UPDATE ON ENCEPHALITIS
Dr. Nagabhushana Rao Potharaju*
B.Sc (Spl), M.D (Pediatrics), D.C.H., D.M (Neurology) Professor & Head of the Department of Neurology, Osmania Medical College and Osmania General Hospital, Hyderabad. International Clinical Expert on Japanese Encephalitis and Epidemic Brain Attacks*
Aseptic Meningitis and Encephalitis
Viral infection of the arachnoid membrane and CSF causes headache, stiff neck and initial neutrophil and later lymphocytic CSF pleocytosis with normal protein and glucose. This syndrome is called aseptic meningitis because no bacterial organisms are isolated. The most common agents causing aseptic meningitis are Enteroviruses. Encephalitis caused by viral infection manifests as either acute viral encephalitis or post infectious encephalomyelitis. Acute viral encephalitis is due to direct viral infection of neural cells with associated perivascular inflammation and destruction of gray matter. Involvement of neurons and Glial cells by viruses (viral encephalitis) impairs neurological function and causes seizures, focal neurologic deficits and coma. Clinical presentation and course can be markedly variable. Encephalitis is accompanied by viral meningitis whereas aseptic meningitis may occur alone.

Conventionally viral meningitis refers only to fever, headache, stiff neck and photophobia and if any other CNS symptoms are present, the condition is called meningoencephalitis. Hence, in a setting of febrile aseptic meningitis, the clinical diagnosis of encephalitis is based on the demonstration of involvement of the cerebrum, brainstem, or cerebellum. In Encephalitis, the infectious process and associated inflammatory process involves the brain parenchyma. A host of organisms (Viruses, bacteria, fungi, and parasites) can produce the encephalitic syndrome. Encephalitis may be acute/subacute Post infectious encephalomyelitis follows infection with various viral or bacterial agents. The primary pathologic finding is demyelination of white matter.
Etiology and Epidemiology
More than 150 different viruses can cause acute encephalitis. Of the over 534 arboviruses, approximately 134 cause disease in humans. These are transmitted principally by mosquitoes and ticks. Such viruses cause about 10% of all reported cases of sporadic encephalitis but may account for up to 50% of all cases in epidemic years. Acute encephalitis may occur as an epidemic (Japanese Encephalitis (JE) or sporadic of which Herpes simplex virus (HSV) I & II, cytomegalovirus, mumps, measles, Varicella Zoster virus, Epstein-Barr virus and rabies are most important (Table 1). Subacute or chronic encephalitis include HIV, measles (Subacute Sclerosing Pan Encephalitis [SSPE]), Rubella, JC Papova virus.
Pathogenesis
In general, the virus replicates outside the CNS and gains entry either by hematogenous spread or by traveling along neural (rabies, HSV, VZV) and olfactory (HSV) pathways. The etiology of slow virus infections, like SSPE and progressive multifocal leukoencephalopathy (PML) is poorly understood.

After crossing the blood-brain barrier, the virus enters neural cells. This results in disruption in cell functioning, perivascular congestion and hemorrhage. Inflammatory response affects gray matter more than white matter. Focal pathology is the result of neuron cell membrane receptors found only in specific portions of the brain and accounts for viral neurotropism. For example, HSV has a predilection for the inferior and medial temporal lobes, Enterovirus for meninges, Herpes simplex for temporal lobe, JE for basal ganglia, Varicella Zoster for white matter of cerebellum, Rabies for Ammon's Horn, Polio for motor neurons in anterior horn cells of Spinal Cord & brainstem, Epstein-Barr virus for cerebral blood vessels and mumps for ependymal & choroid plexus cells and Cytomegalovirus for walls of ventricles. So involvement of a particular area in the brain and the resulting symptomatology assist in making a clinical diagnosis.

An immunocompromised host is a key risk factor with some viruses like varicella-zoster virus (VZV) and cytomegalovirus (CMV).

Table 1: Common Viral Infections of Nervous System
Virus Disease Transmission Fatality Rate
Laboratory Confirmation
JE Meningitis
Encephalitis
Mosquitoes/swine
/ducks/herons in
the ponds
6-50% ELISA for IgM or IgG in serum or CSF
Herpes simplex Encephalitis
Meningoencephalitis
Aseptic Meningitis
Cerebellitis
Human >70% if untreated
>30% with treatment
>CSF PCR
Coxsackie and Echovirus
Meningitis
Encephalitis
Paralytic disease
Guillain-Barre syndrome
Transverse Myelitis
Cerebellitis
Peripheral Neuritis
Human
None
Culture of stool and CSF, PCR or CSF, serology
Measles
Encephalitis
SSPE
Human
<5% 100% fatal Serology Elevated CSF globulin
Mumps
Meningitis Encephalitis Human
<1%
Serology, Culture of CSF
Rabies
Encephalitis
Dogs, Cats, Bats,
Squirrels
>99%
Antigen detection in Brain, Culture serology
Polio
Meningitis
Paralytic Polio
Human
5-50%
Culture, PCR

Clinical features
Viruses that differ widely in their morphology, chemical composition, and replication can provoke identical clinical presentation and pathologic changes in brain, namely fever, altered sensorium or focal findings (like aphasia, ataxia, hemiparesis, involuntary movements like myoclonic jerks, and cranial nerve palsies). Temperature dysregulation, diabetes insipidus, or Syndrome of Inappropriate Anti Diuretic Hormone (SIADH) may be the result of involvement of hypothalamo-pituitary axis. Therefore clinical diagnosis at best can only be an educated guess and is made by the association of encephalitis with some symptoms and signs, (Table 2) or presentation as sporadic or epidemic. Identifying the specific cause is the key to efficient management.

