex is lost, and the pupils fail to dilate in response to neck skin stimulation. Breathing may temporarily stabilize, and snoring disappears, but central respiratory failure can rapidly occur.
(4) Brainstem lesion: This is a special type among severe cases. In the initial stage, the patient may have high fever and remain conscious but often exhibits drowsiness, choking cough, and dysphagia. Breathing is shallow and rapid, and drinking water refluxes through the nose. Secretions accumulate in the throat and rapidly increase in a short time, leading to laryngeal obstruction symptoms. The patient may quickly progress to unconsciousness and develop central respiratory failure.
(5) Uncal herniation: Caused by cerebral edema. The patient's condition deteriorates suddenly, progressing from dysphoria, restlessness, vomiting, and headache to unconsciousness, or rapidly shifting from mild to deep unconsciousness. In addition to the aforementioned brainstem compression symptoms, there may be unequal pupil sizes, dilated pupils on the affected side, loss of light reflex, ptosis, bilateral limb paralysis, and positive pyramidal tract signs.
(6) Foramen magnum herniation: Due to cerebral edema and uncal herniation, the brainstem is displaced, leading to foramen magnum herniation. Early symptoms include increased intracranial pressure without changes in pupils or breathing, followed by sudden deep unconsciousness. Alternatively, deviation of the mouth, deafness, and dysphagia may appear first, followed by loss of the swallowing reflex, bilateral pupil dilation, and ultimately central respiratory failure, apnea or sudden respiratory arrest, slowed pulse, decreased blood pressure, and cardiac arrest.
4. Fulminant type: The body temperature rises rapidly, reaching high or extremely high fever, accompanied by repeated or persistent intense spasms. Deep unconsciousness develops within 1–2 days, along with pupil changes, brain herniation, and central respiratory failure. If timely rescue measures are lacking, death often occurs due to respiratory failure. Survivors typically suffer severe sequelae.
In clinical manifestations of Japanese encephalitis, mild and ordinary types are the most common, accounting for about two-thirds of total cases. Severe cases are more frequent in the initial stage of an epidemic, while mild cases predominate in the late stage.
Clinical diagnosis mainly relies on the comprehensive analysis of epidemiological data, clinical manifestations, and laboratory tests, with confirmation depending on serological and etiological examinations.
(1) Epidemiological Data: The disease is most common from July to September, occurring slightly earlier in the south and slightly later in the north. The highest incidence is among children under 10 years of age.
(2) Main Symptoms and Signs: The onset is acute, with manifestations such as high fever, headache, vomiting, and drowsiness. Severe cases may exhibit unconsciousness, spasms, dysphagia, choking cough, and respiratory failure. Signs include meningeal irritation, loss of superficial reflexes, hyperactive deep reflexes, tonic paralysis, and positive sexually transmitted disease reflexes.
(3) Laboratory Tests
1. Blood Picture: The total white blood cell count is often between 10,000–20,000/mm³, with neutrophils accounting for over 80%. In a few mild cases during the late epidemic stage [third stage], the blood picture may fall within the normal range.
2. Cerebrospinal Fluid (CSF): The fluid is colorless and transparent, with only grade I increased pressure. The white blood cell count rises to 50–500/mm³, and in some cases, may exceed 1,000/mm³. In the first 2–3 days of illness, neutrophils predominate, followed by an increase in monocytes. Sugar levels are normal or slightly elevated, proteins are often grade I elevated, and chloride levels are normal. In the first 1–3 days of illness, CSF tests may yield negative results in a few cases.
3. Virus Isolation: Japanese encephalitis virus can be isolated from the brain tissue of fatal cases within one week of the disease course. Viral antigens can also be detected in brain tissue using immunofluorescence (IFT). The virus is rarely isolated from CSF or serum.
4. Serological Tests
(1) Complement Fixation Test: Positivity appears late and is generally only used for retrospective diagnosis and surveys of latent infections in the current year.
(2) Neutralization Test: Highly specific but methodologically complex, with antibodies persisting for over a decade. Used only for epidemiological surveys.
(3) Hemagglutination Inhibition Test: Antibodies appear early, with high sensitivity and long persistence, but specificity is lower, and false positives may occur. Useful for diagnosis and epidemiological surveys.
