HNS11 Infections Of The CNS II Viral Infection Flashcards
Pathogenesis of viral CNS disease
- Direct invasion of CNS / Cytopathic / Cytolytic infection
- Viral replication in CNS —> Neuronal damage —> disease - Post infectious syndromes (e.g. Rubella)
- Viral replication outside CNS (e.g. respiratory/GI tract)
—> cross-reacting immune response (Ab/T-cell response) to myelin / dysregulation of immune response
—> ***Demyelination of CNS
—> disease
- Biphasic illness
—> 1st phase: mild respiratory / GI illness (then recover)
—> 2nd phase: CNS disease
Infections of nervous system
- Life-threatening with high mortality and morbidity
- Presentation: Acute / Subacute / Chronic
Definitions of terms
Infection of:
- Brain —> Encephalitis
- Meninges —> Meningitis
- Spinal cord —> Myelitis
- Peripheral nerves —> Neuritis / Neuropathy
Many viral infections involve more than one site e.g. Meningo-encephalitis
***Clinical signs and symptoms
- Meningeal irritation (inflammation and pain sensitive)
- Neck stiffness (difficulty stretching meninges)
- Kernig’s sign (flex hip, difficulty extend knee (meninges at sacral spinal cord)) - Encephalopathic signs (brain involvement)
- Alteration of consciousness
- Fits - Increased ICP (swelling of brain)
- Headache
- Vomiting - Focal neurological signs
- e.g. motor neuron paralysis, hemiplegia, spasticity - Fever
- systemic signs of infection - Other features
- mumps —> parotitis (inflammation of parotid gland)
- enterovirus —> skin rash
Meningitis clinical signs and symptoms
- Infection —> fever
- Meningeal irritation —> neck stiffness, Kernig’s sign
- Increased ICP —> headache, vomiting
If progresses to brain parenchymal involvement —> Meningo-encephalitis
4. Alteration of consciousness, fits/seizures
5. Focal neurological signs —> paralysis
CSF findings in CNS infection
- Appearance
Pyogenic: Turbid
Viral: Clear / slightly turbid
TB/Fungal: Clear / slightly turbid - Total cell (per mm^3)
Pyogenic: >500
Viral: <500
TB/Fungal: <500 - WBC
Pyogenic: PMN (Neutrophil)
Viral: Lymphocyte
TB/Fungal: Lymphocyte - Glucose
Pyogenic: Very low
Viral: Normal
TB/Fungal: Low - Protein
Pyogenic: ++
Viral: +
TB/Fungal: ++ - Gram stain
Pyogenic: 65-95%
Viral: Negative
TB/Fungal: Negative (but +ve in acid-fast stain for TB)
Distinguish between pyogenic, viral, TB/fungal infection
Viral vs Pyogenic:
- Clear CSF
- Low cell count
- Lymphocyte
Viral vs TB/Fungal:
- Normal glucose
Laboratory diagnosis of infection
- Virus detection
- CSF (main stay)
- brain biopsy / autopsy
- throat swab (mumps, enterovirus)
- stool (enterovirus) - Serology
- Serum
—> Rising antibody titres (paired sample; early vs 14 days): Flu A/B, VZV, HSV, enterovirus, mycoplasma, (mumps, measles)
—> IgM (single sera): JE, EBV, (CMV)
- Intra-thecal Ab synthesis in CSF (compared to serum)
—> detectable only later in illness (>10 days)
—> paired serum / CSF specimens —> Ab index - Serology for enterovirus: problem: many serotypes and no common antigen
- Virus isolation / culture
- limitations: isolation rate from CSF in meningitis is good (∵ close contact), but poor in encephalitis (e.g. HSV/enterovirus) —> brain biopsy only reliable specimen in encephalitis to isolate virus
- unlikely to isolate virus from post-infectious encephalitis (∵ autoimmune attack)
- isolation rate best early in illness
- many enterovirus serotypes (most coxsackie A) do not grow on cell culture - Viral nucleic acid (RNA/DNA) (***method of choice for CNS disease)
- PCR of CSF
—> herpes simplex encephalitis
—> CMV encephalitis / myelitis
—> VZV encephalitis / meningitis / myelitis
—> more sensitive than culture in diagnosis of enterovirus
Etiology of viral meningitis
Common:
1. Enterovirus (ECHO, Coxsackie A/B) (summer months)
2. Herpes simplex type 2 (genital herpes)
Less common:
1. Mumps (∵ immunisation)
2. Lymphocytic choriomeningitis (LCM) (associated with rodents)
3. HIV seroconversion illness (very early phase)
Rare:
Other viruses
Enterovirus
- One genus within family Picornaviruses
- single +ve stranded RNA
- non-enveloped
- ***summer seasonality