Most of the encephalitic illnesses are sporadic. But it is only JE which spreads in epidemic proportions though sporadic cases are also reported.

Table 2. Educated guess about probable Virus

Symptoms and signs

Probable causative Virus

Small grouped vesicles (usually on vermillion border of lips) with burning/stinging/stabbing pain Herpes Simplex
Smell/Taste/behavioral abnormality/Motor
aphasia
Herpes Simplex
Pain along the course of a nerve followed by painful grouped vesicular lesions. Unilateral Varicella Zoster
Polymorphous, umbilicated, multilocular eruptions Varicella Zoster
Respiratory symptoms/Epidemics of cold
Adenovirus
Summer Colds/diarrhea/pharyngitis/abdominal pain/rash/Respiratory symptoms/herpangina/
pleurodynia/myocarditis
Enterovirus
Preceding epidemics of conjunctivitis
Enterovirus 70
Rash
Dengue, West Nile, Enterovirus, Adenovirus, Measles.
Conjunctivitis
Adenovirus, Enterovirus 70, Measles.
Parotitis
Mumps, Enterovirus, Epstein-Barr virus, HIV
Pharyngitis
Adenovirus, Enterovirus, Epstein-Barr virus, other respiratory viruses
Adenopathy
Epstein-Barr Virus, Cytomegalovirus, HIV
Croup
Measles, Adenovirus, Influenza
Bronchiolitis
Adenovirus, Influenza
Pneumonia
Adenovirus, Measles, Varicella,
Cytomegalovirus, Dengue
Enteritis - Diarrhea, Abdominal Colic Epidemic Brain Attack, Enterovirus
Hepatitis
Adenovirus, Cytomegalovirus, Varicella, Epstein-Barr virus
No S/S of Meningeal irritation, CSF normal except for raised tension, Diarrhea, Abdominal Colic Epidemic Brain Attack

Complications
When the inflammatory and immune reactions of viral encephalitis subside, the lesions heal with Glial scar formation. The neurons lost usually do not regenerate. So in the aftermath of viral infections, patients are often left with severe permanent neurological deficits.
Differential Diagnosis
First exclude a non-viral cause of encephalitis like vascular disease, abscess, fungal, parasitic, Leptospiral, rickettsial, and tuberculous infections, tumors, Reye's syndrome, toxic encephalopathy, subdural hematoma, Systemic Lupus Erythematosus, Listeria, Mycoplasma, Cryptococcosis, Mucor infections, Toxoplasmosis. After non-viral causes are excluded, Herpes Viruses must be considered since effective and specific therapy is available. In all other encephalitis, the therapy is supportive and symptomatic. Next observe for any epidemiological evidence. Our experience in Andhra Pradesh suggests that epidemiologic evidence is extremely useful in early diagnosis and management of JE, before serological confirmation is available. Viral neurotropism and resulting clinical findings are useful in clinically diagnosis (discussed above in pathogenesis).
Indications in Pediatric Age Group
JE is the only encephalitis which presents in epidemic form in India. Making a probable diagnosis of encephalitis on clinical grounds is extremely important to manage them not only as an individual case but also for the community since the management of JE and EBA (Epidemic Brain Attack) call for immediate reporting to the Health Authorities for a wider coordinated intervention by many departments to contain the epidemic and manage large number of cases. Differential diagnosis of Epidemic coma is possible with clinical examination (Table 3).

A simple mnemonic for remembering the characteristics in this table is "PAID".

Table 3. Approach to epidemic coma without rash

Characteristic

JE

Epidemic Brain Attack

Cerebral Malaria

Reye Syndrome

P = Pyrexia + + + <-
A = Asymmetrical or Focal S/S

+

+

-

-

I = Irritation of Meninges/CSF abnormality

+

-

-

-

D = Diagnostics Positive JE serology CT scan of brain (between 2-4 days after onset) Peripheral smear for Malarial parasite Liver function tests. Blood glucose and ammonia


West Nile Encephalitis: Finding dead birds indicates the prevalence of West Nile Virus (WNV). Mosquitoes transmit the virus from birds to humans. A truncal maculopapular rash may be present in nearly half of patients. Virus has been found in breast milk. Virus may be transmitted in organ transplants. There is no specific treatment.
Investigation of Viral Encephalitis in General
Most of the routine investigations are within normal limits.

Liver Function tests in encephalitis

Serum glutamic-oxaloacetic transaminase (SGOT) elevations are not a feature of most encephalitides due to arboviral infection. Mild elevations of the SGOT/SGPT in a patient with encephalitis should suggest West Nile encephalitis, Human herpesvirus 6, Epstein-Barr virus, Ehrlichiosis, Legionnaires disease or Rocky Mountain spotted fever.

Table 4 shows the laboratory diagnosis of coma presenting in epidemics.

