Brain and Behavior Flashcards
1
Q
Acute Viral Encephalitis Overview
A
- Approximately 20,000 cases of encephalitis occur in the US each year, almost all of which are caused by viruses - Hallmark of encephalitis is acute onset of febrile illness accompanied with headache and altered mental status - HSV is most frequent etiology of sporadic encephalitis in US - HSV-1 associated with severe focal encephalitis in adolescents and adults - Untreated, disease has 70% mortality rate and 97% of untreated survivors left with permanent neurologic deficits HSV-2 associated with newborns
2
Q
HSV Encephalitis Diagnosis
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- Diagnosis of herpes encephalitis is suspected if adult pts have fever and focal cerebral cortical lesions, particularly in the frontal and temporal lobes - Increased CSF protein occurs in 90% of cases but rarely exceeds 200mg/dL - CSF glucose almost always normal - EEGs provide clues as 90% of pts have focal or generalized slowing - Presence of periodic sharp wave complexes in the temporal leads superimposed on a slow amplitude background is highly suggestive of HSV encephalitis - MRI shows abnormal areas involving the temporal lobes and orbitofrontal cortex in more than 90% of cases - Biopsy has been replaced by detection of HSV DNA in the CSF by PCR (specificity is 100% and sensitivity is 95%)
3
Q
HSV Encephalitis Treatment
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- Early recognition of HSV encephalitis is essential because effective antiviral therapy (acyclovir) is available, and prompt treatment can significantly decrease the morbidity and mortality of the disease - Acyclovir acts by inhibiting the viral DNA poly, thus interfering with viral replication - Acyclovir reduces mortality from 70% -> 19% in adults - Neurological impairment can still occur in 40%-60% of pts (outcome is related to the severity of disease at the time antiviral therapy is begun, hence the urgency) - Intravenous therapy should be continued for 14 to 21 days
4
Q
Neonatal Herpes Simplex Virus
A
Case Study: - Case of neonatal HSV contracted during birth - During a breech presentation, a fetal monitor was placed on buttocks of baby, and due to the greatly prolonged labor, the baby was delivered by cesarean section - On sixth day, vesicles with an erythematous base appeared at the site where the fetal monitor had been placed - HSV was grown from vesicle fluid, as well as from spinal fluid, cornea, saliva, and blood - Baby became moribund w/ frequent apneic episodes and seizures - IV treatment w/ adenosine arabinoside (ara-A; vidarabine) - Baby also developed bradychardia and occasional vomiting while vesicles spread to cover lower extremities, back, palm, nares, and right eyelid - Within 72 hrs of ara-A treatment, Baby’s condition began improving - Normal development was reported at 1 and 2 years of age - 6 wks after birth, herpes lesion was found on mother’s vulva - Virus (HSV-2) was probably acquired through an abrasion caused by the fetal monitor while neonate was in birth canal - Ara-A has since been replaced with all around better drugs (acyclovir, valacyclovir, and famciclovir)
5
Q
HSV infection in the neonate
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- Devastating and often fatal disease (most often caused by HSV-2) - May be acquired in utero but more commonly is contracted either during passage of infant through the vaginal canal because the mother is shedding herpesvirus at the time of delivery, or it acquired postnatally from family members or hospital personnel - Baby initially appears septic, and vesicular lesions may be present - Because cell-mediated immune response is not yet developed, HSV disseminates to liver, lung, and other organs, as well as to the CNS - Progression of the infection to the CNS results in death, mental retardation, or neurologic disability, even with treatment
6
Q
Varicella-Zoster Virus
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- VZV causes chickenpox (varicella) and upon recurrence causes herpes zoster, or shingles - VZV shares many characteristics with HSV (as both are alphaherpesviruses) 1) Ability to establish latent infection of neurons and recurrent disease 2) Importance of cell-mediated immunity in controlling and preventing serious disease 3) Characteristic blister-like lesions - VZV also encodes a thymidine kinase and is susceptible to antiviral drugs - VZV spreads predominantly by the respiratory route
7
Q
Varicella-Zoster Virus Structure and Replication
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- Smallest genome of the human herpesviruses - Slower and in fewer types of cells than HSV - Establishes a latent infection of neurons, but unlike HSV, several viral RNAs and specific viral proteins can be detected in the cells - Large, enveloped virus that contain double-stranded DNA that is surrounded by an icosadeltahedral capsid
8
Q
