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Flashcards in NEurotropic Agents Deck (44)
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Neurotrophic Agents

- aseptic meng




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


Endothelial cells


- 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

- 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

- more white cells, polys
- lots of proteins, low glucose
- elevated intracranial pressure, do serial taps to keep pressure down

- 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



- 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


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

Almost universally fatal once symptoms evident


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


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


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


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)


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


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


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


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


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
- 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


Human Enteroviruses

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

- 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


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


Polio pathogenesis

No animal reservoir

- 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


Polio Vaccines

Mix to type 1, 2, and 3

Live oral polio vaccine (OPV) - the Sabin vaccine
- taken orally once; sterilizing immunity
- live attenuated—> Induces cellular and humoral immunity, given orally and induces good immunity in the gut
- vaccine virus replicates, is shed, and. Can infect (immunize) others in the community
- but at a low rate, virus mutates and becomes virulent and can cause paralytic polio

Inactivated poliovirus vaccine (IPV)- the Salk Vaccine
- induces Abx, protects the CNS, induces humoral immunity
- safer no risk of reversion
- but doesnt protect the gut as well as OPV, takes 4 doses and is not shed so no bystander effect

When polio incidence is high, use OPV
When polio incidence is low, use IPV