REVIEW ARTICLE

Acute Encephalitis Syndrome: Approach to a Changing Paradigm

Bidisha Banerjee1, Muhammed Hafis2, Archana Mahalingam3, Ullas Acharya4

A b s t r ac t​
Purpose: Acute encephalitis syndrome (AES) poses challenges to physicians owing to acute presentation, often rapid neurologic deterioration,
myriad causes including noninfective inflammatory disorders of central nervous system (CNS) and low microbiologic yield. We broadly discuss
common and less common causes of AES and their clinical, laboratory including radiologic features as specific diagnosis guides management
and improves outcome.
Materials and methods: Literature search was performed using keywords “Paediatric acute encephalitis” in MEDLINE database from 2009 to
2019 and all relevant articles (barring case reports) in English language were reviewed. Landmark articles prior to 2009 were also reviewed.
Conclusion: Acute encephalitis remains a diagnostic and therapeutic challenge in neurocritical care. The recognition of etiological agent and
encephalitis mimics by investigations is important for specific therapeutic measures. Judicious use of neuroimaging, cerebrospinal fluid (CSF)
analysis and appropriate lab tests helps in diagnosing specific entities especially noninfective mimics of AES which has important treatment
and prognostic implication. Initial stabilization and institution of supportive measures remains key to successful management.
Keywords: Acute encephalitis, Encephalitis mimics, Etiology, Neuroimaging.
Pediatric Infectious Disease (2019): 10.5005/jp-journals-10081-1210

I n t r o d u c t i o n​ 1–4
Manipal Hospitals, Bengaluru, Karnataka, India
Acute encephalitis syndrome (AES) is a commonly encountered Corresponding Author: Bidisha Banerjee, Manipal Hospitals,
problem in clinical practice. It poses challenges due to acute Bengaluru, Karnataka, India, Phone: +91 9980946290, e-mail:
presentation often requiring intensive care, myriad causes from [email protected]
infective to noninfective inflammatory disorders of central nervous How to cite this article: Banerjee B, Hafis M, Mahalingam A, et al. Acute
system (CNS) and low microbiologic yield. Though etiology in Encephalitis Syndrome: Approach to a Changing Paradigm. Pediatr Inf
outbreaks of AES have been ascertained, however there is less clarity Dis 2019;1(3):86–94.
in diagnosis and management of sporadic acute encephalitis.1 Source of support: Nil
Hence we broadly discuss common and less common causes of Conflict of interest: None
AES and their clinical, laboratory including radiologic features as
specific diagnosis guides management and improves outcome. are corner stone of management. Identification of a specific etiology
is guided by the observations of astute clinicians and supported by
Definition
laboratory data and neuroradiology.
Acute encephalitis syndrome was coined in 2008 by the World
Health Organization for surveillance and research in India.
Encephalitis is characterized by an acute onset of fever and Key Points in History10
encephalopathy (altered sensorium ranging from irritability to
• Fever
coma) with/without seizures or other neurologic signs due to CNS
• Duration and progression of symptoms (seizure, psychiatric,
inflammation.2
other systemic)
Encephalopathy on the other hand is a noninflammatory, often • Change in behavior/cognition/personalit y or altered
biochemical; hence, cerebrospinal fluid (CSF) shows no pleocytosis.2 consciousness
• New onset seizure
C au s e s ​/ E t i o lo g y​ • Focal neurological symptoms.
The cause varies based on the season and geographical location. • Etiologic clues
Viruses have been mainly attributed to be the cause of AES in India Demography/outbreaks/travel
though other microbes and toxins have been reported over the Recent vaccination (acute disseminated encephalomyelitis
past few decades.1–7 Noninfective causes of acute encephalitic (ADEM))
presentation are increasingly being recognized worldwide.8 Contact with animals (rabies), consumption of raw milk
Various infective and noninfective etiologies of AES have been (brucellosis)
tabulated in Table 1. Contact with unchlorinated fresh water (amoeba) contaminated
with animal urine (leptospirosis) and exposure to mosquito/tick
Approach to Diagnosis bites (arboviruses, Lyme disease, tick borne encephalitis)
Acute encephalitis syndrome is a medical emergency. Though the Known risk factors for HIV/immunocompromised.
causes of acute encephalitis are many, initial presentation may be Pre-illness epilepsy/developmental status
similar. High index of suspicion with awareness of “encephalitis Siblings with similar illness/multiple episodes of encephalopathy:
mimics,” prompt, focused clinical evaluation and initial stabilization classically seen in some inborn errors of metabolism.

