Acute encephalitis syndrome

Dr Prateek Kumar Panda

MD, DNB, DM (Pediatric Neurology), FEBN
Co-convenor, DM Pediatric Neurology Program
Co-chair, Pediatric Neurology division
Assistant Professor
Department of Pediatrics
AIIMS, Rishikesh
 Overview of presentation

1. Acute encephalitis syndrome

2. Epidemiology and etiological agents of viral encephalitis
3. Etiological clues from history and examination
4. Diagnostic evaluation
5. Management and prevention
6. Features of specific viral encephalitis
Case 2
• 3 year old boy presented with acute onset profound encephalopathy
with a history of fever seven days back lasting for two days
• CSF showed lymphocytic pleocytosis and elevated protein
• MRI brain showed diffuse bilateral white matter lesions with variable
contrast enhancement and basal ganglia involvement
• Serum MOG antibody was found to be positive
Case 3
• A 4 year old boy presented with fever and cough for 2 days, followed
by acute onset encephalopathy and seizures
• CSF showed lymphocytic pleocytosis and elevated protein
• MRI brain showed target sign in thalamus
• H1N1 PCR was positive in nasopharyngeal aspirate
Please rule out…….
• ADEM
• ANE
• AESD (acute encephalopathy with biphasic seizures and late reduced
diffusion)
• MERS (Mild encephalitis/encephalopathy with reversible splenial
lesions)
• ALERD
• FIRES
• Autoimmune encephalitis
 Acute encephalitis syndrome

• A case of acute encephalitis syndrome (AES) is defined as

1. A person of any age, at any time of year, with
2.  Acute onset of fever and
3. A change in mental status (including symptoms such as confusion,
disorientation, coma, or inability to talk) AND/OR
4. New onset of seizures (excluding simple febrile seizures)

Consensus Guidelines on Evaluation and Management of Suspected Acute Viral

Encephalitis in Children in India.S Sharma et al.Indian Pediatrics. 2012
 Viral

Bacterial
Infectious

Rarely Parasitic/Fungal/
Spirochetal/Rickettsial/others

ADEM
Acute onset encephalopathy in a child
Parainfectious/Autoimmune

Autoimmune encephalitis

Toxic
Noninfectious

Metabolic/Dyselectrolytemia
Features ADEM Acute viral encephalitis
Preceding prodromal illness or Usually present Absent(Fever occurs along with
vaccination illness)
Neuroimaging Predominantly patchy, discrete, Predominantly cortical grey
bilateral cortical white matter matter involvement with gyral
and deep grey matter enhancement
involvement with variable
contrast enhancement
Visual loss(one or both eyes) Common Uncommon
Multifocal including spinal Common Uncommon
cord involvement
Meningism Common Less common
 Acute viral encephalitis-Epidemiology

• Viral infection is the most common and important cause

• More than 100 viruses implicated worldwide
• Symptoms
1. Fever
2. Headache
3. Behavioral changes
4. Altered level of consciousness
5. Focal neurologic deficits
6. Seizures
• Incidence of 3.5-7.4 per 100,000 persons per year
Consensus Guidelines on Evaluation and Management of Suspected Acute Viral
Encephalitis in Children in India.S Sharma et al.Indian Pediatrics. 2012
 Predominant causes of acute encephalitis syndrome in
India
• Herpes group of viruses: HSV 1 and 2(for sporadic encephalitis) predominantly
• Enterovirus
• Other arbovirus like Chandipura virus, West Nile virus, Nipah virus and Kyasanur
Forest disease
• Recently atypical microorganisms like Mycoplasma, Chlamydia, Legionella and
Rickettsiae are also constituting a considerable proportion of AES in India
 Causes of Viral Encephalitis in India

• Herpes viruses – HSV-1, HSV-2, varicella zoster virus, cytomegalovirus, Epstein-

Barr virus, human herpes virus 6
• Enteroviruses-Echovirus, Coxsackie virus, Enterovirus 71, Nonpolio enterovirus,
cVDPV, iVDPV
• Measles, mumps, and rubella viruses
• Rabies
• Arboviruses – Japanese encephalitis, West Nile encephalitis virus; Kyasanur
Forest Disease, Flaviviruses,Nipahvirus, Chandipura viruses, Dengue, Chikungunya
• Adenoviruses
• Influenza A
• Arenaviruses – example: lymphocytic choriomeningitis virus
Consensus Guidelines on Evaluation and Management of Suspected Acute Viral
Encephalitis in Children in India.S Sharma et al.Indian Pediatrics. 2012
Etiology of acute encephalitis syndrome
VIRAL BACTERIAL RICKETTSIAL
Japanese Encephalitis Virus M.tuberculosis Rickettsia rickettsia (Rocky
Mountain spotted fever)
Herpes Simplex Virus Mycoplasma pneumoniae Rickettsia typhi (endemic
typhus)
Entero Encephalitis Listeria monocytogenes Rickettsia prowazeki (epidemic
typhus)
Dengue Encephalitis Leptospirosis Coxiella burnetti (Q fever)
Rabies Encephalitis Brucellosis Fungal
HIV Legionella Ehrlichiosis
Varicella Encephalitis Salmonella typhi Cryptococcus
Influenza Virus All causes of pyogenic Aspergillosis
meningitis
Mycoplasma Encephalitis Parasitic Candidiasis
Cerebral malaria Coccidiomycosis
Toxoplasma gondii Histoplasmosis
AES : Endemic viruses India
• JEV: UP (east), Bihar, West Bengal and Assam,
parts of Tamil Nadu
• Chandipura Virus : Maharashtra (Nagpur) &
Gujarat (2003),parts of Andhra Pradesh
• Nipah virus: first outbreak : Siliguri, West
Bengal(2001) f/b Nadia district of West Bengal
(2007)
• Enterovirus :Gorakhpur, UP (2006)
• Previously suspected Litchi virus in
Muzzafarpur, Bihar & Malda, West Bengal (2013 -
2014) currently found to be due to Hypoglycin
toxin
• Recently increasing incidence of Rickettsial cases
Acute Encephalitis Syndrome in India: The
in Gorakhpur region and UK, previously thought
Changing Scenario. S Ghosh et al.
Ann Neurosci 2016 to be mainly due to JE
Non infectious causes of acute encephalitis
like presentation
• Fever Triggered
• Diabetic Ketoacidosis
• Inborn error of metabolism (IEM)
• Mitochondrial cytopathies
• Reye’s like illness (syndrome)
• Acute disseminated encephalomyelitis (ADEM)
• Autoimmune encephalitis {Fulminant (anti GAD/NMDAR)}
• Dravet Syndrome
Davis LE. Diagnosis and treatment of acute encephalitis. The Neurologist 2000;6:145–
Evaluation and Management

