L11 – Infections of the Nervous System: Viral Infections Flashcards
3 pathogenesis pathways for viral CNS diseases?
1) Delayed/ acoompanying inflammatory reactions
2) Direct cytolytic infection and neruonal damage
3) Post-infectious syndromes and demyelination
Explain how viral CNS infection can cause demyelination.
virus replicates outside CNS»_space; cross-reacting immune response to myelin / dysregulation of immune response»_space; demyelination of CNS
Typical temporal features of viral CNS infection?
Biphasic illness
CNS symptoms follow 2-12 days after initial illness
Presentation may be acute, subacute, or chronic
Relate the terms given to infection of different parts of the CNS.
- Brain = encephalitis;
- Meninges = meningitis
- Spinal cord = myelitis;
- Peripheral nerves = neuritis / neuropathy
Many viral infections may involve more than one site e.g. meningo-encephalitis.
List 5 clinical symptoms and signs of viral CNS infection.
1) Meningeal irritation: Neck stiffness, Kernig’s and Brudzinski’s sign
2) Encephalopathic signs: Alternation of consciousness, fits and seizures
3) Increased ICP: headache, vomiting
4) Focal neurological signs: paralysis, aphonic
5) Systemic signs: fever, lethargy
Compare between pyogenic, viral and TB/ Fungal meningitis: appearance of CSF?
Pyogenic: Turbid
Viral: Clear/ sl. turbid
TB/ Fungal: Clear/ sl. turbid
Compare between pyogenic, viral and TB/ Fungal meningitis: Total cells and predominant WBC.
Pyogenic: >500, PMN
Viral: <500, lymphocytic
TB/ Fungal: <500, lymphocytic
Compare between pyogenic, viral and TB/ Fungal meningitis: Protein and glucose
Pyogenic: Very low glucose, Very high protein
Viral: Normal glucose, high protein
TB/ Fungal: low glucose, very high protein
Compare between pyogenic, viral and TB/ Fungal meningitis: Gram stain and acid-fast stain
Pyogenic: 65 to 95%
Viral: -ve
TB/ Fungal: -ve, TB acid-fast stain only
Viral isolation from CSF is good or poor for which type of CNS infections?
Good isolation: Viral meningitis
Poor isolation: viral encephalitis, Post-infectious encephalitis (doesnt penetrate BBB)
Isolation rate best, early in illness
PCR of CSF is used for Dx of which viral CNS infections.
–herpes simplex encephalitis.
–CMV encephalitis / myelitis.
–VZV encephalitis /meningitis/ myelitis.
–more sensitive than culture in diagnosis of enterovirus.
List all diagnostic tests used for viral CNS infections?
Throat swab (mumps, enteroviruses)
Stool sample (enterovirus)
PCR of CSF (HSV, CMV, VZV, enterovirus)
CSF serology
Brain biopsy
Blood serology
List all serological tests for dx of viral CNS infections?
- Rising Ab titre (paired sera): Flu A/B, VZV, HSV, entero, mycoplasma, (mumps, measles)
- IgM Ab (single sera): JEV, EBV, (CMV)
- Intra-thecal (in CSF) antibody synthesis (late presentation)
Why is serology for enterovirus not indicated in viral CNS infections?
problem of many serotypes and no common antigen
List common and less common viruses that cause viral meningitis
1) Common:
– Enteroviruses (ECHO, Coxsackie A/B).(summer months)
– H.simplex type 2 (genital herpes)
2) Less common:
– Mumps (immunisation has made less common)
– Lymphocytic choriomeningitis (LCM) (assn. with rodents)
– HIV seroconversion illness
Properties of enteroviruses: family, genetic material? Is their protective immunity the same?
Family Picornaviruses.
RNA viruses
Single +ve stranded,
non-enveloped
share a few common antigens, but protective immunity is type specific
List 7 clinically significant enteroviruses?
Polio Cox A Cox B ECHO EV 68, 70, 71
Hand foot and mouth disease is caused by which viruses?
Enterovirus: Cox A (A16), EV71
Which enteroviruses can cause asymptomatic infection?
All types
List some general symptoms caused by most enterovirus infections?
- Asymptomatic
- Fever, rash
- Flaccid paralysis **
- Meningitis
- Carditis
Conjunctivitis is caused by which enterovirus subtypes?