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 Acute Encephalitis Syndrome: Approach to a Changing Paradigm

Table 1: Varied etiologies of acute encephalitis syndrome9,10 Table 2: Lab diagnostic evaluation in acute encephalitis syndrome
In all Complete blood count, blood culture, electrolytes/
blood glucose, liver and kidney function tests,
peripheral smear for malarial parasite, chest X-ray
In most Neuroimaging, CSF analysis after stabilization if no
contraindications*, EEG if seizure or suspicion of
non-convulsive status epilepticus (NCSE) or
autoimmune encephalitis (AE)
In some Autoimmune work up—antineuronal (NMDAR, VGKC),
anti-thyroid microsomal/thyroglobulin antibodies, ANA,
ESR, neuromyelitis optica (NMO) and myelin
oligodendrocyte glycoprotein (MOG IgG) in serum
IEM screen—ABG, plasma lactate, ammonia, urine
ketones, dried blood spot for tandem mass
spectrometry (TMS), urine gas chromatography mass
spectrometry (GCMS)
*Contraindications to lumbar puncture include hemodynamic instability,
features of raised intracranial pressure, bleeding diathesis, local site infec-
tion). A neuroimaging study is done if lumbar puncture is contraindicated

for immunization, charting preventive strategies, implementing

appropriate control measures especially in outbreak situations,
and to formulate rational empirical treatment especially for non-
viral causes of AES. However, there are challenges in the rapid
identification of the etiological agent. Firstly, the number of
infectious pathogens known to cause AES is sizeable; including
Key Points in Examination10 several viruses, bacteria, fungi, and protozoa. Secondly, several
conventional methods available for testing are time-consuming,
• Airway, breathing, circulation, neurologic disability (ABCD) expensive, lack adequate sensitivity, and/or specificity and may
[Glasgow coma scale (GCS), pupils, signs of impending brain not be easily accessible. Thirdly, the small volume of CSF available
herniation] from patients is quite often insufficient for laboratory testing for
• General physical examination—pallor, icterus, skin rashes, all the pathogens.11
oarotid swelling/orchitis, labial herpes, bite marks* Cerebrospinal fluid should be collected in sterile, screw
• Systemic examination a. Hepatosplenomegaly, lymphadenop- capped containers and immediately stored at 2–8°C until
athy-TB, Brucella testing. If a delay in testing is expected, CSF samples must be
• Neurological examination—level of consciousness, signs of frozen at −20°. If testing for bacterial pathogens, the CSF must
impending brain herniation, signs of meningeal irritation, focal not be refrigerated.11 Additional samples may be stored for
neurologic deficit, evidence of subtle motor seizures (twithing antibody testing if needed. The CSF is examined for cytology,
of mouth, eyelid, digit), papilledema, flaccid paralysis (anterior biochemistry, Gram’s stain, wet mount for motile amoeba, Ziehl–
horn cell involvement), movement disorders, including Neelsen stain for acid fast bacilli, PCR for HSV 1 and 2, nucleic
parkinsonism acid amplification test (NAAT) for MTB, bacterial culture, IgM
Peripheral blood can show relative lymphocytosis in viral antibodies for JE and dengue virus if suspected. Multiplex PCR
encephalitis. Peripheral blood smear (thick and thin smear) is the may be performed wherever feasible esp. if already received
most sensitive and specific test for cerebral malaria. Cytoplasmic antimicrobials. Blood sugar has to be checked just prior to the
inclusions in the peripheral blood monocytes are characteristic of lumbar puncture to measure the CSF to blood sugar ratio.
ehrlichiosis, 10% of these children develop meningoencephalitis. Cerebrospinal fluid analysis may provide invaluable information
Rickettsial infection and viral hemorrhagic fevers characteristically about the nature of the infectious process. Lymphocytic pleocytosis
show the presence of leukopenia and thrombocytopenia. (>5 lymphocytes/mm3) is present in >95% of the cases along
Mycoplasma, legionella or tuberculosis infections can be diagnosed with normal glucose and protein or mildly raised protein in viral
by the characteristic findings in chest radiography. Blood glucose, encephalitis indicating meningeal inflammation. Alternative
kidney and liver function tests will help to pick-up metabolic etiology (encephalopathy) is considered if CSF lymphocytosis is
encephalopathy (Table 2). absent. Delay in analysis of the CSF sample is avoided because
Identification of etiological agent is necessary for prompt the cells in CSF lyse during storage and transport of the sample.
initiation of specific therapy, epidemiology, identifying targets An inflammatory response may not be seen in the initial stages
of atypical HSE and among immunocompromised (by cancer
*
Pallor in cerebral malaria/intracranial bleed. Icterus in leptospirosis, chemotherapy or irradiation).
cerebral malaria, hepatic encephalopathy. Skin rashes—meningococcemia Other specimens which may be collected depending on
(purpuric), dengue (face/blanching), measles (erythematous maculo-
papular starting from face), varicella (vesicular/trunk), rickettsial (papules
the clinical presentation and suspected etiology of AES are
on palms and soles), arboviral and enteroviral (vesicular in HFMD). nasopharyngeal/throat swabs, swabs from vesicles, rectal swabs/
Parotid swelling/orchitis in mumps. Labial herpes in herpes simplex virus stool specimens, urine and brain biopsy.11,12
encephalitis. Table 3 CSF analysis in various infective causes of AES (Table 4).