- > 100 human types (original classification: coxsackie A, B, ECHO, polio; current classification: enterovirus A, B, C, D; recent identification: numerically e.g. EV68-71)
- EV types share a few common antigens, but protective immunity is type specific
Clinical syndromes associated with enterovirus (Polio, Cox A, Cox B, ECHO, EV70, EV71)
- Asymptomatic:
ALL enterovirus - ***Meningitis:
ALL enterovirus - ***Flaccid paralysis (anterior horn of spinal cord infected):
ALL enterovirus (Polio, EV71, EVD68 ++) -
**Hand foot and mouth disease
- Cox A (A16) +
- **EV71 ++
- Cox B -
- ECHO - - Carditis
- Cox A +
- Cox B ++
- ECHO + - Conjunctivitis
- Cox A (A24) +
- EV70 ++
Hand foot and mouth disease (HFMD)
- Usually only skin / mucosal lesions —> mild
- but occasionally (esp. EV71) causes:
1. Lower motor neuron —> Flaccid paralysis
2. Brainstem encephalitis
Herpes simplex virus meningitis
- Usually Herpes simplex type 2
- > 30% of female, 11% of male with primary (1st time) genital HSV have meningitic involvement
- Self-limited (unlike HSV encephalitis)
- Acyclovir role/need unclear
- Latent in ganglion, can recur from time to time
- young adults with ***aseptic meningitis —> think of HSV2 possibility esp. during winter months
Etiology of viral encephalitis
Common:
- Herpes simplex type 1 (antiviral available) (HSV2 in neonates)
- Enterovirus
- VZV
Less common:
- Febrile exanthems (measles, rubella, HHV-6)
- Arboviruses (e.g. Japanese encephalitis) (travel in last 3 weeks)
- Other: EBV, influenza, mumps, adenovirus, HIV, LCM etc.
- Rabies
How does herpes simplex virus get into brain
- Follow primary infection / reactivation
- Entry into CNS via:
1. Spread along **olfactory nerve (from nasopharynx) —> through cribriform bone —> affects frontal lobe
2. Reactivation from **trigeminal ganglion (innervates ***pia mater) —> infection of brain
Herpes simplex encephalitis (HSE) lesions
- Usually Temporal lobe / Orbital surface of frontal lobe
- but adjacent frontal, parietal, occipital lobe, cingulate gyri may also be involved
HSE clinical features
- History
- altered consciousness
- headache
- seizures
- vomiting
- memory loss - Clinical findings
- fever
- personality change
- dysphasia
- autonomic dysfunction
- ataxia
- hemiparesis
- seizures
- cranial nerve deficits
HSE CSF findings
- Protein >40 mg/dL
- Lymphocyte pleocytosis > 5/mm^3: 96% (median 130)
- RBC >50: 42% (not diagnostic of HSE) (necrosis of brain —> bleeding into CSF)
- Normal CSF: blood glucose ratio 95%
HSE Lab diagnosis
- ***HSV DNA detection by PCR in CSF (method of choice)
—> HSV DNA may still be detectable up to 7 days after start of ACV therapy
- intrathecal CSF Ab may confirm, but usually later in illness - Virus rarely cultured from CSF
- Isolating HSV in throat / mouth is of little significance
—> may be reactivation of latent virus unconnected with CNS
—> ~1% of healthy persons have HSV isolated from mouth - Serology in blood little use, not conclusive
HSE treatment
- Life threatening, medical emergency
- if untreated, 70% mortality, many survivors have permanent brain damage
- Start treatment on clinical suspicion while waiting for CSF PCR results
- ***IV acyclovir is life and function saving
- Relapse of HSE is being recognised with early stopping of acyclovir —> ***14-21 day acyclovir therapy
Japanese encephalitis
- Arbovirus (arthropod borne)
- common in South China and SE Asia, present but rare in HK
- Mosquito-borne
—> present in water bird
—> transmitted by mosquitoes
—> pigs bitten by mosquitoes
—> peri-domestic amplifier host (pigs have a lot of virus)
—> bitten by mosquitoes again
—> mosquitoes bite human - transmission between animals is by a mosquito typically associated with rice fields
- considered as Zoonosis (maintained in an animal reservoir (water birds and pigs))
- human infection is “dead end” —> NO human-to-human transmission (very rare case via blood transfusion)
Clinical features:
- Asymptomatic (90-95%)
- Symptomatic —> 10-30% mortality, many survivors have permanent brain damage
Vaccine:
- Available for prevention in endemic areas
Myelitis / Neuropathy etiology
- Enterovirus (EV71, Polio, others)
- VZV
- EBV
- CMV
- Exanthems
- Mumps