• Rapid assessment and stabilization

• Focused history and examination

• Empirical treatment

• Investigations

• Supportive care

Emergency Neurologic Life Support: Meningitis and Encephalitis.

Neurocritical care December 2015
ACUTE ENCEPHALITIS SYNDROME IS A MEDICAL EMERGENCY

Evaluation, intervention & investigation should go hand

in hand
Airway maintenance

Consider Intubation if
• GCS < 8
• Abnormal respiratory pattern
• Impaired airway protective reflexes
• If ↑ICP – mild hyperventilation ( PaCO2 30 -35 mm Hg)

Emergency Neurologic Life Support: Meningitis and Encephalitis. Neurocritical care

December 2015
• Circulation
– HR
– CFT
– Central/peripheral Pulse
– BP
– Urine output
 Intervention
• Secure IV access
• Fluid bolus if in circulatory failure (20 ml/kg NS – 1-3 times),
inotropes if required (As per PALS guidelines)
Management of acute complications

• Hypoglycaemia

• Shock

• Treat fever and hypothermia

• Treat ongoing seizures

• Identify signs of raised ICP

• Relevant serology (RDT, Dengue)

Emergency Neurologic Life Support: Meningitis and Encephalitis.
Neurocritical care December 2015
Investigation in the first hour
• Labs: Electrolytes, Hemogram, PT/PTT, chemistries, blood gas,
blood cultures, lactate

• Based upon prevalent epidemiological scenario other

investigations can be ordered like Dengue card test, skin
scrappings for meningococus , rickettsial serology.

Emergency Neurologic Life Support: Meningitis and Encephalitis.

Neurocritical care December 2015
Evaluation and Management

• Rapid assessment and stabilization

• Focused history and examination

• Empirical treatment

• Investigations

• Supportive care

Emergency Neurologic Life Support: Meningitis and Encephalitis.

Neurocritical care December 2015
 History

Enteroviru Influenza,
s, Rota Paramyxoviru
virus, s,
shigella Mycoplasma

Diagnosis and treatment of viral encephalitis. Postgrad Med J

2002;78:575–583
What Are the Epidemiologic and Clinical Clues
that Suggest a Specific Etiology of Encephalitis?
• Season
• Geographical region
• Prevalence of disease
• Travel history
• Occupational exposures
• Insect or animal contacts
• Vaccination history
• Immune status
The Management of Encephalitis: Clinical Practice Guidelines
by the Infectious Diseases Society of America 2008
How was the onset of neurological
symptoms?
• Duration of fever- before encephalopathy

– Explosive onset (esp with seizures): viral encephalitis

– Acute- evolution in 1-4 days: bacterial meningitis, cerebral

malaria
– Slow evolution (days) of encephalopathy (usually without
seizures): malaria, enteric, systemic infections (Sepsis associated
encephalopathy) Diagnosis and treatment of viral encephalitis. Postgrad Med J
2002;78:575–583
Possible Viral Etiologies based on Clinical
Presentation
Clinical presentations Possible etiological agent

Cerebellar ataxia Varicella Zoster virus

Dementia HIV; Measles virus
Poliomyelitis-like flaccid paralysis JE; Poliovirus; enterovirus; West-Nile virus; tick-borne encephalitis virus

Extrapyramidal signs JE; West-Nile virus; Nipah virus

Retinitis CMV; West Nile virus
Rash VZV; HHV-6; Rubella virus; Measles; Handfoot and mouth disease

Diarrhea Enterovirus
Respiratory tract findings H1N1 and other influenza virus; Adenovirus
Parotitis Mumps virus
Lymphadenopathy HIV; EBV; Measles; Rubella; West Nile virus
Hepatitis Coxiella burnetii
Evolution of Neurological Symptoms

• Duration between systemic symptoms and neurological

symptoms
• History of febrile illness or immunisation preceding
neurological symptoms
• Multifocal neurological signs affecting optic nerves, brain, spinal
cord, and peripheral nerve roots
Other history

• Consanguinity, developmental delay, siblings deaths, unexplained

metabolic acidosis ( lactic acidosis): metabolic encephalopathy
• H/o primary / secondary immunodeficiency states: Atypical
organisms
• History of trauma, CSOM, bleeds, other foci of infection
• Urine analysis:
• 64% had metabolites of Hypoglycin A
• 45% had Methylene cyclopropyl glycine (MCPG) metabolites
• 44% contained both
• Abnormal acyl carnitine profile (90%)