Varicella-Zoster Virus Pathogenesis and Immunity
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- VZV is generally acquired by inhalation, and primary infection begins in the tonsils and mucosa of the respiratory tract - Virus then progresses via bloodstream and lymphatic system to the cells of the reticuloenothelial system - Secondary viremia occurs 11 to 13 days and spreads the virus throughout the body and to the skin - The virus infects T cells and is transmitted on cell-cell interaction - Virus causes a dermal vesiculopustular rash that develops over time in successive crops. - Fever and systemic symptoms occur w/ rash - Virus becomes latent in dorsal root or cranial nerve ganglia after primary infection - On reactivation, virus overcomes interferon-alpha to spread the rash along the entire dermatome known as herpes zoster, or shingles - Antibody is IMPORTANT for limiting the viremic spread of VZV
9
Q
Varicella-Zoster Virus Epidemiology
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- VZV is extremely communicable, with rates of infection exceeding 90% among susceptible household contacts - Disease spread principally by respiratory route but may also be spread via contact with skin vesicles - More than 90% of adults in developed countries have the VZV antibody - Herpes zoster results from reactivation of patient’s latent virus - The disease (zoster) develops in approx. 10%-20% of the population infected with VZV, and incidence rises with age
10
Q
Varicella-Zoster Clinical Syndromes
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- Varicella (chickenpox) is one of the 5 classic childhood exanthems - Maculopapular rash appears after 14 days and each lesion forms a thin-walled vesicle on an erythematous base (“dewdrop on a rose petal”) - Herpes zoster (zoster means “belt”) is a recurrence of a latent varicella infection acquired earlier in pt’s life - Severe pain in the area innervated by the nerver usually precedes the appearance of the chickenpox-like lesions - Rash is typically limited to a dermatome and resembles varicella - Cowdry type A intranuclear inclusions seen in infected cells as well as syncytia (use Tzanck smear) - Antigen detection and PCR are sensitive means of diagnosing VZV infection
11
Q
What is Postherpetic Neuralgia?
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- Chronic pain syndrome called postherpetic neuralgia, which can persist for months to years, occurs in as many as 30% of pts older than 65 years in whom herpes zoster develops - No good treatment, however analgesics and other painkillers, topical anesthetics, or capsaicin cream may provide some relief from the post-herpatic neuralgia that follows zoster
12
Q
Varicella-Zoster Treatment, Prevention, Control
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- Treatment is appropriate for adults and immunocompromised pts, but is typically unnecessary for children - Acyclovir, famcyclovir, and valacyclovir are drugs of choice (latter two have improved pharmacodynamics) - Because VZV infection in children is generally mild and provides “lifelong” immunity, their exposure is typically encouraged - Immunocompromised pts may be protected from serious disease via varicella-zoster immunoglobin (VZIG) - Live-attenuated vaccines are available to induce production of protective antibody and cell-mediated immunity in immune-deficient children and others - A stronger version of said vaccine is available for older adults to prevent the onset of zoster
13
Q
Picornaviruses (Enteroviruses)
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- Plus-strand RNA surrounded by a naked icosahedral capsid resembles messenger RNA - Enteroviruses do not usually cause enteric disease, but they do replicate within and are transmitted by the fecal-oral route - Upper respiratory tract, oropharynx, and the intestinal tract are the portals of entry for enteroviruses - Virions are impervious to stomach acid, proteases, and bile - Viral replication is initiated in the mucosa and lymphoid tissue of the tonsils and pharynx, and the virus later infects lymphoid cells of Peyer patches underlying the intestinal mucosa - Most enteroviruses are cytolytic, replicating rapidly and causing direct damage to the target cell - Enteroviruses are exclusively human pathogens - Poliovirus is a type of Enterovirus
14
Q
Poliovirus Overview
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- Poliovirus gains access to the brain by infecting skeletal muscle and traveling up the innervating nerves to the brain, like the rabies virus - Poliovirus is cytolytic for the motor neurons of the anterior horn and brain stem - The location and number of nerve cells destroyed by the virus govern the extent of paralysis and whether and when other neurons can re-innervate the muscle and restore activity - The combined loss of neurons to polio and to old age may result in paralysis later in life, termed postpolio syndrome - Antibody is the major protective immune response to the enteroviruses - Asymptomatic shedding can occur for up to a month, putting virus into the environment (summer is major season for enterovirus disease) - Wild-type poliovirus has been eliminated from Western Hemisphere and most of world via vaccine
