Cns Infections

Front 1

Routes of infection

Back 1

–Blood spread - arteries or veins
–Direct spread, e.g. surgery, trauma, cribriform plate
–Extension of a local infection (sinuses, mastoids)
–Retrograde axonal transport

Front 2

Streptococcus pneumoniae

Back 2

–Neutralises secretory IgA
–Capsule resists binding of factors that activate complement
–Binds to receptors on endothelial cells, internalised to CSF

Front 3

Neurological infections in immunosuppressed

Back 3

•Immunosuppresion
–HIV
–Immunosuppresive treatment
–Monoclonal antibody therapy (e.g. natalizumab for MS)

•Common organisms
–Cytomegalovirus
–Toxoplasmosis
–Cryptococcus
–Viruses: progressive multifocal leukoencephalopathy (JC virus), herpes simplex and zoster

Front 4

Patterns of Neurological Infections

Back 4

•Meningitis
–Infection in the subarachnoid space
–Acute or subacute
•Encephalitis/myelitis
–Widespread infection within the brain and/or spinal cord, usually due to a virus
•Abscess
–Localised collection of pus
–Non-localised collection of pus: empyema
•Prion diseases
–Spongy change in brain

Front 5

Acute meningitis

Back 5

•Organisms via blood or nearby infection (e.g. sinuses, nasal colonisation with meningococcus)
•Fever, headache, photophobia, NECK STIFFNESS
•Diagnosis via CSF examination or blood culture
•Bacterial (pyogenic) or viral (aseptic)

Front 6

Acute bacterial meningitis
- complications

Back 6

•CSF shows numerous neutrophils, low glucose, high protein
•Acute inflammatory exudate in subarachnoid space
– Complications: block of CSF outlets with hydrocephalus, cranial nerve damage (especially 6 and 8), occlusion of blood vessels with infarction

Front 7

Acute bacterial meningitis common organisms

Back 7

–
Meningococcus (nasal), pneumococcus (blood), Hemophilus influenzae B (especially infants, vaccination has reduced incidence)
–
Encapsulation helps bacteria infect CNS

Front 8

Acute viral meningitis
- common organisms
- CSF

Back 8

•Common organisms
–Echo, coxsackie, mumps, measles
•CSF shows lymphocytes, normal glucose, protein ± raised
•Good prognosis

Front 9

Chronic meningitis

Back 9

•Gradual onset of non-specific symptoms (lethargy, headaches, confusion)
•Common organisms
–Tuberculosis
–Cryptococcus
-Syphilis
•CSF organisms may be found (may need PCR, or India ink and antigen detection for Cryptococcus)
•Complications common

Front 10

Encephalitis Definition

Back 10

Encephalitis (from Ancient Greek ἐνκέφαλος enképhalos “brain”,[1] composed of ἐν “in” and κέφαλος “head”, and the medical suffix -itis “inflammation”) is an acute inflammation of the brain.

Front 11

Encephalitis Aetiology

Back 11

•Commonly due to viruses, but the cause of most cases of encephalitis remains unknown (some due not to viruses, but to antibodies against CNS proteins)
•Different viruses have predilections for different parts of the CNS
•Clinically: headaches, fever, focal neurological signs
•Microscopic: perivascular lymphocytes, neuronophagia, glial nodules, viral inclusion bodies

Front 12

Herpes encephalitis

Back 12

Herpes simplex virus type 1
•Alterations in mood, memory, behaviour
•Focal necrosis in temporal lobes, headache, confusion
•Treated with acyclovir
•Previous herpes in only 10% (not sexually transmitted)
•Different presentation in immunosuppressed

Commonest cause of severe sporadic encephalitis
1. Primary HSV infection, especially in the newborn,
often associated with generalised infection
- mainly due to HSV-2
2. Reactivation of HSV, with spread from dorsal root
ganglia to the brain (older children, adults)
- mainly due to HSV-1

