Viral Meningoencephalitis | Pathogenesis, Diagnosis & Management

Previously asked questions on Encephalitis and related topics.

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Introduction

Viral meningoencephalitis	It is an acute inflammatory process involving the meninges and, to a variable degree, brain parenchyma.
Encephalitis	It is an inflammation of the brain parenchyma with or without the involvement of the meninges. Even though encephalitis technically refers to the brain parenchyma, the inflammation usually overlaps.
Encephalopathy	It refers to an inflammation that includes infectious as well as non-infectious causes of inflammation.
Myelitis	It is an inflammation of the spinal cord, manifesting as weakness, bladder dysfunction, flaccid paralysis, and reduced or absent reflexes

Epidemiology

Most commonly occurs in young children, with the incidence decreasing with age.
As against pure meningitis which is mostly bacterial in origin, encephalitis is most commonly caused by viruses, commonest being enteroviruses like Coxsachie and Echoviruses.
HSV 1 (~90%) and 2, rank as the most common cause of viral meningitis in many places and overall second most common in the world. HSV 1 is an important sporadic etiology in India. They cause a life-threatening form of encephalitis with high mortality and morbidity.
In India, most reported cases are of Jap B (JEV) ranging from 5-35%. (several outbreaks)
In countries with high rates of immunization coverage, viral meningitis is more common than bacterial meningitis.
Vaccinations for Haemophilus influenza type B, Streptococcus pneumonia, and Neisseria meningitides have significantly decreased cases of bacterial meningitis.

Age Group

The epidemiological studies in India showed an increased trend of the meningococcal disease among adolescent and adults.

Etiology

Herpes viruses - Several members of the herpes family of viruses can cause meningoencephalitis. HSV-1 and HSV-2 are most commonly implicated throughout the world.
However, in India, most reported cases are of Jap B (JEV) ranging from 5-35%.
Enteroviruses are also a common cause of viral meningoencephalitis. Eg. Poliovirus, coxsackievirus, echovirus.
Arboviruses are arthropod-borne agents, responsible for some cases of meningoencephalitis during the summer months
Other Viruses
- Respiratory viruses such as Influenza A virus and parainfluenza virus, Adenovirus
- West Nile virus,
- Chandipura virus
- Mumps, measles, Rubella
- Dengue virus
- Parvovirus B4
- Epstein-Barr virus
- Rabies virus
- SARS COV-2
- HIV
- Zika Virus

Pathogenesis and pathology

Fig 1. Pathogenesis of Viral meningoencephalitis in children

Routes of transmission

Inhalation of infective droplets
Contaminated food or drink
Mosquitos, ticks, and insect bites / Vector bourne transmission

Spread to CNS

Most reach the spinal cord or CNS, via a hematogenous route.
HSV, rabies, and herpes zoster virus reach the CNS from nerve endings in a retrograde manner

Neurologic damage

A normal neurological function is disrupted by the direct invasion and destruction of neural tissues by actively multiplying viruses and by an inflammatory response to viral antigens or antigen+antobody complexes.

An inflammation cascade is triggered in infected and adjacent areas throughout the cerebral hemispheres, brain stem, cerebellum, and, occasionally, the spinal cord.

This might result in severe edema and vascular congestion resulting in features of raised ICP. Sometimes petechial hemorrhages in the brain parenchyma may be present in severe infections.

Some viruses have a predilection for certain areas of the brain and this can help in zeroing down to the diagnosis (by neuroimaging) such as

Temporal lobe, Focal areas of necrosis	HSV
Basal structures	Rabies
Entire brain, Calcifications	Arbovirus
Significant necrosis	JE

Clinical features

General

Fever, nausea, vomiting, and photophobia
Pain in the neck, back, and legs is common.
The presenting manifestations in older children are headaches and hyperesthesia. Headache is most often frontal or generalized; adolescents frequently complain of retrobulbar pain.
In infants presenting features can be irritability and lethargy.
As body temperature increases, there may be mental dullness, progressing to a stupor in combination with bizarre movements and convulsions.
Exanthems often precede or accompany the CNS signs.

Specific

Japanese encephalitis may present with extrapyramidal symptoms which mimic Parkinson's disease.
Tremor, myoclonus, ataxia, and cranial nerve palsies can be seen in enteroviral infections. Other clinical clues - conjunctivitis, pharyngitis, rash, herpangina, and hand-foot-mouth disease.
HSV infection can present with fever, altered mental status, focal neurologic deficits, and seizures.
Epstein-Barr virus Other organ dysfunction can be present. It is an uncommon cause of CNS infection in immunocompetent children
Nipah virus may present with brainstem and cerebellar signs.
Microcephaly is typically seen in Zika virus infection.