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 Acute Encephalitis Syndrome: Approach to a Changing Paradigm

Table 3: Treatment options in autoimmune encephalitis

Treatment options Dose and schedule Duration
First line IV methyl prednisolone 20–30 mg/kg/day 3–5 days
Intravenous immunoglobulin 2 g/kg in divided doses Over 2–5 days
Plasmapheresis 5–7 cycles
Second line Cyclophosphamide 750 mg/m2
Rituximab 375 mg/m2 followed by second dose after
2 weeks

Table 4: CSF analysis in various infective causes of AES

Investigation Normal Bacterial Viral Tuberculosis Fungal
Opening Pressure 10–20 cm High Normal/high High High/very high
Color Clear Cloudy “Gin” color Cloudy/yellow Clear/cloudy
Cells <5 High/very high Slightly increased Slightly increased Normal–high
100–50,000 5–1,000 <500 0–1,000
Differential Lymphocytes Neutrophils Lymphocytes Lymphocytes Lymphocytes
CSF/plasma glucose 50–66% Low <40% Normal Low–very low (<30%) Normal–low
Protein (g/L) <0.45 High Normal–high High–very high Normal–high
>1 0.5–1 1.0–5.0 0.2–5.0

Acute encephalitis syndrome—neuroimaging • Examination of CSF reveals lymphocytic pleocytosis (10–500

Neuroimaging should be done in all; magnetic resonance imaging μL, >50%) with raised proteins >100 mg/dL, low sugar (20–40
(MRI) is preferred over CT as it is more sensitive however where mg/dL) and/or positive ZN stain, acid fast bacilli (AFB) culture,
imaging needs to be urgently performed, intracranial bleed PCR for MTB
suspected and sedation not possible, contrast enhanced CT scan • Imaging reveals basal meningeal enhancement, tuberculoma,
may be obtained. Use of limited sequences on MRI like diffusion and hydrocephalus, infarct, pre-contrast basal hyperdensity
fluid-attenuated inversion recovery (FLAIR) and compressed sense • Evidence of TB in other sites (Fig. 4).
imaging softwares can reduce scan times remarkably (to <5 minutes). Outcome depends on early identification (when symptoms are
non-specific) and adequate treatment.14
Role of Neuroimaging
MRC staging of TBM consists of 3 stages with increasing severity
• Excludes encephalitis mimics† • prodrome, no neurologic signs and symptoms
• Presence and extent of inflammation, radiologic signs of raised • meningeal signs, normal sensorium, cranial nerve palsy±
intracranial pressure‡ • altered sensorium, seizures, focal neurodeficits/involuntary
• Etiologic clues in some based on “pattern recognition” (Figs 1 to 3)# movements.
†
Helps in diagnosis of specific entities like TBM, ADEM, ANE, AESD, MERS
with therapeutic and prognostic significance. Acute Necrotizing Encephalopathy of Childhood
‡
Presence of midline shift, obliteration of basal cisterns and slit ventricles Suspect if fever (esp. viral illness) followed by rapid neurologic
are radiological contra-indications of LP. deterioration (sensorium/tone/raised ICP). Management includes,
In MRI, FLAIR sequences are useful for detection of vasogenic edema, stabilization, neuroimage (CT/MRI brain which typically show
diffusion weighted images for cytotoxic edema and post gadolinium for
multiple bilateral brain lesions in thalami or putamina, internal
meningeal enhancement/inflammation,9 susceptibility weighted imaging
for mico/macro bleeds and vasculitic infarcts. capsule of the cerebrum or white matter of the cerebellum and
#
Typical geographic patterns and etiology.9,10 tegmentum (Fig. 5).15 Definite treatment guidelines are not available,
however standard supportive care, immunotherapy—usually high
dose pulse methylprednisolone, therapeutic hypothermia before
Affected Region—Etiology
12 hours (decreases cytokines) and anti-edema measures are
Cortical gray (medial temporal, orbito-frontal, insular, cingulate)— beneficial.16 Outcomes in acute necrotizing encephalopathy (ANE)
HSV are heterogeneous but potentially devastating with 30% mortality
• Basal ganglia/thalamus—Japanese encephalitis, West Nile and 10% intact survival. Predictors of outcome include, age (>4
• Brain stem and spinal cord (anterior horn cells)—enterovirus years, <1 year), increased CSF protein/transaminases, presence of
• Cerebellum—mycoplasma, varicella zoster virus, dengue, scrub hemorrhage/cavitation/brainstem lesions on neuroimaging and
typhus, rotavirus ANE-severity score.17
Encephalitis Mimics
Acute Disseminated Encephalomyelitis
Diagnosis of Tubercular Meningitis13
Acute disseminated encephalomyelitis is first polyfocal clinical
• Clinical—fever (>5 days), headache, vomiting, altered event affecting CNS characterized by encephalopathy not due to
sensorium/focal neurologic deficit fever/post ictal phase/systemic illness. Brain MRI shows diffuse,