Pathogenesis of HSE: acute necrotising encephalitis - disease is due to destruction of infected neurons as a result of virus-induced cytopathology (±immunopathology)
Untreated case fatality rate of HSE is ~70% (~30% with acyclovir therapy)
- high proportion of survivors have permanent neurological sequelae
- infants may require long-term suppressive therapy

Front 13

HIV encephalitis

Back 13

HIV
–Direct invasion of virus (microglia), dementia, multinuclear giant cells
–Opportunistic infections, primary cerebral lymphoma

Front 14

OTHER Encephalitis types

Back 14

•Arbovirus (insect-borne)
–Australian (Murray Valley) encephalitis, West Nile virus, Ross river fever (mostly arthritis/rash/fatigue)
•Fruit-bat borne
–Hendra virus (from fruit-bats to horses, then from horses to humans)
•Subacute sclerosing panencephalitis (SSPE)
–Measles virus, children, lasts for months until death, inclusions
•Progressive multifocal leukoencephalopathy (PML)
–Mainly in patients with deceased immunity. White matter lesions, JC virus, inclusions
–Release of latently infected immune cells
•Rabies
–Retrograde axonal spread
–Negri body
–Similar to lyssa virus

Front 15

Negri Body

Back 15

Negri bodies are eosinophilic, sharply outlined, pathognomonic inclusion bodies (2–10 µm in diameter) found in the cytoplasm of certain nerve cells containing the virus of rabies, especially in Ammon's horn of the hippocampus.

Front 16

Murray Valley Encephalitis

Back 16

•Mostly in south-eastern Australia
•Most infections are subclinical (up to 1/3 of population may be sero-positive)
•Wide disease spectrum (mild to death)
•Mosquito vector spreads virus from water birds to humans
•Epidemics every 5-10 years, depending on rainfall (sentinel chicken flocks)

Front 17

West Nile encephalitis

Back 17

•Bird-mosquito cycle of virus, with humans incidentally infected
•Took only 4 years to spread from the east to the west coast of the USA, with 2 million infections and 10,000 cases of encephalitis/meningitis
•Good example of human activity facilitating the emergence and spread of novel pathogens

Front 18

Lyssavirus

Back 18

•In 1996, a fruit bat in northern NSW was found to have an encephalitis due to Lyssavirus, which is closely related to rabies
•At the same time, an animal carer in Queensland developed a rabies-like illness and died after being scratched by a fruit bat; she was found to have Lyssavirus infection
•An 8 year old Queensland boy died of Lyssavirus infection in 2013 (third case in Australia)
•Fruit bats should not be approached or handled unnecessarily

Front 19

Encephalomyelitis

Back 19

•Brain and spinal cord involved
•
Poliomyelitis
–Poliovirus enters motor neurons selectively
–Receptors on motor neurons
•
Varicella-zoster
–Virus resides in the (sensory) posterior root ganglion after chicken-pox, when activated causes “shingles”
–Can also affect blood vessels (vasculopathy)
–Early treatment with acyclovir to prevent neuralgia

Front 20

Parasites

Back 20

•
Protozoa
–Toxoplasma: immunosuppressed, cats
–Amoeba: free-living, e.g. from water entering nose
–Malaria: falciparum form (sequestration of parasitised RBCs can be seen on fundoscopy)
•
Worms
–Dog tapeworm (Echinococcus: hydatid disease); sheep
–Pig tapeworm (Taenia: cysticercosis)
–Rat lungworm (Angiostongylus cantonensis: molluscs)

Front 21

Abscess: from blood septic emboli

Back 21

•Bacterial endocarditis
•Chronic intrathoracic infections (bronchiectasis, lung abscess, empyema)
•Other (paradoxical with congenital heart disease, immunodeficiency, ?dental extractions)
•10% unknown cause

Front 22

Abscess: from local spread

Back 22

•
Pericranial infections
–Sinusitis
–Otitis
–Mastoiditis
–Face/teeth
•
Chronic suppurative otitis media/mastoiditis
–Adhesion between temporal bone and temporal lobe or cerebellum
–Septic thrombophlebitis of draining veins → abscess

