NEurotropic Agents Flashcards
Neurotrophic Agents
Definitions
Encephalitis
Meng
- aseptic meng
Myelitis
Encephalomyelitis
Meningoencephalitis
Neurotropism
Neurovirulence
Encephalitis - infx of brain parenchyma
Meng - infx of meninges
- aseptic meng- viral infx of meninges
Myelitis- infx of spinal cord
Encephalomyelitis- brain and spinal cord
Meningoencephalitis- brain and meninges
Neurotropism- ability of an infectious agent to infect cells of nervous system
- potential to get past BBB
Neurovirulence - potential to cause disease once within the nervous system
Blood Brain Barrier
Meninges:
Endothelial cells
Impact
Meninges:
- dura mater
- arachnoid matter
- pia mater
Endothelial cells:
- tight junctions between endothelial cells in CNS vessels that restrict the passage of solutes to much greater extend than do endothelial cells
Impact;
- barrier to entry of infectious agents
- barrier to protective components of the immune response: Ab, inflammatory cells, complement
- barrier to penetration of antimicrobial drugs
- restrictive nature of intracranial and intravertebral spaces: inflammation and swelling — increase intracranial pressure
Pathogen entry into CNS
Hematogenous route
- direct infx of endothelial cells
- entry at choroid plexus due to lack of tight junctions
- entry via migration of infected inflammatory cells
- eg polio
Neural Route
- retrograde movement in axons from site of infx eg HSV, rabies, travel along axons
- eg herpes
- Olfactory nerve endings - only CNS element in direct contact with environment (rabies, inhale a lot of rabies virus)
Other ways
- directly infect endothelial cells or by crossing the cells via transcytosis (virus endocytosed and transported to the other side of the cell)
- infect migratory cell (eg HIV) like a lymphocyte that cross the BBB
CNS infections: common agents
Acute meng
Acute encephalitis
Acute brain abscess
Acute meng
- bacterial causes; strep pneumo, GBS, NEisseria meningitidis, H flu, Ecoli
- viral: arboviruses (WNV, SLEV), enterovirus (Echo, Coxsackie)
Acute encephalitis
- viral: arboviruses, enteroviruses, Herepsviruses
Acute brain abscess
- bacteria: staphylococci, mixed anaerobic/aerobic flora, GAS
Typically encephalitis is a viral infx - examining the CSF via lumbar puncture distinguishes viral vs bacterial
Bacteria typically cause meningitis
CNS infections: epidemiology viral
Age: HIV encephalitis more frequently impacts adults, at least in this country
Time of year: arboviruses, like West Nile are spread by mosquitoes. Thus, West Nile infx peak in the late summer and early fall, enterovirus infx (spread by fecal oral route) also peak in the late summer and early fall. HSV exhibits no particular dependence on time
Geographic distribution: examples: California encephalitis virus is restricted to the western US, Jap encephalitis virus is limited to Asia where it is quite common
Risk factors: immunocompromised individuals are at increased risk for most everything, with florid reactivation with varicella zoster being an example
Pattern: West Nile activity is epidemic; herpes is sporadic
CNS infections epidemiology (bacterial)
Age: GBS is the major cause of bacterial meng in newborn infants
Pattern: N meningitidis can cause an epidemic of meningitis (college campuses)
Risk factors immunocompromised individuals are at risk for many bacterial pathogens, listeria and various gram negative organisms are particularly problematic
Encephalitis- Clinical Signs
Acute onset of febrile illness with headache and altered mental status
Key: early mental status changed, can be focal or diffuse **
More commonly viruses
- HSV most common cause sporadic
- WNV most common cause epidemic
- Enteroviruses most common in children
Beavhioral or speech problems, neurological signs, seizures
Differences from meningitis: less likely fever, more likely personality/behavioral changes
Clinical hallmark of acute encephalitis = onset of febrile illness and altered mental status (focal or diffuse)
Encephalitis - major viral causes
HSV - most frequent sporadic cause
WNV - seasonal, most common epidemic cause of encephalitis in Western Hemisphere
Enteroviruses (like coxsackie) usually cause meningitis, but can cause encephalitis, typically milder typically kids