The Lancet, Volume 5, Issue 4,  PE458-E466, April 01, 2017

Clues for aetiology from history Probable agent

History of herpetic lesions in mother in immediate perinatal period, especially HSV

for neonatal herpes
Any evidence for focality in form of focal seizures, aphasia or behavioural
changes without seasonal predominance
Prodromal illness with loose stools/ biphasic pattern and maculopapular rash Enterovirus
during summer and rainy season
H/o painful rash in dermatomal distribution, with or without cerebellar signs VZV
Endemic areas for JE with high mosquito density and rice fields, altered JE
sensorium with generalized seizures and changing CNS signs, psychotic
features, with or without extrapyramidal signs/ basal ganglia involvement,
occurrence in clusters in monsoon season
H/o fever, cough, coryza, conjunctivitis and sometimes diarrhoea in a child Measles
unvaccinated for measles vaccine encephalitis
Clues for aetiology from history Probable agent
History of animal bite with inadequate immunization Rabies encephalitis
Immunosuppression/immunocompromised state Reactivation of
Varicella, CMV, JC
virus(usually chronic
course)
Prodromal respiratory illness Influenza, Adenovirus
History of exposure to rodents Lymphocytic
choriomeningitis virus
With petechial rash and eschar/ summer season with or without h/o travel/ Rickettsiae
capillary leak
 Viral meningoencephalitis
Clues for aetiology from examination Probable agent

Focal neurological deficit or focal seizures, PLEDs in EEG, presence of vesicular HSV
rash on body, hepatic an d disseminated involvement in neonates
Maculopapular rash , Biphasic fever, concomitant Herpangina , Hand Foot Enterovirus
Mouth disease, myocarditis, pleurodynia, hemorrhagic conjunctivitis
Presence of Varicella zoster(rash in dermatomal distribution), VZV
immunocompromised state, territorial stroke or cerebellar ataxia with history
of vesicular rash
Altered sensorium with generalized seizures and changing CNS signs/ psychotic JE
features , mutism, significant extrapyramidal sequelae
Bulging AF Eschar

MENINGOCOCCEMIA

FULMINANT SEPSIS
Clues for aetiology from examination Probable agent

Thrombocytopenia, petechiae, ecchymoses and hemorrhages elsewhere Dengue virus

Arthalgia and arthritis along with rash Chikungunya virus
Associated neuritis, myeloneuritis, opthalamoplaegia, autonomic and sensory EBV
neuropathy, sometimes presence of pharyngitis, lymphadenopathy
,splenomegaly
Immmunocompromised/immunosuppressed state, multisystemic invovement CMV
including hepatic, gastrointestinal, pulmonary and hematological
involvement
Clues for aetiology from examination Probable agent
Parotitis and orchitis(concomitantly or prodromal illness) in a child Mumps
unvaccinated for mumps vaccine

Hydro/aerophobia, neuropsychiatric features, agitation/aggressiveness, Rabies

autonomic instability, rapidly progressive course, sometimes rapid onset
ascending flaccid paralysis
Maculopapular rash, Koplik spot Measles virus
Roseola infantum, recurrent, prolonged febrile seizure HHV 6
Clues for aetiology from examination Probable agent
Recently received polio vaccine, sometimes associated acute flaccid paralysis VDPV
with even bulbar involvement, biphasic fever
Associated aplastic anemia or pure red cell apalasia Parvovirus

Acute respiratory infection, keratoconjunctivitis Adenovirus

Acute respiratory infection, opisthotonous, ataxia, transverse myelopathy Influenza
Neurological Examination- pupil
Etiology/localization Pupil appearance
Pontine Pinpoint
Opiate/ Organophosphate poisonings Pinpoint
Hypothalamic Small reactive
Metabolic Small reactive
Midbrain Mid position, fixed
Oculomotor nerve, uncal herniation Ipsilateral pupil fixed and dilated
Hypoxic ischemic encephalopathy Bilateral fixed dilated
Tectal Large, nonreactive, hippus
Anticholinergic, sympathomimetic, anti depressant Dilated and fixed
poisoning
Neurological examination
• Localizing features: hemiparesis, cranial nerve palsies
• Fundus: papilledema, retinal hemorrhages, exudates
• Extra-pyramidal features: Jap B encephalitis, IEM
• Cerebellar ataxia: Varicella zoster virus
• Poliomyelitis like flaccid paralysis
• Rhombenecephalitis
Evaluation and Management

• Rapid assessment and stabilization

• Focused history and examination

• Empirical treatment

• Investigations

• Supportive care

Emergency Neurologic Life Support: Meningitis and Encephalitis.