- Cox A (A24)
- EV70
Herpangina is caused by which enterovirus subtype? *small, blister-like ulcers on the roof of the mouth and in the back of the throat. *
Cox A
URTI is caused by which enterovirus subtype?
Cox A
Cox B
ECHO
Enterovirus infection has a biphasic seasonality. True or false?
False
Enteroviruses have a summer seasonality
HSV meningitis is usually caused by? Both sex affected equally or not?
herpes simplex type 2, but genital lesions may not be seen
> 30% females, 11% males with primary genital HSV have meningitic involvement
HSV meningitis requires urgent medical attention. True or False?
Self-limited (2-3 days: unlike HSV encephalitis)
List common and less common viruses that cause viral encephalitis?
Common:
– Herpes simplex type 1 (HSV 2 in neonates)
– Enteroviruses
– Varicella-zoster virus •
Less common:
– Febrile exanthems (measles, rubella, HHV-6)
– Arboviruses (eg.Japanese encephalitis) (travel in last 3 weeks).
– Other: EBV, influenza, mumps, adenovirus, HIV, LCM. RABIES
2 routes of spread of HSV into brain?
- May follow primary infection or reactivation.
- Entry into CNS via
– a) spread along olfactory nerve (from nasopharynx) – affects frontal lobe
– b) reactivation from trigeminal ganglion - innervates pia mater – infection of brain
Explain how HSV can become latent?
Primary infection: mild pharyngitis, fever(, genital herpes)
> > viral transit up peripheral nerve
> > latent virus in neuron in dorsal root ganglion (spinal cord)
What can trigger HSV reactivation?
trigger factors (e.g. fever, physical trauma, stress, hormonal balance, age, immunosupression)
Area of brain most affected by HSV encephalitis?
Characteristically in:
- Temporal lobe; or
- Orbital surface of frontal lobe
May also involve:
- Adjacent frontal / parietal / occipital lobes
- Cingulate gyri
List some general symptoms of Herpes encephalitis?
General: altered consciousness; headache; seizures; vomiting; memory loss, fever
List some clinical findings of Herpes encephalitis? (think neruonal damage effects, which part of brain?)
personality change; dysphasia; autonomic dysfunction; ataxia; hemiparesis (weakness of one entire side of the body) seizures; cranial nerve deficits.
Typical CSF findings of Herpes encephalitis?
CSF findings: High Protein >40mg/dL Normal CSF:blood glucose ratio: 95% WBC pleocytosis (lymphocytes) High RBC >50:
List the lab tests used to dx herpes encephalitis and lab tests that are not useful?
Useful: HSV DNA detection by PCR in CSF; Intrathecal CSF antibody may confirm diagnosis
Not useful: rarely cultured from the CSF; Isolating HSV in throat / mouth, serology in blood
Why Isolating HSV in the throat / mouth is of little significance?
– may be reactivation of latent virus unconnected with the CNS
– Approx 1% of healthy persons have HSV isolated from mouth)
HSV DNA detection by PCR in CSF may still be detectable up to 7 days after start of acyclovir. True or False
True
Herpes meningitis is not life treatening, but Herpes encephalitis is. True or False?
True
Consequence of untreated herpes encephalitis?
- Life threatening, medical emergency
* If untreated, mortality is 70%. Many survivors have permanent brain damage
Course of action if Herpes encephalitis is suspected?
- Start treatment on clinical suspicion, while waiting for CSF PCR result
- Early treatment with i.v. acyclovir is life and function saving: Use 14 - 21 days therapy to prevent relapse
Locality, reservoir, transmission, host and vector of JEV?
- Common in South China, southeast Asia
- animal reservoir/ host =water birds & pigs
- Vector = mosquitoes associated with rice field
- Human infection = end-host (no human- human transmission)
Sequalae and prevention of JEV?
Most infections = asymptomatic (90-95%)
Symptomatic: Mortality = 10-30%; Many of the survivors have permanent brain damage
Prevention: vaccine available for endemic areas
List viruses that can cause myelitis/ Neuropathy?
