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CNS infection
Lecture 45-48
| Question | Answer |
|---|---|
| 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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