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 Acute Encephalitis Syndrome: Approach to a Changing Paradigm

Figs 2A and B: Japanese encephalitis—Axial T2 weighted images showing

(A) Bilateral thalamic; (B) Bilateral substantia nigra hyperintensities
Figs 1A and B: Herpes simplex encephalitis (HSE): (A) Axial FLAIR
showing bilateral periSylvian cortex hyperintense signals; (B) Coronal
T1 post-gad shows focal enhancement of the same

Figs 4A and B: TBM: (A) Plain CT head showing hydrocephalus with left
thalamic hypodensity (infarct); (B) Gad-enhanced MRI brain showing
basal exudates

Fig. 3: Glutaric aciduria type I—Axial T2 weighted image shows fronto-

temporal atrophy with widened Sylvian fissure (Bat’s wing appearance)
and hyperintense signals in bilateral globus pallidi, putamina

Fig. 6: ADEM-Axial T2 weighted image showing asymmetric, multifocal,

subcortical white matter and bilateral thalamic hyperintensities
Fig. 5: ANE-Axial FLAIR images showing symmetric hyperintensities in
bilateral thalami, brainstem and cerebellar white matter Cerebrospinal fluid may show pleocytosis with raised
proteins; oligoclonal bands might be present in a small subset.
poorly demarcated, large white mater lesions with or without Where appropriate serum antibodies to myelin oligodendrocyte
lesions in deep grey/spinal cord. There should be no new clinical glycoprotein (MOG IgG) and neuromyelitis optica (NMO) IgG/anti-
symptoms and MRI abnormalities (Fig. 6) after the first 3 months aquaporin antibodies may be obtained.
from symptom onset.18 Treatment is with high dose pulse methylprednisolone of 30
Long tract (pyramidal) signs, cranial nerve palsies, meningism, mg/kg/day, with a maximum dose of 1 g/day over 3–5 days followed
signs of opticospinal involvement may be seen in addition to by oral steroid taper. Prognosis is generally favorable.18
encephalopathy.19 Autoimmune encephalitis (AE)—clinical clues include,20

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 Acute Encephalitis Syndrome: Approach to a Changing Paradigm

• Acute/subacute neurologic dysfunction (altered sensorium, • Bilateral brain abnormalities on T2-weighted/fluid-attenuated