• Enteroviruses (EV71, Polio, other) • VZV, • EBV, • CMV, • exanthems, • mumps, • HSV 2 • Japanese encephalitis • Zika (Guillain Barre syndrome)
Pathogenesis of Varicella-zoster virus? (think primary and reactivation infections)
1) Primary infection: chickenpox > viral transit up peripheral nerve > latent virus in neuron in dorsal root ganglion (spinal cord)
2) Recurrence: trigger factors (e.g. fever, physical trauma, stress, hormonal balance, age, immunosuppression) > reactivation of virus in neuron > viral transit down peripheral nerve (usually unilateral) > shingles / skin lesions (affect dermatome)
VZV CNS infection may not cause skin lesions. True or false?
True
Skin lesions may precede or follow CNS disease.
or completely absent - “zoster sine herpete
What is the consequence of VZV reactivation in an AIDS patient’s brain?
Chronic progressive encephalitis
Ventriculitis
40% have no rash
Which enteroviruses can cause flaccid paralysis?
All types
Especially Polio, EV71, EV68
Which 5 viruses cause CNS infection most in immunocompromised patients?
1) Cytomegalovirus: encephalitis, cranial nerve palsies, poly-radiculopathy, neuritis, pneumonia, gastrointestinal
2) VZV: myelitis, encephalitis (acute / chronic progressive), radiculitis, ventriculitis
3) JC virus: progressive multifocal leukoencephalopathy
4) HIV
5) Chronic enteroviral meningo-encephalitis in agammaglobulinaemics
Family, reservoir, transmission of Rabies?
Rhabdovirus family
Animal reservoir: Dogs mainly, cats, other mammals (e.g. fox, wolves, jackals, mongoose etc)
Animal saliva = infectious if introduced on mucosal surface / broken skin
Human-human transmission = unknown
Local incidence of rabies?
In Hong Kong: Last local human case 1981; last animal rabies 1987.
Common in neighboring countries
Imported cases seen
Exposure of dog bites overseas needs to be managed
Pathogenesis of rabies? 4 steps (think at the infectious site, travel to CNS, effects on brain, descending infections)
- Virus inoculation»_space; replicates in striated muscle at the site of the bite»_space; acetylcholine receptor serves as virus receptor»_space; enters sensory nerve endings (peripheral nervous system) via stretch spindles
- Carried by axonal transport (passive ascent) to spinal cord»_space; replication in dorsal ganglion
- Replication in brain (brain stem, cerebellum, other structures)»_space; encephalitis
- Descending infection (exam): virus travels down peripheral nerves via sensory, autonomic nervous system to salivary glands (virus present in saliva), skin, muscle, retina, cornea, nasal mucosa, other organs
How does the site of bite affect the time span of rabies infection to reach brain?
Bites on the face: virus has less distance to travel =usually shorter incubation period
Bite on leg: longer (e.g. 1 year)
Inoculation, symptoms and signs of rabies (incl. furious and paralytic rabies)?
Incubation: usually 20-90 days, may be >1 year
Prodromal: non-specific, onset of itching at site of healed bite wound
Furious rabies (hyperreflexia):
- Hydrophobia (muscle of swallowing goes into spasm, scared of water)
- Aerophobia (wind causes spasm)
- Meningo-encephalitis
Paralytic rabies: paralysis begins in bitten limb and spreads
Dx of rabies CNS infection?
Viral antigen by immunofluorescence (also skin biopsy, corneal scrap)
Inclusion bodies (pink-staining Negri bodies)
Course of action after rabies bite?
• No treatment once symptoms appear - fatal
• Prevention: Management of dog bite:
– Good wound toilet, aggressive washing, use local anaesthesia if needed. Avoid suturing. Manage tetanus risk (tetanus vaccine may be needed).
– Assess rabies risk
- Post exposure prophylaxis by immunization
What are the 4 criteria for assessment of rabies risk?
1) What animal? Rabies only affects mammals (dogs, cats)
2) Where? Endemic area/ travel history/ imported case
3) Behavior of animal? unprovoked bite, paralysis, increased salivation, other bites?
4) Animal alive or not?
Alive after 7 days = exclude rabies; Dead = examine animal brain for antigens and inclusion bodies
Compare active and passive immunization for Rabies?
Active = Human diploid cell vaccine (killed vaccine); Immunisation course can be aborted
Passive = human rabies immunoglobulin
Local: infiltrate bite wounds thouroughly
Systemic: inject any remainder intra-muscularly