(4) Specific IgM Antibody Detection: Specific IgM antibodies can appear as early as 4 days post-infection, peaking within 2–3 weeks. The positivity rate for specific IgM antibodies in blood or CSF reaches 70–90% within 3 weeks, enabling early diagnosis. When combined with the hemagglutination inhibition test, the concordance rate can reach 95%.
(5) Specific IgM Antibody Detection: A fourfold or greater increase in antibody titer during the convalescent stage compared to the acute stage has diagnostic value.
(6) Monoclonal Antibody Reverse Hemagglutination Inhibition Test: This test, using sheep red blood cells sensitized with Japanese encephalitis monoclonal antibodies, has a positivity rate of 83%. It is simple, rapid, and commercially available as a kit, requiring no special equipment.
5. Te-99m HMPAO (Hexamethyl Propyleneamine Oxime) Brain Single-Photon Emission CT (SPECT) Examination: Some studies using Te-99m HMPAO brain SPECT in children with viral encephalitis (including Japanese encephalitis) found changes in all cases of acute sexually transmitted disease viral encephalitis. The positivity rate was higher than with CT or MRI alone, providing clearer localization, manifested as regional increases in cerebral blood flow. Most cases showed normalization of regional cerebral blood flow after the acute phase. Normal SPECT results during the subacute phase often indicate a favorable clinical prognosis, with no neurological deficits after one year.
bubble_chart Treatment Measures
The patient should be hospitalized, and the ward should be equipped with mosquito prevention and cooling facilities. Close observation of the patient's condition and meticulous care are essential to prevent complications and sequelae, which are of great significance for improving treatment efficacy.
(1) General Treatment: Pay attention to diet and nutrition, and provide adequate hydration. Patients with high fever, unconsciousness, or convulsions are prone to dehydration, so sufficient fluids should be administered. Adults generally require 1,500–2,000 ml daily, while children need 50–80 ml/kg daily. However, excessive fluid infusion should be avoided to prevent cerebral edema and worsening of the condition. Nasogastric feeding is recommended for unconscious patients.
(2) Symptomatic Treatment:
1. Management of High Fever: Aim to reduce the room temperature below 30°C. Physical or pharmacological cooling methods can be used for patients with high fever to maintain body temperature between 38–39°C (rectal temperature). Analgin (0.5 g for adults) can be administered intramuscularly every 4–6 hours, while suppositories may be used for young children. Excessive use of antipyretics should be avoided to prevent collapse due to profuse sweating.
2. Management of Convulsions: Sedatives and anticonvulsants such as diazepam, chloral hydrate, phenytoin sodium, or amobarbital sodium may be used. Corresponding measures should be taken based on the cause of convulsions: - If caused by cerebral edema, dehydration therapy should be prioritized, such as intravenous infusion of 20% mannitol (1–1.5 g/kg) over 20–30 minutes, repeated every 4–6 hours if necessary. Furosemide and corticosteroids may also be combined to prevent rebound after dehydration therapy. - If caused by hypoxia due to airway obstruction or respiratory difficulty, oxygen therapy and airway clearance should be provided, with tracheostomy and assisted ventilation if necessary. - If caused by high fever, cooling measures should be the main focus.
3. Management of Respiratory Distress and Failure: For deeply unconscious patients with excessive phlegm obstructing breathing, secretions should be suctioned via the mouth or nose, and postural drainage or nebulization may be used to maintain airway patency. For respiratory failure due to cerebral edema or herniation, dehydration agents and corticosteroids may be administered. If breath-holding occurs due to convulsions, anticonvulsant treatment should be applied. If respiratory arrest occurs due to pseudobulbar palsy or medullary paralysis, immediate tracheostomy or intubation with positive-pressure ventilation is required. For weak or shallow breathing, respiratory stimulants such as lobeline, nikethamide, methylphenidate, or dimefline may be used (alternately if needed).
4. Management of Circulatory Failure: For circulatory failure caused by cerebral edema or herniation, presenting with pallor, cold extremities, and narrow pulse pressure, dehydration therapy should be used to reduce intracranial pressure. For cardiogenic heart failure, cardiac glycosides like cedilanid should be added. If circulatory failure is due to hypovolemia caused by high fever, unconsciousness, or excessive dehydration, volume expansion should be prioritized.
