Lecture 45-48
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| CNS vulnerability | closed box structure: any inflammation very damaging potentially, not many immune defenses
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| general rules | encephalitis is viral, acute meningitis is viral or bacterial, chronic meningitis is tubercle bacteria or fungi, brain abscesses are polymicrobial
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| 4 major syndromes of the CNS | meningitis, (bacterial, fungal, viral, non-infectious), encephalitis (viral), myelitis (rabies/polio), brain abscesses (aerobic and anaerobic, fungal, parasites)
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| Clues about etiology | demographics, onset, epidemiology, etiology, exposure history
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| meningitis | infection of meninges, worldwide more than 1 million cases/year , over 50% are viral, bacterial are more serious (higher mortalitly)
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| Causes of aseptic meningitis | Common viral: enteroviruses (most), arboviruses, HSV-2. Uncommon viral: mumps, CMV, HIV, HHV-8. Common bacteria: borrelia burgdorferi, partially treated bacterial meningitis. Uncommon bacterial: M. tuberculosis, Leptospira, M. pneumoniae
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| Septic meningitis | birth-3 months: S. agalactiae (E. coli, Listeria). 3-60 months: S. pneumoniae (N. meningitidis, H. influenzae B). >60 months: S. pneumoniae (N. meningitidis, L. monocytogenes, other gram-). Cranial surgery: S. aureus. Immunosuppressed: L. monocytogenes
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| symptoms of meningitis | Early: fever, malaise, aches and pains, nausea, vomitig, headache. Late: photophobia, neck stiffness, drowsiness, fits, inconsolable crying (babies), vasculitic rash
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| Encephalitis | infection of brain parenchyma, acute onset of febrile illness, signs and symptoms of meningitis along with focal neurological signs, seizures, altered consciousness, behavioral and speech disturbances
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| Myelitis | acute inflammation of the spinal cord, can be acute flaccid paralysis, headache, fever, signs of meningeal irritation, weakness of one or more extremities. Caused by polio previously, now WNV mostly
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| Brain abscess | localized pyogenic infection of the brain parenchyma and subdural or epidural meningeal spaces. symptoms reflective of space occupying lesion: headache, changes in mental status, seizure. Triad: headache, low grade fever, focal deficit
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| Mechanism of entry: direct extension | 25%, sinuses, teeth, middle ear/mastoid enable access to brain. Aerobic/anaerobic streptococci, Bacteroides, Enterobacteriaeae, Pseudomonas, Fusobacterium, Prevotella, Peptococcus. Normal flora of region or common opportunistic pathogens
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| Hematogenous spread | important cause of abscesses. Initial infection: lungs (strep, Fusobacterium, Corynebacterium, Peptococcus), heart (S. viridans, S. aureus), urinary tract (enterobacteriacaea, pseudomonas), wound (S. aureus), mouth (mixed flora)
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| penetrating head wound/neurosurgery | 37%, S. aureus most common, opportunistic in organ transplant or HIV (nocardia, aspergillus, candida)
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| vectors/reservoirs | encephalitis: mosquitoes or ticks. May be non human vertebrate host that are intermediary to transmission. Arboviruses: humans are usually dead end hosts
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| routes of entry: hematogenous | from circulatory system most common, may be introduced via insect bites (arboviruses), initial site may be elsewhere (pneumonia, sinusitis), choroid plexus is most common site of entry for bacteria: highly vascularized; inflammation increases entry,
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| Neural entry | viral infections, rabies enters in axon of peripheral nerve, travels to anterior horn of spinal cord
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| Direct inoculation by surgery or trauma | brain abscesses most relevant
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| CSF normal values | leukocytes 0-6, neutrophils 0%, RBC 0-2, glucose 40-80, protein 20-50
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| CSF acute bacterial meningitis | leukocytes >1000, neutrophils >50%, RBC 0-10, glucose <30, protein >100
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| CSF chronic mycobacterial and fungal meningitis | leukocytes 100-500, neutrophils <10%, RBC 0-2, glucose <40, protein 50-100 fungal, >100 bacterial
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| CSF acute viral meningitis | leukocytes <300, neutrophils predominate first 24 hr then <50%, RBC 0-2, glucose 40-80, protein 50-100
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| CSF viral encephalitis | leukocytes 10-500, neutrophils predominate first 24 hours then <50%, RBC 10-500, glucose 40-80, protein 50-100
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| CSF brain abscess | leukocytes 10-100, neutrophils <50%, RBC 0-2, glucose 40-80, protein 50-100
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| neuroimaging | used in suspected encephalitis, CT/MRI first step. Can distinguish between causes: Japanese B virus: grey matter involved. Nipah virus: multiple small white matter lesions
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| CSF PCR | used to diagnose viral encephalitis, polio. Rapid, highly sensitive and specific, small volume CSF required
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| Culture | important for bacterial pathogens, abscess fluid