Table 4. Laboratory diagnosis of coma without rash presenting in Epidemics

Observation

Encephalitis

Epidemic Brain Attack

Cerebral Malaria

Encephalopathy

CSF Elevated tension, Lymphocytic pleocytosis Elevated tension. No pleocytosis Elevated tension. No pleocytosis Normal


In encephalitis, CSF reveals lymphocytic pleocytosis, elevation of protein and almost always normal glucose. Rarely hypoglycorrhachia may be seen in HSV and Mumps.

Serological studies and antibody detection have a limited utility of retrospective diagnostic confirmation rather than acute diagnosis since the best results with these types of assays are available after the first week of illness. IgM Capture a ELISA is best after 7 days and any sample of less than 7 days may be only 50% sensitive. IgG antibodies appear by 10-14 days. Four fold or greater rise in titer of IgG antibodies in 2 samples taken 7-14 days apart confirm the infection. CSF antibodies are conclusive for diagnosis of brain infection whereas serum antibodies require other corroborative evidence for confirmation. Rising titer in paired samples of serum may be acceptable in many situations. On the other hand, viral antigen detection may be possible early in the course of the illness. PCR amplification of viral nucleic acid is the diagnostic procedure of choice for HSV, CMV, EBV, VZV and Enteroviruses.

Neuroimaging (CT, MRI) and EEG: These tests establish the existence of a focal or diffuse encephalitic process or exclude alternative diagnosis (Space Occupying lesion, SOL).
Investigation of Viral Encephalitis in General
  1. Hemorrhagic CSF
  2. Periodic focal spikes on a background of slow or low-amplitude activity with a temporal predominance of EEG.
  3. Temporoparietal areas of low absorption, mass effect, and contrast enhancement on CT
  4. Areas of increased signal intensity in the frontotemporal, cingulated, or insular regions of the brain on T2 -weighted spin-echo MRI images.

Rarely, infectious acute asymmetric hemicerebellitis may occur, requiring MRI rather than computed tomography to reach the correct diagnosis.

Brain Biopsy: The need for brain biopsy to diagnose HSV and other forms of viral encephalitis has declined greatly with the widespread availability of a CSF PCR diagnostic tests for HSV and many other viruses.
Management
General Management: There is no specific treatment for most encephalitides, meaning that there is only supportive treatment. Antibiotics are not effective and no effective anti-viral drugs are available. The main reason for high morbidity and mortality rates in India is improper or inadequate nursing care.

The commonest cause of death is trying to shift the patient to the biggest hospital in the state without giving first aid and lack of medicare during transport. Principles of management of comatose children must be followed in general. The purpose of arresting or minimizing the damage, preventing complications and death is achieved by symptomatic treatment alone and is similar for all viral encephalitides except for Herpes Encephalitis (Simplex, Varicella Zoster).

The main causes of mortality and morbidity are mostly preventable and they are: Status epilepticus, Hypoxia, Pulmonary aspiration of saliva or vomiting, Secondary bacterial infections, Pulmonary infections, Raised ICT, Hypoglycemia, Stress ulcers and gastric hemorrhage, Hyperpyrexia, Brainstem involvement, Airway block by the secretions, Bedsores, Pulmonary Edema, Intractable Hypotension, Thromboembolism, SIADH and corneal ulceration.

The treatment is mainly directed towards preventing and treating complications. By prevention/treatment of complications, more than 95% of mortality and morbidity can be prevented. Management in small hospitals where average medical and nursing care can be given, but there is no ventilator facility includes:


  1. An adequate airway is established. Ambu bag is used as often as necessary.
  2. If excess throat secretions are a problem, the child is kept on its side with the head slightly lowered. The throat secretions are cleared from the throat and mouth as and when necessary with a mucus sucker. If vigorous suction is done in supine position from the throat, there is a risk of excessive throat stimulation resulting in cardiac arrest due to vagal stimulation. Therefore, turn the patient to one side to avoid aspiration and such the throat secretions from the cheek with a mucus sucker.
  3. A nasogastric tube is passed and suction from the stomach is done if necessary.
  4. Oxygen is administered; even if there is no cyanosis.
  5. Failure of autoregulation of the brain makes the cerebral circulation depend solely on systemic blood pressure. So, a large bore IV catheter is inserted (for less than 3 years 23G, for more than 3 years 22G) and circulation is stabilized. Fluids, plasma, blood or even a dopamine drip (5-20 mg/kg/min) might be necessary in cases of hypotension. Considering the fact that clinical signs appear when intracranial pressure is usually above 15-20 mmHg, it is imperative to maintain a mean arterial pressure above 75 mmHg in mild and moderate grade coma and more than 85 mmHg in severe grade coma.
  6. Fluid overload is avoided.
  7. Hypoglycemia is very frequent. Blood glucose is estimated and 1 ml/kg of 50% Dextrose is pushed at the rate of 1 ml/kg/min which contains 0.5 gm glucose and supplies 1.7 cal.ml. IV dextrose suppresses gluconeogenesis and provides a substrate that can be oxidized directly, especially by the brain, RBC & WBC.
  8. Seizures: First-aid management to prevent injury and protect the child's airway during and following the seizure should not be forgotten. For the treatment of seizures, give diazepam IV or PR. IV Diazepam is given at the dose of 0.1 - 0.3 mg/kg in 1-5 minutes. If the fits are not controlled, repeat in 5-20 minutes. Rectal diazepam in a dose of 0.2-0.5 mgm/kg can be given in emergency situations were intravenous access is not feasible. Alternate drugs for immediate control of seizures include:
    • Lorazepam (0.1 mg/kg IV) is preferable to diazepam because of its longer half life.
    • Midazolam at the loading dose of 0.5-2 mg/kg stat followed by infusion at a rate of 1-5 μg/kg/min may be given.
    • Inj. Paraldehyde 4% (fresh solution), 0.1-0.3 ml/kg, deep IM into deep gluteal region or diluted 1:1 with olive oil and given rectally. It can be repeated after 15-30 minutes.
    For prolonged seizures, use Phenytoin IV or Phenobarbitone.
    • Phenytoin is given at the dose of 10-20 mg/kg over 10-20 minutes at a rate of less than 1 mg/kg/minute. ECG monitoring is desirable because arrhythmia may develop if phenytoin is injected rapidly. The dose is repeated at 5-10 mg/kg IV after 1 hour, up to a maximum of 1000 mg.
    • Fosphenytoin is a pro-drug that requires metabolism to the active form. Fosphenytoin is absorbed IM and can be administered rapidly. Fosphenytoin should be infused at =100 to 150 mg/min; sub therapeutic levels may occur if infused slowly. Therapeutic blood levels occur in 30 minutes if drug is rapidly infused. Dosing is the same as for phenytoin. The equimolar dose of fosphenytoin is 1.5 mg for every 1 mg of phenytoin. For example, 375 mg fosphenytoin is equivalent to 250 mg of sodium phenytoin and is labeled as fosphenytoin 250 mg PE. In the treatment of status epilepticus, the IV loading dose of fosphenytoin is 15 to 20 mg PE (phenytoin sodium equivalents) administered at 100 to 150 mg PE/min. Adverse effects are the same as with phenytoin. Fosphenytoin may be preferable because it causes less respiratory depression. The clinical advantages of fosphenytoin include the fact fosphenytoin is water-soluble and therefore more stable in IV fluids and does not require an additional IV filter. As a consequence it has been found to have a lower incidence of pain and burning associated with intravenous administration and can be administered safely utilizing the intramuscular route. administered safely utilizing the intramuscular route.


For prolonged seizure management it is preferable to avoid Phenobarbitone as it sedates the child and interferes with the assessment of depth of coma. It may be used if sedation also is desired along with seizure control. Phenobarbital 10 mg/kg loading dose is given i.v. over 30 minutes. Additional 5- to 10 mg doses may be given until 40 mg/kg or maximum dose of 1 g is reached.

Other antiepileptics that may be tried include:
Valproate Suspension can be given at the dose of 30 mg/kg orally or 30-60 mg/kg diluted 1:1 in water as retention enema; it may be repeated 3 times daily in a dose of 10-20 mg/kg/dose. Intravenous sodium valproate is infused in a dose of 20 mg/kg at 20 mg/min if above regimen fails. The drug may be repeated whenever required. It may be continued at the dose of 30-50 mg/kg/day in 3 divided doses.

Clobazam may be used in a dose of 1 mg/kg. The status responds in 20 to 30 min without significant sedation or other side effects. Continue with 0.25 - 1 mg/kg/day up to a maximum of 40 mg/day.

If these measures too fail seek anesthetist's consultation to paralyze and ventilate the child using Thiopentone infusion.

For raised Intracranial Tension: Patients with signs of shock (tachycardia, reduced skin perfusion, poor skin turgor) should be resuscitated with fluid on the standard lines. Otherwise fluid input should be restricted to about two thirds normal requirements, using 0.45% saline in 5% dextrose. In an emergency situation, the head end is elevated 30o to reduce the ICP. Flexion of neck is avoided to prevent the possible obstruction to jugular venous outflow by turning the head to a side.

  • Osmotic diuretics must be used in minimum necessary doses for the minimum period only. Mannitol infusion at the loading dose of 5 ml/kg (1g/kg) of 20% Mannitol, given IV rapidly over less than 20 minutes, followed by 1.25 ml/kg (0.25 g/kg) every 6-12 hours to treat the persistent ICP elevation. Mannitol is contraindicated in Congestive Cardiac Failure and Pulmonary edema. Response to mannitol depends upon intracranial tension, dose given over the previous 3 hours (better effect with lesser doses), and rate of administration. Rapid administration is more effective in reducing intracranial pressure (ICP) for a shorter duration, whereas a slower infusion rate reduces the ICP to a lesser degree, but for a longer duration.
    It is better to give Mannitol for the first three days followed by glycerol (either orally or through nasogastric tube) for a few more days and then to taper it off over the next few days. Osmotic diuretics like mannitol/glycerol must be used in minimum necessary doses for the minimum necessary period only.
  • Normalize temperature. The increased metabolic demand from Hyperthermia increases cerebral blood flow CBF), cerebral blood volume (CBV) and intracranial tension/pressure (ICP). Increased CBV & ICP result in increased cerebral edema, reduced CBF and deterioration of the supply to demand ratio. Shivering (which can occur during sponging) increases ICP by increasing pleural (intrathoracic) pressure. This can be prevented by promethazine 1 mg/kg in 3 divided doses in a day.
  • Role of steroids in encephalitis is controversial.
  • Hyperventilation using an Ambu bag can be used to reduce the intracranial tension immediately.
  • Long-term hyperventilation worsens the outcome by inducing oligemia of the brain in the marginally perfused brain tissue.
  • Sedation: Restlessness and agitation require diazepam (over 6 months, initial dose:1-2.5 mg (0.04-0.2 mg/kg or 1.17-6 mg/m2) b.i.d. or t.i.d.) or chloral hydrate (25 to 125 mg/kg/dose three times a day orally after meals or rectally) or Haloperidol (25-50 micrograms/kg daily in two divided doses to a maximum of 10 mg, or 30 mg in adolescents).
  • Control seizures

