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CNS infection

Lecture 45-48

CNS vulnerability closed box structure: any inflammation very damaging potentially, not many immune defenses
general rules encephalitis is viral, acute meningitis is viral or bacterial, chronic meningitis is tubercle bacteria or fungi, brain abscesses are polymicrobial
4 major syndromes of the CNS meningitis, (bacterial, fungal, viral, non-infectious), encephalitis (viral), myelitis (rabies/polio), brain abscesses (aerobic and anaerobic, fungal, parasites)
Clues about etiology demographics, onset, epidemiology, etiology, exposure history
meningitis infection of meninges, worldwide more than 1 million cases/year , over 50% are viral, bacterial are more serious (higher mortalitly)
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
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
symptoms of meningitis Early: fever, malaise, aches and pains, nausea, vomitig, headache. Late: photophobia, neck stiffness, drowsiness, fits, inconsolable crying (babies), vasculitic rash
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
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
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
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
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)
penetrating head wound/neurosurgery 37%, S. aureus most common, opportunistic in organ transplant or HIV (nocardia, aspergillus, candida)
vectors/reservoirs encephalitis: mosquitoes or ticks. May be non human vertebrate host that are intermediary to transmission. Arboviruses: humans are usually dead end hosts
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,
Neural entry viral infections, rabies enters in axon of peripheral nerve, travels to anterior horn of spinal cord
Direct inoculation by surgery or trauma brain abscesses most relevant
CSF normal values leukocytes 0-6, neutrophils 0%, RBC 0-2, glucose 40-80, protein 20-50
CSF acute bacterial meningitis leukocytes >1000, neutrophils >50%, RBC 0-10, glucose <30, protein >100
CSF chronic mycobacterial and fungal meningitis leukocytes 100-500, neutrophils <10%, RBC 0-2, glucose <40, protein 50-100 fungal, >100 bacterial
CSF acute viral meningitis leukocytes <300, neutrophils predominate first 24 hr then <50%, RBC 0-2, glucose 40-80, protein 50-100
CSF viral encephalitis leukocytes 10-500, neutrophils predominate first 24 hours then <50%, RBC 10-500, glucose 40-80, protein 50-100
CSF brain abscess leukocytes 10-100, neutrophils <50%, RBC 0-2, glucose 40-80, protein 50-100
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
CSF PCR used to diagnose viral encephalitis, polio. Rapid, highly sensitive and specific, small volume CSF required
Culture important for bacterial pathogens, abscess fluid
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
Serotypes (N. meningitidis) A: large scale epidemics B:epidemics and outbreaks C:local outbreaks W135:pilgrimage to Mecca in 2001-2002 Y: occasional cases
Factors necessary for outbreak (meningitis) susceptible individuals, high level of transmissibility, virulent encapsulated strain
N. meningitidis pathogenicity serious disease only in a small percent due to hyperinvasive strains, host factors: lack of bactericidal Ab, complement system dysfunction
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)
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
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
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
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
hemolysis patterns Streptococci beta hemolytic:hemolysin production pyogenes, agalactiae. Alpha hemolytic: H2O2 production, methahemoglobin, pneumoniae, mitis
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
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
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
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)
Listeria monocytogenes gram+, motile, intracellular rod, reservoir: soil, water, decaying vegetation, animals, asymptomatic humans (5-10%). Acquired by ingestion, meningitis in immunocompromised, crosses placenta
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
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
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)
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
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.
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.
Poliovirus acute flaccid paralysis, infection of anterior horns cells of gray matter, signs common to meningeal irritation with weakness in one or more extremities.
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
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
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
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
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
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
WNV pathogenesis pg 17 chart
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
WNV non-structural proteins RNA dependent RNA polymerase (NS5), helicase, protease, interferes with infected cell's normal response to viral infection
WNV epidemiology S. europe, Africa, central and S Asia. Vector:mosquitoes, many avian host species
WNV diagnosis ELISA of CSF to detect virus specific IgM RT-PCR less sensitive than serological assays
St. Louis encephalitis encephalitis, aseptic meningitis. <1% clinically apparent. Canada, US, central america
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
Rabies viral characteristics enveloped, ss-RNA, rod shaped, helical
Rabies epidemiology highest in Asia, all warm blooded animal susceptible, urban and sylvatic spread, worldwide
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
Rabies diagnosis Ag by immunofluorescence, virus isolation, histological changes, ELISA of CSF, DNA amplification (most sensitive), latex agglutination
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)
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.
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
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
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
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
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)
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
Subacute sclerosing panencephalitis late complication of measles (5-15yr later), rare, personality change, intellectual deterioration, motor/autonomic dysfunction
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
Created by: kamarsh



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