Neurocritical care December 2015
Empirical therapy

• Antibiotics: ceftriaxone ± vancomycin in meningitic dosage if

suspected bacterial meningitis
• Antiviral: Aciclovir
– Dose: 10-15 mg/kg/dose TDS as 1 hour infusion
– Acyclovir should be initiated in all patients with suspected
encephalitis, pending results of diagnostic studies
• (IDSA Guidelines for Management of Encephalitis, 2018 Update)

•
• Antimalarials (Artesunate)- Smear positive, RDT positive cases,
Empiric treatment if resident of P.falciparum endemic area, short
history (<48 hrs), anemia, hypoglycemia, retinal hemorrhages and
absent meningeal signs
• Consider Azithromycin for mycoplasma and Doxycycline for
Rickettsial infections if clinical suspicion is high
When to start Acyclovir in suspected encephalitis ??
• All patients with clinical features suggestive of clinical encephalitis
pending the results of diagnostic studies
• HSE should be considered in any patient. with a progressively
deteriorating level of consciousness with fever, focal seizures and
focal neurological abnormalities in the absence of other cause
• Behavioural changes
• Aphasia
• Suggestive CT (fronto-temporal changes)
• Hemorrhagic CSF
When not to start Acyclovir ??
• Children with febrile seizures

• Seizures without documented fever or history of fever unless

immunocompromised

• Other obvious case like blocked VP shunt , epilepsy with exacerbation

due to febrile illness

• CSF and clinical picture suggestive of bacterial meningitis

• Drug over dosage

When to stop Acyclovir in suspected HSE ??

• If there is no ongoing clinical suspicion of HSE and definitive

alternate diagnosis is made.

• If a negative HSV DNA PCR obtained at 72 hours following onset of

neurological symptoms and low clinical suspicion of HSE ( Clinical
recovery, normal Neuroimaging and csf cells <5/mm3)
Evaluation and Management

• Rapid assessment and stabilization

• Focused history and examination

• Empirical treatment

• Investigations

• Supportive care

Emergency Neurologic Life Support: Meningitis and Encephalitis. Neurocritical care

December 2015
Investigations

• CSF
• Neuroimaging
• EEG
• Other laboratory investigations
LP-Recommendation
• Should be performed as soon as possible unless there is a clinical
contraindication
• Clinical assessment and not Neuroimaging should be used to
determine if it is safe to perform LP
• If there is clinical contraindication CT scan should be performed
as soon as possible
• Decision of LP after CT scan is on case to case basis
Contraindications of immediate LP in a child
with encephalitis
• Moderate to severe impairment of consciousness GCS<11 and
change of GCS>2
• Signs of hypertension and bradycardia
• Abnormal Dolls eye movement
• Focal neurological deficits
• Papilledema
• After seizure until stabilized

Journal of infection 2012 (64) 449-

Contraindications on CT

Diffuse cerebral edema White cerebellum sign

Uncal Herniation Midline shift

LP vs CT scan
• LP should be done after imaging unless
– Brain shift
– Alternative diagnosis
– Clinical condition changes
• If LP is not possible on day 1 it should be reviewed every 24 hours
whether it is safe now to do LP
• If initial LP is non diagnostic than a repeat LP can be performed
48 hours later
Lumbar Puncture

• Cell count

• Glucose, protein

• Gram stain, Ziehl-Neelson stain, India ink

• Bacterial culture

• Viral polymerase chain reaction (Herpes Simplex

virus/Enterovirus/Mumps/Rabies/VZV)
CT scan- Usually only CECT Brain

• NCCT: If suspected
• Infarction
• CNS bleed
• Hydrocephalus
• Herniation
• NCCT F/b CECT: if suspected
• Venous thrombosis
• Neuroinfection- Bacterial meningeal enhancement
• Some viral encephalitis HSV – fronto-temporal involvement
• JE – Thalamic involvement
• Mass lesions – Granulomas/ ICSOL
• Serology for JE/Dengue/Measles/Chandipura
• Latex agglutination test
• Additional cultures guided by clinical suspicion (fungal or tubercular)
• NMDA & VGKC antibodies
• PCR: Bacterial primers to detect the nucleic acid of S. pneumoniae, N.
meningitidis, E. coli, L. monocytogenes, H. influenzae, and
Streptococcus agalactiae
• Serology for enteric fever/Leptospira
Keep CSF sample for further analysis
Clinical Infectious Diseases, Volume 57, Issue 8, 15 October 2013, Pages
1114–1128
IDSA Guidelines for Management of Encephalitis, 2018 Update
Investigations- Serology

• JE serology: If thalamic involvement on neuroimaging / extrapyramidal

involvement on examination / residence in endemic regions /
clustering of cases / monsoon season
• Dengue serology if endemicity/edema/ abdominal pain/ low
platelet count/ petechiae / epidemic
• Serology for Rickettsial illness, mycoplasma and Leptospira if clinical
history or examination is suggestive
Clinical Infectious Diseases, Volume 57, Issue 8, 15
October 2013, Pages 1114–1128
HSV DNA PCR
• Negative in initial 48 hours and after 10-15 days of infection
• As the viral load is less in the initial phase of illness.
– 96% sensitivity and 99% specificity of PCR within 10 days
– 30% within 10-20 days
– 19%- 21-40 days.
• Overall sensitivity of HSV DNA PCR is 70 – 75%
• RBC’s in CSF inhibit PCR reaction leading to false negative result.

Euro J of Ped. Neurol, 2008, Textbook of Tropical Neurolog

MRI Brain

• MRI is the most sensitive neuroimaging test to evaluate patients

with encephalitis
• Useful for detection of early changes

• Diffusion-weighted imaging superior to conventional MRI for

detection of early signal abnormalities in viral encephalitis
caused by herpes simplex virus, enterovirus 71, and West Nile
virus.
HSV Encephalitis
• T1
• may show general oedema in the affected region
• if complicated by subacute haemorrhage there may be areas of hyperintense signal
• T2
• hyperintensity of affected white matter and cortex
• more established haemorrhagic components may be hypointense

Prominent swelling, increase T2 signal involving the left

temporal lobe and insular cortex. The right mesial
temporal lobe appears normal. No evidence of
haemorrhage.

