CNS infections : recent advances in

diagnosis and management

Nelly Amalia Risan
Dr Hasan Sadikin Hospital, Faculty of medicine
Universitas Padjadjaran

APCP 2018-BALI
 Overview

CNS infection :
∗ Pathogen
∗ Virus
∗ Tuberculousis
∗ Bacteria
∗ Diagnosis
∗ Management
 Introduction

CNS infections are the most challenging

disease to diagnose and treat
• combination of antimicrobial and anti viral is often
used

High mortality and significant sequelae

with negative impact on quality of life
 Introduction

Impose substantial burden on health care, even greater à

include subsequent rehabilitation and social cost.

Rapid and accurate detection of CNS infection is important,

accurate diagnosis provide best therapies for patient and avoiding
unnecessary medication.
 Viral Encephalitis

A syndrome of neurological dysfunction caused by inflammation of

the brain parenchyma.
•Terminology of meningitis and encephalitis sometimes blurred, both can produce
some degree of meningeal and parenchymal inflamation.

The incidence is difficult to establish

•Western countries 10.5-13.8 per 100,000 children.

 Viral Encephalitis

The majority (50-70%) of etiology are unknown

Children with symptoms suggestive of encephalitis

Doctors should be aware!

HSV encephalitis specific treatment is effective if started promptly,

delays in treatment à worse prognosis.
 Viral Encephalitis

The most common etiology :

Herpes simplex (HSV) , Varicella-zoster (VZV), and
Entero-virus.

• Untreated HSV encepalitis, mortality 70%, out of surviving patient have significant
sequelae 97%
• Early diagnosis and acyclovir is a key for reducing mortality and morbidity
 Diagnosing Viral Encephalitis

History of behavioural changes

illness: difficult to arouse
rash (measles, varicella)
a travel history to an endemic area

Clinical No pathognomonic symptom for spesific virus

manifestation
Some virus associated with specific neurologic
presentation, ie HSV affect temporal lobe.
 Diagnostic Features For Specific
Etiologies Of Virus

First clue to differentiate viral or bacterial à CSF

•Cell count (5 – 100 cells/mm3), lymphocyte dominance

•Normal glucose ratio and protein slightly raised

Virus is difficult to culture, PCR is ideally detect DNA / RNA in CSF

in short time confirm specific organism

Real-time PCR assay is a diagnostic method of choice

 Diagnostic Features For Specific
Etiologies Of Virus

∗ RT-PCR test in acute phase HSV:

∗ specificity and sensitivity > 95%
∗ negative in first few days of disease
∗ Ig M anti-HSV antibody is 50% sensitivity by 10 day
à useful for retrospective diagnosis, not for treatment
 Imaging and EEG

∗ CT scan generally done before LP to rule out brain shift or space

occupying lesion
∗ MRI is more sensitive, high signal intensity in affected area
∗ EEG :
- Non specific diffuse high amplitude slow waves
- Periodic lateralized epileptic discharges (PLED) sugestive HSV
 Imaging and EEG

Martins, Palmini, Neuro-Psiquiatr. vol.73 no.12 São Paulo Dec. 2015

 Management

Three elements of treatment

• Consider anti-viral therapy

• Control immediate complications (seizure, cerebral edema, SIADH)
• Prevent late complication, body position, pasive physiotherapy

Acyclovir is highly effective against HSV and some VZV

In developing country cost is an issue
 Management

∗ Acyclovir
∗ 10 mg/kg, 3 x daily, 14-21 days à reduces fatal outcome from 70%
to 20%
∗ If PCR detection negative, other features consistent with HSV,
acyclovir continue to 10 days
∗ LP and PCR should be repeated
 Tuberculous Meningitis (TBM)

∗ Diagnosis of TBM remains difficult, presentation is non-

specific à mimic other CNS infection
∗ Once the classic neurological symptoms present à sign of
advance disease and poor prognosis
∗ Complications : hydrocephalus, infarction, hyponatremia
∗ Rapid recognition of TBM is crucial, as delay in treatment à
worse prognosis.
 Laboratory diagnosis of TBM

Acid-fast smear is a common diagnostic test à low sensitivity.

