CNS

INFECTIONS
Sam Craven
Lyn Lam

Nick Voon

QUESTION 23
(2013 RECALL PAPER A)

What presentation of invasive Neiserria species

infection has the highest mortality?
a)
b)
c)
d)
e)

Gonoccocal infection
Pneumonia
Meninogocaemia
Meningitis
Disemminated gonococcal infection

QUESTION 40 (2013 RECALL PAPER B)

Mrs Higginbottom is on natalizumab for multiple sclerosis. She

reports feeling a wee bit off, love. She thus has an MRI brain
which looks like this:

What is the best test to diagnose her brain infection?

a. Cryptococcal antigen.
b. Toxoplasma culture
c. John Cunningham virus PCR
d. Herpes simplex 1 virus PCR
e. Mycoplasma culture

QUESTION 7
(2010 RECALL PAPER B)
A man who has recently had surgery for nasal
polyps presents with fevers and signs of
meningism. CSF shows gram positive diplococci.
What is the most appropriate initial antibiotic
therapy?

A. Ceftriaxone + benzylpenicillin
B. Ceftriaxone + vancomycin
C. Benzylpenicillin + gentamicin
D. Vancomycin
E. Benzylpenicillin

QUESTION 53
(2009 RECALL PAPER A)

In the immunocompetent host, what is the most

common cause of recurrent viral meningitis?
a. CMV
b. Mumps
c. HSV 1
d. HSV 2
e. Varicella zoster

QUESTION 41 (2006 PAPER A)

An 18-year-old male develops a rash and becomes critically

ill. The rash is demonstrated above. The most likely finding
on blood cultures would be:

A. gram negative rods.

B. gram positive rods.

C. gram negative diplococci.

D. gram positive diplococci.
E. gram positive cocci.

QUESTION 27
(2006 PAPER B)

A 45-year-old Australian-born woman with rheumatoid

arthritis on long term prednisolone therapy presents with
a third nerve palsy, left sided cerebellar signs and altered
consciousness. She has a fever of 39C and neck stiffness.
Computed tomography (CT) scan of the brain is normal.
Lumbar puncture reveals an opening pressure of 20 cm [<
20 cm], white cell count of 80 x 106/L (80% lymphocytes),
protein 0.6 g/L [< 0.45], glucose 3.5 mmol/L (blood glucose
4.0 mmol/L) and no red cells. Gram stain reveals no
organisms and culture is pending. The most appropriate
initial treatment is:

A. observation, pending culture results.

B. aciclovir and ceftriaxone and benzylpenicillin.
C. ceftriaxone and benzylpenicillin.
D. isoniazid, rifampicin, ethambutol and pyrazinamide.
E. vancomycin and penicillin

QUESTION 45
(2005 PAPER A)

Which of the following is the most important reason

for not recommending gentamicin for the treatment
of coliform central nervous system (CNS) infections?

A. It is not active in an acidic environment.

B. It is not active in a low oxygen tension
environment.
C. It has poor CNS penetration.
D. It may precipitate seizures.
E. Ototoxicity risk is accentuated.

QUESTION 45
(2004 PAPER A)
A 37-year-old man presents to the emergency
department with symptoms of meningitis. Gram
stain of the cerebrospinal fluid reveals the
presence of gram-negative diplococci.
His 12-week pregnant partner should receive
which one of the following as prophylaxis?

A. Ciprofloxacin.
B. Ceftriaxone.
C. Penicillin.
D. Meningococcal vaccine.
E. Erythromycin.

What cell type is preferentially infected by JC

virus in progressive multifocal
leucoencephalopathy?

A. Astrocyte
B. Ependyma
C. Microglia
D. Oligodendrocyte
E. Schwann cell

A 64-year-old woman presents with fever and speech disturbance

over the past week. Her temperature is 37.9 C. The patient is
alert and oriented with respect to time but unable to name objects
properly. Dysarthria and occasional word substitution are noted.
The patient is able to follow simple but not three step commands.
Part of her magnetic resonance imaging of the brain is shown
below. What is the most likely diagnosis?