Front 23

Brain Abscess

Back 23

•Headaches, fever, focal neurological signs
•Focal inflammation followed by necrosis and formation of pus, then fibrous capsule formation
•Organisms from blood, nearby infections, or direct injury
•Abscess can spread (daughter abscesses)
•Four layers microscopically (pus, macrophages, granulation tissue, astrocytes)
•Often mixed organisms, anaerobes
•Can be intracerebral, subdural or extradural (rare)

Front 24

Subdural abscess or empyema

Back 24

•Usually an empyema, not an abscess
•Mostly young people
•Most often caused by spread from the paranasal sinuses or middle ear (esp. via thromobophlebitis)
•MRI better than CT for diagnosis
•Rapidly fatal without prompt diagnosis and treatment

Front 25

Recent advances in neurological infections

Back 25

•In young people with suspected encephalitis, antibodies to NMDA receptor are more common than any single viral cause
•Herpes simplex virus encephalitis in immunocompromised people can present atypically, and PCR of the CSF is needed
•Detection of parasite histidine-rich protein might be a useful marker for cerebral malaria
•A new vaccine for meningococcus serogroup B will soon be available
•Some bacteria attack from outside the CNS using toxins, e.g. E. coli

Front 26

Bacterial Meningitis in the 80s

Back 26

25 yr old data (HiB used to be the worst cause), vaccination for HiB in the 90s and so you don’t see it anymore

Front 27

Contiguous Focus Meningitis

Back 27

In majority of cases of meningitis
Colonisation of the nasopharynx by potential pathogens is followed by mucosal invasion
May follow direct extension of bacteria across a skull fracture in the area of the cribriform plate
Streptococcus pneumoniae
Neisseria meningitidis
Staphylococci – more likely post trauma
Gram negatives – rarer eg. post neurosurgery

Front 28

Circulation Spread (Meningitis)

Back 28

Meningitis may follow bacteremia
pneumonia (S.pneumoniae), meningococcaemia
endocarditis (S.aureus), urinary tract infection
Other predisposing conditions include asplenia, complement deficiency, HIV infection
Haemophilus influenzae
Streptococcus pneumoniae
Neisseria meningitidis
Listeria monocytogenes

Front 29

Drugs Relief conundrum

Back 29

Once u treat the patient the inflammation goes down and the BBB closes and thus no more drug entry to brain (conundrum)

Front 30

Antimicrobials crossing the BBB

Back 30

Enter the CSF by:
diffusion through endothelial cells
diffusion between tight junctions of endothelial cells
active transport through choroid villi


Leave the CSF by:
bulk transport through arachnoid villi
active transport across endothelial cells

Front 31

Factors affecting CSF Antibiotic concentration

Back 31

Molecular characteristics, viz:
Drug’s lipid solubility
Drug’s size and configuration
Degree of meningeal inflammation
(may reach therapeutic levels only when the meninges are inflamed)
Free plasma concentration, as determined by:
Plasma protein binding
Mode and dose of drug administration
Presence of an active transport system
Therapeutic ratio

Front 32

B-lactams and BBB

Back 32

β-lactams (eg penicillin) penetrate CSF poorly when BBB normal.
In meningeal inflammation, increased permeability occurs, a result of separation of intercellular light junctions (or increased numbers of pinocytotic vesicles in endothelial cells).
Entry decreases as inflammation subsides

Front 33

CSF drug levels

Back 33

Front 34

Bactericidal activity in purulent CSF

Back 34

pH of CSF decreased by lactate accumulation
inhibits bactericidal activity (aminoglycosides).
 CSF protein reduces efficacy of highly protein bound drugs - free drug needed for effect.
Drugs may be removed by active transport system in choroid plexus (penicillins, cephalosporins), or may be converted to inactive metabolites.
Other drugs influence activity in CSF. Antagonism when bactericidal and static agents co-administered (e.g., chloramphenicol + penicillin).
Synergy.

