L11 – Infections of the Nervous System: Viral Infections

Question 1

3 pathogenesis pathways for viral CNS diseases?

Answer 1

1) Delayed/ acoompanying inflammatory reactions
2) Direct cytolytic infection and neruonal damage
3) Post-infectious syndromes and demyelination

Question 2

Explain how viral CNS infection can cause demyelination.

Answer 2

virus replicates outside CNS&raquo_space; cross-reacting immune response to myelin / dysregulation of immune response&raquo_space; demyelination of CNS

Question 3

Typical temporal features of viral CNS infection?

Answer 3

 Biphasic illness
 CNS symptoms follow 2-12 days after initial illness

Presentation may be acute, subacute, or chronic

Question 4

Relate the terms given to infection of different parts of the CNS.

Answer 4

• Brain = encephalitis;
• Meninges = meningitis
• Spinal cord = myelitis;
• Peripheral nerves = neuritis / neuropathy

Many viral infections may involve more than one site e.g. meningo-encephalitis.

Question 5

List 5 clinical symptoms and signs of viral CNS infection.

Answer 5

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

Question 6

Compare between pyogenic, viral and TB/ Fungal meningitis: appearance of CSF?

Answer 6

Pyogenic: Turbid
Viral: Clear/ sl. turbid
TB/ Fungal: Clear/ sl. turbid

Question 7

Compare between pyogenic, viral and TB/ Fungal meningitis: Total cells and predominant WBC.

Answer 7

Pyogenic: >500, PMN
Viral: <500, lymphocytic
TB/ Fungal: <500, lymphocytic

Question 8

Compare between pyogenic, viral and TB/ Fungal meningitis: Protein and glucose

Answer 8

Pyogenic: Very low glucose, Very high protein
Viral: Normal glucose, high protein
TB/ Fungal: low glucose, very high protein

Question 9

Compare between pyogenic, viral and TB/ Fungal meningitis: Gram stain and acid-fast stain

Answer 9

Pyogenic: 65 to 95%
Viral: -ve
TB/ Fungal: -ve, TB acid-fast stain only

Question 10

Viral isolation from CSF is good or poor for which type of CNS infections?

Answer 10

Good isolation: Viral meningitis
Poor isolation: viral encephalitis, Post-infectious encephalitis (doesnt penetrate BBB)

Isolation rate best, early in illness

Question 11

PCR of CSF is used for Dx of which viral CNS infections.

Answer 11

–herpes simplex encephalitis.
–CMV encephalitis / myelitis.
–VZV encephalitis /meningitis/ myelitis.
–more sensitive than culture in diagnosis of enterovirus.

Question 12

List all diagnostic tests used for viral CNS infections?

Answer 12

Throat swab (mumps, enteroviruses)

Stool sample (enterovirus)

PCR of CSF (HSV, CMV, VZV, enterovirus)

CSF serology

Brain biopsy

Blood serology

Question 13

List all serological tests for dx of viral CNS infections?

Answer 13

• 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)

Question 14

Why is serology for enterovirus not indicated in viral CNS infections?

Answer 14

problem of many serotypes and no common antigen

Question 15

List common and less common viruses that cause viral meningitis

Answer 15

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

Question 16

Properties of enteroviruses: family, genetic material? Is their protective immunity the same?

Answer 16

Family Picornaviruses.

RNA viruses
Single +ve stranded,
non-enveloped

share a few common antigens, but protective immunity is type specific

Question 17

List 7 clinically significant enteroviruses?

Answer 17

Polio 
Cox A
Cox B 
ECHO
EV 68, 70, 71

Question 18

Hand foot and mouth disease is caused by which viruses?

Answer 18

Enterovirus: Cox A (A16), EV71

Question 19

Which enteroviruses can cause asymptomatic infection?

Answer 19

All types

Question 20

List some general symptoms caused by most enterovirus infections?

Answer 20

• Asymptomatic
• Fever, rash
• Flaccid paralysis **
• Meningitis
• Carditis

Question 21

Conjunctivitis is caused by which enterovirus subtypes?

Answer 21

• Cox A (A24)

- EV70

Question 22

Herpangina is caused by which enterovirus subtype? *small, blister-like ulcers on the roof of the mouth and in the back of the throat. *

Answer 22

Cox A

Question 23

URTI is caused by which enterovirus subtype?

Answer 23

Cox A
Cox B
ECHO

Question 24

Enterovirus infection has a biphasic seasonality. True or false?

Answer 24

False

Enteroviruses have a summer seasonality

Question 25

HSV meningitis is usually caused by? Both sex affected equally or not?

Answer 25

herpes simplex type 2, but genital lesions may not be seen >30% females, 11% males with primary genital HSV have meningitic involvement

Question 26

HSV meningitis requires urgent medical attention. True or False?

Answer 26

Self-limited (2-3 days: unlike HSV encephalitis)

Question 27

List common and less common viruses that cause viral encephalitis?