cognition, speech) inversion recovery MRI highly restricted to the medial temporal
• Seizures-facio brachial dystonic in LGI1 lobes†
• Behavioural/psychiatric disturbance At least one of the following
• Movement disorderorofacial dyskinesia, catatonia
Cerebrospinal fluid pleocytosis (WBC count >5 cells/mm3)
• Insomnia/somnolence
EEG with epileptic or slow-wave activity involving the temporal
• Autonomic-central hypoventilation
lobes
Probable anti-N-methyl-D-aspartate (NMDA) receptor Reasonable exclusion of alternative causes
encephalitis—diagnosis is made when all of the three criteria are met:
Diagnostic Criteria for Probable (Seronegative)
• Rapid onset (<3 months) of at least four of the six following major Autoimmune Encephalitis
groups of symptoms: Diagnosis can be made when all four of the following criteria have
• Abnormal (psychiatric) behavior or cognitive dysfunction been met:
Speech dysfunction mutism, verbal reduction, pressured
speech) • Rapid progression in less than 3 months with short-term memory
Seizures loss, altered mental status or psychiatric symptoms
Movement disorder, dyskinesia or rigidity/abnormal posture • Well defined syndromes of autoimmune encephalitis like typical
Decreased consciousness/autonomic dysfunction or central limbic encephalitis, Bickerstaff’s brainstem encephalitis and
hypoventilation ADEM have to be excluded
At least one of the following laboratory study results • Absence of well characterized autoantibodies in the serum and
Abnormal electroencephalogram (EEG) (focal/diffuse slow/ CSF and at least 2 of the following criteria:
disorganised activity/epileptic activity/extreme delta brush) • MRI abnormalities suggestive of autoimmune encephalitis
Cerebrospinal fluid with pleocytosis or oligoclonal bands • Cerebrospinal fluid pleocytosis
Reasonable exclusion of other disorders • Cerebrospinal fluid specific oligoclonal bands or elevated CSF
IgG index or both
Diagnosis can be made with any of the 3 of the above group of • Inflammatory infiltrates in the brain biopsy and excluding other
symptoms along with a systemic teratoma disorders like tumor
Definite anti-NMDA receptor encephalitis: • Reasonable exclusion of alternate causes
Diagnosis is made in the presence of one or more of the 6
major groups of symptoms and IgG anti–GluN1 antibodies, after
reasonable exclusion of other disorders. Less Common Causes of AES
Hashimoto encephalopathy (HE) is characterized by encephalopathy
with presence of thyroid microsomal antibody and good response
Anti-NMDAR Encephalitis (Anti-NMDARE)
to glucocorticoid. The clinical presentations in HE is variable, so
It is “A multistage illness that progresses from psychosis, memory diagnosis has to be highly considered when such a presentation
deficits, seizures, and language disintegration into a state of is present. Presentation in some is dramatic with acute onset
unresponsiveness with catatonic features often with abnormal unexplained seizures resistant to anti-epileptic dugs, confusion,
movements and autonomic and breathing instability.” Children/ hallucinations, impairment of cognitive function, behavioral and
young adults are affected predominantly. It can occur with or mood disturbances, disturbance of consciousness, headaches,
without tumor (usually ovarian teratoma in women >18 years), stroke-like episodes, focal neurodeficits, ataxia and presence of
patients with tumor resection and immunotherapy respond high thyroid antibody levels, esp. TPO Ab. Pathogenesis is not clear,
faster, less often need 2 line immunotherapy in comparison with however vasculitis and autoimmunity are thought to be causal.
patient without a tumor. Substantial recovery is seen in around Thyroid function is normal/decreased; rarely increased. To rule out
75% of all patients in inverse order of symptom development, other etiologies CSF, EEG, MRI brain are needed. Once diagnosis
associated with a decline of antibody titers. First line treatment is made, corticosteroids provide dramatic recovery.22
pulse methylprednisolone and IVIG. Second line being rituximab/
cyclophosphamide (lack of response to 1st line within 1 month). 21
Usually LGI1 respond to steroids alone. Anti-N-methyl-D-aspartate Bickersta’s Brainstem Encephalitis
receptor (NMDAR) needs more intensive immunotherapy. End When both the criteria given below are fulfilled the diagnosis of
point is clinical response. There is no consensus on duration of Bickerstaff brainstem encephalitis is made: (1) subacute onset
treatment especially for long-term immunosuppression which is (rapid progression of less than 4 weeks) of all the following
individualized according to benefits/risks. symptoms: decreased level of consciousness, bilateral external
ophthalmoplegia, ataxia (2) alternative causes has to be reasonably
Diagnostic Criteria for Definite Autoimmune Limbic excluded.20,23
Definite diagnosis of Bickersta’s brainstem encephalitis can
Encephalitis
be made with positive IgG anti-GQ1b antibodies even if there is
Diagnosis can be made when all four of the following criteria have no complete bilateral external ophthalmoplegia or ataxia cannot
been met: be assessed.20
• Subacute onset (rapid progression of less than 3 months) of FIRES is “Febrile Infection Related Epilepsy Syndrome.” It is defined
working memory deficits, seizures, or psychiatric symptoms as “a subtype of new onset refractory status epilepticus (NORSE) that
suggesting involvement of the limbic system requires a prior febrile infection, with fever starting between 2 weeks

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 Acute Encephalitis Syndrome: Approach to a Changing Paradigm

and 24 hours prior to onset of refractory SE, with or without fever at be associated with symmetrical white matter lesions. Delirious
onset of SE.” This definition excludes prolonged febrile seizures.24 FIRES behavior is the most common neurological symptom. It is followed
includes all ages. It is an immune disorder triggered by an infection by disturbance in consciousness, seizures. These symptoms
and it affects the brain with an intrinsic predisposition toward an auto- completely recover within a month. Intramyelinic edema, interstitial
sustaining epileptogenic process. These are suggested by its biphasic oedema in tightly packed fibers, and a transient inflammatory
clinical course. In this otherwise drug refractory condition ketogenic infiltrate are the postulated reasons for the transiently reduced
diet (KD), therapeutic hypothermia, cannabidiol (CBD), anakinra diffusion within the lesions.26
(recombinant, modified human interleukin-1 receptor antagonist) Clinical pointers of an underlying IEM in AES include
and continuous intravenous administration of magnesium sulfate unexplained rapidly progressive encephalopathy and seizures,
have provided therapeutic benefit.25 recurrent episodes of encephalopathy/ataxia especially with
New-onset refractory status epilepticus is not a specific intercurrent illness, persistent vomiting or failure to thrive,
diagnosis. It is a clinical presentation in a patient with new onset consanguinity/family history of neonatal/infant deaths, alopecia
refractory status epilepticus, with no other relevant neurological and seborrheic dermatitis, periorificial rash and high anion gap
disorder/active epilepsy, without any acute/active structural o toxic metabolic acidosis, hypoglycaemia.28
or metabolic cause.
Management
Acute Encephalopathy with Biphasic Seizures and Late It should focus on initial stabilization, arriving at a specific diagnosis
Reduced Diffusion (AESD) and preventing secondary brain injury. Though variety of infective
The initial neurological symptom on day 1 is a febrile seizure (usually and noninfective etiologies are implicated in AES, initial stabilization
>30 minutes). This is followed by secondary seizures at day 4–6. It is should precede, a targeted approach (antimicrobials and/or
reported only in East Asian infants. A variable level of neurological immunotherapy) for specific etiology (Table 5).
sequelae is displayed among these children. MRI can be normal The mortality and morbidity associated with AES can be reduced
with no abnormality in first two days; frontal or fronto-parietal by stabilizing the airway, breathing and circulation along with other
subcortical white matter shows reduced diffusion during days 3–9, supportive care measures. Patients are managed in intensive care
then disappears between days 9 and days 25. Excitotoxic injury with unit when the GCS <8 with features of raised intracranial pressure,
delayed neuronal death is hypothesized as a possible mechanism status epilepticus and shock. Supportive care includes, maintaining
based on MR spectroscopic findings.26 The clinical course of acute euvolemia and normoglycemia, and preventing hyponatremia
encephalopathy can be improved by early administration of by isotonic maintenance intravenous fluids. Hypoglycemia and
vitamins (B1, B6, and L-carnitine). Favorable results can be obtained hyperglycemia should be avoided by regular monitoring of blood
by mitochondrial rescue and neuroprotection.27 glucose. Hyperthermia is to be avoided.9,12
Prompt recognition and management of raised ICP is important.
Clinically Mild Encephalitis/Encephalopathy with a Reversible Reduced mean arterial pressure (MAP) or raised intracranial pressure
Splenial Lesion (MERS) (ICP) or both can reduce the cerebral perfusion pressure (CPP) (CPP =
It is a reversible lesion with homogeneously reduced diffusion MAP–ICP) and hence the CPP has to be maintained. Intubation
in the corpus callosum (at least involving the splenium). It can and ventilation is considered (if GCS <8, or evidence of irregular

