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
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 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
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
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
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
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
Polio eradication
India polio free for 6 years
Just Afghanistan and Pakistan’s aren’t
Spongiform encephalopathies (prions)
Slide 38
Spontaneous form of the human disease = Creutzfeldt-Jakob Disease or CJD
- chronic degenerative disorders of the brain
- can arise spontaneously or can be transmitted
- spongiform degeneration and gliosis
- long incubation time- usually years, invariably fatal
- disease results from aberrant folding of a single protein called prion protein- or prP for short
- all mammals have PrP and can all misfold
Characteristic pathology in the nervous system
- small holes; no fibroblasts, no collagens - get holes where cells used to be and can arise spontaneously and transiently
- disease is fatal and incubates for many years
- disease results from aberrant folding of a single protein called prion protein—> cascade of misfolding but need normal prions to have this cascade effect
- all mammals and all ppl have Prp, and so all are capable of acquiring this disease that fortunately is rare
- spontaneous form of human disease (creutzfeldt-Jakob disease or CJD)
Spongiform encephalopathies: animal and human diseases
Prion protein in all mammals
Each tends to cause disease in its specific host
Humans: CJD
Scrapie: sheep and goats
BSE: cows (mad cow disease)
TME: mink
CWD: chronic wasting diseasemule deer, elk
Same disease caused by the same protein but arising in humans due to different causes
Prion diseases can be transmitted between species by inoculation or dietary exposure. But, transmission between species is less efficient than within species; BSE may be an exception to this
Spongiform encephalopathy in humans - Creutzfeldt Jacob Disease
Progressive dementia (over months)
Insomnia, fatigue, visual sx including cortical blindness
Startle myoclonus (involuntary twitching), ataxia (cant coordinate muscular movements), seizures
Abnormal EEG
No treatment, inevitably fatal
Not an infection; no fever systemic signs
History of Disocvery: Kuru and other spongiform encephalopathies
Kuru = CJD
Due to ritual cannabalism, only women get it because they eat brains (less desirable parts)
Incubation period can exceed 50 yrs so it may still exist
Prions identified - pursiner’s work
Scrapie is caused by a protein- prion - PrPsc or PrPres for protease resistant
Spongiform lesions are related to deposits or fibrils of PrPsc in brain - scrapie
Infectivity(mouse or hamster bioassay) resistant to heat, nucleases
Infectivity resistant to X-rays, UV
Infectivity sensitive to proteases; no RNA or DNA
Agent has been purified - it is a 25 kDA membrane glycoprotein called PrPsc
Normal brain has very similar protein called PrPc- cellular
Mechanism of CJD
PrPc and PrPsc are biochemically the same but they fold differently
Normal prion protein PrPc is alpha helical
Abnormal prion protein (PrPsc) has more beta sheets (model only)
Prion disease results from misfolding of prion protein—> cascade of prion folding, conversion of PrPc to PrPsc is due to change in protein conformation
As a result, the PrPsc protein forms toxic aggregates
Many diseases especially neurodegenerative diseases, arise when a protein misfold and forms toxic aggregates- seen in Parkinson’s and Alzheimer’s disease
MEchanism continued: prion diseases result from misfolding of normal PrPc
PrPsc can induce PrPc to misfold - cascading process that can also lead to transmission
Abnormal prion interacts with normal prion; converts it to abnormal form and sets off a cascade of misfolding, convert normal molecules into misolfded
More likely to happen with the same species
Can be infectious if you ingest malfolded PrP from an animal and this protein causes your own PrP to misfold, or one of your own PrPc molecules misfold due to a mutation or by chance, settting off this cascading process
Experimental Proof
Disease is not transmitted to PrPc knockout mice
Normal Prp is needed for the disease to occur, PrPsc does not cause disease by itself- has to cause normal PrP to misfold
Since spongiform encephalopathies result from abnormally folded prion protein binding to normally folded prion protein and converting to to abnormal form—> abnormally folded prion proteins from one species will interact with normal protein from a different species less well—> Barrier to Transmission etween species but this barrier is not absolute — variable incubation times
How does misfolding process get started?
Sporadic CJD: protein folding is close to perfect, but not quite
- somatic mutations or spontaneous conversion of PrPc to PrPsc, de novo
Familial forms of CJD: germline mutations in PrPc that cause it to misfold
Transmitted forms of CJD: Kuru which arose from ingesting brains of individuals who had the disease
Iatrogenic CJ- infection from contaminated human growth hormone, dura mater grafts
- variant CJD- ingest beef from a cow with BSE
Mad cow disease - BSE
Disease in UK spread over next several years
Classic spongiform encephalopathy + for prions
Linked to contaminated feed ingredients
- meat and bone meal derived from cattle
- prions were not inactivated
- thought to have arisen from mutation of normal bovine or sheep prion protein
End of epidemic: massive culling and banning the use of meat and bone derived from ruminants to other ruminants
Variant CJD - linked to bSD
Resembles normal CJD must strikes mostly younger individuals
Linked to consumption of beef and beef products taken from BSE-afflicted animals
First human cases of vCJD came to attention in 1996, and increased over the next several years before subsiding, thus lagging th eBSE infx curve in cattle
All humans with vCJD have been homozygous for polymorphism at position 129 in prion protein with methionine in place of a valine
Gold standard for diagnosing= neuropathology exam
Neuropathology, tissue distribution, and symptoms are different fro more classical CJDs (sporadic, familial)
Link between BSE and vCJD
Prions
Exposure in country linked to endemic BSE
In all cases of primary vCJD to date victims were homozygous M129 for PrPc (MM type)
Normal codon is valine many people are heterozygous
Something new G127V polymorphism in PrPc is resistant to being converted to PRPsc, may have been selected for in the face of prion epidemics in New gUinea
Median age of death of pt with classic CJD in US is 68 and very few cases occur in persons under 30
But median age of death of pt with vCJD is 28 years, much younger
How do people get CJD
Bad luck- some of normal prion protein spontaneously misfold—> cascade of misfolding
More bad luck - mutation in prion protein that leads to misfolding
Terrible luck- mutation in prion that makes you more susceptible to misfolding and you consume misfolded prion protein from another species like cow
Bad luck- iatrogenic introduction of malfolded prion protein (from medical exam or treatment)
Your own fault- eat the brain of someone with CJD
Get CJD