A. Cerebral toxoplasmosis
B. Herpes simplex encephalitis
C. Meningococcal meningitis
D. Multiple sclerosis
E. Progressive multifocal leucoencephalopathy

MENINGITIS

BEWARE THE FEVER,

HEADACHE AND NUCHAL
RIGIDITY
Nuchal rigidity is the pathognomonic sign of
meningeal irritation, present when neck resists
passive flexion

MAKING THE DIAGNOSIS

FBE
-usually unrevealing, WCC may be raised
Coags
- may be in DIC
UEC
- hyponatraemia
Blood cultures
- 50-90% have positive blood cultures,
Obtain prior to a/b
CSF - EVERY PATIENT SHOULD HAVE LP
UNLESS CONTRAINDICATED

WHO TO CT PRIOR TO LP
History of CNS disease
- mass lesion, stroke, focal infection
New onset seizure
Papilledema
Abnormal level of consciousness
Focal neurological deficits
Immunocompromised state

ACUTE BACTERIAL
MENINGITIS

Most common bacterial pathogens - N. meningitidis,

Streptococcus pneumoniae and Haemophilus
influenzae type b (80% of cases)

Infants < 1 month, adults > 60 years, alcoholics, cancer,

immunosuppressed - Listeria monocytogenes
Head trauma, neurosurgery - Staphylococcus aureus
and coagulase negative staphylococci
In neonates - group B streptococci (Streptococcus
agalactiae) are the most important pathogen, but
gram-negative rods such as Escherichia coli may also
be responsible. Dramatic decrease in bacterial
meningitis caused by H. influenzae type b as a result
of Hib conjugate vaccine

PATHOPHYSIOLOGY
S. pneumoniae and N. meningitidis colonize the
nasopharynx

Transported across epithelial cells in membrane bound

vacuoles into intravascular space
In blood stream, they avoid phagocytosis by neutrophils and
complement mediated bactericidal activity with
polysaccharide capsule
Reaches the intraventricular choroid plexus, infects the
choroid plexus epithelial cells and gains access to CSF
Because CSF has few WBC and small amounts of
complement and immunoglobulins, this prevents effective
opsonisation and bacterial phagocytosis and so bacteria
are able to multiply rapidly

CLINICAL PRESENTATION

Classic triad - fever, nuchal rigidity, change of mental

state

Headache - severe & generalized

Nausea, vomiting, photophobia

N. meningitidis - petechiae and palpable purpura

Listeria meningitis - higher tendency for seizures and
focal neurological deficits (ataxia, cranial nerve palsy,
nystagmus)
Complication - raised ICP (reduced level of
consciousness, papilledema, sixth nerve palsy, poorly
reactive pupils)
Disastrous complication - cerebral herniation

CSF abnormalities in Bacterial Meningitis

Opening pressure

> 30cmH20

WCC

raised; neutrophils predominate

RBC

Absent in non traumatic tap

Glucose

< 2.2mmol/L

CSF/ Serum glucose

< 0.4

Protein

> 0.45g/L

Gram stain

Positive in > 60%

Culture

Positive in > 80%

Latex agglutination

S. pneumoniae, N. meningitides, H.
influenzae type B, group B streptococci

Limulus

Gram negative meningitis

PCR

Detects Bacterial DNA

BACTERIAL PCR
If CSF culture and gram stain negative - 16S rRNA can detect
small numbers of viable and non viable organisms in CSF

Latex agglutination test

- being replaced by CSF bacterial PCR assay
- Specificity of 90% for S. pneumonia and N. meningitidis,
sensitivity of 70-100% for S.Pneumoniae and 33-70% for N.
meningitides
Limulus amebocyte lysate assay - rapid diagnostic test for
detection of gram negative endotoxin in CSF
- Specificity of 85-100% and sensitivity of 100%

TREATMENT
Bacterial meningitis is a medical emergency - begin a/b within
60minutes of arrival
If the organism or susceptibility is unknown, use dexamethasone
10mg IV starting before or with the first dose of antibiotic then 6
hourly for 4 days + ceftriaxone 4g IV daily or 2g BD
If suspecting Listeria - add Benzylpenicilin 2.4g IV 4 hourly
If Gram positive cocci seen on Gram stain, consider vancomycin
If meningococci suspected, then use:
Benzylpenicillin 2.4g IV or IM