The Xpert MTB/RIF is a RT – PCR based assay, detect M. Tuberculosa and

Rifampicin resistance

In sputum smear positive, sensitivity 93 – 98 % and specificity 83 – 99 %

Interferon ɣ release assay (IGRA) have limited value in TBM

Vassal et. all, PLoS Med 2011;8:e1001120

 Marais' Case Definition Criteria
Diagnostic score
Clinical Criteria Max score: 6
Symptom duration of more than 5 days 4
Systemic symptoms suggestive of TB (one or more of the
following): weight loss (or poor weight gain in children), night 2
sweats, or persistent cough for more than 2 weeks
History of recent (within past year) close contact with an
individual with pulmonary TB or a positive TST or IGRA (only in 2
children <10 years of age)
Focal neurological deficit (excluding cranial nerve palsies) 1
Cranial nerve palsy 1
Altered consciousness 1
 Marais' Case Definition Criteria
Diagnostic score
CSF criteria Max score: 4
Clear appearance 1
Cells: 10–500 per μl 1
Lymphocytic predominance (>50%) 1
Protein concentration greater than
1
1 g/L
CSF to plasma glucose ratio of less
than 50% or an absolute CSF
1
glucose concentration less than
2·2mmol/L
 Marais' Case Definition Criteria

Diagnostic score
Cerebral imaging criteria Max score: 6
Hydrocephalus 1
Basal meningeal enhancement 2
Tuberculoma 2
Infarct 1
Pre-contrast basal hyperdensity 2
 Marais' Case Definition Criteria
Diagnostic
score
Evidence of TB elsewhere Max score: 4
Chest radiograph suggestive of active TB (signs of TB: 2;
2/4
miliary TB: 4
CT/ MRI/ ultrasound evidence for TB outside the CNS 2
AFB identified or MTB cultured from another source
4
(sputum, lymph node, gastric washing, urine, blood culture)
Positive commercial MTB NAAT from extra-neural specimen 4
 Marais' Case Definition Criteria
Exclusion of alternative diagnoses
An alternative diagnosis must be confirmed microbiologically
serologically, or histopathologically .
The list of alternative diagnoses that should be considered, dependent
upon age, immune status, and geographical region, include: pyogenic
bacterial meningitis, cryptococcal meningitis, syphilitic meningitis, viral
meningo-encephalitis, cerebral malaria, parasitic or eosinophilic
meningitis, cerebral toxoplasmosis and bacterial brain abscess and
malignancy.

The Individual points for each criteria (one, two, or four points) were
determined by consensus and by considering their quantified diagnostic
value as defined in studies.
 Marais' Case Definition Criteria

Probable TBM
When imaging is available, a diagnostic score of 12 or above is
required, and when imaging is not available, a diagnostic score of
10 or above is required.

Possible TBM
When imaging is available, a diagnostic score of 6-11 is required,
and when imaging is not available, a diagnostic score of 6-9 is
required.
 Management of TBM

∗ Anti-tuberculosis drug :
∗ 2 month inisiation phase with 4 drugs (Rifampicin, Isoniazid,
Pirazinamid & Etambutol) followed by 10 month continuation phase of
2 drugs (Rifampicin, Isoniazid)
∗ Adjuntive anti-inflamantory therapies :
∗ Corticosteroid (dexamethasone) reduces CSF protein & IFN ɣ
consentration
 Bacterial Meningitis

∗ High mortality, severe neurologic disfunction

∗ Early diagnosis is important for proper treatment
∗ Introduction of conjugate vaccine in developed
country have reduced the incidence
∗ Incidence : 1,2 million /year world-wide
∗ 3 main pathogen :
- Neisseria meningitidis
- Streptococcus pneumoniae
- Haemophilus influenzae
 Clinical manifestation

∗ Fever 92%
∗ Headache 75% in older child
∗ Neck stiffness 40-60%
∗ Vomiting 55-60%
∗ Altered consciousness 13-36%
∗ Seizure 10-36%
 Diagnosis

∗ Lumbar puncture (LP) should be done if no contra

indicatation
∗ CT scan before LP as indicated, if mass effect
(increased intracranial pressure) present, CT scan
must be done à clinical judgement, empiric antibiotic
with adjunctive therapy (dexamethasone) should be
started promptly
 CSF Abnormalities in Meningitis
Condition Appearance Cells/cu mm Gram Protein Glucose

Normal Clear, 0-5 lymphocytes

colourless

Bacterial Cloudy, turbid 100-2000 Orgs High Low

polymorphs

TB Clear, slightly 10-500 High Low

cloudy lymphocytes
 Laboratory diagnosis
• CSF stain and culture is a gold standard
• CSF culture may take >48 hours for identification, and
positive in 70-85% of patients who have no prior
antibiotic therapy
• PCR is useful for diagnosis bacterial meningitis
FilmArray Meningitis Encephalitis Panel average time from sample
collection to diagnosis is 3 hours, and 1 hour for 14 pathogen which
are the most common bacterial, viral.
 Treatment

The same as encephalitis, except for antibiotic as

indicated
 Take Home Message

∗ CNS infections are the most challenging disease to diagnose and treat
∗ High mortality and significant sequelae with negative impact on quality of
life
∗ Rapid and accurate detection of CNS infection is important, accurate
diagnosis provide best therapies for patient and avoiding unnecessary
medication
∗ Rapid PCR detection may lead to early diagnosis and treatment à shorter
hospital stay and better prognosis