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| Neisseria meningitidis | bacterial meningitis, purulent (75%) rest septicemic and rash without meningitis. carried by 5-10% of population. Gram-, intracellular, transmission by droplets (close contact), 2/3 in first 5 years of life, small peak 15-19
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| Serotypes (N. meningitidis) | A: large scale epidemics B:epidemics and outbreaks C:local outbreaks W135:pilgrimage to Mecca in 2001-2002 Y: occasional cases
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| Factors necessary for outbreak (meningitis) | susceptible individuals, high level of transmissibility, virulent encapsulated strain
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| N. meningitidis pathogenicity | serious disease only in a small percent due to hyperinvasive strains, host factors: lack of bactericidal Ab, complement system dysfunction
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| N. meningitidis microbial virulence factors | iron acquisition capability, LOS: causes most clinical manifestations, IgA1 protease, Pili: antigenetically variable (phase variation), capsule: production regulated according to disease (down regulated in initial attachment, upregulated intracellular)
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| N. meningitidis epidemiology | temperate and cold climates, peaks in winter, more irregular in tropical countries, meningitis belt of Africa: epidemics in dry season every 5-10 years, outbreaks last 2-3 years
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| N. meningitidis culture | humid conditions enriched with 5-10% CO2, chocolate agar for blood or CSF, modified Thayer-Martin agar for nasopharyngeal sample, latex agglutination, PCR, gold standard: culture with serogroup ID
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| N. meningitidis prevention | vaccine (A,C,Y,and W135). Limits: vaccine is group specific, limited to 3 years, doesn't prevent carriage, poorly immunogenic in children. New conjugate vaccine raises T cell dependent response and reduces carriage. May be penicillin resistant due to PBP
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| Streptococci | meningitis, brain abscesses. divided into 7 main groups based on 16srRNA: 1.pyogenic 2.anginosus 3.mitis (pneumoniae, mitis) 4.salivarium 5.bovis 6.mutans 7.unclustered
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| hemolysis patterns Streptococci | beta hemolytic:hemolysin production pyogenes, agalactiae. Alpha hemolytic: H2O2 production, methahemoglobin, pneumoniae, mitis
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| S. pneumoniae | gram+, leading cause of invasive disease in US, normal flora in 20% adults and 75% kids, mortality rate 25% in meningitis, 50% neurological sequelae
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| S. pneumoniae pathogenesis | 1. pneumolysin: pore forming toxin, potent neurotoxin, can trigger apoptosis. 2. hydrogen peroxide: contributes to apoptosis, large amounts produced in growth due to lack of catalase. 3. May have retrograde axonal transport: teichoic/lipoteichoic acid
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| S. agalactiae | early or late onset neonatal meningitis, group B, beta hemolytic, normal flora of female genital tract, 40% colonization in pregnant women, neonatal sepsis and meningitis, premature birth is risk factor
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| E. coli | gram-, motile, fermentative metabolism, systemic infection from initial in GIT respiratory or urinary, 80% in neonatal meningitis possess K1 Ag (antiphagocytic), S finbriae: adhesion, CNF-1: activates CTPases in Rho family (regulates cell functions)
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| Listeria monocytogenes | gram+, motile, intracellular rod, reservoir: soil, water, decaying vegetation, animals, asymptomatic humans (5-10%). Acquired by ingestion, meningitis in immunocompromised, crosses placenta
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| L. monocytogenes virulence factors | Literiolysin O: pore forming cytotoxin (hemolysi) enables escape from phagosome into cytosol, Internalins: trigger entry, Actin based motility: use host cell actin to move within and between host cells
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| viruses | after transient viremia seeding of RES and muscle--> replication--> seeding of secondary sites (CNS). CNS infection common but usually benign, neurological symptoms most common, post infectious encephalopathy
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| Herpes simplex virus 1&2 | HSVE, meningitis, myelitis. linear, dsDNA, enveloped. 1/1000000, most important treatable cause of encephalitis in US (90% HSV1, rest 2:immunocompromised, neonates)
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| HSV infection | primary: genital accompanied by meningitis in 30% women and 11% men. Reactivation of latent. Re-infection. No specific seasonal pattern, most frequent in 50-70 year olds
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| HSV pathogenesis | direct neuronal transmission from peripheral site via trigeminal or olfactory nerve-->brain. Mechanism of damage and predisposing factors unclear. Dx important because Acyclovir reduces mortality significantly.
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| Enteroviruses | >90% of viral meningitis, some encephalitis and myelitis. ss+RNA, non-enveloped, isocahedralm include polio, coxsackie, echovirus, enterovirus. humans are main reservoir, worldwide distribution, asymptomatic infection common.
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| Poliovirus | acute flaccid paralysis, infection of anterior horns cells of gray matter, signs common to meningeal irritation with weakness in one or more extremities.