- HSV2
- Japanese encephalitis
- Zika (Guillain Barre syndrome)
Varicella-zoster virus
Primary infection: Chicken pox —> virus latent in dorsal root ganglion
Recurrence: activation of virus by trigger factors —> transmit down peripheral nerves / spinal cord —> Shingles —> restricted to dermatome (unilateral)
Skin lesions may precede / follow CNS disease
—> may be absent: Zoster sine herpete: only dermatomal pain with absence of rash
Zoster causes:
- Encephalitis
- Myelitis
Reactivation in AIDS (40% no rash):
- Myelo-radiculitis
- Chronic progressive encephalitis
- Ventriculitis
Etiology of CNS infection in immunocompromised patients
- Cytomegalovirus
- encephalitis
- cranial nerve palsies
- poly-radiculopathy - VZV
- myelitis
- encephalitis (acute/progressive)
- radiculitis
- ventriculitis - JC virus
- progressive multifocal leukoencephalopathy - HIV
- Chronic enteroviral meningo-encephalitis in agammaglobulinaemics
Rabies
- Rabies virus
- RNA virus, Rhabdovirus
- Zoonosis, main reservoir: Dogs
- In HK: last local human case 1981, last animal rabies 1987
- common in neighbouring countries
—> imported cases seen
—> exposure of dog bites overseas need to be managed - animal saliva is infectious if introduced on mucosal surface / broken skin
- human-to-human transmission very uncommon
Pathogenesis:
Virus replicates at site of bite (e.g. muscles)
—> enter peripheral nervous system via stretch spindles
—> **passive ascend via **sensory fibres (slow axonal transport: long incubation period)
—> **replication in dorsal ganglion
—> **rapid ascend in **spinal cord (axonal transport)
—> infection of spinal cord, brainstem, cerebellum, other brain structures
—> **descending infection via sensory, autonomic nervous system to retina, cornea, salivary glands, skin, nasal mucosa, other organs
Clinical features and managment of Rabies
Long incubation period: usually 20-90 days, can be >1 year
Prodromal: non-specific, onset of itching at site of healed bite wound
2 presentations:
1. Furious rabies (typical): hydrophobia (spasm of swallowing reflex), aerophobia, meningo-encephalitis
2. Paralytic rabies: paralysis begins in bitten limb and spreads, may be confused with myelitis / encephalitis due to other causes
—> Both invariably fatal
Laboratory diagnosis —> demonstration of virus:
1. Brain (Viral inclusion bodies / Negri bodies)
2. Skin biopsy (after descending infection)
3. Corneal impression smear
Management:
- No treatment once symptoms appear —> fatal
- Prevention only
Prevention:
1. Management of dog bites
- good wound toilet, aggressive washing of bite to physically wash out virus, use local anaesthesia if needed
- avoid suturing
- manage Tetanus risk (Tetanus vaccine)
- Assess rabies risk (where, what animal, unprovoked, break in skin / mucosal exposure)
- rabies only affect ***mammals (no risk from insects, reptile, bird, fish), domestic rats in HK are NOT infected
- endemic area: no endemic rabies in HK, infection in China / other parts of Asia. is the animal imported? Bite occur overseas?
- behaviour of animal: unprovoked bite? has animal bitten other human/animal? clinical signs of rabies (paralysis, increased salivation) of the animal?
- is animal available for observation? If animal is alive after 7 days —> rabies excluded, animal brain submitted for virology examination —> infection can be diagnosed by looking for viral inclusion bodies (Negri bodies) / virus antigens by IF - Post-exposure prophylaxis
- possible due to long incubation period
- active / passive immunisation (for risk present / high risk present respectively)
- Active immunisation: **Human diploid cell vaccine (killed vaccine), 4 doses give IM to deltoid at days 0, 3, 7, 21 —> immunisation course can be aborted if animal later shown to be NOT infected
- Passive immunisation: **Human rabies immune globulin (HRIG) —> infiltrate bite wounds thoroughly —> inject any reminder IM to thigh (at a site different to vaccine) - Control of source
- control stray dogs
- vaccination of dogs (done in HK) - Pre-exposure prophylaxis
- vaccine for high risk individuals (e.g. vets, long term travel in endemic areas)
