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) Gonoccocal infection

b) Pneumonia

c) Meninogocaemia

d) Meningitis

e) 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

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

CSF abnormalities in Bacterial Meningitis

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 TNF-

alpha 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 (15-30mg/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

involvement of brain parenchyma

Meningoencephalitis

brain parenchyma and meninges

Encephalomyelitis/myeloradicutitis

spinal cord and nerve roots

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, enteroviruses, adenoviruses, Mycoplasma, influenza

VIRAL ENCEPHALITIS

CAUSES

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

CTB- generally not useful

MRI- look for focal frontal lobe or temporal lobe abnormalities

CSF

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

~50% will have no or mild sequelae

~15% will not return to premorbid function

~35% will be severely impaired

HSV PCR on CSF

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

Ubiquitous asymptomatic primary infection in childhood

Reactivates in the immunosuppresed

Biologics play a role in reactivation (natalizumab)

Clinical features

Visual defecits

Cognitive changes- confusion, dementia, behavioural changes

Motor defecits

Imaging

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