Serum Sodium is maintained within normal limits.Current opinion is that the high ADH levels probably represent compensatory mechanisms to maintain cerebral perfusion in the presence of cerebral edema. Cerebral salt wasting (CSW) syndrome is far less well-known than SIADH and also different from SIADH in diagnosis and treatment.

Management of Acute SIADH

If serum Na>125, the treatment is water restriction. Fluid restriction to less than 75% of maintenance (i.e., 1000 mL/m2/d) usually allows for the slow excretion of retained excess fluid and results in a decrease in ECF volume with a concomitant fall in urinary sodium excretion.

Improvement of the clinical state with water restriction is considered a retrospective diagnostic criterion. Limit fluid intake to the amount that keeps the serum sodium concentration within the reference range for the duration of the underlying condition. Fluid intake can be increased as serum electrolytes and osmolality normalize.

If the patient does not respond to fluid restriction or water restriction is not possible or if Na <125, furosemide must be given in a dose of 1-2 mg/kg iv repeated as necessary, with replacement of electrolyte losses.

If this strategy is unsuccessful at raising serum sodium, treatment with hypertonic saline may be necessary to save the child whose hyponatremia (i.e., serum sodium <120 mmol/L has induced seizures or coma. Hypertonic sodium chloride solution provides only temporary and symptomatic relief until fluid restriction, or treatment of the underlying condition, can take effect.

The use of a combination of a loop diuretic (e.g., furosemide) and the replacement of urine output with a solution that contains a higher sodium concentration (i.e., 3% sodium chloride solution) can be dramatically successful in some patients. Concomitant use of furosemide increases free water excretion relative to sodium excretion by the kidneys, thus correcting fluid expansion induced by hypertonic sodium chloride solution.

Thiazide diuretics must never be used since they decrease free water excretion at the cortical diluting segment and can severely aggravate hyponatremia in patients with SIADH.

Add steroids to saline replacement when adrenal insufficiency cannot be ruled out. Mannitol promotes a rapid free water diuresis and corrects hyponatremia.

  • If there is pulmonary edema Inj. Frusemide is given at the dose of 1 mg/kg/dose IM 2 times daily. It is avoided if there is dehydration.
  • Urinary catheterization in all unconscious children is a must. If not done, bladder distension makes the child restless. This restlessness will not respond to sedatives. Intermittent clamping of Catheter must be done to maintain bladder tone. Catheter may be removed when the child regains consciousness.
  • Turn the child from one side to the other at least hourly to prevent bedsores. Clean with spirit and apply any talcum powder to the dependent parts.
  • External stimulation is minimized since it will increase brain metabolism and so increase brain damage in the face of limited oxygen and nutrient supplies. Bright lights and loud noises and vigorous tactile stimulation are to be avoided as far as possible. Crying or conversation, even by parents, near the child must be avoided.
  • Restlessness and agitation during recovery may require diazepam )0.04 to 0.2 mg/kg) or chloral hydrate (4-40 mg/kg/dose) orally or rectally every 8 hours or Haloperidol (0.05 to 0.15 mg/kg/day {maximum 6 mg/day} in 2 or 3 divided doses) may be used. Sudden withdrawal of chloral hydrate results in delirium or seizures.
  • An extremely hypothermic or febrile child may require vigorous cooling or warming to save life.
  • Give a sponge bath daily.
  • Oral Hygiene. Cleaning the mouth regularly with salt water reduces oral sepsis
  • Pain is prevented and if it occurs it is treated.
  • Nutrition and fluids are given by Ryle's tube if there is no risk of aspiration. Routes of oral feeding may be nasogastric or orogastric. Enteral nutrition is better than total parenteral nutrition in the critically ill patient because of its beneficial effects directly on the gastrointestinal integrity and indirectly on hormones and immune function. Gastric emptying and colonic motility are decreased in critically ill patients but small intestinal motility, digestion and absorption remain adequately functional. Bowel sounds are not reliable indicators or small intestine function. Early enteral feeding blunts the hypermetabolic or hypercatabolic response (breakdown of skeletal muscle, gastrointestinal mucosa, and other tissues (to provide nutrients to vital organs) to critical illness by the neuroendocrine system. Therefore the dictum is "If the gut is available, use it".
  • IV Fluids: If there is risk of aspiration, IV maintenance fluids are given.Avoid fluid overload.75% of maintenance (100 ml/kcal/day) fluids with allowances for fever, hyperventilation and urine output are desirable except when there is deep coma. 5 Dextrose solution for maintenance is avoided. Always ½ Normal saline in 5% Dextrose is used in a dose of 70 ml/kg/24 hours from the 1-15 years and 35 ml/kg/24 hours at the age above 15 years. Ringer's lactate may also be used. Any other equivalent solution containing electrolytes to retain water in the intravascular compartment may be used. Any losses such as vomiting or loose motions have to be compensated in addition. Supplement therapeutic doses of vitamins like B Complex, C, D, E & K and other micronutrients (iron, zinc, copper, chromium) must be given. Urine output must be maintained at 0.5 ml/kg/hr. Urine volume must be checked 4th hourly. Bowel care is a must to prevent and treat impaction. Each eye is cleaned separately with 2 pieces of cloth dipped in water. Corneal injury and subsequent exposure keratitis in unconscious patients is prevented by using by methylcellulose eye drops and taping the eyelids closed.
  • Antibiotics:When lumbar puncture is traumatic or withheld Inj Ampicillin 300-400 mg/kg/d IV in 4 to 6 divided doses and either chloramphenicol 50-100 mg/kg/day in 4 divided doses or a third generation cephalosporin like ceftriaxone 100 mg/kg/day IV, are given till CSF findings are available. The treating doctor can use other antibiotics depending on necessity as urinary tract infection or/and pulmonary infections, nosocomial infections (Hospital acquired infections from other inpatients) can occur. For aspiration pneumonia, Crystalline Penicillin in a dose of 2 lakh units/kg/day may be used.
  • Stress ulcers occur occasionally and are often multiple and associated with hemorrhagic gastritis and erosions, and may be terminal events. Cimetidine (20-40 mg/kg/day in 4 doses) or Ranitidine (3 mg/kg/day in 2 doses) may be used orally or Inj Ranitidine may be used.
  • Regular limb and chest physiotherapy is a must to prevent contractures.