Front 35

Antibiotic Combination (synergy)

Back 35

Front 36

Achieving Therapeutic CSF levels

Back 36

HIGH IV DOSES:
Beta-lactams
Penicillins
3rd generation Cephalosporins (eg. cefotaxime, ceftriaxone, ceftazidime)
Carbapenems
Vancomycin
Therapeutic CSF levels NOT achievable
Aminoglycosides (eg.gentamicin)
1st / 2nd generation cephalosporins (eg.cephazolin) (acetylation during entry into CSF, loses activity)

Front 37

Therapeutic CSF levels reliably achievable by standard doses and routes

Back 37

Chloramphenicol
Trimethoprim-sulphomethoxazole
Quinolones (ciprofloxacin, moxifloxacin)
Metronidazole
Linezolid______________________________________________________
Anti-TB drugs (isoniazid, rifampicin…)
Antifungals: (fluconazole, voriconazole). Not echinocandins
Antiretrovirals (zidovudine…)

Front 38

Required MIC in CSF

Back 38

5-10x MIC in CSF
and for >40% of the dosing interval

Front 39

Antibiotic concentration in blood and CSF over time. The area under the curve represents cephalosporin penetration into the CSF

Back 39

Front 40

The right compartment and a drug can or cant be affective

Back 40

thus when recieving the suceptibility reading on blood tests first think is the required MIC going to be achieved in the target area?

Front 41

Penicillin in pneumonia vs meningitis

Back 41

Front 42

S.pneumoniae Tx

Back 42

Penicillin iv or amoxycillin antibiotics of choice in respiratory infection
Cefotaxime / ceftriaxone recommended in meningitis due to better CSF penetration, lower MICs
For empiric therapy, when MICs not yet available often vancomycin added
Rare strains with cefotaxime MICs > 4 mg/L
Penicillins do not eliminate carriage of PRSP and may select for such strains
Answers may lie in better vaccines

Front 43

Bacterial Meningitis Acute MX

Back 43

Suspected bacterial meningitis is a medical emergency
Untreated, the mortality is ~100 percent,
Even with optimal therapy, high failure rate
Empiric treatment should begin when diagnosis is suspected (thats why there is ceftrioxone in the doctors bag)
Use bactericidal agent(s) that achieve significant CSF levels
Immediate diagnostic steps to establish the cause (CSF examination)

Front 44

Use bactericidal Agents

Back 44

Use bactericidal agent(s) that achieve significant CSF levels
Bacteriostatic drugs, such as clindamycin and tetracycline, are inadequate
Chloramphenicol is a bacteriostatic drug for most enteric Gram negative rods; however, it is usually bactericidal for H.influenzae, N.meningitidis, and S.pneumoniae

Front 45

Antibiotics in treatment of meningitis

Back 45

Prompt Rx is associated with lower mortality and morbidity.
If bacterial meningitis suspected, 1 dose of iv / im penicillin, should be given before transfer to hospital as meningococcal septicaemia may be rapidly fatal.
Ceftriaxone an alternative in patients hypersensitive to penicillin or where further treatment may be delayed.

Front 46

Empiricial Therapy

Back 46

Covers the 3 major pathogens.
Intravenous. 7 – 10 days (unless meningococcus)
3rd generation cephalosporins
ceftriaxone/(cefotaxime) + penicillin/(ampicillin).
increasingly, vancomycin if ? pen-R pneumo
penicillin not required 3 months - 15 years.(ie. Listeria rare unless neonate, immune suppressed, pregnancy, alcoholism, >60yo)
Penicillin or cephalosporin ceased once organism identified and susceptibility available.