Diagnosis

History and PE

History is extremely important, the above clinical features might help in initial screening.
A history of exposure to viruses such as measles can help narrow down the diagnosis.
Rash, vesicles, and past history of chickenpox for possible reactivation.
Residence of child: Rural/urban, endemic for cerebral malaria, any epidemic of AES in the neighborhood such as Jap B
History of animal contact, insect bite, dog bite for Rabies.
Drug or toxin exposure- enquire about presence of any drugs at home
Recent history of travel
Recent immunizations
History of recurrent episodes of encephalopathy: These are characteristic of some inborn errors of metabolism (urea cycle defects, organic acidemias, and fatty acid oxidation defects), but may also be present in migraine, epilepsy, substance abuse, and Munchausen syndrome by proxy.
Other concurrent systemic illnesses e.g. jaundice (hepatic failure), pneumonia (hypoxic encephalopathy), diarrhea (dys-electrolytemia), dysentery (shigella encephalopathy)
Past medical illness: Diabetes, congenital heart disease, chronic kidney or liver disease
Family history of previous infant/child deaths
Pre-morbid developmental/ neurological status of the child
Risk factors for immunodeficiency- HIV risk factors, cancer treatment, steroid/immunosuppressant treatment
The geographic location as well as recent travel history could be of relevance (examples from recent outbreaks include acute respiratory syndrome, severe acute respiratory syndrome, Nipah virus, avian H5N1 influenza A infection, Zika virus)
The investigation plans mostly compromises CSF analysis and neuroimaging.

Investigations

The diagnosis of viral meningoencephalitis is usually made on the basis of the clinical presentation of nonspecific prodrome followed by progressive CNS symptoms. The following investigation can confirm the diagnosis.

CSF examination

CSF analysis is the key
CSf should be examined for total and differential cell count, glucose, protein, and culture.

How to differentiate Bacterial, viral and Tubercular meningitis, meningo-encephalitis ?

Clinical and laboratory features of viral and bacterial meningitis in children, note a considerable variation may exist in CSF values.

Feature	Viral meningitis	Bacterial meningitis	Tubercular
Seasonal pattern	Enteroviral infections (the most common cause of viral meningitis) occur mostly in summer and fall	Non seasonal pattern	Non seasonal pattern
Clinical features
Fever, headache, stiff neck, photophobia	Common	Common	Common but may be subacute, Cranial nerve palsies etc.
Ill appearance	Uncommon	Common	Common
Petechiae or purpura	Absent	+/-	Mostly not seen
Other manifestations of viral infection (eg, rash, conjunctivitis, pharyngitis)	Common	Not common	Not common
Symptoms after LP	Often, there is improvement	No improvement	No improvement
CSF parameters
WBC count	10 to 500 cells/microL	Typically >1000 cells/microL, lower, in early presentation	Typically 100 to 500 cells/microL. In early course lower cell count but rarely below 10
Differential	Mononuclear predominance	Neutrophil predominance	lymphocytic pleocytosis, Early in the course neutrophilic predominance
Glucose	Normal or slightly reduced Usually ≥40% of serum value	<60% of serum value, <40 mg/dL	<60% of serum value, <40 mg/dL
Protein	Normal to slightly elevated, Usually <150 mg/dL	Typically 100 to 500 mg/dL	Typically 100 to 500 mg/dL,

Table showing features of viral vs bacterial vs tubercular meningitis/

Clues to identify various viral etiologies from CSF examination

Virus	WBC^* (cells/mm³)	RBC	Glucose (mg/dL)	Protein (mg/dL)
Enterovirus	0 to 1000	-	N or Slightly ↓	<160
Parechovirus	N or Slightly ↑	-	N or Slightly ↓	N
Herpes simplex virus	~100	-/+	N or Slightly ↓	100 or More
Epstein-Barr virus	↑	-	N	↑
Cytomegalovirus	↑	-	↓	↑
Lymphocytic choriomeningitis virus	↑	-	N or Slightly ↓	N or Slightly ↑
Influenza	N or Slightly ↑	-	N	N or Slightly ↑
Arboviruses
Eastern equine encephalitis	400 to 4000	-	N	↑
Western equine encephalitis	≤2000	-	N	↑
West Nile virus	<200	-	N	Up to 900

Read CSF • OSCE Station

A. Analysis of cells

The diagnosis is supported by an examination of the CSF, which usually shows a predominant lymphocytosis but can show a neutrophilic predominance in the beginning.
Note that CSF analysis can show borderline changes in the initial hours and this can lead to misdiagnosis, In case of strong clinical suspicion, CSF should be repeated.
In HSE and enterovirus-related encephalitis, 10% can have normal CSF findings in the early course of the disease.