T2 WEIGHTED
 FLAIR

HSV
Encephalitis

• Temporal lobes (83%)

• Insula (12%)
• Basal part of frontal lobe
(6%)
• White matter (6%)
• Less commonly thalamus ,
occipital lobe and
cerebellum involved

DWI Apparent Diffusion Coefficient T2 WEIGHTED

 JE Encephalitis
FLAIR T2 T2

T2 and FLAIR images involving

Pons hyperintensities Substantia nigra
bilateral thalami,. Patchy focal
areas of blooming are seen
within the thalami and pons,
suggestive of haemorrhage
VZV Encephalitis

Cerebellitis
Rabies Encephalitis

Symmetrical hyperintensity on T2 is seen involving the bilateral

thalami, Basal ganglia, midbrain, dorsal pons.
Enteroviral Rhombencephalitis

FLAIR T2 WEIGHTED
Hyperintense lesions in the midbrain, dorsal aspect of
the pons (pontine tegmentum),
Dengue encephalitis

FLAIR: Bilateral Thalamic and periventricular white matter Involvement

Scrub typhus

Magnetic resonance imaging brain, FLAIR sequences showing

hyperintensities in bilateral thalami with features of cerebral
edema
H1N1 Encephalitis

Bilateral perirolandic T2 hyperintensities with restricted

diffusion and round T2 hyperintense lesions in both thalamus.
Litchi Encephalitis
• May 26 to July 17, 2014: 390 patients
• 31% mortality
• Clinical features:
• Altered sensorium
• Seizures ( GTCS/Generalized tonic seizures)
• Vomiting (18%)
• Fever (39%)
• No focal neurological signs

The Lancet, Volume 5, Issue 4,  PE458-E466, April 01, 2017

• MRI:
• No focal lesions/signal abnormalities/inflammation
• Eight pts showed mild to moderate cerebral edema
• CSF:
• Normal WBCs count (84%)
• Normal protein (94%)
• Normal Glucose (79%)
• Blood Glucose levels: Subcortical white matter with caudate lobe involvement
• Mean BS: 47.8 mg/dl
• 52% had BS <50mg/dl

The Lancet, Volume 5, Issue 4,  PE458-E466, April 01, 2017

• Urine analysis:
• 64% had metabolites of Hypoglycin A
• 45% had Methylene cyclopropyl glycine (MCPG) metabolites
• 44% contained both
• Abnormal acyl carnitine profile (90%)

The Lancet, Volume 5, Issue 4,  PE458-E466, April 01, 2017

Clues for aetiology from history Probable agent

History of herpetic lesions in mother in immediate perinatal period, especially HSV

for neonatal herpes
Gastrointestinal prodrome, biphasic fever, H/o rash Enterovirus
H/o painful rash in dermatomal distribution VZV
Endemic areas for JE with high mosquito density and rice fields JE
H/o fever, cough, coryza, conjunctivitis and sometimes diarrhoea in a child Measles
unvaccinated for measles vaccine encephalitis
Clues for aetiology from history Probable agent
History of animal bite with inadequate immunization Rabies encephalitis
Immunosuppression/immunocompromised state Reactivation of
Varicella, CMV, JC
virus(usually chronic
course)
Prodromal respiratory illness Influenza, Adenovirus
History of exposure to rodents Lymphocytic
choriomeningitis virus
 Viral meningoencephalitis
Clues for aetiology from examination Probable agent

Focal neurological deficit or focal seizures, PLEDs in EEG, presence of HSV

vesicular rash on body, hepatic an d disseminated involvement in neonates
Maculopapular rash , Biphasic fever, concomitant Herpangina , Hand Foot Enterovirus
Mouth disease, myocarditis, pleurodynia, hemorrhagic conjunctivitis
Presence of Varicella zoster(rash in dermatomal distribution), VZV
immunocompromised state, territorial stroke or cerebellar ataxia with history of
vesicular rash
Altered sensorium with generalized seizures and changing CNS signs/ psychotic JE
features , mutism, significant extrapyramidal sequelae
Clues for aetiology from examination Probable agent

Thrombocytopenia, petechiae, ecchymoses and hemorrhages elsewhere Dengue virus

Arthalgia and arthritis along with rash Chikungunya virus
Associated neuritis, myeloneuritis, opthalamoplaegia, autonomic and sensory EBV
neuropathy, sometimes presence of pharyngitis, lymphadenopathy
,splenomegaly
Immmunocompromised/immunosuppressed state, multisystemic invovement CMV
including hepatic, gastrointestinal, pulmonary and hematological
involvement
Clues for aetiology from examination Probable agent
Parotitis and orchitis(concomitantly or prodromal illness) in a child Mumps
unvaccinated for mumps vaccine

Hydro/aerophobia, neuropsychiatric features, agitation/aggressiveness, Rabies

autonomic instability, rapidly progressive course, sometimes rapid onset
ascending flaccid paralysis
Maculopapular rash, Koplik spot Measles virus
Roseola infantum, recurrent, prolonged febrile seizure HHV 6
Clues for aetiology from examination Probable agent
Recently received polio vaccine, sometimes associated acute flaccid paralysis VDPV
with even bulbar involvement, biphasic fever
Associated aplastic anemia or pure red cell apalasia Parvovirus