Danger signals are open eyelids, hanging jaw, Dilated nonreacting pupils, rapid breathing, accumulation of bronchial secretions, appearance of excessive sweating, abnormal spontaneous eye movements or dolls eye movements, pupils not constricting to light, persistence of fever, refractory seizures, decerebrate posture, and decorticate posture. If a child with these problems is being shifted to a tertiary care hospital a medical attendant must accompany the patient.

Referral patient may be referred to tertiary care hospital after providing medical and nursing supervision during transport if there is
  1. Brainstem involvement indicated by respiratory and cardiac irregularities.
  2. Cardiac arrest requiring resuscitation measures.
  3. Uncontrolled seizure activity
Management in tertiary level hospitals
Additional complications requiring management in critical care units:
  1. Hypoxia is alleviated by intubation, positive pressure ventilation, and ensuring and arterial PaO, of 65 mm Hg or more.
  2. Hypotension is treated in a stepwise fashion by first volume infusion with isotonic fluids to normovolemia. Next vasopressors such as dopamine or phenylephrine are added to raise Mean Arterial Pressure (MAP) so that the difference between MAP and Intracranial Pressure (ICP) {Cerebral Perfusion Pressure (CPP)} is greater than 50. Finally treatment is directed at reducing ICP in an effort to maintain CPP greater than 50.
  3. Central Venous Pressure should be used to guide fluid therapy. Full maintenance fluids are given if there is hypovolemia or if the patient is on diuretic therapy or after 48 hours if there is no elevation of ICT.
  4. Brainstem involvement (which may be due to brainstem herniation resulting from raised intracranial pressure or due to viral damage causing inflammation within the brainstem) is evidenced by an abnormal papillary reaction to light-asymmetrical reaction, or unreactive pupils; abnormal oculocephalic (doll's eye) reflex; abnormal respiratory pattern, neurogenic hyperventilation, shallow, ataxic or apneic; 'decerebrate posturing', which may be spontaneous, or seen in response to pain. It may necessitate intubation and mechanical ventilation.
  5. Cardiac arrest requires resuscitation measures.
  6. Uncontrolled seizures require a general anesthetic.
  7. For raised ICT, Hyperventilation is done either with bag and mask or after endotracheal intubation with 4% lignocaine as local spray or slow IV. Lignocaine at 1 mg/kg/dose prevents further rise of ICT during intubation.
  8. Patients with signs of raised intracranial pressure not responding to usual treatment should be paralyzed, incubated and ventilated to PCO2 of 3.5-4.0 kPa (25-30 mmHg). For paralyzing the child, Pancuronium, 0.05-0.1 mg/kg intravenously may be used along with a loading dose of thiopentone at 5 mg/kg. Succinyl choline and ketamine should be avoided. While doing the tracheal suctioning, boluses of IV lignocaine 0.5-1 mg/kg may be used to prevent rise of ICP.
  9. Secondary Complications common to JE are Pneumonia (due to aspiration and reduced mobility), malnutrition (due to inadequate feeding), bedsores (due to inadequate nursing care), contractures (due to lack of physiotherapy) and Keratitis (due to inadequate nursing care). Pneumonia should be treated with broad spectrum antibiotics and physiotherapy.
Specific Treatment
Acyclovir (ACV) is useful in HSV encephalitis (Flow chart 1) and selected cases of severe encephalitis due to EBV or VZV. Acyclovir, 10 mg/kg every 8 hours, in the form of 20 mg/mL solution must be administered over 1 hour for a 14 to 21 day course. Maintain adequate hydration. Reduce the dose in renal dysfunction. Adverse reactions include rashes, gastro-intestinal disturbances, rises in bilirubin, liver enzymes, blood urea and creatinine, decreases in blood indices, headache, dizziness, fatigue. With IV therapy, severe local inflammation, confusion, hallucinations, agitation, tremors, somnelescence, psychosis, convulsions and coma may occur. Rate of mortality from HSE before use of acyclovir was 60-70% - since Acyclovir, it is approximately 30%. Encephalitis may recur despite appropriate antiviral therapy.