Rabies- rare but many receive prophylaxis
Other ones we wont cover
VZV- rare, older pets, immunocompromised used
California encephalitis viruses- seasonal only few cases per year
Japanese encephalitis virus- most common epidemic cause of encephalitis in Asia
MEalses- rare due to vaccine
Meningitis Clinical Signs
Classic Triad
- fever
- headache (severe, frontal, photobia, n/v)
- neck stiffness
Can have altered mental status, symptoms usually appear rapidly, may include nausea vomiting
Meninges signs - if you stretch the meninges and you have pain they are probs inflamed around the nerve routes and cause pain upon stretching
- jolt accentuation- turn head rapidly does headache increase
- Kermig sign: one leg with hip flexed, pain in back with extension of knee
- brudzinski sign: flexion of legs and thighs when neck is flexed
Typically no altered mental status, atleast early on
CSF findings
Aseptic meng- means you cant culture anything
Bacterial
- more white cells, polys
- lots of proteins, low glucose
- elevated intracranial pressure, do serial taps to keep pressure down
Viral
- less white cells, lots of lymphocytes
- normal glucose
- protein levels lower and glucose levles are normal
Herpes Simplex Virus
See image 14/54
Most frequent cause of sporadic encephalitis
- 10-20% of all cases several thousand per year
Usually severe focal encephalitis
70% mortality rate if not treated
Usually HSV1; rarely HSV2
Often temporal and frontal lobe via trigeminal nerve (where HSV1 lives)
Scans usually show frontotmeporal lesions
Detect viral DNA in CSF 95% sensitive
Treat with IV acyclovir immediately!!
- reduces mortality from 70 to 20%
Rabies virus pic 15/54
Rabdovirus (bullet shaped)
Negative stranded RNA
Enveloped
Nonsegmented
Epidemiology
- before vaccine, bite from a rabid dog led to certain death with the characteristic symptom of hydrophobia (fear of water)
50,000 human cases each year,m most via infected dogs, most are children and most die
When rabies reaches the CNS it is almost certainly fatal
Raccoons> bats> skunks> foxes
- east coast think raccoons, Europe. Foxes
Typical rabies case
Girl with arim pain—> increased arm pain, numbness and vomiting
—> febrile, speech difficulty loss of appetite, sore throat and neck pain
—> difficulty swallowing (hydrophobia)
—> incubated
—> bat bit her (leading vector for human infx in the US, bites not apparent)
Women malled by rapid beaver- if you are bitten by a wild animal (including bats) assume its is rabid- you must get treatment
What are the most common vector for human rabies in the US
Bats!
Rabies is the classic zoonotic infection and can infect almost any mammal, but only a few have become important vectors
In Europe,foxes are the primary reservoir; in Latin America, dogs are the primary transmitter as they are in most parts of the world
US, foxes and raccoons
Vaccines helpful
If bitten by wide animal assume it is rabid
Although bats may not be the most common carriers, they are th emost important for human disease - most of these cases escape preventative immunization because the exposure was not recognized because the bat bite was too small
How does rabies virus spread
Pic of negri bodies slide 20
Centripetal = from muscle along axon through nerve to the CNS where it replicates (—> necrotizing encephalitis—> down nerves and into saliva where it can spread again)
- site of inoculation influences time to symptoms
Once in the CNS…
Centrifugal = from CNS to cornea and salivary glands
What are NEgri Bodies
Slide 20
Negri bodies are eosinophilic inclusions in the neurons of patients with rabies infections
- example of the cytopathic effect
Rabies infects neurons in CNS and then get lymphocyte infiltration
Rabies Virus symptoms?
Long and variable incubation period - without symptoms usually 4 - 6 weeks but can be comnths
Prodrome phase: low Titus virus in CNS/brain; fever, nausea, vomiting, loss of appetite (malaise, fever, headache)
Neurologic phase: anxiety, confusion, agitation with delirium, pharyngeal spasms and hydrophobia: fear of water due to difficulty in swallowing (paralysis, confusion, disorientation, focal and generalized seizureslasts 2 - 7 days)
Coma - 0 - 14 days
Death
Almost universally fatal once symptoms evident