Acute respiratory infection, keratoconjunctivitis Adenovirus

Acute respiratory infection, opisthotonous, ataxia, transverse myelopathy Influenza
 CSF examination: Viral encephalitis
• Clear, Lymphocytic pleocytosis
• Elevated CSF protein with normal CSF glucose
• Absent CSF pleocytosis –immunocompromised, glucocorticoid,malignancies
  >5 cells/ul -90 % cases
 >1000 cells/ul –mumps ,LCMV
• Atypical lymphocytes – EBV
• Recurrent benign lymphocytic meningitis(Mollaret’s menigitis_-HSV 2, EBV
• Mollaret cells –Also in WNV
• Neutrophils >40%- WNV, echovirus, early cases of viral meningitis, in younger
children
• >20% RBC – HSV hemorrhagic encephalitis
• Decreased CSF glucose – Mumps, LCMV
CSF PCR in viral encephalitis

• Primary test for CMV,HSV,VZV

• Sensitive and specific for HSV
• Positivity increases with duration of illness
• Not affected by less than 1 week of therapy
• Next specific for enteroviruses
• Also for measles, mumps virus
• Not established for EBV
Virus Diagnostic test
JE Virus specific IgM in CSF or serum, by IgM capture ELISA, also paired sera
IgG titer
Enterovirus RT PCR for EV genome, isolation from throat swab/stool/serum
Dengue NS1 antigen, IgM Ab by IgM capture ELISA
HSV CSF HSV DNA PCR
VZV CSF VZV PCR
Mumps CSF mumps RNA PCR
Measles CSF IgM antibody specific for measles
Rabies virus Corneal imprint smear, nuchal biopsy, PCR for rabies virus in CSF
Radiological features Probable agent
Frontotemporal hyperdensities/significant edema and hemorrhage in HSV
temporal lobes
Caudate, putamen, substantia nigra+/-thalamic involvement JE

Basal ganglia+/- thalamic involvement Rabies

Corpus callosum H1N1
Evidence of vasculopathy and stroke Varicella
Brainstem, dentate nuclei, Anterior horn cell of spinal cord Enterovirus
White matter lesion mimicking demyelination West Nile virus
 Neuroimaging in HSV encephalitis
• CT Brain may be normal in initial 3-5 days(sensitivity 50%)
• When typical findings of HSV encephalitis are observed on CT scan, they often are
associated with severe brain damage and a poor prognosis
• MRI brain: Preferentially temporal lobe and orbital surfaces of the frontal lobes
(IC spread along meningeal branches of V CN.)
• Extend to insular cortex, posterior occipital cortex, and cerebral convexity
• Basal ganglia are spared
• Bilateral involvement is frequent; usually asymmetric
• Hemorrhage: seen as increased signal on T1W and decreased in GRE sequences
• Herpes encephalitis DWI MRI findings predict response to treatment and
prognosis on follow up
Involved areas in MRI brain
A: Temporal lobes
B. Insular cortex and Thalamus
C. Insula Temporal lobe hypodensity in CT brain
D. cingulate gyrus
 MRI brain in neonates in HSV encephalitis

• Hemorrhage rare
• Early DW restriction with normal MRI
• Meningeal enhancement is occasional
• Evolve to cystic encephalomalacia and atrophy
• Medial temporal, inferior frontal may be spared
• Temporal, frontal, parietal, and subcortical regions; cerebellum 50%
• Cerebral calcification is frequent
• HSV2 : Brainstem is rare
Atypical Neonatal
herpes: Serial
Imaging
Brainstem
Involvement in
Neonatal Herpes
Simplex Virus Type 2
Encephalitis
Gustavo Pelligra et al. Pediatrics
2007
 MRI brain in Infant with HSV encephalitis
• Signal abnormalities that mirrored the anterior, middle, or posterior cerebral
artery vascular territories
• Contrast: diffuse enhancement was shown in the cortex and white matter but not
in the overlying meninges
• Minimal hemorrhage and no involvement of the medial temporal or inferior
frontal lobes,
• This pattern suggests hematogenous spread rather than spread through meninges
Posterior right MCA territory
involvement with right high
frontoparietal signal changes in
MRI brain in infant with HSV
encephalitis
Leonard JR, Moran CJ, Cross DT III et al
(2000) MR imaging of herpes simplex type 1
encephalitis in infants and young children:
a separate pattern of findings. AJR
174:1651–1655
Cerebellitis due to Varicella with Vasculitis with Varicella with
cerebellar signal changes MCA involvement bilaterally
Varicella: Focal cerebral arteriopathy
A. Diff restriction:
Mesial temporal,
amygdala, post
occipital
B. ADC map
C. MRA: filling defect
in ACA branch
D. After 1 month:
resolution but
narrowing in ACA
branch
MRI brain in Japanese Encephalitis

• Involves bilateral thalamic, substantia nigra, basal ganglia, brain stem,

cerebellum, cerebral cortical, and white matter lesions
• Bilateral, often asymmetric lesion of thalami
• Mostly involves the hippocampus, usually sparing the rest of the temporal lobe
Temporal Lobe Involvement in Japanese Encephalitis: Problems in Differential Diagnosis. S.K. Handique, R.R. Das, K.
Barman, N. Medhi, B. Saharia, P. Saikia and S.A. Ahmed.American Journal of Neuroradiology May 2006,  27 (5) 1027-1031
 A. Lesions are MRI brain in JE
seen in both
caudate heads
and thalami
(arrows)
B. bilateral
hippocampal
body involvement
(arrows)
C. lesions
involving the
hippocampal tails
and caudate
heads (white
arrowheads).