Both Ganciclovir and fascine are useful in the treatment of CMV related CNS infections.

Fungal infections require drugs like amphotericin B, 5-flucytosine, fluconazole, penicillin, tetracycline, sulfadiazine or Cotrimoxazole.
Amebic meningoencephalitis caused by Naegleria fowleri is extremely rare. It presents 3-5 days after swimming in fresh water. CSF is hemorrhagic, 400-2400 cells predominantly Neutrophils/mL, low to normal glucose and elevated protein. High-dose IV and Intrathecal amphotericin B, along with miconazole, rifampin and sulfisoxazole are useful.
Sequelae
Incidence and severity of sequelae varies in patients surviving viral encephalitis (Photographs 1 and 2). Intellectual impairment is seen in 30% cases, speech disturbance in 34% and motor deficits in 49%. Long Term Therapeutic Measures: Physiotherapy and rehabilitation measures may be instituted in survivors with residual neurological deficits.

Drug therapy of sequelae: Sequelae include seizures, paralysis, psychiatric problems, movement disorders etc.

Spasticity: Baclofen (0.75-2 mg/kg/day in 3 divided doses. Titrate to a maximum of 40 mg/day if less than 8 years of age and to a maximum of 80 mg/day if more than 8 years of age), Dantrolene (initial, 0.5 mg/kg b.i.d.; then increase to 0.5 mg/kg t.i.d. - q.i.d.; dose may then be increased by increments of 0.5 mg/kg to 3 mg/kg b.i.d. - q.i.d. (doses should not exceed 400 mg/day), Tizanidine (Guidelines for use in children are not well established. In adults the initial dose is 2-4 mgrs at four hour intervals and increased to 36 mgrs as needed), Clonidine 5-400 mcg/kg/day in 2 doses), Phenytoin + Chlorpromazine, Vigabatrin. The recommended starting dose of Vigabatrin in children is 40 mg/kg/day, increasing to 80 to 100 mg/kg/day depending on response. Therapy may be started at 0.5 g/day, and raised by increments of 0.5 g/day weekly depending on clinical response and tolerability. Benzodiazepines - Diazepam (over 6 months, 0.04-0.2 mg/kg or 1.17-6 mg/m² b.i.d. - t.i.d.).

Hemiballismus - Chlorpromazine (Children 6 months to 12 years of age: The usual dose is 0.55 mg per kg of body weight, every four to six hours).

Choreoathetosis - Haloperidol (blocks dopamine receptors) For children 3 to 12 years of age or weighing 15 to 40 kilograms, the usual dose is 25 to 150 micrograms per kilogram a day divided into 2 or 3 doses. Tetrabenazine (depletes central monoamines) (Start with 12.5 to 25 mg per day in 2 divided doses and increase weekly to 12.5 to 25 mg to target of 100 mg per day), Pimozide (initiated at 1 mg/day, and dosage is gradually increased (only if needed), to a maximum of 6-10 mg/day), Chlorpromazine (Children 6 months to 12 years of age: The usual dose is 0.55 mg per kg of body weight, every four to six hours).

Dystonia - Diazepam (over 6 months, 0.04-0.2 mg/kg or 1.17-6 mg/m²> b.i.d.-t.i.d.),Baclofen (0.75-2 mg/kg/day in 3 divided doses. Titrate to a maximum of 40 mg/day if less than 8 years of age and to a maximum of 80 mg/day if more than 8 years of age).Carbamazepine Children, 6-12 years: initial, 100 mg b.i.d. on day 1 [50 mg q.i.d. of suspension]: then, increase slowly, at weekly intervals, by 100 mg/day or less; dose is divided and given 1 6-8 hr. Daily dose should not exceed 1,000 mg. Maintenance: 400-800 mg/day. Children, less than 6 years: 10-20 mg/kg/day in two to three divided doses [4 times/day with suspension]; dose can be increased slowly in weekly increments to maintenance levels of 35 mg/kg/day [not to exceed 400 mg/day], amantadine(Children 1 year - 9 years of age 4.4 to 8.8 mg/kg/day in 102 doses after breakfast and lunch [not to exceed 150 mg per day]. Amantadine hydrochloride syrup should be used for ease and flexibility in administering doses not in 100 mg increments. Children 9 years - 12 years of age: The total daily dose is 200 mg given as one capsule of 100 mg twice a day. The 100 mg daily dose has not been studied in children. Therefore, there are no data which demonstrate that this dose is as effective as or is safer than the 200 mg daily dose in this patient population, trihexyphenidyl (Dosing is not well established in children. Starting dose is 0.25 mg per day in children younger than 4 years of age and 1 mg per day in older children. The dose should be increased by 1 mg every 3 to 5 days three times daily until benefit or side effects), Levodopa (starting dose 1 mg/kg per day in 3-4 divided doses, gradually increasing until complete benefit or dose-limiting side effects. Most individuals respond to 4 to 5 mg/kg per day in divided doses Carbidopa/Levodopa should be given as 25/100 mg tablets in children. They can be crushed and dissolved in an ascorbic acid solution or in orange juice and used within 24 hours), and for focal dystonia Botulinum A toxin.