B. Biochemistry

Note that

Normal CSF to plasma glucose level is 0.6.
In case of hemorrhagic lumbar puncture tap, reduce 0.1 mg/dL protein from obtained value for every 1000 red cells/μL present in CSF
Even though CSF might suggest a viral picture, a bacterial infection is likely especially if there is exposure to empirical antibiotics.

1. CSF to plasma glucose

In viral encephalitis, it is mostly normal. however some of the viruses in particular can have low CSF: Plasma glucose (Hypoglycorrhachia) levels such as

Mumps
Varicella-zoster
Herpes simplex infection

2. CSF Proteins

Only a mild elevation of CSF protein that is < 150 mg/dL can be seen in viral encephalitis. As much as 50% cases of Herpes simplex encephalitis (HSE) can have a normal value in early course.

C. Molecular diagnosis

Involves Isolation of the virus from the CSF

Nucleic acid tests such as PCR can help in the detection of viruses with high sensitivity and specificity
This holds true for very small amounts of viral DNA or RNA.
Sometimes in the early course of the disease, PCR can be negative and repeat testing may be needed.
The turnaround time of the test is short and antivirals can be stopped safely in case of negative tests.
PCR is available for HSV-1, HSV-2, VZV, HSV 6 and HSV7, CMV, EB virus, dengue virus, enteroviruses, respiratory viruses, and HIV from CSF samples

D. Cultures

CSF culture is gold standard for bacterial encephalitis, however for viral infection, they are not routinely used since yield is very low.

Neuroimaging in Viral Meningo-encephalitis

In meningoencephalitis, neuroimaging helps in confirming the diagnosis as well as the prognosis.
MRI gives more information than CT, however, in emergency situations, CT can be quite a useful tool.
At times the MRI can help narrow down the responsible virus depending on the area of involvement (Refer to Table 1).

Indications for imaging before performing a lumbar puncture.

Focal neurological signs
Papilledema
Refractory and persistent seizures
Glasgow Coma Score less than 12.

Pediatric CT • OSCE Pediatric MRI • OSCE

Electroencephalography (EEG)

EEG is a nonspecific investigation for meningoencephalitis.
More importantly, It helps in distinguishing focal encephalitis such as temporal discharges in HSV encephalitis from generalized encephalopathy like diffuse bi-hemispheric slowing.
It might typically show generalized slow-wave activity, usually without focal changes. However, in cases such as HSE, SSPE it can help with diagnosis. In HSE EEG might additionally show periodic temporal lobe epileptiform discharges.

Read more about SSPE caused by the measles virus.

Treatment

A. Empirical Therapy

Empirical antibiotics

It is difficult to exclude bacterial meningitis based on clinical feature and the initial blood testing. Even the CSF picture can sometimes overlap between these. Definitive diagnosis needs negative CSF culture or identification of viral DNA/RNA using PCR test.

And, therefore the initial management includes empiric antibiotic therapy along with antivirals in acute viral meningitis/meningoencephalitis.

Bacterial meningitis prediction rules can be used to identify the low vs high risk of bacterial meningitis.

Age group	Causative pathogens	Empirical therapy
Infants and children	S. pneumoniae, N. meningiditis, H. Influenzae, S. agalactiae	Ceftriaxone 50 mg/kg iv, plus Vancomycin 15 mg/kg iv
Adults	S. pneumoniae, N. meningiditis	Ceftriaxone 2 g IV q 12 hrs, plus Vancomycin 15 mg/kg q 12 h
Neonates and elderly	S. pneumoniae, N. meningiditis, L. monocytogenes	Ampicillin 2g iv q 6h, plus Ceftriaxone 2 g IV q 12 hrs, plus Vancomycin 15 mg/kg q 12 h
Immunocompromised	S. pneumoniae, N. meningiditis, H. influenzae, aerobic Gram-negative bacilli	Ampicillin 2g iv q 6h, plus Ceftazidime 2 g iv q8h or Cefipime 2g iv q8h, plus Vancomycin 15 mg/kg q 12h
Nosocomial	S. aureus, S. epidermidis, aerobic Gram-negative Bacilli	Ceftazidime 2 g iv q8h or Cefipime 2g iv q8h or Meropenem 40 mg/kg iv q8h, plus Vancomycin 15 mg/kg q 12h

Table - Empiric antimicrobial therapy in acute meningitis/meningoencephalitis

When to stop antibiotics?