15
Q
Poliovirus can cause 4 outcomes in unvaccinated people:
A
1) Asymptomatic illness: Results if viral infection is limited to the oropharynx and the gut. At least 90% of poliovirus infections are asymptomatic 2) Abortive poliomyelitis: the minor illness, is a nonspecific febrile illness occurring in approx. 5% of infected people (fever, headache, sore throat, vomiting, etc.) 3) Nonparalytic poliomyelitis (aseptic meningitis): Occurs in 1% - 2% of pts with poliovirus infections. In this disease, the virus progresses into the CNS and the meninges, causing back pain and muscle spasms along with the minor illness 4) Paralytic polio: the major illness, occurs in 0.1% - 2.0% of persons. Most severe outcome. Biphasic illness that comes 3-4 days after minor illness subsides. Virus spreads from blood to anterior horn cells of the spinal cord and to the motor cortex of brain.
16
Q
Paralytic Poliomyelitis
A
- Characterized by an asymmetrical flaccid paralysis with no sensory loss - Poliovirus Type 1 is responsible for 85% of the cases of paralytic polio - The degree of paralysis can vary and may involve few muscles or all four extremities - Most recoveries occur within 6 mnths., but as long as 2 yrs. may be required (if they don’t die or stay paralyzed that is) - Bulbar poliomyelitis can be more severe, may involve the muscles of pharynx, vocal cords, and respiration, and may result in death in 75% of pts
17
Q
Polio-like Disease from Coxsackie A Virus
A
Clinical Case: - 4 y.o. has onset of abdominal pain, distended abdomen, inability to urinate, and inability to walk - All abdominal reflexes were gone, accompanied by bladder and rectal dysfunction - Pain and temp sense was normal - CSF showed an increase in cell count with 95% neutrophils and 5% lymphocytes - CSF protein and glucose normal values - Serological analysis negative for poliovirus - Antibody to Coxsackie A10 was detected during acute phase and after 4 weeks - Three wks after admission, pt was able to walk again, but mild dysfunction of bladder and rectum remained, even 3 mnths after admission - Case just shows that even though polio has been basically eliminated, polio-like disease can be caused by other picornaviruses and revertants of the vaccine-related strains of polio
18
Q
Viral (aseptic) Meningitis
A
- An acute febrile illness accompanied by headache and signs of meningeal irritation, including nuchal rigidity - Petechiae or a rash may occur in pts w/ enteroviral meningitis - Recovery is uneventful, unless the illness ins associated with encephalitis or occurs in children younger than 1 y.o. - Outbreaks of picornavirus meningitis (echovirus 11) occur each year during the summer and autumn
19
Q
Rabies Virus
A
- Rabies virus is a zoonotic pathogen classified in the family Rhabdoviridae, genus Lyssavirus - Mainly a disease of DOGS in developing countries (responsible for 90% of all rabies deaths), in developed countries, it is perpetuated by wildlife, such as bats and mammalian carnivores (foxes, skunks, coyotes, mongooses, jackals, etc.) - Is transmitted to humans by the bite of an infected wild or domesticated animal - Virus spreads from site of bite via nerves in peripheral nervous sys. to the CNS, the virus then travels back from the brain to peripheral sites - Variable incubation period (typically 1-3 mnths) - Signs and symptoms: Acute, progressive fever, headache, difficulty swallowing, paresthesia, increased muscle tone, hypersalivation, paralysis, and hydrophobia - Diagnosed postmortem by fluorescent antibody demonstration of viral antigen in brain or antemortem by detection of viral antibody in pt serum or CSF - Treatment/Prevention: Rabies can be controlled by vaccination of animals (both wild and domesticated), stray animal management, and local leash laws - Prevented in humans by combination of local wound treatment, passive administration of rabies immune globulin, and rabies vaccination - NO PROVEN EFFECTIVE CURE
20
Q
Rabies Virus Structure
A
- Large, rod/bullet-shaped and contain an envelope - Genome consists of only five genes that each encodes a single protein - Envelope glycoprotein (G protein), a matrix (M) protein underlying the envelope, and a helical ribonucleoprotein (RNP) core, or nucleocapsid, in which the unsegmented, single-stranded RNA is tightly encased with the nucleoprotein (N protein) - A phosphoprotein (P protein) is also found in the RNP core - Negative polarity, thus the virions contain an RNA-dependent RNA poly (L protein) - NEGRI BODY INCLUSIONS can be seen in cytoplasm
21
Q
What percentage of people bitten by a KNOWN rabid dog gets rabies? Why or Why not?