If penicillin allergy - use Ceftriaxone 2g IV or IM

IF ORGANISM KNOWN
1. Pneumococcal meningitis

- Benzylpenicillin 2.4g IV 4 hourly for 10-14 days

-Ceftriaxone 4g IV daily for 10-14 days or cefotaxime 2g IV 6 hourly for 10-14 days
- Should have repeat LP at 24-36 hours after a/b to document sterilization of CSF

2. Neisseria Meningitidis
- Benzylpenicillin 1.8g IV 4 hourly for 5 days
- Hypersensitive to penicillins - ceftriaxone 4g IV Daily for 5 days or cefotaxime 2g IV
6 hourly for 5 days
- Immediate hypersensitivity - ciprofloxacin 400mg IV 8 hourly for 5 days
3. Haemophilus Influenzae type B
- ceftriaxone 4g IV daily for 7 days or cefotaxime 2.4g for 7 days

4. Listeria monocytogenes
- benzylpenicillin 2.4g IV 4 hourly for at least 3 weeks
- if hypersensitive - trimethoprim+ sulfamethoxazole 160/800mg IV 6 hourly

5. Group B streptococcus
- benzylpenicillin 2.4g IV 4 hourly for 14-21 days
6. Streptococcus suis
- cause of acute bacterial meningitis in Southeast asia
- associated with hearing loss
- treat 10-14 days as per pneumococcal meningitis
7. Gram negative bacilli
- mostly E.coli and Klebsiella
- neonates and children < 2 months and health care associated or shunt
related meningitis
- third generation cephalosporins - ceftriaxone, ceftazidime or cefotaxime for
3 weeks
- if pseudomonas - ceftazidime or cefepime or meropenem

ROLE OF DEXAMETHASONE
Bacteriacidal antibiotics releases bacterial cell wall
components leading production of inflammatory
cytokines IL-1beta and TNF-alpha in the subarachnoid
space
Dexamethasone - inhibits synthesis of IL-1beta and TNFalpha at the level of mRNA, decreases CSF outflow
resistance and stabilises blood brain barrier
Only works if administered before the macrophages and
microglia are activated by endotoxin (ie prior to
antibiotics being given)
Give dexamethasone 15-20 minutes or at time of a/b
administration - 0.15mg/kg every 6 hours for four days
(particularly if pneumococcal meningitis)

Prognosis - mortality rate

- H. influenza, N meningitidis or group B streptococci - 3 to 7%
- L. Monocytogenes - 15%
- S.pneumoniae - 20%

Increased risk of death:

1. decreased level of consciousness on admission

2. onset of seizures within 24 hours of admission

3. Signs of raised ICP
4. Young age (infants) and > 50
5. Other co-morbidities - shock or need for ventilation

6. any delay in treatment

7. CSF glucose < 2.2mmol/L and CSF protein > 3g/L

Common sequelae
- decreased intellectual function, memory impairment, seizures, hearing loss,
dizziness,
gait disturbance

ACUTE VIRAL
MENINGITIS

Common >85% enteroviruses

- coxsackieviruses, echoviruses, human enterovirus 68-71
Less Common
- HSV, VZV, Cytomegalovirus, EBV, Herpes virus 6,7,8
CSF cultures are positive in 30-70%
2/3 of culture negative cases have viral aetiology
identified by CSF PCR
Most common non bacterial, non viral cause of
meningitis is Cryptococcus neoformans

Symptoms - headache, fever, signs of meningeal irritation

Constitutional signs - malaise, myalgia, anorexia,
Nausea/vomiting, abdominal pain, diarrhoea
If summer/autumn/ local epidemic - think enterovirus
HSV-2 meningitis is nearly always associated with acute
primary genital herpes

VZV - Suspect with concurrent chickenpox/shingles

HIV - Suspect in any patient with known/ suspected risk factors
Mild lethargy or drowsiness is common BUT NOT profound
alterations in consciousness - THINK OF ENCEPHALITIS
Seizures and focal neurological signs are not typical of viral
meningitis

TREATMENT
Largely symptomatic and use of analgesics,
antipyretics, antiemetics
If immunocompetent, can have monitoring at home
with medical follow up
If severe HSV, EBV or VZV, consider IV acyclovir (1530mg/kg per day) followed by oral acyclovir,
famciclovir or valacyclovir for total of 7-14 days
If deficient in humoral immunity, consider IVIG