Table 5: Summary of antiviral, antibiotics and antifungal agents

Indication Choice of drug Dose and schedule Duration
HSV Acyclovir 3 months to 12 years: 500 mg/m2 every 8th hourly 14–21 days
VZV Above 12 years: 10 mg/kg every 8th hourly
Meningococci Ceftriaxone/cefotaxime + vancomycin 100 mg/kg/day 10–14 days
Pneumococci 200 mg/kg/day
60 mg/kg/day
Salmonella Ceftriaxone/cefotaxime/meropenem 100 mg/kg/day 4 weeks (up to 6 weeks
in presence of abscess)
200 mg/kg/day
40 mg/kg/dose 8th hourly
Brucella Doxycycline + rifampicin + ceftriaxone 2–4 mg/kg/day 4–6 months
15–20 mg/kg/day 4–6 months
100 mg/kg/day 4 weeks
Rickettsia Doxycycline 4 mg/kg/day 5–7 days
Azithromycin* 10 mg/kg/day 5 days
Cryptococcus Induction: amphotericin B + flucytosine 0.7–1 mg/kg/day 2 weeks
Maintenance therapy: fluconazole/ 100 mg/kg/day 2 weeks
amphotericin B flucytosine
12 mg/kg/day 10 weeks
0.7–1 mg/kg/day 6–10 weeks
100 mg/kg/day

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 Acute Encephalitis Syndrome: Approach to a Changing Paradigm

respirations and inability to maintain airway or herniation) to maintain Immunotherapy