A
- Only 15% as humans are somewhat refractory to the rabies virus - Percentage rises to more than 60% with severe bites on the face and head as it makes it a shorter distance from the brain and shorter incubation period - #AWESOME
22
Q
How does the rabies virus move?
A
- Passively through the axoplasm of peripheral nerves to the CNS in a retrograde fashion - From the brain, the virus often returns to the periphery using the same axoplasmic route as used for centripetal movement - A favored peripheral site is the highly innervated salivary glands - The virus replicates at peripheral sites (1,000x more concentrated at salivary glands than levels found in brain)
23
Q
If the animal who bit someone is still healthy/normal after ___ days, it is safe to assume the person did not become infected with rabies.
A
A: 11 days
24
Q
Venezuelan equine encephalitis
A
- Arbovirus (Alphavirus) - Icosahedral capsid and a positive-sense, single-stranded RNA genome that resembles mRNA - Surrounded by an envelope - Vector: Aedes, Culex - Host: Rodents, horses - Distribution: North, South, and Central America - Disease: Mild systemic; severe encephalitis - The displacement of cellular mRNA from the protein synthesis machinery prevents rebuilding and maintenance of the cell and is a major cause of the death of the virus-infected cell - Humans are “dead-end” hosts in that they cannot spread the virus back to the vector because they do not maintain a persistent viremia (not in the blood, thus vector can’t pick it up) - Typically more a problem for livestock than humans
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Prognosis of Venezuelan equine encephalitis?
- The encephalitis typically resolves without sequelae, but there is the possibility of paralysis, mental disability, seizures, and death - There is a vaccine for domestic animals and prevention is through elimination of vector and breeding grounds
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Japanese encephalitis virus
- Arbovirus (Flavivirus) - Vector: Culex - Host: Pigs, birds - Distribution: Asia - Disease: Encephalitis w/ some fluilike symptoms
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West Nile Encephalitis Virus
Clinical Case: - 38 y.o. Massachusetts woman who presents w/ progressively worsening headache, with photophobia and fever - Summer time, had just recently traveled to St. Louis, and walked in the woods and visited the zoo while there - Had been aware she had been bitten by mosquitoes - Fever, chills, tachycardia, confusion, lightheadedness, and lethargy - Neck was rigid with present Kernig sign - CSF contained IgM to West Nile Virus and low titers of St. Louis Encephalitis Virus (SLE) - Treated for meningitis and for HSV (acyclovir) - After 11 days she had fully recovered as flavivirus meningoencephalitis usually resolves with limited sequelae \* MRI will not show specific localization of lesions (unlike in herpes simplex virus encephalitis)
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St. Louis Encephalitis Virus
- Arbovirus (Flavivirus) - Vector: Culex - Host: Birds - Distribution: North America - Disease: Encephalitis
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La Crosse Virus
- Bunyavirus (California encephalitis virus group) - Enveloped, segmented, negative-strand RNA virus - Genome has complementary ends and forms circles - Insect Vector (Arbovirus): Mosquitoes found in the forests of North America - Pathologic condition: Febrile illness, encephalitis, febrile rash - Vertebrae hosts: Rodents, small mammals, primates, marsupials, birds - 48 hr incubation time and fevers typically last 3 days - Encephalitis illness are sudden in onset after 1 week incubation with symptoms of fever, headache, lethargy, and vomiting (seizures in 50%) - Illness lasts 10-14 days and less than 1% of pts die, but seizure disorders may occur as sequelae in as many as 20% - Prevention via vector control
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HIV-1