Front 47

Corticosteroids

Back 47

Antibiotic therapy results in cell lysis
Bacterial components cause inflammation. Peptidoglycan fragments are immunostimulatory.
PMNs can be toxic to host tissues – release protease, elastases, O2 radicals– result in cytokine release - TNF, IL1– disruption of blood brain barrier
Early in a/b therapy TNF levels rise
Ability to downregulate host response reduces inflammatory damage if given prior to or simulatneously to antibiotics

HELPS with the morbidity of meningitis

Early dexamethasone in paediatric meningitis - reduced neurologic complications + deafness esp. in developed countries
4 x risk of deafness and late neurological sequelae in controls c/w steroid Rx
2 days as effective, less toxic than longer Rx
Role in adult meningitis variable but overall supports role of early steroids
 before or with 1st dose then q6 for 4 days

Front 48

Brain abscess or empyema aeriology

Back 48

Most polymicrobial with oral flora (Strep milleri, and anaerobic bacteria) predominating.
If otic origin, Gram-negative bacilli common
After trauma / surgery consider Staph aureus
Aspiration or biopsy essential to guide therapy.
3’GC + metronidazole. Duration of treatment depends on clinical and radiological response - ~ 4-6 weeks usually.
If brain abscess post neuroSx, usual to add vancomycin & use broad-spectrum Gram- β-lactam
Consider other aetiology in immune compromised (eg. nocardia, toxoplasma)

Front 49

Epidural Abscess

Back 49

Frequently associated with adjacent osteomyelitis or disc infection.
Likely to be caused by a single organism, usually Staph aureus.
Urgent surgery is essential.
Treatment should be based on the Gram stain and culture results of operative material.

Front 50

TB meningitis

Back 50

In childhood an early post-primary event, coincident with miliary spread. High mortality.In adults often results from a breakdown of an old meningeal focus. - ie. may present as an isolated event. 75% have extra-meningeal TBIncreasing association with HIV / AIDSMulti-drug, and XDR TB a threat to TB control

Kids wont wall it off life In adults that wall it off and then 50-60yrs late may present as an isolated event (have to look for signs of TB elsewhere)

Front 51

Abcesses after Tx

Back 51

expand parodoxically thus use CS

Front 52

Cryptococcal meningitis

Back 52

Australian disease (in euclypus)
Yeast with big capsule

Cryptococcal antigen test from the blood without CSF testing

Front 53

Cryptococcus neoformans

Back 53

C.neformans (C.grubbii), widespread - urban AustraliaC.gattii, association with eucalyptsC.gattii, - more severe disease eg. hydrocephalus, host usually immuno-competentpulmonary source evident in ~25%C.neformans (C.grubbii), immuno-compromised - eg. AIDS, lymphoma, TxAIDS presentation often more indolentAssociated with dissemination - skin, prostate.

Front 54

Invasive Aspergillosis

Back 54

risky in T cell deficent patients (HIV)
- lots of oedema around it

Aspergious is a mould thus they grow across tissue planes and they cause infartion as the move along causing death as it moves along, thus early Dx is required

Front 55

Fungal meningitis
Tx

Back 55

Cryptococcal meningitis
Amphotericin B +/- flucytosine
Fluconazole
HIV/AIDS maintenance Rx to prevent relapse

Invasive Aspergillosis
Liposomal amphotericin B
Voriconazole, posaconazole

Front 56

Antibiotics for meningitis OVERVIEW

Back 56

Front 57

Optic Nerve: Papilloedema

Back 57

Papilloedema usually indicates raised intracranial pressure (ICP)

Front 58

Triad of raised ICP

Back 58

headache
vomiting
papilloedema

Front 59

Contraindication to lumbar puncture?

Back 59

•
Papilloedema is a contra-indication to a lumbar puncture unless a mass lesion, such as a tumour or abscess, has been excluded
•
A lumbar puncture in the presence of papilloedema due to a cerebral abscess carries a mortality rate of approximately 25%!!

however no papilloedema doesnt mean no pressure thus need to scan first

Front 60

Extraddural inflammatory process between temporal bone and brainstem affects

Back 60

CN V, VI, VII, VIII

Front 61

VII

Back 61

•
Generally, if patients have ataxia due to vestibular irritation, they will have vertigo and nystagmus.
•
It is much more likely that James’ ataxia was directly due to the cerebellar abscess

Front 62

neurological sequels of chronic ear disease

Back 62

Repeated or inadequately healed acute otitis media led to chronic mastoiditis, then bone breakdown with a posterior fossa extradural abscess, causing the V, VI and VII palsies. Initially, the extradural pus was walled off but tracked into the cerebellum. This caused hydrocephalus and papilloedema. Finally, the organisms broke through into the subarachnoid space to cause frank meningitis.