Pleoconaril- investigational drug for enteroviral

infections

ASEPTIC MENINGITIS
Clinical and laboratory evidence of meningeal inflammation with negative routine
cultures

most common cause - enterovirus

ENCEPHALITIS

DEFINITIONS

Encephalitis

Meningoencephalitis

involvement of brain parenchyma

brain parenchyma and meninges

Encephalomyelitis/myeloradicutitis

spinal cord and nerve roots

VIRAL ENCEPHALITIS
CAUSES
HSV 1 (HSV 2 in neonates)
Arboviruses:
-Murray Valley encephalitis and Kunjin virus in
Aus
-Japanese B encephalitis in SE Asia, PNG, far
NQ
-West Nile encephalitis in Africa, West Asia,
Middle
East and North
America
VZV
EBV
CMV
HIV
Others:
Lyssavirus, Hendra virus, Nipah virus,

CLINICAL PRESENTATION
Altered Mental State
Seizures
Focal neurological defecits

Hemiparesis
Cranial nerve palsies
Abnormal reflexes
Ataxia

Confusion
Behavioural Changes
If meningoencephaitis- nuchal rigidity

DIAGNOSIS

Imaging

CSF

CTB- generally not useful

MRI- look for focal frontal lobe or temporal lobe
abnormalities
Essential unless increased ICP
CSF similar to viral meningitis
PCR for HSV, VZV, EBV, CMV, Enterovirus
If low glucose think bacterial

General Management

Supportive- monitor ICP, watch fluids, suppress fever,

seizure prophylaxis

HSV ENCEPHALITIS
10-20% of all viral encephalitis
HSV1 in adults, HSV2 in neonates
Commonly affects unilateral temporal lobe
Treated has a 70-80% survival

HSV PCR on CSF

~50% will have no or mild sequelae

~15% will not return to premorbid function
~35% will be severely impaired
94-100% specific, 98% sensitive
Positive within 24hrs of symptom onset

Treatment

Aciclovir at high dose for 14-21 days

Better outcomes if treated early

ACUTE DISSEMINATED
ENCEPHALOMYELITIS (ADEM)
Autoimmune demyelinating disease of CNS
No active infection, caused by an inflammatory
response to previous infection

Exact pathology is not understood

Uncommon condition
Characterised by multifocal neurological defecits
with rapid progression
Precipitants

Measles, Rubella, Varicella, Influenza, Vaccinations

Treatment is with immunosuppression

Most will recover with few sequelae (5-10%
Mortality)

PROGRESSIVE MULTIFOCAL
LEUKOENCEPHALOPATHY
Rare disease which is usually fatal
Caused by reactivation of the JC virus

Clinical features

Visual defecits
Cognitive changes- confusion, dementia, behavioural
changes
Motor defecits

Imaging

Ubiquitous asymptomatic primary infection in childhood

Reactivates in the immunosuppresed
Biologics play a role in reactivation (natalizumab)

MRI shows multifocal asymmetric white matter lesions

No Effective therapy

PRIONS
Proteinaceous infectious particles
Disorder of protein conformation

PrPC normal cellular isoform, rich in -helix and

little structure
PrPSC disease causing isoform, less helix, high
amount of structure
The abnormal PrPSC binds to the normal PrPC
inducing conformational change and accumulation
Leads to neuronal loss and proliferation of glial cells.
Appearance of vacuoles- spongiform appearance

PRIONS

Two infectious prion diseases in humans

Variant CJD
Infection from consuming beef products from cows infected
with bovine spongiform encephalopathy (Mad Cow)
Iatrogenic infections (human derived growth hormone and
dura mater grafts most common)

Kuru
Infection among the Fore people of PNG as a result from
ritualistic canabalism
Practice ceased in 1950s
Long incubation period
11 cases reported between 1996 to 2004

REFERENCES
Med J Aust 2002; 176 (8): 389-396. Acute community acquired meningitis and
encephalitis
Karen L Roos, Kenneth L Tyler, 2015, Meningitis, Encephalitis, Brain Abscess and
Empyema. Harrisons Principals of Internal Medicine, 19th edition.
Therapeutic guidelines
Uptodate