Answer 27

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

Question 28

2 routes of spread of HSV into brain?

Answer 28

* 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

Question 29

Explain how HSV can become latent?

Answer 29

Primary infection: mild pharyngitis, fever(, genital herpes) >> viral transit up peripheral nerve >> latent virus in neuron in dorsal root ganglion (spinal cord)

Question 30

What can trigger HSV reactivation?

Answer 30

trigger factors (e.g. fever, physical trauma, stress, hormonal balance, age, immunosupression)

Question 31

Area of brain most affected by HSV encephalitis?

Answer 31

Characteristically in: - Temporal lobe; or - Orbital surface of frontal lobe May also involve: - Adjacent frontal / parietal / occipital lobes - Cingulate gyri

Question 32

List some general symptoms of Herpes encephalitis?

Answer 32

General: altered consciousness; headache; seizures; vomiting; memory loss, fever

Question 33

List some clinical findings of Herpes encephalitis? (think neruonal damage effects, which part of brain?)

Answer 33

``` personality change; dysphasia; autonomic dysfunction; ataxia; hemiparesis (weakness of one entire side of the body) seizures; cranial nerve deficits. ```

Question 34

Typical CSF findings of Herpes encephalitis?

Answer 34

``` CSF findings:  High Protein >40mg/dL  Normal CSF:blood glucose ratio: 95%  WBC pleocytosis (lymphocytes)  High RBC >50: ```

Question 35

List the lab tests used to dx herpes encephalitis and lab tests that are not useful?

Answer 35

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

Question 36

Why Isolating HSV in the throat / mouth is of little significance?

Answer 36

– may be reactivation of latent virus unconnected with the CNS – Approx 1% of healthy persons have HSV isolated from mouth)

Question 37

HSV DNA detection by PCR in CSF may still be detectable up to 7 days after start of acyclovir. True or False

Answer 37

True

Question 38

Herpes meningitis is not life treatening, but Herpes encephalitis is. True or False?

Answer 38

True

Question 39

Consequence of untreated herpes encephalitis?

Answer 39

* Life threatening, medical emergency | * If untreated, mortality is 70%. Many survivors have permanent brain damage

Question 40

Course of action if Herpes encephalitis is suspected?

Answer 40

* 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

Question 41

Locality, reservoir, transmission, host and vector of JEV?

Answer 41

- 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)

Question 42

Sequalae and prevention of JEV?

Answer 42

Most infections = asymptomatic (90-95%) Symptomatic: Mortality = 10-30%; Many of the survivors have permanent brain damage Prevention: vaccine available for endemic areas

Question 43

List viruses that can cause myelitis/ Neuropathy?

Answer 43

• Enteroviruses (EV71, Polio, other) • VZV, • EBV, • CMV, • exanthems, • mumps, • HSV 2 • Japanese encephalitis • Zika (Guillain Barre syndrome)

Question 44

Pathogenesis of Varicella-zoster virus? (think primary and reactivation infections)

Answer 44

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)

Question 45

VZV CNS infection may not cause skin lesions. True or false?

Answer 45

True Skin lesions may precede or follow CNS disease. or completely absent - “zoster sine herpete

Question 46

What is the consequence of VZV reactivation in an AIDS patient's brain?

Answer 46

 Chronic progressive encephalitis  Ventriculitis  40% have no rash

Question 47

Which enteroviruses can cause flaccid paralysis?

Answer 47

All types Especially Polio, EV71, EV68

Question 48

Which 5 viruses cause CNS infection most in immunocompromised patients?

Answer 48

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

Question 49

Family, reservoir, transmission of Rabies?

Answer 49

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

Question 50

Local incidence of rabies?

Answer 50

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

Question 51

Pathogenesis of rabies? 4 steps (think at the infectious site, travel to CNS, effects on brain, descending infections)

Answer 51

1. Virus inoculation >> replicates in striated muscle at the site of the bite >> acetylcholine receptor serves as virus receptor >> enters sensory nerve endings (peripheral nervous system) via stretch spindles 2. Carried by axonal transport (passive ascent) to spinal cord >> replication in dorsal ganglion 3. Replication in brain (brain stem, cerebellum, other structures) >> encephalitis 4. 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

Question 52

How does the site of bite affect the time span of rabies infection to reach brain?

Answer 52

 Bites on the face: virus has less distance to travel =usually shorter incubation period  Bite on leg: longer (e.g. 1 year)

Question 53

Inoculation, symptoms and signs of rabies (incl. furious and paralytic rabies)?

Answer 53

 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

Question 54

Dx of rabies CNS infection?

Answer 54

 Viral antigen by immunofluorescence (also skin biopsy, corneal scrap)  Inclusion bodies (pink-staining Negri bodies)

Question 55

Course of action after rabies bite?

Answer 55

• 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

Question 56

What are the 4 criteria for assessment of rabies risk?

Answer 56

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

Question 57

Compare active and passive immunization for Rabies?

Answer 57

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