S.K. Handique et al. AJNR Am J Neuroradiol 2006;27:1027-

1031
HHV-6
• MRI brain: 2 patterns
1. Medial temporal lobe and limbic system (hippocampus, amygdala and
parahippocampal gyrus) without contrast enhancement and diffusion
restriction
2. ANEC with diffusion restriction
EEG in viral encephalitis

• Periodic Lateralized Epileptiform Discharges (PLEDs) are seen in at least 50%

cases of HSV encephalitis, localizing to temporal lobe
• Differential diagnosis for PLEDs-stroke, other localized structural destructive
lesions like brain tumor
• Nonspecific diffuse/bihemispheric slowing is common in in other viral
encephalitis
• Generalized Periodic Epileptiform Discharges(GPEDs) in SSPE(latent infection of
measles virus(also in Cruetzfelt Jacob disease, which is rare in children)
Supportive Treatment

• Seizure-antiepileptics
• Management of raised ICP
• Hemodynamic, respiratory, fluid and electrolyte status monitoring
• Physiotherapy, occupational therapy and tonolytics in rehabilitation phase
• Isolation and post exposure prophylaxis in required cases
Virus Specific drug
HSV Acyclovir 10 mg/kg/dose q8hrly for 14-21 days, depending on CSF PCR
Varicella Acyclovir 10 mg/kg/dose q8hrly for 14-21 days, depending on CSF PCR
CMV Gancyclovir 5 mg/kg/dose BD, Foscarnet 60 mg/kg/dose q8hourly, Cidofovir
H1N1 Oseltamivir
SSPE(latent Isoprinosine, Interferon, Ribavirin, Amantadine
infection of
measles virus)
Indications of acyclovir in acute encephalitis syndrome

• Clinical features localizing to frontotemporal involvement

• Prominent focal seizures
• Focal deficit/hemiparesis
• PLEDs in EEG
• Evidence of HSV infection in mother in recent per natal period in neonates
• Hemorrhagic CSF with nontraumatic lumber puncture
• MRI brain suggestive of temporal/orbitofrontal lobe involvement/hemorrhages
• MRI brain suggestive of parenchymal lesion corresponding to vascular territory in
infants
Indications of acyclovir in acute encephalitis syndrome

• Evidence of varicella zoster or other varicella lesions elsewhere

• Immunocompromised host
• CSF HSV/varicella PCR positivity
• In all cases of suspected sporadic viral encephalitis-discretion of clinician
recommended
• Since early acyclovir treatment for HSE is essential, more patients than those
actually having HSE will be initiated on this treatment based on clinical suspicion
• Acyclovir toxicity more common in children with renal impairment
• May rarely cause a toxic encephalopathy and confound the clinical findings
 When to stop acyclovir in AES?

• CSF HSV PCR negative and alternative diagnosis established

• Neuroimaging (preferably MRI brain) isnormal
• CSF HSV PCR negative and no alternative diagnosis----To give acyclovir for at least
10 days and then to stop
• If initial CSF HSV PCR positive, to repeat CSF HSV PCR at 14 days and to give
acyclovir for at least 14-21 days or CSF HSV PCR negative(whichever is later)

Recurrence risk of HSV encephalitis is about 5% and it is more if acyclovir duration is <10 days
Virus Prevention
Measles, SSPE Measles,MR, MMR vaccine
Mumps MMR vaccine
CMV Gancyclovir prophylaxis in immunosuppressed cases at high risk/systemic
CMV infection
H1N1 Oseltamivir prophylaxis for contacts
VDPV Mass vaccination with live attenuated vaccine f/b switch to inactivated
vaccine (End Game Polio Strategy)
JE Vero cell-derived, inactivated and alum-adjuvanted JE vaccine based on
the SA 14-14-2 strain, prevention of mosquito bite
Rabies Cell culture vaccine and Rabies Immunoglobulin
Dengue, Prevention of mosquito bite
Chikungunya,
West Nile virus
KFD Formalin inactivated KFDV vaccine, prevention of Tick bite
 Encephalitis due to Herpes group of viruses
• Remains latent with reactivation, Neurotropism (diffuses through vessels
or along meninges)
• Herpes family: HSV1 , HSV 2, VZV, EBV, CMV and HHV 6
• HSV-most common cause of non-epidemic focal encephalitis in children
older than 6 months and 25–30% of cases occur in children
• Most common cause of fatal sporadic encephalitis

• Henry J. Baskin & Gary Hedlund. Neuroimaging of herpesvirus infections in children.

Pediatr Radiol (2007) 37:949–963
HSV encephalitis

• Children and adults: HSV-l viral reactivation (90%); Neonates: HSV 2

infection (2/3rd cases)
• Initial HSV-l infection usually occurs in oronasopharynx through
contact with infected secretions; remains dormant in trigeminal
nerves
• Invades along cranial nerves (via lingual nerve, a division of the
trigeminal nerve) to ganglia
• Causes acute hemorrhagic, necrotizing encephalitis (primarily
involving temporal lobe and limbic system)
 HSV encephalitis

Adults : Pediatric:
• Transneuronal transmission •Hematogenous spread
• Only 15% extra temporal •Extra temporal 40%
• Basal ganglia and Thalamic •Thalamus and BG not uncommon
involvement uncommon
• HSV-1 >90% •Neonate: HSV 2 > HSV 1
• Outcome : Good in HSV 1 •Sequelae significant in HSV2
Neonatal Herpes

• 70% caused by HSV 2; 85% trasmission during labour

• CNS involvement in 1/3rd cases, associated with disseminated
infection usually
• Mortality(in treated cases) 4%; Sequelae 60-70%
• Untreated cases have high mortality
• Prognosis worse in HSV2 Vs HSV 1: Microcephaly, Seizure, cerebral
palsy in HSV2 is common
Mollaret’s meningitis