**_Overview_**: Retroviridae family (lentivirus group), causes immunodeficiency, neoplasia, and neurologic disease, invades CNS via "Trojan horse" by infecting monocytes and admission by the BBB where monocytes mature into long lived perivascular macrophages
Causes neurologic disease via primary (HIV directly causes), secondary (aka opportunistic, it interacts with other pathogens causing opportunistic infection or tumors), or treatment-related (i.e. immune reconstitution inflammatory syndrome [IRIS])
**_Pathogenesis_**: HIV can infect capillary endothelium, microglic, monocytes, macrophages, astrocytes, and choroid plexus
SUMMARY OF THIS CARD IMMEDIATELY BELOW
*Mild neuro involvement with primary infection. Chronic infection leads to HIV-associated neurocognitive disorder (HAND), HIV-Associated Vacuolar Myelopathy, HIV-Associated Distal Peripheral Sensory Neuropathy (HIV DSPN), Inflammatory Demyelinating Polyneuropathy (IDP), PML (JC virus), CMV, Cryptococcal Meningitis, Toxoplasmosis Encephalitis, Primary CNS Lymphoma in AIDS, Immune Reconstitution Inflammatory Syndrome*
***_See below for specifics on each_***
_Primary Infection_- flu or mononucleosis like symptoms, early CNS infection is usually asymptomatic, most common neuro syndrome is acute aseptic meningitis or meningoencephalitis (fever, headache, still neck, and photophobia)
_Chronic Infection_- most commonly has cognitive, central motor, and behavioral abnormalities, HIV-associated neurocognitive disorder (HAND), HAND subdivided into 1) assymptomatic neurocog impairment (ANI) 2) minor neurocog disorder (MND) 3) HIV-Associated dementia (HAD), also get other stuff, see below
_HAND_- attention/concentration and working memory and executive function deficits, ataxia, motor slowing, apathy, irritability, psychomotor retardation, gross appearance of brain is normal until advanced disease where atrophy may be noted (caudate, putamen, nucleus accumbens),HAND not as common with cART treatment
_HIV-Associated Vacuolar Myelopathy_- spinal cord disease, slowly progressive leg weakness, spasticity, dorsal column sensory loss, ataxia, urinary frequency and urgency, erectile disfuction, no treatment, distinguish from B12 deficiency
_HIV-Associated Distal Peripheral Sensory Neuropathy (HIV DSPN)_- most common neurologic problem in AIDS, paresthesias beginning in the feet, burning, numbness, temp sensations, demyelination followed by Wallerian degeneration
_Inflammatory Demyelinating Polyneuropathy (IDP)_- rare, rapid onset of ascending weakness, areflexia, ANS instability, bowel and bladder function spared, similar to Guillain-Barre but with mile lymphocytic pleocytosis, treat with cART and supportive care
_PML (JC virus)_- occurs during severe immunosuppression, diagnosis via JCV PCR, no treatment
_CMV_- infects brain, spinal cord, meninges, retina, dorsal root ganglion, directly kills neural cells by inducing apoptosis, CMV and HIV transactivate each other, CSF CMV PCR is gold standard diagnostic tech, treat with IV ganciclovir and cART
_Cryptococcal Meningitis_- affinity for CNS bc of consumption of catecholamines, malaise, headache, fever, seizures, very lethal, treat with amphotericin B, important to manage increased intracranial pressure
_Toxoplasmosis Encephalitis_- headache, foval neurologic deficit, cognitive dysfunction, seizures, altered mental status, highly inflammatory lesions with necrosis and mass effect, diagnose via IgG antibodies in blood, treat with pyrimethamine and sulfadiazine
_Primary CNS Lymphoma in AIDS_- associated with EBV, confined to CNS, caused by immunosuppression and lack of CD4+ cells, lethargy, confusion, memory problems, headaches, seizures, focal weakness, possibly diagnosis by EBV PCR in CSF, definitiely by tissure examination, treat with chemotherapy
_Immune Reconstitution Inflammatory Syndrome_- complication associated with treatment of AIDS, occurs within first 4-8 weeks of starting cART, unknown inflammatory response cause by cART that involves massive infiltration of CD8+ cells
31
JC Virus
Member of Polyomaviridae family
DNA genome, requires host replicaton machinery
Enter via respiratory tract, latent infection in kidney, B cells, monocytes, others
