cns infections
DESCRIPTION
caseTRANSCRIPT
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CNS
INFECTIONS Sam Craven
Lyn Lam
Nick Voon
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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
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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
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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
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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
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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.
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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
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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.
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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.
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What cell type is preferentially infected by JC
virus in progressive multifocal
leucoencephalopathy?
A. Astrocyte
B. Ependyma
C. Microglia
D. Oligodendrocyte
E. Schwann cell
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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
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MENINGITIS
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BEWARE THE FEVER,
HEADACHE AND NUCHAL
RIGIDITY
Nuchal rigidity is the pathognomonic sign of
meningeal irritation, present when neck resists
passive flexion
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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
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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
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ACUTE BACTERIAL
MENINGITIS
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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
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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
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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
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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
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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%
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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
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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
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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
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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)
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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
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ACUTE VIRAL
MENINGITIS
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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
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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
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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
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ASEPTIC MENINGITIS Clinical and laboratory evidence of meningeal inflammation with negative routine
cultures
most common cause - enterovirus
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ENCEPHALITIS
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DEFINITIONS
Encephalitis
involvement of brain parenchyma
Meningoencephalitis
brain parenchyma and meninges
Encephalomyelitis/myeloradicutitis
spinal cord and nerve roots
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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
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CLINICAL PRESENTATION
Altered Mental State
Seizures
Focal neurological defecits
Hemiparesis
Cranial nerve palsies
Abnormal reflexes
Ataxia
Confusion
Behavioural Changes
If meningoencephaitis- nuchal rigidity
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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
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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
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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)
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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
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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
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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
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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