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| polio symtoms | May be asymptomatic, non-paralytic, or paralytic (<2%): invasion of CNS from blood, spread by peripheral nerves, viral replication causes damage or destruction of nerves causing asymmetrical paralysis. 85% cases due to poliovirus type 1
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| polio pathogenesis | contact with contaminated stool& virus ingested, infects enterocytes in GIT, transverses intestinal wall by crossing basement membrane, moves into GALT, viremia seeds liver, lungs, and CNS
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| Polio replication | attaches by poliovirus receptor CD155, triggers conformational change in virion, viral RNA released into cell cytosol &binds to ribosomes, translated into polyprotein, cleaved by proteinases, new viral RNA synthesized, released via host cell lysis: 5-10hr
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| polio prevention | IPV: Salk, formalinised, injected, no induction of secretory Ab, used where eradicated. OPV: Sabin, stable at room temp with MgCl, live virus replicates in GIT, better immunity, can potentially revert or be spread to contacts
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| Arboviruses | arthropod borne, fever with or without maculopapular rash, encephalitis, or hemorrhagic fever. Many subclinical, geographic localization, transmitted by insect vectors. Prevent with vector control and vaccines
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| West nile virus | ss+RNA, enveloped, no symptoms in 80%, WN fever: 20%, mild flu like, duration 1-2 wks. Neuroinvasive: <1%, 10% hospitalized patients developed acute flaccid paralysis
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| WNV pathogenesis | pg 17 chart
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| WNV structural proteins | E=enveloped glycoprotein, elicits neutralizing Ab, structural domains:I antigenic II fusion of E II binds to host cells. prM=premembrane protein, block premature viral fusion
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| WNV non-structural proteins | RNA dependent RNA polymerase (NS5), helicase, protease, interferes with infected cell's normal response to viral infection
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| WNV epidemiology | S. europe, Africa, central and S Asia. Vector:mosquitoes, many avian host species
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| WNV diagnosis | ELISA of CSF to detect virus specific IgM RT-PCR less sensitive than serological assays
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| St. Louis encephalitis | encephalitis, aseptic meningitis. <1% clinically apparent. Canada, US, central america
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| Rabies | fatal meningoencephalitis, initial prodrome of non-specific symptoms then symptoms relating to wound site, then encephalitis (2/3 of people) then paralytic illness. Mortality 100% with symptoms. incubation 20-90d, depends on bit proximity to brain
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| Rabies viral characteristics | enveloped, ss-RNA, rod shaped, helical
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| Rabies epidemiology | highest in Asia, all warm blooded animal susceptible, urban and sylvatic spread, worldwide
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| Rabies pathogenesis | entry via cut, attach by surface glycoprotein to receptors (ACh receptor too), viral entry by endocytosis, 5 viral mRNA made (N,L,NS,G,internal membrane), travels via axons to CNS, spread to other tissues
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| Rabies diagnosis | Ag by immunofluorescence, virus isolation, histological changes, ELISA of CSF, DNA amplification (most sensitive), latex agglutination
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| Rabies treatment/prevention | immediate washing of wound with soap, debridement of wound and use of antiseptic, HRIG vaccine, initiation with inactivated vaccine (1,3,7,14,28, and 60 d post exposure with 2 boosters)
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| Crytococcus neoformans | meningoencephalitis, encapsulated yeast, asexual and sexual (filobasidium neoformans) in lifecycle. both true and opportunistic pathogen, associated with HIV (undiagnosed/untreated), or corticosteroid use.
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| C. neoformans symptoms | slow onset of non-specific symptoms, later mental status change, weight loss, coma. 45% with advanced HIV in underserved countries. Mortality 10-25%, found in bird droppings
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| C. neoformans pathogenesis | inhalation results in colonization: asymptomatic colonization, symptomatic pneumonitis, asymptomatic of lungs and lymph nodes. cellular immune response-->granulomatous inflammation-->yeasts killed or dormant-->defects allow replication and spread
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| C. neoformans virulence | GMX capsule: large, shed in tissues, antiphagocytic, inhibits leukocyte migration, induces apoptosis. Melanin: laccase enzyme-converts diphenolic compounds to melanin, protects against oxidative stress, prevents Ab mediated phagocytosis. Growth at 37
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| Prions | TSEs, chronic degenerative fatal infections, no NA, spongy appearance of cerebrum due to vacuole formation, survive for extended time in brain tissue, modified protein accumulates in neurons
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| Prions unique characteristics | highly resistant to some inactivation methods, lack humor or inflammatory immune response, absence of virus like particles, disease confined to CNS, long incubation, can be inherited (PrP gene)
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| CJD | sporadic (85%) or inherited, classic and variant forms. BSE: human exposure when eating contaminated meat (vCJD form). vCJD: early onset (29yr), slow progression (14mo), longer course of illness
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| Subacute sclerosing panencephalitis | late complication of measles (5-15yr later), rare, personality change, intellectual deterioration, motor/autonomic dysfunction
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| SSPE pathogenesis | measles nucleocapsids in neurons and glial cells. may be due to mutation of viral genome (restricted expression prevents formation of infection). Dx: high levels of measles Ab in CSF and serum, detection in defective brain cells
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