If the cultures are negative after 48 to 72 hours
If viral antigen is identified on viral PCR
When alternate diagnosis is established

Empirical Acyclovir

Empirical acyclovir can be started in the following situations

Immunocompromised patients
Presence of Focal Deficits
Altered mental status
Seizures
Abnormal neuroimaging
Abnormal electroencephalography

B. Specific treatment

Specific antiviral drugs targeted to a suspected or identified virus

Acyclovir for HSV encephalitis, Acyclovir can also be useful in patients with varicella Zoster related CNS infection.
A combination of Ganciclovir with or without Foscarnet is recommended for CMV encephalitis.
Oseltamavir and other newer anti-influenza drugs can be useful in Influenza virus-related meningo-encephalitis.
Antiretrovirals for HIV-associated cases. Other viruses do not have specific treatment and the main stay is supportive care.

What is the Duration of Acyclovir in HSV meningitis?

The usual duration of Acyclovir is 14 to 21 days, in the neonatal age group minimum of 21 days of therapy is advised.

C. Supportive Treatment

With the above exceptions, treatment of viral meningoencephalitis is mostly supportive.
Analgesics and antipyretics for headaches and viral prodrome help. The milder disease may require only symptomatic relief.
IV fluids should take care of reduced oral intake during hospitalization.
More severe diseases may require hospitalization and intensive care.
If cerebral edema or seizures become evident, antiedema measures and antiepileptics will be needed.
Poor GCS might need intubation for airway safety.

D. Use of steroids in viral Meningo-encephalitis

In viral encephalitis, adjuvant steroids can help reduce cerebral edema in the delayed phase (day 4 onward), thereby improving outcomes however In early phases, the use of steroids may increase viral replication and should be avoided.

Prevention

Widespread use of effective viral vaccines for polio, measles, mumps, rubella, and varicella.
The availability of domestic animal vaccine programs against rabies has reduced the frequency of rabies encephalitis.
Control of encephalitis due to arboviruses has been less successful because specific vaccines for arboviral diseases are not available.
Control of insect vectors by suitable spraying methods and eradication of insect breeding sites.
Furthermore, minimizing mosquito bites through the application of DEET-containing insect repellents on exposed skin and wearing long-sleeved shirts, long pants, and socks when outdoors, especially at dawn and dusk, reduces the risk of arboviral infection.

References

Chaudhuri A, Kennedy PGE. Diagnosis and treatment of viral encephalitis. Postgraduate Medical Journal 2002;78:575-583 [ext link/ Good for overview]
Benninger F, Steiner I. CSF in acute and chronic infectious diseases. Handb Clin Neurol. 2017;146:187-206. doi: 10.1016/B978-0-12-804279-3.00012-5. PMID: 29110770; PMCID: PMC7150022. [ext link]
Consensus Guidelines on Evaluation and Management of Suspected Acute Viral Encephalitis in Children in India. Indian Pediatr 2012;49: 897-910 [ext link]
Ghia CJ, Rambhad GS. Meningococcal Disease Burden in India: A Systematic Review and Meta-Analysis. Microbiol Insights. 2021 Nov 29;14:11786361211053344. doi: 10.1177/11786361211053344. PMID: 34866912; PMCID: PMC8637695. [ext link]
Sapra H, Singhal V. Managing Meningoencephalitis in Indian ICU. Indian J Crit Care Med. 2019 Jun;23(Suppl 2):S124-S128. doi: 10.5005/jp-journals-10071-23189. PMID: 31485120; PMCID: PMC6707493. [ext link]

Author

Vasu Burli | DNB (Pediatrics) Fellowship in Pediatric Critical Care

Vasu completed his Pediatrics residency at Kanchi KamaKoti Childs Trust Hospital, Chennai and received further training in Pediatric Intensive care in India and UK