Flashcards in NEurotropic Agents Deck (44)
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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
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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
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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
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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
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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
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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
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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)
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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
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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
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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
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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%
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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
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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
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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
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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
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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
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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
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After a rabies exposure should you treat?
Rabies immune globulin is a limiting resource but untreated rabies is fatal
Type of exposure (bite vs nonbie)
Epidemiology of animal rabies in the area where the contact occurred and species of animal involved
Availability of exposing animal for observation and rabies testing
Exposure to bats deserve special assessments
**Regard skunks, bats, raccoons, and foxes as rabid unless otherwise proven**
If you wake up and find a bat in your room, consider yourself exposed becuase the bite size is too small to really know
Dogs cats and ferrets
- if animal available observe for 10 days, if no sx dont treat
- if rabid or suspected rabbit, treat
- if unknown..
Skunks bats raccoons and foxes
- rabid unless proven otherwise, treat!
Livestock, small rodents, large rodents
- dont really treat with postexposure prophylaxis
Once symptoms have appeared, only treatment is supportive
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Rabies Treatment
Post exposure prophylaxis for non immunized individuals
- wound cleansing - soap and water
- RIG - rabies immune globulin - around wound
- vaccine- inactivated virus vaccine
Post exposure prophylaxis for previously immunized individuals
- wound cleansing
- do not give RIG
- give Vaccine
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What is the rabies vaccine
Killed inactivated vaccine
Virus grown in cells in lab, purified then inactivated
HDCV - Human diploid cell vaccine
PCECV - purifided chick embryo cell vaccine
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West Nile Virus - flavivirus
Member of the flavivirus family
- other members include yellow fever, dengue, Japanese encephalitis
Spread by mosquitos between animal hosts (birds) and humans
Enveloped, icosahedral virion, 40 -50 mM diameter, transmitted by body fluids
Surface is covered by vial E protein dimers which is the target for neutralizing Ab and is responsible for viral attachment to cells and membrane fusion
Positive RNA genome
Transmitted by mosquitos - so it is also called an arboviruses (viruses that are transmitted by biting insects)
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Flaviviruses are major causes of viral encephalitis
What are the main ones in the US
St. Louis encephalitis - mosquito
West Nile virus - mosquito
Not all flaviviruses cause encephalitis: dengue, hep C. Yellow fever virus
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WNV - an arboviruses, how does it spread
Spread by biting insects
Humans are a dead-end host for WNV because they have very low levels of viremia
- if a mosquito feeds on a WNV infected person the chances of that mosquito picking up the virus is remote
Birds, especilaly corridas (jays, crows) have high levels of WNV viremia
Cases peak in summer/early fall along with mosquito populations
Life cycle of WNV involves a vertebrate vector, commonly birds, and a mosquito vector
Human to human transmission can occur through transfusions and transplants
WNV is endemic in the lower 48 stats and can infect almost any animal, particularly bird with high levels of viremia
Then mosquitos that primarily feed on birds get it —> avian mosquito life cycle—> mosquito feeds on humans they are infected
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WNV introduction
Introduced into the US in NYC in 1999
Over the next several years, this mosquito borne virus that infects many bird species spread throughout the US
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WNV Neuroinvasive diseases cases in US by year
WNV has produced the largest outbreaks of encephalitis/meningitis ever reported in the Western Hemisphere
- US had largest WNV encephalitis epidemic ever recorded in 2002
WNV is now the dominant cause of epidemic encephalitis in US
Deaths almost exclusively limited to those 55 and older
Can cause paralysis due to death of motor neurons
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WNV symptoms
Most cases asymptomatic, most in late summer, early fall; almost all serious infx involve pt older than 55 yo
Get headaches, sometimes self limited rash
Clinical features of more severe cases
WN fever
- fever, HA, myalgia, anorexia
Mild - WNF (20% of cases
- 3 - 6 days
- GI complaints
- fever, HA, myalgia, anorexia
Severe
- can cause flaccid paralysis - guillain barre syndrome
- case fatality rate 5 - 10%
Virus has a predilection for motor neurons so it can cause flaccid paralysis similar to poliovirus
Biggest risk factor is age, no antiviral drugs or vaccines
West Nile meningoencephalitis sever (1%) of cases
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Human Enteroviruses
IMAGE SLIDE 32
Family picornaviridae
Small RNA viruses
102 serotypes in 4 groups
Aseptic meningitis
- EVs can cause 85-95% of community acquired cases, coxackieviruses B2 and B4 & echoviruses 4, 6, 9, 11, 16, 30
Encephalitis
- EVs account for 10-20% of acute encephalitis: group A coxsackie virus
- brain stem encephalitis with EV71 infx
- chronic meningoencephalitis with echovirus in agammaglobulinemia, bone marrow and organ transplants, other immunodeficiencies
Polio is the most famous (and notorious) human enterovirus
Petechiae or a rash may occur
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Polio: dread disease of 1900s
Common in 1900s, polio was circulating but didn’t become an issue until hygiene improved
When small children are infected, incidence of paralysis is low but if you get infected for the first time when you ar older, the chances of a bad outcome are increased
So improved hygiene and water supplies (polio, like other enteroviruses, is spread fecal-oral) so people got infected later
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Polio pathogenesis
No animal reservoir
Enterovirus
- three serotypes: types 1,2, 3 and vaccines are a mix of all these serotypes
- transmitted fecal-orally
- replication in tonsils and peyer’s patches in the gut, replicates to high levles in gut (peyers patches) because if you get exposed you get exposed in the GI tract
- excreted in throat and feces
- infection cycle repeats
Sometimes causes CNS infx
- invades the CNS
- localized in and kills anterior horn cells
- lower motor neuron paralysis without sensory loss
90% of infx are asymptomatic
5% minor infx, self limited, no CNS involvement
1 - 2% aseptic meningitis
.1-2% paralytic polio
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