Myoclonus - Valproate (20 to 60 mg/kg per day in two or three divided doses), Clonazepam (initial dose for infants and children (up to 10 years of age or 30 kg of body weight) is 0.01-0.03 mg/kg/day in two or three divided doses. Dosage should be increased by no more than 0.25 to 0.5 mg every third day until a daily maintenance dose of 0.1 to 0.2 mg/kg of body weight has been reached unless seizures are controlled or side effects preclude further increase. Whenever possible, the daily dose should be divided into three equal doses. If doses are not equally divided, the largest dose should be given before retiring), 5-Hydroxy Tryptophan (Starting dosage is 50 mg, one to three times daily. If there is an inadequate clinical response in the first two weeks, dosage may be increased to 100 mg, three times daily).
  1. Tremor
    1. Rest-Trihexyphenidyl(Dosing is not well established in children. Starting dose is 0.25 mg per day in children younger than 4 years of age and 1 mg per day in older children. The dose should be increased by 1 mg every 3 to 5 days three times daily until benefit or side effects).
    2. Action - Propranolol (1-4 mg/kg/day divided into 2 equal doses). If treatment is stopped; this drug must be gradually reduced over a 7 to 14 day period.
    3. Intention - Serotonin agonist - Buspirone (Age> 5 years - 5 mg 18am and q11am on weekdays)
  2. Seizures - Carbamazepine

    (Children, 6-12 years: initial, 100 mg b.i.d on day 1 (50 mg q.i.d. of suspension); than, increase slowly, at weekly intervals, by 100 mg/day or less; dose is divided and given q 6-8 hr. Daily dose should not exceed 1,000 mg. Maintenance: 400-800 mg/day. Children, less than 6 years: 10-20 mg/kg/day in two to three divided doses (4 times/day with suspension); dose can be increased slowly in weekly increments to maintenance levels of 35 mg/kg/day (not to exceed 400 mg/day), Valproate (10-20 mg/kg/dose, 3 doses daily) etc.

    Mental handicap - various training programs are available.
Prognosis
Mortality and morbidity are related to host factors, such as age and preexisting CNS injury and the virulence of infecting organism. Poor outcomes are seen in infants younger than 1 year.

Potential deficits include intellectual, motor, psychiatric, visual, and auditory abnormalities. Epilepsy is frequent.

Rabies, JE, and untreated HSE have high rates of mortality and severe morbidity, including mental retardation, hemiplegia, and seizures. Untreated HSE has a mortality rate of 50-75% and 100% of survivors have long-term motor and mental disabilities. Treated HSE correlates strongly with severity of illness at the time of medical intervention, and morbidity is 20%.

JE is equally as catastrophic as untreated HSE, but other arboviruses are associated with a more benign clinical course. For example, WNE have a mortality rate of 2-20%. He incidence of neurologic sequelae is around 25% but highly variable.

VZV encephalitis has a mortality rate of 15% in immunocompetent patients and virtually 100% in immunosuppressed patients. The mortality rate for EBV encephalitis is 8%, and the morbidity rate is 12%. Rabies encephalitis and acute disseminated encephalitis are virtually 100% fatal, though the medical literature reports of occasional survivors.

CNS immunity status has an effect on prognosis. So flow cytometric analyses of CSF CD4 (+) and the helper T cell subsets may serve as effective means of assessment.

Supportive care and rehabilitation are important after the patient recovers. Because some sequelae of encephalitis may be subtle, neurodevelopmental and audiologic evaluations should be part of routine follow-up.

Prevention
Vaccines are available for Polio, Measles, Mumps and Rabies and JE. Measles and Rabies vaccines may be given immediately after exposure to virus. JE vaccine is recommended only for children in epidemic prone areas.
Conclusion
Global demographic and social changes and modern transportation have provided the mechanisms for certain pathogens to establish new geographical locations where susceptible arthropod vectors and hosts provide permissive conditions for them to cause major epidemics. Atypical presentations if investigated properly my led to new discoveries like Epidemic Brain Attack saving thousands of precious lives.

Key messages:

  1. More than 150 different viruses can cause acute Meningoencephalitis.


  2. Arboviruses form an important group and are transmitted principally by mosquitoes and ticks


  3. Viruses that differ widely in their morphology, chemical composition and replication can provoke identical clinical presentation and pathologic changes in brain


  4. In some cases viral neurotropism is responsible for focal pathology which can help in clinical diagnosis


  5. JE is the only encephalitis which presents in epidemic form in India.


  6. Serological studies and antigen detection have a limited utility of retrospective diagnostic confirmation.


  7. Herpes simplex encephalitis has specific treatment.


  8. There is NO SPECIFIC TREATMENT for most other encephalitides.


  9. IGNORANCE is killing more children than the etiologic virus per se.


  10. 10 The commonest cause of death is trying to shift the patient to the biggest hospital in the state without giving first aid and lack of Medicare during transport.

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