Front 63

arcuate fasciculus

Back 63

a

Front 64

What area of the brain determines level of alertness?

Back 64

RAS

Front 65

Empirical treatment Meningitis

Back 65

A/B: cefotaximne (3rd gen cephalsporin)
IV acyclivor

Front 66

CNS viral diseases

Back 66

1. Viral (aseptic) meningitis
2. Viral encephalitis – disease of the CNS parenchyma
- disease manifestations depend on the region affected
3. Post-infectious encephalomyelitis – disease of the brain and/or spinal cord mediated by immunopathological mechanisms in response to viral infection

Many viral infections of the CNS are opportunistic – they only manifest in hosts with an immunosuppressive disorder/treatment that increases their susceptibility to infection

Front 67

Aseptic meningitis

Back 67

Aseptic meningitis is a clinical syndrome of meningeal inflammation in which common bacterial pathogens cannot be identified in the cerebrospinal fluid (CSF)

mostly caused by enteroviruses
- certain bacteria, mycoplasmas and fungi and autoimmune disorders can also cause aseptic meningitis

Front 68

Aseptic meningitis
viral causes

Back 68

• Common
Enteroviruses*
Herpes simplex type 2 (HHV2)
Arboviruses (flaviviruses, alphaviruses)
• Uncommon
Mumps virus (commonest cause before vaccine)
Human herpes virus type 6 (HHV6)
Human immunodeficiency virus (HIV)
• Rare
Herpes simplex type 1 (HHV1)
Varicella-zoster virus (HHV3)
Cytomegalovirus (HHV4)
Epstein-Barr virus (HHV5)
Measles virus
*80% of aseptic meningitis is caused by enterovirus infection

Front 69

Seasonal Enterovirus

Back 69

late summer to early autumn

Front 70

Enteroviruses

Back 70

• Enteroviruses form a genus within the family Picornaviridae
>100 strains belonging to four species (A-D)
- replicate in the intestinal tract
• Enteroviruses occasionally spread to other tissues:
– central nervous system (meningitis, poliomyelitis, encephalitis)
– childhood rash illnesses (hand, foot and mouth disease)
• Enteroviruses are found in all human populations
Most infections occur in children under five years old
Virus activity peaks in late summer and autumn (temperate
regions)
• Transmission
Faecal-oral transmission person-to-person
• Most enterovirus strains have been associated with aseptic
meningitis
– 2-3 strains tend to dominate for a period (1-5 years) and are gradually
replaced by new strains
– 15 strains account for >80% of CNS disease (US data)

Front 71

Stages of enterovirus Infection

Back 71

Front 72

Clinical presentation of enterovirus meningitis

Back 72

Enterovirus meningitis may occur throughout life, although it is much more common in young children
The illness commences with fever, vomiting and headache
- neck stiffness and photophobia indicate the presence of inflammation in the meninges
Duration of illness is generally less than one week and almost all patients recover fully after a short (2-3 week) convalescence
- management is mainly supportive
Collection of a cerebrospinal fluid (CSF) specimen generally reveals a moderate white blood cell count (50 - 500 cells) and the absence of bacterial pathogens (“aseptic” meningitis)
Enteroviruses may be isolated from CSF by cell culture in 50-60% of cases. Molecular diagnostic assays, such as the polymerase chain reaction, can identify the presence of enteroviruses in the CSF in >90% of cases