• A form of recurrent benign lymphocytic meningitis (RBLM)

• >3 episodes of fever, meningismus, headache lasting 2-5 days with spontaneous
resolution
• Associations with HSV 2, intracranial epidermoid cyst have been postulated
 CNS infections due to varicella

Cerebellitis
1. Neurotropism to cerebellum rather than immune mediated
2. Different from postinfectious cerebellar ataxia after 1-2 weeks of Varicella infection, in
which cerebellum will be normal in MRI brain
VZV encephalitis/ VZV multifocal vasculopathy/leukoencephalopathy
3. Most common presentation in acute state
4. Common in Immuno compromised
5. Small vessel arteriopathy
VZV Vasculitis
6. Large vessel vasculopathy- HZ ophthalmicus, Granulomatous angitis, VZV associated
stroke
7. MRA- necrotising arteriopathy causing aneurysm/occlusion
8. Immunocompetent
9. Delayed presentation
 Epstein Bar Virus

•A ubiquitous pathogen found in almost all people by the end of their second
decade
•Infects the nasopharyngeal epithelium and circulating peripheral B lymphocytes
•Remains dormant within circulating B-cells but occasionally activates in the
presence of mucosal epithelium, then sheds silently into infectious saliva
CNS manifestation due to EBV

• Encephalitis or meningoencephalitis
• Cerebellitis, optic neuritis, brainstem encephalitis, myelitis
• No symptoms of IM in case of CNS complications
• Immune mediated/ not direct invasion
• Tropism for: deep grey nuclei
• MRI: striatum, thalami, subcortical WM, ON, chiasma, Brain stem
• Lack of Diffusion restriction usually
• Excellent clinical outcome
CNS involvement with CMV

• Congenital infection: Lissencephaly, intracranial calcification, white matter signal

change
• Later in life: Primary or recurrent infection
• CNS Presentation: Meniongoencephalitis usually
• Common in children with cellular immunodeficiency like SCID,AIDS
• D/D-HIV Encephalopathy : clinical deterioration rapid in CMV
• Ventricular ependymal enhancement in CMV
HHV 6
• Primary infection: Roseola infantum
• HHV-6B : 30% of first Febrile seizure
• Prolonged , recurrent seizures
• Most children are infected with the B variant before the age of 2 years .
• Virus enters the body through the salivary glands, where it replicates and sheds
further particles via infectious saliva
• HHV-6 encephalitis: in immunocompromised children usually
• Diagnosis: CSF PCR detection of HHV-6
• Mortality 50%
Japanese encephalitis

• Vector-borne
• Incubation period: 6 to 8 days
• Enzootic cycle
 Mosquitoes: Culex species
 Culex tritaeniorhynchus
 Reservoir/amplifying hosts
 Pigs, bats, Ardeid (wading) birds
 Possibly reptiles and amphibians
 Incidental hosts
 Horses, humans, others
 Japanese encephalitis
• Most cases asymptomatic or mild signs
• Children and elderly have highest risk for severe disease
• Acute encephalitis
 Headache, high fever, stiff neck, stupor
 May progress to paralysis, seizures, convulsions, coma, and death
• Neuropsychiatric sequelae
 45 to 70% of survivors
• In utero infection possible
 Abortion of fetus
• Tentative diagnosis
 Antibody titer: HI, IFA, ELISA
 JE-specific IgM in serum or CSF
• Definitive diagnosis
 Virus isolation: CSF, brain
Rabies encephalitis

• Usually after category II/III bite by infected animal(doig/bat usually)

• Encephalitis rabies (furious rabies) :
1. Fever,neuropsychiatric features
2. Altered sensorium
3. Autonomic hyperactivity
4. Hydorphobia
5. Aerophobia
• Paralytic dumb rabies-Acute ascending paralysis
• Incubation period-few weeks to few years
• Basal ganglia involvement in neuroimaging
• Almost universally fatal except few survivors in case reports
Enteroviral encephalitis

• Cox -sackie B virus, Enterovirus 71 and Non polio Enterovirus

• During the summer or rainy season
• Most common cause of viral meningitis
• Associated with prodromal acute gastrointestinal illness frequently
• May be associated with Herpangina , hand, foot and mouth disease
• CSF PCR or nucleic acid amplification test for Enterovirus
• Virus isolation from throat and stool culture
• Role of Ribavirin doubtful
• Anterior horn cell involvement leads to long term weakness with slow recovery
Measles encephalitis

1. Acute measles virus encephalitis-fever, cough, coryza, conjunctivitis, CSF

showing lymphocytic pleocytosis
2. Postviral encephalomyelitis-demyelinating illness occuring within 2 weeks of
rash with encephalopathy, seizure or focal deficit
3. Measles inclusion body encephalitis-dementia, behavioral abnormalities,
myoclonic seizures, coma, followed by death within few weeks
4. Sub Acute Sclerosing Panencephalitis-rare late complication due to latent
measles infection of CNS pfresenting as progressive myoclonic epilepsy
phenotype with cognitive decline, myoclonic jerks, sometimes associated with
ataxia, pigmentary or necrotizing retinopathy, or extrapyramidal features.
GPEDS in EEG, death within months to years
Key messages

• Detailed history and physical examination to specifically look for diagnostic clues
• Diagnostic tests like MRI brain and CSF PCR are helpful
• Acyclovir treatment in children with reasonable suspicion of HSV encephalitis