(3) Corticosteroids and Other Treatments: Corticosteroids have anti-inflammatory, antipyretic, and capillary permeability-reducing effects, protect the blood-brain barrier, alleviate cerebral edema, inhibit immune complex formation, and stabilize lysosomal membranes. They should be administered early to severe or confirmed cases. The dosage can be gradually reduced after body temperature remains below 38°C for two days, generally not exceeding 5–7 days. Early discontinuation may lead to symptom recurrence, while prolonged use increases the risk of complications.
Broad-spectrum antiviral drugs such as ribavirin or dipyridamole may be used in the early stages, showing significant fever reduction and good efficacy.
(4) Sequelae and Rehabilitation: Rehabilitation should focus on improving cognitive, swallowing, speech, and motor functions. Physical therapy, exercise therapy, Chinese medicinals, acupuncture, tuina, and other treatments may be employed to promote recovery.
The fatality rate is around 10%. Most patients with mild and ordinary cases recover, while those with fulminant and brainstem types have higher fatality rates, often succumbing to respiratory failure during the critical phase.
Early detection of patients, timely isolation, and treatment are essential, but the primary source of pestilence is livestock, especially young pigs that have not experienced the epidemic season. In recent years, vaccines have been used to immunize young pigs to reduce viremia in swine populations, thereby controlling the spread of Japanese encephalitis among humans. Mosquito prevention and eradication are critical measures to control the epidemic, particularly targeting Culex mosquitoes. Vaccination is a key measure to protect susceptible populations. Currently, China uses an inactivated vaccine produced from hamster kidney tissue culture. Trials during epidemic seasons have shown a protection rate of 60–90%. Typically, two doses are administered, 7–10 days apart, followed by a booster shot the next year. The target groups for vaccination are children under 10 years old and individuals entering epidemic areas from non-endemic regions, though high-risk adults should also be considered. Important precautions for vaccination include: ① It should not be administered simultaneously with the triple vaccine for cold-damage disease; ② It is contraindicated for individuals with central nervous system disorders or chronic alcoholism. Some reports indicate acute disseminated encephalomyelitis occurring about two weeks after Japanese encephalitis vaccination, which resolved quickly with oral prednisolone (2mg/kg/day). Immunity from the vaccine generally begins 2–3 weeks after the second dose and lasts 4–6 months. Therefore, vaccination must be completed at least one month before the epidemic season.
(1) Complications: Pulmonary infection is the most common, as patients are unconscious and have difficulty expelling respiratory secretions, leading to bronchopneumonia and atelectasis. Others include occipital bone pressure sores, skin abscesses, oral infections, and sepsis.
(2) Sequelae: Commonly seen in severe and fulminant cases, affecting approximately 5–20%. Neurological sequelae often include aphasia, followed by limb rigidity paralysis, torsion spasm, contracture deformities, dysphagia, choreiform movements, and epileptic seizures. Autonomic dysfunction may also occur, manifested as profuse sweating and central fever. Psychiatric sequelae include dementia, mental abnormalities, personality changes, and memory decline.
(1) Toxic Bacillary Dysentery It shares the same epidemic season as Japanese encephalitis (JE), occurring mostly in summer and autumn. However, its onset is more acute than JE, often presenting with high fever, spasm, shock, or unconsciousness within one day of illness. Except for fulminant cases, JE rarely causes shock. A 1–2% saline enema can be administered, and the presence of purulent or bloody stools confirms the diagnosis.
(2) Purulent Meningitis The condition progresses rapidly, with severe patients entering unconsciousness within 1–2 days of onset. Signs of meningeal irritation are prominent, and skin petechiae are common. The cerebrospinal fluid (CSF) is turbid, with neutrophils accounting for over 90%. Pathogens can be identified via smear or culture. Peripheral blood leukocyte counts are significantly elevated, reaching 20,000–30,000/mm3, with neutrophils often exceeding 90%. If it is epidemic cerebrospinal meningitis, it exhibits seasonal characteristics. Early atypical cases are difficult to distinguish from JE and require close monitoring and repeated CSF examinations.
(3) Tuberculous Meningitis There is no seasonal pattern. The onset is slow, the course is prolonged, and there is a history of tuberculosis. Both glucose and chloride levels in the CSF are reduced, and Mycobacterium tuberculosis can be detected via thin smear or culture. Chest X-rays, fundus examinations, and tuberculin tests aid in diagnosis.
(4) Others Conditions such as poliomyelitis, mumps encephalitis, other viral encephalitides, heatstroke, and malignant malaria should also be differentiated from JE.