normocapnia and avoid hypoxemia. Adequate analgesia and sedation Indications: Steroids are used in ADEM, Hashimoto encephalopathy,
has to be provided. Avoid noxious stimuli; prior to endotracheal tube and autoimmune encephalitis.19,21 In Bickerstaff encephalitis,
suctioning, ET lignocaine should be administered.12 ADEM and AE, IVIG is also used. Usage of corticosteroids in viral
Osmotherapy in form of hypertonic saline and/or mannitol may encephalitis is not established but may be considered along with
be used when clinical evidence of raised ICP is present. The patient acyclovir in patients with marked cerebral edema or raised ICP.
is hyperventilated to maintain a target of PaCO2—30–35 mm Hg, Though the clinical benefit is not well established, IVIG has been
when there are signs of impending herniation. Mannitol is given at used in EV 71 encephalitis (Table 3).33
a dose of initial bolus of 0.25 g/kg, then 0.25 g/kg, q 6 hours up to
48 hours. In the presence of hypotension, hypovolemia, and renal Corticosteroids
failure, hypertonic (3%) saline is preferred to mannitol. It is given Corticosteroids have been used in therapy of both infective
at a dose of 0.1–1 mL/kg/hour by infusion and the serum sodium and noninfective encephalitis. It is a widely accepted first line
should be targeted to a level of 145–155 mEq/L.9,12 pharmacotherapy of ADEM and other immune mediated encephalitis
The seizures have to be controlled with anticonvulsant in the syndromes. Pulse doses of methyl prednisolone (20–30 mg/kg/day)
background of GCS <8, and features of raised ICP, as seizures may with a maximum dose of 1 g/day for 3–5 days is recommended
further raise the intracranial pressure. for ADEM and other immune mediated encephalitis syndromes
A benzodiazepine is used to abort clinical seizures (Lorazepam (anti-NMDAR encephalitis, anti-VGKC encephalitis, Hashimoto’s
0.1 mg/kg or midazolam 0.1 mg/kg) followed by loading dose of encephalopathy, Bickerstaff encephalitis, etc.).18,19 Pulse steroids
fosphenytoin (30 mg/kg). should be followed with low dose (1–2 mg/kg/day) oral prednisolone
Antimicrobials to taper over 4–6 weeks in ADEM and possibly longer in AE. Systemic
steroids are recommended in the treatment of CNS TB. Prednisolone
Empirical treatment with broad spectrum antibiotic must be started
2 mg/kg/day or dexamethasone 0.6 mg/kg/day in divided doses for at
while awaiting lab investigations. Acute meningoencephalitis
least 4 weeks and then tapering over next 4 weeks is recommended.
due to common bacterial pathogens may be treated with 3rd
It is also recommended in enteric encephalopathy.
generation cephalosporins, ceftriaxone or cefotaxime.12 In suspected
pneumococcal meningitis vancomycin (60 mg/kg/day in 3–4 divided Intravenous Immunoglobulins
dose) should be added to 3rd generation cephalosporin. Crystalline Intravenous immunoglobulin (IVIG) is an alternative/adjunctive
penicillin is the drug of choice for Neisseria infection; however, option for the treatment of ADEM and other immune mediated
ceftriaxone or cefotaxime are acceptable alternatives in case of encephalitis. IVIG in a dose of 2 g/kg divided over 2–5 days is used.
non-availability or resistance. All cases of sporadic viral encephalitis Intravenous immunoglobulin is preferred mode of treatment in
must be started on acyclovir, as outcomes in HSE depend on early Bickerstaff brainstem encephalitis (GBS variant).
and adequate treatment.9,10 When an alternative diagnosis has been
made, or HSV PCR in the CSF is negative and MRI is normal acyclovir Plasmapheresis
should be stopped. However, if the CSF PCR for HSV or MRI may be Plasmapheresis is another first line treatment option for immune
falsely negative, when performed within 48 hours of symptom onset. mediated encephalitis; 5–7 exchanges every other day showed
These studies should be repeated before stopping acyclovir if the favorable outcome. Technical expertise and monitoring for
clinical suspicion of HSE is high. When there is a suspicion of cerebral hemodynamic instability make plasmapheresis difficult compared
malaria, empirical anti-malarial (artemisinin-based combination to IVIG especially in a younger child.
therapy) must be started. This should be stopped if the peripheral
smear and rapid diagnostic tests are negative. Neurobrucellosis is Other Immunosuppressant Drugs
treated with triple drug therapy including doxycycline, ceftriaxone Treatment with other immunosuppressant medicine like
and rifampicin.29 A high index of suspicion of rickettsial encephalitis rituximab or cyclophosphamide should be considered in immune
should be there if from an endemic area with febrile illness with or mediated encephalitis, which is refractory to steroid, IVIG and
without rashes. Doxycycline is considered to be the drug of choice; plasmapheresis.21 Cyclophosphamide in a dose of 750 mg/m2 body
azithromycin can be used as an alternative in doxycycline resistant or surface area intravenously can be given. Good hydration and Mesna
contraindicated patients.30 In primary and granulomatous amoebic should be provided to eliminate the risk of cyclophosphamide
meningoencephalitis rifampicin, co-trimoxazole, azithromycin and induced hemorrhagic cystitis. Cyclophosphamide is known to
fluconazole has been used with reported efficacy of miltefosine.31,32 cause bone marrow suppression, hence a complete hemogram
Evidence for treatment of mycoplasma in AES is poor, however when is advisable. Rituximab, is a monoclonal antibody which acts by
needed azithromycin, doxycycline or fluoroquinolones may be used.9 inhibiting CD-20 also preferred as 2nd line treatment in autoimmune
Pleconaril has been found to be useful in enterovirus encephalitis encephalitis. Rituximab in a dose of 375 mg/m2 followed by a second
except in EV71. 33 There is experimental evidence of benefit of dose after 2 weeks is recommended.
minocycline in JE.34
Acute Management of IEM
Antitubercular agents
Aims of treatment are to
Antitubercular treatment (ATT) for 10–12 months is recommended
for CNS tuberculosis by RNTCP. In a new case with CNS TB or drug • Decrease the substrate (stop feeds) to reduce the formation of
sensitive case previously treated with ATT, initial 2 month of therapy toxic metabolites
is with isoniazid, rifampicin, pyrazinamide and ethambutol followed • Provide adequate calories and prevent endogenous catabolism
by 8–10 months of isoniazid, rifampicin and ethambutol as daily • Enhance the excretion of toxic metabolites
regimens. 35 Strict compliance and adherence to treatment and • Give co-factor therapy for specific disease or empirically if the
monitoring is paramount in any tuberculosis case. diagnosis is not established