Front 73

Pleconaril

Back 73

- Pleconaril is an inhibitor of enteroviruses that is non-toxic, orally bioavailable and systemically acting
- Pleconaril prevents binding of virus to target cells by irreversible binding to the receptor binding pocket on the viral capsid
- Typical MIC90 values are ~0.19M
- Pleconaril has been shown to significantly reduce morbidity from aseptic meningitis and to reduce morbidity and mortality in neonatal
meningoencephalitis and hepatitis
- All Coxsackie B viruses and most echoviruses are highly susceptible to Pleconaril
Problems:
- Not all enteroviruses are susceptible to Pleconaril (need to type isolates)
- Parenteral formulation is not yet available
- Drug interactions via cytochrome P450 → interference with OCP

Front 74

Acute viral encephalitis

Back 74

• Acute viral encephalitis is a severe disease of the grey matter of the brain
• Viral encephalitis usually commences with nonspecific
clinical features such as fever, headache & vomiting
– rapidly progresses to alteration of consciousness, seizures, motor, sensory or language disturbances
• Viral encephalitis is accompanied by high mortality rates and high rates of neurological sequelae
– mental retardation, seizures, motor and sensory deficits

Front 75

Causes of acute viral encephalitis

Back 75

Front 76

Outcome of acute viral encephalitis

Back 76

Front 77

Pathogenesis of acute viral encephalitis

Back 77

Three pathological patterns of encephalitis:
1. Acute necrotising encephalitis eg HSV encephalitis – disease is due to destruction of infected neurons as a result of virus-induced cytopathology
2. Encephalitis resulting from damage due to the
inflammatory response eg flavivirus encephalitis - disease results from the damaging effects of inflammation on the CNS in response to infection
3. Encephalitis resulting from disturbance of neuronal
function eg rabies, HIV encephalitis

Front 78

MRI features of HSE

Back 78

Front 79

Japanese encephalitis

Back 79

• JEV is the major cause of encephalitis in Asia:
– mosquito-borne flavivirus (Culex mosquitoes are the main vector)
– single stranded, positive sense RNA (~11 kb) virus,
enveloped
– antigenically related to Murray Valley encephalitis, West Nile and St Louis encephalitis viruses
– 30-50,000 cases pa, 10,000 deaths (underestimate)
– case fatality rate 25-30%, 50% of survivors have permanent neurological sequelae
– most infections are subclinical – disease to infection ratio 1:500-1,000

Paddy rice farmes ideal conditions

Front 80

JVE Sx

Back 80

• The incubation period of JE varies from 5-15 days
• Clinical disease ranges from nonspecific febrile illness,
aseptic meningitis, meningo-encephalitis and polio-like
flaccid paralysis
• Neurological disease is typically preceded by a 2-3 day
prodromal illness consisting of fever, cough, myalgia etc
• The onset of encephalitis is usually heralded by
convulsions and altered consciousness
• A Parkinsonian syndrome classically occurs early in
convalescence (10-14 days after onset)
• Paralysis is more common in the upper than lower limbs

Front 81

MRI features of JE

Back 81

Front 82

Dx of JVE

Back 82

1. Haemagglutination inhibition requires acute and
convalescent sera at least 7 days apart
2. IgM (antibody capture) ELISA CSF or serum

Front 83

Prevention and control of JE

Back 83

1. Mosquito control
2. Avoidance of exposure
3. Immunisation - most effective means to prevent JE
a. Inactivated mouse-brain-derived (Biken) vaccine
- requires three doses plus regular boosters for protection
- ADEM is a major vaccine-related adverse event
b. Chinese SA-14-14-2 live attenuated vaccine
- seroconversion >99%, efficacy >98% after one dose
- is not currently used widely as it does not comply with good
manufacturing practice (use of certified cell lines etc)
c. Chimeric recombinant attenuated vaccine based on yellow fever
17D vaccine (“ChimeriVax”)
- JE envelope glycoproteins (prM, E) replace those of YF
- phase 3 clinical trial evidence of protection
- recently approved for use in Australia

Front 84

Nipah virus encephalitis

Back 84

• First identified in peninsular Malaysia and Singapore in 1998-99
– outbreak of encephalitis among adult male piggery workers
– 106 fatal cases, CFR 38.5%
– transmission was shown to be pig-to-human
• Since 2001, NV has regularly caused fatal human cases during
small outbreaks in Bangladesh (CFR 67-92%)
– Several outbreaks have involved person-to-person transmission
• nosocomial transmission has been documented
– One outbreak was linked to contaminated date palm sap
• how did virus contaminate the sap?