Activated in Immunosuppression (AIDS), crosses BBB by replicating in endothelial cells of capillaries, lysis of oligodendrocytes causes demyelination
Causes Progressive multifocal leukoencephalopathy (PML)- demyelination in CNS from oligodendrocyte infection of JC virus
Incubation period of years
Most infected by 15 y.o. but it is asymptomatic
32
Measles Virus
**Subacute sclerosing panencephalitis (SSPE)**- serious neurologic sequela of measles, affects 7 in 1 million patients, defective measle virus perissts in brain and acts as a slow virus, slowly progressive demyelination in CNS ending in death, causes changes in personality, behavior, and memory, can get myoclonic jerks, blindness, and spasticity
MMR vaccine helped
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Prions
No virion structure
Infectious prions are resistant to standard means of inactivation (formaldehyde, urea, boiling, EtOH, radiation, proteases), need to use phenol (90%), bleach, ether, NaOH (2M), strong detergents, and autoclaving
Confined to CNS infection
Causes neuro degeneration and spongiform changes
Long incubation periods (months to decades) followed by chronic progressive disease (weeks to years)
**Always fatal**, no host immune response possible
Humans have normal cellular prion protein (PrPC) of unknow function and it has alpha helical structure, it is held in cell membrane (not secreted), encoded on chrom 20
Infectious prion is PrPSc aggregates into amyloid rods (fibrils) and is found in cytoplasmic vesicles but is later secreted (not in membrane), has more of a beta-pleated sheet structure allowing it to aggregated, acts as a template to transmit mutant conformation onto new prions
Can be found in other tissues but only cause disease in brain
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Scrapie
Found in sheep and goats, high titers of prions in brain, spinal cord, and eye, also detected in milk from sheep
Characterized by development of amyloid plaques in CNS
Protease-resistant protein is purified from scrapie-infected brains and is called prio protein (PrP), PrP alone is infectious
PrP is derived from a larger host-encoded protein, PrPSc, which is an altered version of the normal PrPC protein
Normal PrPC is a glycolipil-anchored membrane protein, abnormal PrPSc is resistant to degradation, caused by point mutation
PrPSc can form heterodimer with PrPC and refold it into mutant PrP
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Bovine Spongiform Encephalopathy (BSE)
Mad cow disease in Great Britain
Caused by using cattle feed that was contaminated with bone meal from scrapie-infected sheep and BSE-infected cattle carcasses
Causes New Variant CJD in humans (New Variant CJD = BSE)
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New Variant CJD
First in Great Britain
Variant form of classical CJD disease
Occurs in younger people with pathologic characteristics similar to those of BSE...determined that it was caused by same pathologic agent
Polymorphism in amino acid sequene of human prio protein made people susceptible
**Mainly affects people under age of 30**
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Kuru
Only in New Guinea due to cannibalism of dead relative rituals
No longer exists
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Classic CJD
Gradual development
Causes progressive dementia, ataxia, myoclonus, and death in 5-12 months
**Usually in those over 50 y.o.**
Two familial forms are Gerstmann-Straussler-Scheinker syndrome and fatal familial insomnia, caused by inheritance of mutation in PrP gene
Acidental transmission by hormone prep from human cadaver pituitary glands, corneal transplants, contaminated surgical instruments, and dura mater grafts
Infectious protein is very similar to scrapie PrP
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Spongiform Encephalopathy
Result of infection by prion
Found in CJD, vCJD, Kuru, etc
Describes the appearance of vacuolated neurons as well as their loss of function and lack of immune response or inflammation
results in loss of muscle control, shivering, myoclonic jerks, and tremors, loss of coordination, dementia, and death