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 Acute Encephalitis Syndrome: Approach to a Changing Paradigm

Supportive Care in India. Indian Pediatr 2012;49(11):897–910. DOI: 10.1007/s13312-012-

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euglycemia, treat infection and mechanical ventilation. 2010;10(11):803–812. DOI: 10.1016/S1473-3099(10)70138-9.
Hyperammonemia is managed by 14. Murthy JM. Tuberculous meningitis: the challenges. Neurol India
• Discontinuation of feeds. IV glucose and lipids are given to 2010;58(5):716–722. DOI: 10.4103/0028-3886.72178.
15. Mizuguchi M, Abe J, Mikkaichi K, et al. Acute necrotising
provide adequate calories (GIR −8–10 mg/kg/minute and
encephalopathy of childhood: a new syndrome presenting with
intralipid −0.5–3 g/kg/day). Protein is added gradually after multifocal, symmetric brain lesions. J Neurol Neurosurg Psychiatry
stabilization (0.25–1.5 g/kg/day). 1995;58(5):555–561. DOI: 10.1136/jnnp.58.5.555.
• Rapid removal of ammonia by dialysis (hemodialysis is better 16. Okumura A, Mizuguchi M, Kidokoro H, et al. Outcome of acute
than peritoneal dialysis). Exchange transfusion is not useful. necrotizing encephalopathy in relation to treatment with
• Alternative excretory pathways for ammonia: a loading dose of corticosteroids and gammaglobulin. Brain Dev 2009;31(3):221–227.
250 mg/kg is followed by 250–400 mg/kg/day in 4 divided doses. DOI: 10.1016/j.braindev.2008.03.005.
L-Arginine—200 mg/kg/day, L-carnitine (oral/IV)—200 mg/kg/day. 17. Wong AM, Simon EM, Zimmerman RA, et al. Acute necrotizing
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Management of suspected organics acidemia: outcome. Am J Neuroradiol 2006;27(9):1919–1923.
18. Pohl D, Alper G, Van Haren K, et al. Acute disseminated encephalomyelitis
• Stop feeds and intravenous 10% glucose (up to 1.5× maintenance) updates on an inflammatory CNS syndrome. Neurology 2016;87(9
• Supportive care: hydration, treatment of sepsis, seizures, Suppl 2):S38–S45. DOI: 10.1212/WNL.0000000000002825.
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• Carnitine: 200 mg/kg/day in 3 divided doses IV or oral encephalomyelitis. Neurology 2007;68(16 Suppl 2):S23–S36. DOI:
• Treatment of acidosis: sodium bicarbonate 0.35–0.5 mEq/kg/ 10.1212/01.wnl.0000259404.51352.7f.
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• Metronidazole-to-reduce organic acid by gut flora encephalitis. Lancet Neurol 2011;10(1):63–74. DOI: 10.1016/S1474-
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Algorithm: Diagnostic Approach to AES

Clues to specific diagnosis in AES

Diagnostic entity Clues on history/examination Laboratory investigations
Viral meningoencephalitis Geographic trends MRI
Rapid progression often with seizures/raised ICP CSF-multiplex PCR
Complicated pyogenic Evolving neurologic signs, toxic look with meningeal CSF
meningitis signs CT/MRI
Rickettsial Typical vasculitic rash involving palms/soles, eschar PCR on blood samples
Serology
Response to doxycycline
Cerebral malaria Endemic area/travel, seizure often status, anemia Smear for MP
Dengue Seasonal, facial blanching rash, narrow pulse pressure NS1 Antigen, antibody after 5 days,
thrombocytopenia
Enteric Rash, splenomegaly, mild encephalopathy, Blood culture
>1 week fever
Tubercular Fever >5 days, meningeal signs, cranial nerve palsies, CSF-NAAT for TB, AFB culture
h/o contact, evidence of TB elsewhere CT/MRI
GA for AFB, CXR
ADEM Encephalopathy with multifocal neurologic deficits of Neuroimaging
acute/subacute onset often with recent febrile illness/ Biomarkers-MOG, NMO IgG in serum
vaccination
ANE Abrupt onset of encephalopathy, raised ICP, tone Typical findings on MRI
abnormalities with/without autonomic dysfunction Liver transaminases
Autoimmune encephalitis Acute/subacute onset neuropsychiatric illness with MRI
movement disorder, sleep disturbance CSF-antibodies
Serum antibodies
Neurometabolic disorders (IEM) Recurrent encephalopathy/family history High anion gap metabolic acidosis, ketosis
Hyperammonemia, Persistent hypoglycemia
TMS/GCMS
Neuroimaging

94 Pediatric Infectious Disease, Volume 1 Issue 3 (July–September 2019)