Fruit batsare definitve hosts of both Hendra and Nipah or Henipaviruses

Front 85

NV encephalitis (NVE)
Distinctive features

Back 85

• Distinctive clinical signs include segmental myoclonus,
hypertension, tachycardia, areflexia and hypotonia
• Respiratory symptoms have been prominent in the Bangladesh outbreaks (may account for human-to-human transmission)

Front 86

MRI features of Nipah Virus Encephalitis

Back 86

Front 87

Nipha Virus Dx

Back 87

– Serological diagnosis based on ELISAs using high
affinity mAbs against purified NV antigens
– The complete genome of Malaysian and Bangladeshi
NV strains are known and have allowed RT-PCR
assays to be developed, which have been validated on
serum, urine and CSF

Front 88

Nipha Virus Tx

Back 88

– Ribavirin was shown to reduce mortality in the
Malaysian outbreak
– New agents targeting receptor binding and fusion are
being developed

Front 89

Post-infectious encephalomyelitis

Back 89

• Post-infectious encephalomyelitis is an acute disorder of the CNS that occurs within days to weeks of a viral
illness or vaccination
• The preceding viral illness is typically an upper
respiratory tract infection or chicken pox
• Although associated with viral infection, post-infectious encephalomyelitis does not result from neural tissue invasion by the virus - infectious virus is rarely recovered from the CNS of sufferers
• Post-infectious encephalomyelitis is an autoimmune
disease triggered by the preceding viral infection or
immunisation

Front 90

Causes of post-infectious encephalomyelitis

Back 90

Front 91

Pathogenesis of post-infectious encephalomyelitis

Back 91

• Post-infectious encephalomyelitis is identical to an animal model known as experimental allergic encephalomyelitis (EAE)
• EAE is a demyelinating disorder of the CNS induced by immunisation of animals with myelin extracts or myelin-associated proteins EAE can be passively • transferred to naïve hosts by inoculation of immune T cells
• Post-infectious encephalomyelitis is thought to have a similar pathogenesis – antibodies to myelin basic protein (MBP) are found in all cases
- certain viral infections or vaccinations may express a peptide structurally similar to MBP (molecular mimicry)
- activation of self-reactive immune cells due to the release of cytokines after virus-induced death of host cells

Front 92

MRI features of post-infectious
encephalomyelitis

Back 92

Front 93

Clinical presentation of post-infectious encephalomyelitis

Back 93

• Post-infectious encephalomyelitis usually commences abruptly 2 to 30 days after a viral illness or vaccination
• Demyelinating lesions occur throughout the CNS, usually resulting in multifocal neurological deficits
-visual disturbances, speech disorder, movement disorder, sensory deficits
• Alteration of consciousness ranging from lethargy to coma
• Focal or generalised seizures
• Personality changes
• The disease progresses for 4-5 days, after which the patient begins to recover
- post-measles encephalomyelitis has a mortality rate of 10-20% and neurological sequelae occur in ~25% of survivors

- anti-inflammatory and immunotherapy has been largely unsuccessful

Front 94

Viral Encephalitis Overview (prevention is the key)

Back 94

Viral encephalitis is a severe disease and usually has a rapid onset. Thus, a considerable amount of brain damage occurs before the initiation of therapies (e.g. antiviral or anti-inflammatory agents) designed to limit neuron damage resulting from virus infection
Consequently, it is necessary to prevent infection with viruses capable of causing encephalitis through surveillance and public health intervention, or preferably by the use of vaccines